Browsing by Issue Date, starting with "2021-07"
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- Protein-protein interaction network and biological community detection in Autism Spectrum DisorderPublication . Vilela, Joana; Martiniano, Hugo; Marques, Ana Rita; Santos, João; Rasga, Célia; Oliveira, Guiomar; Vicente, Astrid M.Objective: To identify neurotransmission and synaptic (NS) genes that play a role in ASD and address the impact of ultra-rare variants in these genes in ASD, linking these mutations to the biological pathways affected.
- Hyperammonaemic encephalopathy in a teenage girlPublication . Magalhães, Tiago; Campos, Teresa; Rodrigues, Esmeralda; Vasconcelos, Carla; Fontoura, Manuel; Vilarinho, Laura; Leão‐Teles, ElisaKey Points: - Blood ammonia levels should be measured in every encephalopathy of unknown origin, especially when an intoxication cause is thought; - Late-onset inherited metabolic disorders may only manifest in the presence of triggering environmental factors such as some drugs (e.g. anti-epileptics); an undiagnosed metabolic disorder should be considered in such cases.
- Global, regional, and national burden of mortality associated with non-optimal ambient temperatures from 2000 to 2019: a three-stage modelling studyPublication . Zhao, Qi; Guo, Yuming; Ye, Tingting; Gasparrini, Antonio; Tong, Shilu; Overcenco, Ala; Urban, Aleš; Schneider, Alexandra; Entezari, Alireza; Vicedo-Cabrera, Ana Maria; Zanobetti, Antonella; Analitis, Antonis; Zeka, Ariana; Tobias, Aurelio; Nunes, Baltazar; Alahmad, Barrak; Armstrong, Ben; Forsberg, Bertil; Pan, Shih-Chun; Íñiguez, Carmen; Ameling, Caroline; De la Cruz Valencia, César; Åström, Christofer; Houthuijs, Danny; Dung, Do Van; Royé, Dominic; Indermitte, Ene; Lavigne, Eric; Mayvaneh, Fatemeh; Acquaotta, Fiorella; de'Donato, Francesca; Di Ruscio, Francesco; Sera, Francesco; Carrasco-Escobar, Gabriel; Kan, Haidong; Orru, Hans; Kim, Ho; Holobaca, Iulian-Horia; Kyselý, Jan; Madureira, Joana; Schwartz, Joel; Jaakkola, Jouni J.K.; Katsouyanni, Klea; Hurtado Diaz, Magali; Ragettli, Martina S.; Hashizume, Masahiro; Pascal, Mathilde; de Sousa Zanotti Stagliorio Coélho, Micheline; Valdés Ortega, Nicolás; Ryti, Niilo; Scovronick, Noah; Michelozzi, Paola; Matus Correa, Patricia; Goodman, Patrick; Nascimento Saldiva, Paulo Hilario; Abrutzky, Rosana; Osorio, Samuel; Rao, Shilpa; Fratianni, Simona; Dang, Tran Ngoc; Colistro, Valentina; Huber, Veronika; Lee, Whanhee; Seposo, Xerxes; Honda, Yasushi; Guo, Yue Leon; Bell, Michelle L.; Li, ShanshanBackground: Exposure to cold or hot temperatures is associated with premature deaths. We aimed to evaluate the global, regional, and national mortality burden associated with non-optimal ambient temperatures. Methods: In this modelling study, we collected time-series data on mortality and ambient temperatures from 750 locations in 43 countries and five meta-predictors at a grid size of 0·5° × 0·5° across the globe. A three-stage analysis strategy was used. First, the temperature-mortality association was fitted for each location by use of a time-series regression. Second, a multivariate meta-regression model was built between location-specific estimates and meta-predictors. Finally, the grid-specific temperature-mortality association between 2000 and 2019 was predicted by use of the fitted meta-regression and the grid-specific meta-predictors. Excess deaths due to non-optimal temperatures, the ratio between annual excess deaths and all deaths of a year (the excess death ratio), and the death rate per 100 000 residents were then calculated for each grid across the world. Grids were divided according to regional groupings of the UN Statistics Division. Findings: Globally, 5 083 173 deaths (95% empirical CI [eCI] 4 087 967-5 965 520) were associated with non-optimal temperatures per year, accounting for 9·43% (95% eCI 7·58-11·07) of all deaths (8·52% [6·19-10·47] were cold-related and 0·91% [0·56-1·36] were heat-related). There were 74 temperature-related excess deaths per 100 000 residents (95% eCI 60-87). The mortality burden varied geographically. Of all excess deaths, 2 617 322 (51·49%) occurred in Asia. Eastern Europe had the highest heat-related excess death rate and Sub-Saharan Africa had the highest cold-related excess death rate. From 2000-03 to 2016-19, the global cold-related excess death ratio changed by -0·51 percentage points (95% eCI -0·61 to -0·42) and the global heat-related excess death ratio increased by 0·21 percentage points (0·13-0·31), leading to a net reduction in the overall ratio. The largest decline in overall excess death ratio occurred in South-eastern Asia, whereas excess death ratio fluctuated in Southern Asia and Europe. Interpretation: Non-optimal temperatures are associated with a substantial mortality burden, which varies spatiotemporally. Our findings will benefit international, national, and local communities in developing preparedness and prevention strategies to reduce weather-related impacts immediately and under climate change scenarios.
