Functionalised collagen-MnO2 fibres inhibit oxidative-induced apoptosis in degenerated IVD

Intervertebral disc cell apoptosis has been reported as the major factor responsible in promoting disc degeneration. In this study we hypothesize that collagen fibres with manganese dioxide (MnO2) nanoparticles (NPs) can increase oxygen levels by scavenging ROS species and converting it into byproducts. The specific objective of this study is to fabricate collagen fibres incorporating NPs (Fig. 1), with controlled degradability that are able to scavenge ROS species and generate O2 while inhibiting annulus fibrosus (AF) cell apoptosis under inflamed conditions.Science Foundation Ireland (SFI), the European Regional Development Fund (13/RC/2073)Portuguese Foundation for Science and Technology (SFRH/BD/81356/2011

m5U54 tRNA hypomodification by lack of TRMT2A drives the generation of tRNA-derived small RNAs

Transfer RNA (tRNA) molecules contain various post-transcriptional modifications that are crucial for tRNA stability, translation efficiency, and fidelity. Besides their canonical roles in translation, tRNAs also originate tRNA-derived small RNAs (tsRNAs), a class of small non-coding RNAs with regulatory functions ranging from translation regulation to gene expression control and cellular stress response. Recent evidence indicates that tsRNAs are also modified, however, the impact of tRNA epitranscriptome deregulation on tsRNAs generation is only now beginning to be uncovered. The 5-methyluridine (m5U) modification at position 54 of cytosolic tRNAs is one of the most common and conserved tRNA modifications among species. The tRNA methyltransferase TRMT2A catalyzes this modification, but its biological role remains mostly unexplored. Here, we show that TRMT2A knockdown in human cells induces m5U54 tRNA hypomodification and tsRNA formation. More specifically, m5U54 hypomodification is followed by overexpression of the ribonuclease angiogenin (ANG) that cleaves tRNAs near the anticodon, resulting in accumulation of 5′tRNA-derived stress-induced RNAs (5′tiRNAs), namely 5′tiRNA-GlyGCC and 5′tiRNA-GluCTC, among others. Additionally, transcriptomic analysis confirms that down-regulation of TRMT2A and consequently m5U54 hypomodification impacts the cellular stress response and RNA stability, which is often correlated with tiRNA generation. Accordingly, exposure to oxidative stress conditions induces TRMT2A down-regulation and tiRNA formation in mammalian cells. These results establish a link between tRNA hypomethylation and ANG-dependent tsRNAs formation and unravel m5U54 as a tRNA cleavage protective mark.publishe

Relação entre a prática de atividade fisica e os níveis de concentrações séricas do colesterol total em jovens do ensino superior

As doenças cardiovasculares são a principal causa de mortalidade em Portugal. Controlar os fatores de risco, nomeadamente, a HTA, os níveis de colesterol e de triglicerídeos, o tabagismo, a diabetes, o abuso de álcool, o sedentarismo, a obesidade ou o stress excessivo é de extrema importância (DGS, 2003). Níveis mais elevados de prática frequente de atividade física estão associados a concentrações séricas de colesterol total mais baixas (Katzmarzyk, Church & Blair, 2001; Guedes & Gonçalves, 2007)

Molecular characterization of PDGFR-α/PDGF-A and c-KIT/SCF in gliosarcomas

Gliosarcomas are rare and poorly characterized malignant brain tumors that exhibit a biphasic tissue pattern with areas of gliomatous and sarcomatous differentiation. These tumors are histological variants of glioblastoma, displaying a similar genetic profile and dismal prognosis. Up-regulation of PDGFR subfamily of tyrosine kinase members, PDGFR-α and c-Kit, and their intracellular effectors RAS/RAF/MAPK has a crucial role in the cancer development. In addition, signal transduction mediated by activating mutations of c-Kit and PDGFR can be effectively blocked by specific tyrosine kinase inhibitors, such as Imatinib mesylate. The aim of this study was to characterize the molecular alterations of PDGFR signaling in gliosarcomas. Six cases were analyzed by immunohistochemistry for the expression of PDGFR-α, c-Kit and their ligands PDGF-A and SCF, respectively. The cases were further evaluated for the presence of activating mutations of PDGFR-α (exons 12 and 18) and c-kit (exons 9, 11, 13, and 17), as well as B-RAF (exons 11 and 15). Expression of PDGF-A was found in all cases and co-expression of PDGFR-α was observed in three cases. Four cases showed expression of SCF, and c-Kit was observed only in one case that also expressed SCF. Generally, immunoreaction predominates in the glial component. The mutational analysis of PDGFR-α showed the presence of an IVS17-50insT intronic insertion in two cases, one of them also with a 2472C > T silent mutation; this silent mutation was also found in another case. Glioma cell line analysis of IVS17-50insT insertion showed no influence on PDGFR-α gene splicing. No mutations were detected in c-kit and B-RAF oncogenes. Our results indicate that activating mutations of PDGFR-α, c-kit and B-RAF are absent in gliosarcomas. Nevertheless, the presence of a PDGFR-a/PDGFA and c-Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in the treatment of gliosarcomas.Novartis Portugal

