Percorrer por autor "Martins, Sandra"
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- Genetic Variation in ATXN3 (Ataxin-3) 3′UTR: Insights into the Downstream Regulatory Elements of the Causative Gene of Machado-Joseph Disease/Spinocerebellar Ataxia Type 3Publication . Melo, Ana Rosa Vieira; Raposo, Mafalda; Ventura, Marta; Martins, Sandra; Pavão, Sara; Alonso, Isabel; Bettencourt, Conceição; Lima, ManuelaUntranslated regions are involved in the regulation of transcriptional and post-transcriptional processes. Characterization of these regions remains poorly explored for ATXN3, the causative gene of Machado-Joseph disease (MJD). Although a few genetic modifiers have been identified for MJD age at onset (AO), they only explain a small fraction of the AO variance. Our aim was to analyse variation at the 3'UTR of ATXN3 in MJD patients, analyse its impact on AO and attempt to build haplotypes that might discriminate between normal and expanded alleles.After assessing ATXN3 3'UTR variants in molecularly confirmed MJD patients, an in silico analysis was conducted to predict their functional impact (e.g. their effect on miRNA-binding sites). Alleles in cis with the expanded (CAG)n were inferred from family data, and haplotypes were built. The effect of the alternative alleles on the AO and on SARA and NESSCA ataxia scales was tested.Nine variants, all previously described, were found. For eight variants, in silico analyses predicted (a) deleterious effects (rs10151135; rs55966267); (b) changes on miRNA-binding sites (rs11628764; rs55966267; rs709930) and (c) alterations of RNA-binding protein (RBP)-binding sites (rs1055996; rs910369; rs709930; rs10151135; rs3092822; rs7158733). Patients harbouring the alternative allele at rs10151135 had significantly higher SARA Axial subscores (p = 0.023), comparatively with those homozygous for the reference allele. Ten different haplotypes were obtained, one of which was exclusively found in cis with the expanded and four with the normal allele. These findings, which are relevant for the design of allele-specific therapies, warrant further investigation in independent MJD cohorts.
- Resolvin E1-Chemerin receptor 1 axis is dysregulated in critical COVID-19 patientsPublication . Silva-Pereira, Carolina; Reina-Couto, Marta; Pereira-Terra, Patrícia; Teixeira-Santos, Luísa; Martins, Sandra; Pinho, Dora; Soares, Miguel Luz; Dias, Cláudia Camila; Sarmento, António; Tavares, Margarida; Guimarães, João Tiago; Paiva, José-Artur; Fraga, Sónia; Albino-Teixeira, António; Roncon-Albuquerque, Roberto; Sousa, TeresaResolvin E1 (RvE1) and Resolvin D1 (RvD1) are key resolvins implicated in inflammation resolution of respiratory and infectious diseases. In contrast to cytokines, they have been scarcely explored in COVID-19 and their ability for discriminating COVID-19 severity and patient outcomes has not been compared with that of cytokines. Therefore, among a panel comprising cytokines (interleukin (IL)-1beta, IL-6, IL-10, tumor necrosis factor alpha, interferon gamma and granulocyte-macrophage colony-stimulating factor), RvD1 and RvE1 and their respective receptors (FPR2, Chemerin1), we evaluated which mediators better distinguished COVID-19 severity, the need of mechanical ventilation and patient mortality. Blood was collected from 61 patients with “severe” (n = 27), “critical” (n = 17) and “critical on veno-venous extracorporeal membrane oxygenation (VV-ECMO)” (n = 17) COVID-19 at admission, days 3–4 and days 5–8, and from controls (n = 23) at a single time point. We measured cytokines by multiplex immunoassays, resolvins by enzyme-linked immunosorbent assays, and FPR2 and Chemerin1 mRNA by real-time quantitative polymerase chain reaction. We obtained principal component analysis (PCA)/partial least squares discriminant analysis (PLS-DA) models significantly differentiating (P < 0.001): controls from each patient group; “severe” from all critical patients; patients without or with mechanical ventilation, and survivors from non-survivors. RvE1 consistently showed a variable importance in projection (VIP) score > 2.5 and a p(corr) >0.8, being the most relevant discriminating variable. Univariate and repeated measures multivariate analyses showed higher RvE1 in “critical on VV-ECMO”, mechanically ventilated patients and non-survivors, while Chemerin1 exhibited an opposite profile. RvE1 positively correlated with inflammation and partial pressure of CO2, whereas Chemerin1 correlated with lower inflammation, better respiratory function and lower hospital length of stay. We conclude that RvE1 was the mediator best distinguishing COVID-19 severity and that RvE1-Chemerin1 axis is dysregulated in this disease.