- Qualidade nutricional: um contributo para uma dieta diversificada de base vegetalPublication . Motta, CarlaContributo para uma dieta diversificada de base vegetal - Avaliação da Qualidade Nutricional.
- Antisense oligonucleotide exon-skipping as a therapeutic approach for Mucolipidosis type II α/β: in vitro and in vivo studiesPublication . Gonçalves, Mariana; Matos, Liliana; Santos, Juliana Inês; Coutinho, Maria Francisca; Prata, Maria João; Pires, Maria João; Oliveira, Paula; Alves, SandraMucolipidosis type II α/β (ML II α/β) is one of the most severe Lysosomal Storage Disorders and is caused by the deficiency of the enzyme GlcNAc-1-phosphotransferase. This enzyme is responsible for the addition of the mannose 6-phosphate marker to lysosomal enzymes, which allow their targeting to lysosomes. Of the several mutations that occur in ML II α/β, the deletion of 2 nucleotides from GNPTAB exon19 (c.3503_3504del) is the most frequent, making it a good target for a specific mutation therapy as there is no therapy for this disease. In this study, we explored the possibility of an innovative therapeutic strategy based on the use of antisense oligonucleotides (AOs) for ML II α/β. In a previous in vitro study in ML II α/β patient fibroblasts, AOs were used to promote the exon 19 skipping from the GNPTAB pre-mRNA, resulting successfully in the production of an in-frame mRNA. Currently, our objective is to evaluate the therapeutic potential of this approach, both in vitro in C57BL/6 fibroblasts and in vivo in C57BL/6 mice. For this, 18 animals were used, divided into 6 groups: groups 1 and 4 were injected with saline solution, groups 2 and 5 were injected with AO at 25 mg/kg and groups 3 and 6 were injected with AO at 50 mg/kg. All animals were injected by intraperitoneal route and were sacrificed after 4 days (groups 1, 2, 3) or 7 days (groups 4, 5, 6) post-treatment. At the end of the experiment, the organs were collected and frozen at -80ºC, for later RNA extraction, cDNA synthesis and RT-PCR. After results analysis, the exon 19 skipping was not observed using any of the tested doses or incubation periods. So, we can theorize that the doses administered were not sufficient to achieve a response or the AO might have had a high clearance rate. As for the in vitro experience, the C57BL/6 fibroblasts were seeded in 6-well plates and subsequently transfected with concentrations of AO ranging from 10nM to 600nM. After 24h or 48h of incubation, cells were collected and cDNA analysis revealed a full length transcript but also another one of lower molecular weight compatible with exon-skipping. These are preliminary data, so in the near future more experiments will be done.