Macromolecular modulation in a tissue-to-tissue model system differentially regulates the behaviour of hBMSCs

The simultaneous creation of multiple tissues and their functional assembly leading to complex organ systems has recently created interest in tissue engineering strategies. The structural and mechanical gradient present on tissues has its main focus at the interface since it seems that tissue-to-tissue interfaces are crucial for multitissue repair strategies. Thus, well-defined gradient model systems are of great importance in the study cell-matrix interactions at a biophysical level. It was hypothesized that by modulating the macromolecular enviroment, cells will assume a differential behaviour as a consequence of targeting specific intracellular signaling events leading to desirable cell fate patterning. Thus, cell viability and biofunctionality, as well differential paracrine secretory profiles and gene/cell marker expression, can be engineered by using human bone marrow stromal cells (hBMSCs).Science Foundation Ireland (SFI), co-funded under the European Regional Development Fund under Grant Number 13/RC/2073Portuguese Foundation for Science and Technology (SFRH/BD/81356/2011

Novel peptides derived from dengue virus capsid protein translocate reversibly the blood−brain barrier through a receptor-free mechanism

© 2017 American Chemical SocietyThe delivery of therapeutic molecules to the central nervous system is hampered by poor delivery across the blood-brain barrier (BBB). Several strategies have been proposed to enhance transport into the brain, including invasive techniques and receptor-mediated transport (RMT). Both approaches have several drawbacks, such as BBB disruption, receptor saturation, and off-target effects, raising safety issues. Herein, we show that specific domains of Dengue virus type 2 capsid protein (DEN2C) can be used as trans-BBB peptide vectors. Their mechanism of translocation is receptor-independent and consistent with adsorptive-mediated transport (AMT). One peptide in particular, named PepH3, reaches equilibrium distribution concentrations across the BBB in less than 24 h in a cellular in vitro assay. Importantly, in vivo biodistribution data with radiolabeled peptide derivatives show high brain penetration. In addition, there is fast clearance from the brain and high levels of excretion, showing that PepH3 is a very good candidate to be used as a peptide shuttle taking cargo in and out of the brain.The authors thank the Portuguese Funding Agency, Fundação para a Ciência e a Tecnologia, FCT IP, for financial support (grants SFRH/BPD/94466/2013; SFRH/BPD/109010/2015; IF/01010/2013; PTDC/BBBNAN/1578/2014; HIVERA/ 0002/2013) and Marie Skłodowska-Curie Research and Innovation Staff Exchange (MSCA-RISE), call 20-MSCARISE-2014 (grant agreement H20 644167 − INPACT). M.M., L.G., C.F., and J.D.G.C. gratefully acknowledge FCT support through the UID/Multi/04349/2013 project.info:eu-repo/semantics/publishedVersio

Regulation of biological paternity investigation: comparative perspective

O objetivo deste artigo analisar comparativamente a legisla o relativa investiga o de paternidade biológica de crianças nascidas fora do casamento no brasil e em países europeus, com base em pesquisa de documentos legislativos pela internet e na consulta de bibliografia jurídica no mbito do direito da família. Foi elaborada uma tipologia legislativa verdade biológica absoluta e verdade biológica relativa atendendo s seguintes variáveis: formas de atribui o da paternidade (voluntária/ordem do tribunal); tipo de consentimento exigido para realiza o do teste genético (voluntário/forçado); autor da investiga o (estado/outros); e limite temporal da investiga o (existência de prazos processuais/ausência de prazo processual). A verdade biológica absoluta ocorre quando a investigação de paternidade decorre obrigatoriamente, podendo ser ordenado e forçado pelo tribunal o recurso ao teste genético. observou-se a prevalência da verdade biológica relativa. Em todos os países analisados verificou-se que o recurso ao teste genético preponderante no estabelecimento das relações de filiação. Mesmo em países em que necessário o consentimento para a realização de teste de DNA existem modalidades de submiss o mais subtis, que incluem a aplicação de multas ou a gera o da presunção da paternidade com base na recusa em realizar exame genético.The aim of this article is to do a comparative analysis relative to the investigation of biological paternity of children born out of wedlock in Brazil and european countries, based on the research of legislative documents through the internet and the consultation of legal bibliography in the area of family law. The legislative typology was made - absolute biological truth and relative biological truth according to the following variables: forms of paternal attribution (voluntary/court ordered), type of demanded consent for the performance of the genetic test (voluntary/forced), author of the investigation (state/other) and the time limit of the investigation (existence of process deadlines/no process deadlines). The absolute biological truth occurs when the investigation of paternity is compulsory and the court might order and force the submission to a genetic test. The dominating trend is relative biological truth. In all analysed countries it has been verified that the resource to genetic testing is preponderant when establishing affiliation relations. Even in countries where it's not possible to force an individual to the submission of a genetic exam, there are more subtle ways of submission, that include the application of fines or the assumption of paternity based on a refusal to perform the genetic exam.info:eu-repo/semantics/publishedVersio

Is gut microbiota the key?

