RCAAP Repository

Working paper on the Quality of the European News Ecology.

The Tn antigen (GalNAc-α-1-O-Thr/Ser) is a well-known tumor-associated carbohydrate determinant. The use of glycopeptides that incorporate this structure has become a significant and promising niche of research owing to their potential use as anticancer vaccines. Herein, the conformational preferences of a glycopeptide with an unnatural Tn antigen, characterized by a threonine decorated with an sp2-iminosugar-type α-GalNAc mimic, have been studied both in solution, by combining NMR spectroscopy and molecular dynamics simulations, and in the solid state bound to an anti-mucin-1 (MUC1) antibody, by X-ray crystallography. The Tn surrogate can mimic the main conformer sampled by the natural antigen in solution and exhibits high affinity towards anti-MUC1 antibodies. Encouraged by these data, a cancer vaccine candidate based on this unnatural glycopeptide and conjugated to the carrier protein Keyhole Limpet Hemocyanin (KLH) has been prepared and tested in mice. Significantly, the experiments in vivo have proved that this vaccine elicits higher levels of specific anti-MUC1 IgG antibodies than the analog that bears the natural Tn antigen and that the elicited antibodies recognize human breast cancer cells with high selectivity. Altogether, we compile evidence to confirm that the presentation of the antigen, both in solution and in the bound state, plays a critical role in the efficacy of the designed cancer vaccines. Moreover, the outcomes derived from this vaccine prove that there is room for exploring further adjustments at the carbohydrate level that could contribute to designing more efficient cancer vaccines.

No summary/description provided

Complex organisms are associations of different cells that coexist and collaborate creating a living consortium, the holobiont. The relationships between the holobiont members are essential for proper homeostasis of the organisms, and they are founded on the establishment of complex inter-connections between all the cells. Non-coding RNAs are regulatory molecules that can also act as communication signals between cells, being involved in either homeostasis or dysbiosis of the holobionts. Eukaryotic and prokaryotic cells can transmit signals via non-coding RNAs while using specific extracellular conveyors that travel to the target cell and can be translated into a regulatory response by dedicated molecular machinery. Within holobionts, non-coding RNA regulatory signaling is involved in symbiotic and pathogenic relationships among the cells. This review analyzes current knowledge regarding the role of non-coding RNAs in cell-to-cell communication, with a special focus on the signaling between cells in multi-organism consortia.

Galectin-3 binding protein (LGALS3BP or 90 K) is a secreted glycoprotein found in human body fluids. Deregulated levels were observed in cancer and infection and its study in neurological diseases is more recent. Here, we have investigated 90 K from human cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS, n = 35) and other neurological diseases (n = 23). CSF was fractionated by ultrafiltration/size-exclusion chromatography (SEC) and eluted fractions were analysed by complementary techniques including immunoblotting, electron microscopy and nano-liquid chromatography-tandem mass spectrometry. A fraction of 90 K appeared as nanoparticles of irregular shape with heterogeneous dimensions of 15-60 nm that co-eluted with extracellular vesicles in SEC. Median levels of 90 K quantified by ELISA were not different between ALS patients (215.8 ng/ml) and controls (213.3 ng/ml) in contrast with the benchmark biomarker for ALS phosphoneurofilament heavy chain (1750 and 345 pg/ml, respectively). A multiregression model supported age is the only independent predictor of 90 K level in both groups (p < 0.05). Significant correlation was found between 90 K levels and age for the ALS group (r = 0.366, p = 0.031) and for all subjects (r = 0.392, p = 0.003). In conclusion, this study unveils the presence of 90 K-containing nanoparticles in human CSF and opens novel perspectives to further investigate 90 K as potential aging marker.

Os gregos fizeram descoberta surpreendente: uma pedra metálica escura, que podia repelir ou atrair objectos de ferro - era a origem do estudo do magnetismo. Na época das grandes navegações, não se conseguia localizar um navio no mar pelas duas coordenadas, a latitude e a longitude; a determinação desta exigia um relógio a bordo que indicasse a hora exacta no meridiano de referência, e a determinação astronómica da longitude dava erros inaceitáveis. Durante a viagem até à Índia, D. João de Castro levou a cabo um conjunto de experiências que conseguiu detectar fenómenos, nomeadamente relacionados com o magnetismo e com as agulhas magnéticas a bordo. É de supor que devia esses conhecimentos a Pedro Nunes, naturalmente o directo inspirador de todas as observações que realizou nas suas viagens. Quando em 5 de Agosto de 1538, D. João de Castro decidiu determinar a latitude de Moçambique, encontrou a causa que ditava o «espantoso desconcerto» das agulhas: notou o desvio da agulha, descobrindo-o 128 anos antes de Guillaume Dennis (1666), de Nieppe, o qual é registado na História da Navegação como se fosse o primeiro a conhecer esse fenómeno. A sua observação nas proximidades de Baçaim, em 22 de Dezembro de 1538, de um fenómeno magnético, pelo qual se verificavam variações da agulha devido à proximidade de certos rochedos, confirmadas quatro séculos mais tarde, foi denominado atracção local. D. João de Castro refutou a teoria de que a variação da declinação magnética não se fazia por meridianos geográficos. As suas observações são o mais importante registo de valores da declinação magnética no Atlântico e no Índico, no século XVI, e úteis para o estudo do magnetismo terrestre. Foi uma das personalidades da ciência experimental europeia desse século, relacionando a importância desse estudo com as navegações. O seu nome ficou ligado à ciência pelas suas obras que evidenciavam uma tendência para o moderno espírito científico.