- Targeted RNA-based therapies for MucopolysaccharidosisPublication . Santos, Juliana Inês; Gonçalves, Mariana; Matos, Liliana; Gaspar, Paulo; Pires, Maria João; Oliveira, Paula; Prata, Maria João; Coutinho, Maria Francisca; Alves, SandraOver the last years, most of our work has been focused on the development of alternative, RNAbased therapies for a number of Lysosomal Storage Disorders (LSD), being Mucopolysaccharidosis (MPS) one of the most relevant. Currently, there are two major research lines being pursued: the first relies on the design of mutation-specific approaches to correct abnormal splicing processes in LSD-related genes whenever they underlie pathology and the second depends upon selective downregulation of one gene involved in the very early stages of the glycosaminoglycans’ (GAG) biosynthethic cascade to promote substrate reduction in MPS diseases. There are substantial differences between these two approaches, but they also face common challenges. Two major possible drug types, depending on the genotype that underlies pathology, are being used: U1snRNA and siRNAs. U1snRNAs are specifically designed to overcome particular splicing mutations. These RNA drugs are, therefore, mutation-specific and constitute patient-tailored approaches. We have already demonstrated in fibroblasts that a modified U1snRNA vector (comprising exon 1 to exon 3) designed to improve the definition of exon 2 5’ SDS of the HGSNAT can restore the splicing defect caused by the mutation c.234+1G>A, that leads to MPSIIIC disease (Matos et al., 2014). Currently, our goal is to evaluate in vivo the therapeutic potential of that modified U1 snRNA by testing it in mice expressing the human splicing defect. A preliminary assay was performed and showed promising results. The second group of RNA drugs, siRNAs, holds a different potential. By acting over the GAGs’ biosynthethic cascade, siRNAs will promote an overall decrease of the accumulating substrate. So far, we have already tested this approach in MPSIII patients’ fibroblasts and the overall results are quite promising. We observed a high inhibition of the XYLT1 (a gene that encodes an enzyme involved in an early stage of the HS biosynthetic cascade) mRNAs (around 80%) and a decrease in GAGs storage (only assessed for types C and D until now). Currently, we are evaluating the effect of that decrease on the overall GAGs storage 7 days post-transfection, also with promising results. Here we present an overview on our results with both approaches on MPS diseases.
- Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohortPublication . Cerván‐Martín, Miriam; Bossini‐Castillo, Lara; Rivera‐Egea, Rocío; Garrido, Nicolás; Luján, Saturnino; Romeu, Gema; Santos‐Ribeiro, Samuel; IVIRMA Group, Lisbon Clinical Group; Castilla, José A.; Gonzalvo, María del Carmen; Clavero, Ana; Vicente, Francisco Javier; Guzmán‐Jiménez, Andrea; Burgos, Miguel; Barrionuevo, Francisco Javier; Jiménez, Rafael; Sánchez‐Curbelo, Josvany; López‐Rodrigo, Olga; Peraza, María Fernanda; Pereira‐Caetano, Iris; Marques, Patrícia Isabel; Carvalho, Filipa; Barros, Alberto; Bassas, Luís; Seixas, Susana; Gonçalves, João; Larriba, Sara; Lopes, Alexandra Manuel; Carmona, Francisco David; Palomino‐Morales, Rogelio JesúsBackground: Severe spermatogenic failure (SpF) represents the most extreme manifestation of male infertility, as it decreases drastically the semen quality leading to either severe oligospermia (SO, <5 million spermatozoa/mL semen) or non-obstructive azoospermia (NOA, complete lack of spermatozoa in the ejaculate without obstructive causes). Objectives: The main objective of the present study is to analyze in the Iberian population the effect of 6 single-nucleotide polymorphisms (SNPs) previously associated with NOA in Han Chinese through genome-wide association studies (GWAS) and to establish their possible functional relevance in the development of specific SpF patterns. Materials and methods: We genotyped 674 Iberian infertile men (including 480 NOA and 194 SO patients) and 1058 matched unaffected controls for the GWAS-associated variants PRMT6-rs12097821, PEX10-rs2477686, CDC42BPA-rs3000811, IL17A-rs13206743, ABLIM1-rs7099208, and SOX5-rs10842262. Their association with SpF, SO, NOA, and different NOA phenotypes was evaluated by logistic regression models, and their functional relevance was defined by comprehensive interrogation of public resources. Results: ABLIM1-rs7099208 was associated with SpF under both additive (OR = 0.86, p = 0.036) and dominant models (OR = 0.78, p = 0.026). The CDC42BPA-rs3000811 minor allele frequency was significantly increased in the subgroup of NOA patients showing maturation arrest (MA) of germ cells compared to the remaining NOA cases under the recessive model (OR = 4.45, p = 0.044). The PEX10-rs2477686 SNP was associated with a negative testicular sperm extraction (TESE) outcome under the additive model (OR = 1.32, p = 0.034). The analysis of functional annotations suggested that these variants affect the testis-specific expression of nearby genes and that lincRNA may play a role in SpF. Conclusions: Our data support the association of three previously reported NOA risk variants in Asians (ABLIM1-rs7099208, CDC42BPA-rs3000811, and PEX10-rs2477686) with different manifestations of SpF in Iberians of European descent, likely by influencing gene expression and lincRNA deregulation.
- Auto-Disinfectant Acrylic Paints Functionalised with Triclosan and Isoborneol - Antibacterial AssessmentPublication . Machado Querido, Micaela; Paulo, Ivo; Hariharakrishnan, Sriram; Rocha, Daniel; Pereira, Cristiana Costa; Barbosa, Nuno; Bordado, João Moura; Teixeira, João Paulo; Galhano dos Santos, RuiEnvironmental surface contamination with microorganisms is a serious concern worldwide. Triclosan and isoborneol present good antimicrobial activity. Their immobilisation to paint substrates allows for development of a material that stays effective over a longer time. In this work, we disclosed the preliminary studies to evaluate the antimicrobial activity of the active molecule after being functionalised with isocyanates for further immobilisation on the paint substrate. Overall, the newly developed non-release antimicrobial coating provides an effective way of preventing the spread of diseases and has been proven to inhibit bacterial growth and with a considerable antimicrobial activity towards S. aureus, E. coli, and K. variicola at the tested concentrations.
- Effects of Hot Nights on Mortality in Southern EuropePublication . Royé, Dominic; Sera, Francesco; Tobías, Aurelio; Lowe, Rachel; Gasparrini, Antonio; Pascal, Mathilde; de’Donato, Francesca; Nunes, Baltazar; Teixeira, João PauloBackground: There is strong evidence concerning the impact of heat stress on mortality, particularly from high temperatures. However, few studies to our knowledge emphasize the importance of hot nights, which may prevent necessary nocturnal rest. Objectives: In this study, we use hot-night duration and excess to predict daily cause-specific mortality in summer, using multiple cities across Southern Europe. Methods: We fitted time series regression models to summer cause-specific mortality, including natural, respiratory, and cardiovascular causes, in 11 cities across four countries. We included a distributed lag nonlinear model with lags up to 7 days for hot night duration and excess adjusted by daily mean temperature. We summarized city-specific associations as overall-cumulative exposure-response curves at the country level using meta-analysis. Results: We found positive but generally nonlinear associations between relative risk (RR) of cause-specific mortality and duration and excess of hot nights. RR of duration associated with nonaccidental mortality in Portugal was 1.29 (95% confidence interval [CI] = 1.07, 1.54); other associations were imprecise, but we also found positive city-specific estimates for Rome and Madrid. Risk of hot-night excess ranged from 1.12 (95% CI = 1.05, 1.20) for France to 1.37 (95% CI = 1.26, 1.48) for Portugal. Risk estimates for excess were consistently higher than for duration. Conclusions: This study provides new evidence that, over a wider range of locations, hot night indices are strongly associated with cause-specific deaths. Modeling the impact of thermal characteristics during summer nights on mortality could improve decisionmaking for preventive public health strategies.
- Prevenção da COVID-19: o que sabemos?Publication . Alves, HelenaSumário: SARS-Cov-2, aparecimento e evolução da pandemia. Estirpe original e variantes. Ligação do vírus às células e resposta do hospedeiro. Factores de risco genético. Diagnóstico, formas clínicas de apresentação, sintomas e diferentes formas de evolução da doença. Sintomas pós-Covid. Tratamentos e sua evolução ao longo da pandemia. Formas de transmissão. Riscos a evitar. Novas variantes. Vacinação e eficácia das vacinas para as novas variantes. Re-infecções. Biosegurança, como lição para evitar novas pandemias.