O presente estudo tem como finalidade analisar os estados emocionais dos candidatos ao primeiro ano da Academia Militar, nomeadamente a ansiedade, a depressão e o stress, explorando e tentando compreender o papel das Estratégias de Coping. Adoptou-se o Modelo de Lazarus e Folkman (1984) como fundamento relativamente à problemática de stress e coping. A amostra é constituída por 192 candidatos à Academia Militar, com idades compreendias entre os 17 e os 26 anos. Para a recolha dos dados foram utilizados dois questionários de auto-relato, a saber: a Escala de Depressão, Ansiedade e Stress (EADS) (Lovibond & Lovibond, 1995) e o Ways of Coping Questionnaire (Folkman & Lazarus, 1988b). Os resultados obtidos, revelam baixos níveis de ansiedade, depressão e stress quer para o sexo masculino, quer para o sexo feminino. Este facto pode dever-se à utilização de estratégias de coping direccionadas para o problema, sendo que a estratégia de Resolução Planeada do Problema, apresenta um valor elevado, para o sexo masculino e feminino, quando comparado com as restantes estratégias de coping. Verificou-se também que não existem diferenças significativas entre os sexos, no que respeita ao tipo de estratégias de coping utilizadas. Todavia, quando analisados os níveis de ansiedade, depressão e stress entre os sexos, verificam-se níveis significativamente mais elevados de stress e ansiedade para o sexo feminino. Os resultados permitem conhecer em maior profundidade os candidatos à Academia Militar e a forma como lidam com o processo de transição/adaptação, assim como permite verificar as estratégias mais utilizadas pelos mesmos.

Background: How intestinal epithelial cells interact with the microbiota and how this is regulated at the gene expression level are critical questions. Smarcad1 is a conserved chromatin remodeling factor with a poorly understood tissue function. As this factor is highly expressed in the stem and proliferative zones of the intestinal epithelium, we explore its role in this tissue. Results: Specific deletion of Smarcad1 in the mouse intestinal epithelium leads to colitis resistance and substantial changes in gene expression, including a striking increase of expression of several genes linked to innate immunity. Absence of Smarcad1 leads to changes in chromatin accessibility and significant changes in histone H3K9me3 over many sites, including genes that are differentially regulated upon Smarcad1 deletion. We identify candidate members of the gut microbiome that elicit a Smarcad1-dependent colitis response, including members of the poorly understood TM7 phylum. Conclusions: Our study sheds light onto the role of the chromatin remodeling machinery in intestinal epithelial cells in the colitis response and shows how a highly conserved chromatin remodeling factor has a distinct role in anti-microbial defense. This work highlights the importance of the intestinal epithelium in the colitis response and the potential of microbial species as pharmacological and probiotic targets in the context of inflammatory diseases.

Background: Hereditary Transthyretin Amyloidosis Polyneuropathy is a rare life-threatening neurologic disease that imposes considerable mortality and it is associated with progressive related disabilities. In this study, we aimed to assess the effect of the disease across health-related quality of life dimensions, in both carriers of the mutation and patients, to compare health-related quality of life with general population, as well as to explore health-related quality of life prognostic factors among patients, including disease progression and treatment. Methods: This study was a multi-institutional, longitudinal, prospective, observational study of hereditary Transthyretin Amyloidosis Polyneuropathy Portuguese adult subjects (621 asymptomatic carriers and 733 symptomatic patients) enrolled in the Transthyretin Amyloidosis Outcomes Survey. Health-related quality of life was captured with the preference-based instrument EQ-5D-3 L. For general population the dataset included all subjects enrolled in a representative national study (n = 1500). Different econometric models were specified; multivariate probit, generalized linear model and generalized estimating equations model; including demographic and clinical covariates. Results: Hereditary Transthyretin Amyloidosis Polyneuropathy patients have their health status severely impaired in all quality of life dimensions and more anxiety/depression problems were found among asymptomatic carriers. No differences on utility were found between carriers and general population (p = 0.209). Among patients, the utility value is estimated to be 0.51 (0.021), a decrement of 0.27 as compared with general population utility. Higher disease duration, advanced disease stage and not receiving treatment are associated with impaired health-related quality of life. No differences were found between genders (p = 0.910) or between late (≥50 years) and early-onset patients (p = 0.254). The utility estimate ranged from 0.63 (0.009) in stage I to 0.01 (0.005) in stage IV. Conclusions: Hereditary Transthyretin Amyloidosis Polyneuropathy symptoms and progressive associated disabilities substantially decrease patient's health-related quality of life. Clinical strategies focused on health-related quality of life preservation such as close follow-up of asymptomatic carriers, prompt diagnosis and adequate, early treatment would benefit patient's long-term outcomes, slowing the progressive decline in health-related quality of life.

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Dengue virus (DENV) represents a public health threat and economic burden in affected countries. The availability of genomic data is key to understanding viral evolution and dynamics, supporting improved control strategies. Currently, the use of high-throughput sequencing (HTS) technologies, which can be applied both directly to patient samples (shotgun metagenomics) and to PCR-amplified viral sequences (amplicon sequencing), is potentially the most informative approach to monitor viral dissemination and genetic diversity by providing, in a single methodological step, identification and characterization of the whole viral genome at the nucleotide level. Despite many advantages, these technologies require bioinformatics expertise and appropriate infrastructure for the analysis and interpretation of the resulting data. In addition, the many software solutions available can hamper the reproducibility and comparison of results. Here we present DEN-IM, a one-stop, user-friendly, containerized and reproducible workflow for the analysis of DENV short-read sequencing data from both amplicon and shotgun metagenomics approaches. It is able to infer the DENV coding sequence (CDS), identify the serotype and genotype, and generate a phylogenetic tree. It can easily be run on any UNIX-like system, from local machines to high-performance computing clusters, performing a comprehensive analysis without the requirement for extensive bioinformatics expertise. Using DEN-IM, we successfully analysed two types of DENV datasets. The first comprised 25 shotgun metagenomic sequencing samples from patients with variable serotypes and genotypes, including an in vitro spiked sample containing the four known serotypes. The second consisted of 106 paired-end and 76 single-end amplicon sequences of DENV 3 genotype III and DENV 1 genotype I, respectively, where DEN-IM allowed detection of the intra-genotype diversity. The DEN-IM workflow, parameters and execution configuration files, and documentation are freely available at https://github.com/B-UMMI/DEN-IM).

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Background: Ischemic stroke is a frequent neurologic complication of infective endocarditis. This systematic review aims to evaluate the efficacy and safety of thrombectomy in comparison to thrombolysis and to combined treatment in patients with infective endocarditis associated acute ischemic stroke. Methods: A systematic literature review was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The review included case reports, cases series, cross-sectional studies, case control studies, randomized controlled trials or nonrandomized controlled trials, which reported the treatment of endocarditis-related acute ischemic stroke with mechanical thrombectomy, intravenous or intra-arterial thrombolysis in adult patients. Data sources: Scielo, b-on, Pubmed and Cochrane, from inception to April 2019. Reference lists were also checked. We compared the efficacy (independence, neurological improvement) and safety (intracranial bleeding, death) of acute ischemic stroke treatment with thrombolysis, thrombectomy and combined therapy. Results: Through systematic review 37 articles describing 52 patients met criteria. The risk of intracranial hemorrhage was 4.14 times higher in patients treated with intravenous thrombolysis (P = .001) and 4.67 times higher in patients treated with combined treatment (P = .01). There was trend for independence (P = .09) and neurological improvement (P = .07) in favor of thrombectomy, when comparing this group to the group treated with intravenous thrombolysis. Conclusions: With the limitation of the low quality of the available evidence, thrombectomy in infective endocarditis associated stroke appears to be safer than thrombolysis, or combined treatment. These results may be useful to guide clinical decisions, in selected patients.

The epigenetic and functional reprogramming of immune genes during induction of trained immunity is accompanied by the metabolic rewiring of cellular state. This memory is induced in the hematopoietic niche and propagated to daughter cells, generating epigenetically and metabolically reprogrammed innate immune cells that are greatly enhanced in their capacity to resolve inflammation. In particular, these cells show accumulation of H3K4me3 and H3K27Ac epigenetic marks on multiple immune gene promoters and associated enhancers. However, the mechanism governing how these epigenetic marks accumulate at discrete immune gene loci has been poorly understood, until now. Here, we discuss some recent advances in the regulation of trained immunity, with a particular focus on the mechanistic role of a novel class of long non-coding RNAs in the establishment of epigenetic marks on trained immune gene promoters.

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Background: Acquired perforating dermatosis (APD) comprises an uncommon group of skin disorders that develop in adulthood in association with systemic diseases. The aim of this study was to characterize clinicopathologic features and treatment outcomes in a series of patients diagnosed with APD. Methods: Retrospective study of all patients diagnosed with an APD over a 10-year period (2009-2018) at a tertiary teaching hospital in Lisbon, Portugal. Results: Fifty-seven patients with APD were identified. Thirty-five patients presented lesions in multiple anatomic areas (61.4%), and the lower limbs were the most common location. Forty-six patients reported pruritus (80.7%), which was classified as severe in 21 of them (36.8%). An underlying systemic disease was identified in 53 patients (93.0%). Diabetes mellitus (DM) and chronic kidney disease (CKD) were the most common associated systemic diseases, but psychiatric disorders, malignancies, and chronic infections were present in a significant number of patients. The combination of topical steroids with antihistamines was the most prescribed initial treatment, but only 37.8% of the patients had a complete response. Acitretin, systemic steroids, and phototherapy were the treatments associated with the best outcome. Conclusion: Acquired perforating dermatosis can be associated with many systemic disorders that have pruritus as a common factor. Chronic viral infections and an occult malignancy should be sought, particularly in the absence of DM and CKD. The management of APD is challenging and is best achieved with the control of the underlying systemic diseases.

Kidney transplant (KT) recipients have an increased risk for urothelial carcinoma. A role for JC virus (JCV) in human cancers is not yet proved but there is an increasingly reported association between BK virus (BKV) nephropathy and renourinary neoplasms. We report a KT recipient who developed a high-grade urothelial carcinoma 5 years after a diagnosis of JCV nephropathy and 9 years after kidney transplantation. Neoplastic tissue was positive for JCV DNA by real-time polymerase chain reaction (PCR). Immunochemical staining showed strong positivity for cell cycle markers (p16, p53, and Ki67) and for early viral protein JCV large T antigen (JCV LTag; using a broad polyomavirus antibody); however, late viral protein (VP1) stained negative. In contrast, in non-neoplastic urothelium, JCV DNA and all immunochemical markers were negative. These facts suggest that malignancy was induced by JCV. To the best of our knowledge, this is the first report of urothelial high-grade carcinoma associated with JCV nephropathy in a KT recipient.

O Modelo da Complementaridade Paradigmática segue uma perspectiva integrativa e conceptualiza sete pares de necessidades psicológicas (Vaz-Velho, Vasco & Conceição, 2011; Vaz-Velho & Vasco, 2010; Vasco, 2011, 2010, 2009a, 2009b), concebendo o bem-estar como resultante da regulação de satisfação das necessidades através de um processo contínuo de negociação e equilíbrio dos pares dialécticos. Com base na literatura da área da produtividade e do lazer, numa perspectiva psicológica, construiu-se uma escala de avaliação do grau de regulação do par de necessidades Produtividade/Lazer. Esta escala foi aplicada a 562 participantes através de uma plataforma Web e os resultados foram relacionados com as escalas de Bem-Estar Psicológico e Distress Psicológico, do Inventário de Saúde Mental (ISM). Os resultados apoiam a consistência interna dos instrumentos e mostram o contributo das variáveis na variância dos resultados, revelando a relação positiva da Produtividade e do Lazer com o Bem-Estar Psicológico e negativa com o Distress Psicológico. Dividindo os sujeitos por 4 grupos com base nas medianas dos resultados no par de necessidades Produtividade/Lazer, o grupo de resultados mais elevados nos dois pólos revela resultados mais elevados de Bem-Estar Psicológico e mais baixos de Distress Psicológico, quando comparado com os restantes grupos. Apresentam-se as limitações do estudo, as implicações dos resultados para futuras investigações e para a prática psicoterapêutica e sugerem-se linhas de investigação futuras.

Protein behavior is closely regulated by a plethora of post-translational modifications (PTMs). It is therefore desirable to develop approaches to design rational PTMs to modulate specific protein functions. Here, we report one such method, and we illustrate its successful implementation by potentiating the anti-aggregation activity of a molecular chaperone. Molecular chaperones are a multifaceted class of proteins essential to protein homeostasis, and one of their major functions is to combat protein misfolding and aggregation, a phenomenon linked to a number of human disorders. In this work, we conjugated a small-molecule inhibitor of the aggregation of α-synuclein, a process associated with Parkinson's disease (PD), to a specific cysteine residue on human Hsp70, a molecular chaperone with five free cysteines. We show that this regioselective conjugation augments in vitro the anti-aggregation activity of Hsp70 in a synergistic manner. This Hsp70 variant also displays in vivo an enhanced suppression of α-synuclein aggregation and its associated toxicity in a Caenorhabditis elegans model of PD.

No summary/description provided