Funding: This study was supported by ERDF through the operation POCI-01-0145-ERDF-007746 funded by Programa Operacional Competitividade e Internacionalização—COMPETE2020 and by National Funds through FCT—Fundação para a Ciência e a Tecnologia within CINTESIS, R&D Unit (reference UID/IC/4255/2013) and CHRC (UIDB/04923/2020 and UIDP/04923/2020). This study was also supported by Emilio Peres grant from the Portuguese Society of Diabetology.The Mediterranean diet (MD) has been recommended for type 2 diabetes (T2D) treatment. The impact of diet in shaping the gut microbiota is well known, particularly for MD. However, the link between MD and diabetes outcome improvement is not completely clear. This study aims to evaluate the role of microbiota modulation by a nonpharmacological intervention in patients with T2D. In this 12-week single-arm pilot study, nine participants received individual nutritional counseling sessions promoting MD. Gut microbiota, biochemical parameters, body composition, and blood pressure were assessed at baseline, 4 weeks, and 12 weeks after the intervention. Adherence to MD [assessed by Mediterranean Diet Adherence Screener (MEDAS) score] increased after the intervention. Bacterial richness increased after 4 weeks of intervention and was negatively correlated with fasting glucose levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Prevotella to Bacteroides ratio also increased after 4 weeks. In contrast, glycated haemoglobin (HbA1c) and HOMA-IR were only decreased at the end of study. Alkaline phosphatase activity was assessed in fecal samples and was negatively correlated with HbA1c and positively correlated with bacterial diversity. The results of this study reinforce that MD adherence results in a better glycemic control in subjects with T2D. Changes in gut bacterial richness caused by MD adherence may be relevant in mediating the metabolic impact of this dietary intervention.publishersversionpublishe

A distinct spectrum of copy number aberrations in pediatric high-grade gliomas

As genome-scale technologies begin to unravel the complexity of the equivalent tumors in adults, we can attempt detailed characterization of high-grade gliomas in children, that have until recently been lacking. Toward this end, we sought to validate and extend investigations of the differences between pediatric and adult tumors. Purpose: As genome-scale technologies begin to unravel the complexity of the equivalent tumors in adults, we can attempt detailed characterization of high-grade gliomas in children, that have until recently been lacking. Toward this end, we sought to validate and extend investigations of the differences between pediatric and adult tumors. Experimental Design: We carried out copy number profiling by array comparative genomic hybridization using a 32K bacterial artificial chromosome platform on 63 formalin-fixed paraffin-embedded cases of high-grade glioma arising in children and young people (<23 years). Results: The genomic profiles of these tumors could be subclassified into four categories: those with stable genomes, which were associated with a better prognosis; those with aneuploid and those with highly rearranged genomes; and those with an amplifier genotype, which had a significantly worse clinical outcome. Independent of this was a clear segregation of cases with 1q gain (more common in children) from those with concurrent 7 gain/10q loss (a defining feature of adults). Detailed mapping of all the amplification and deletion events revealed numerous low-frequency amplifications, including IGF1R, PDGFRB, PIK3CA, CDK6, CCND1, and CCNE1, and novel homozygous deletions encompassing unknown genes, including those at 5q35, 10q25, and 22q13. Despite this, aberrations targeting the “core signaling pathways” in adult glioblastomas are significantly underrepresented in the pediatric setting. Conclusions: These data highlight that although there are overlaps in the genomic events driving gliomagenesis of all ages, the pediatric disease harbors a distinct spectrum of copy number aberrations compared with adults.National Health Service funding to the NIHR Biomedical Research Centre. This work was supported by The Royal Marsden Children's Department Fund, Fundação para a Ciência e Tecnologia, Portugal, and Breakthrough Breast Cance

The MEDITAGING study: protocol of a two-armed randomized controlled study to compare the effects of the mindfulness-based stress reduction program against a health promotion program in older migrants in Luxembourg.

peer reviewed[en] BACKGROUND: Migration is a phenomenon worldwide, with older migrants, particularly those with fewer socioeconomic resources, having an increased risk of developing adverse cognitive and health outcomes and social isolation. Therefore, it is of utmost importance to validate interventions that promote healthy aging in this population. Previous studies have shown a positive impact of mindfulness based-stress reduction (MBSR) on outcomes such as cognition and sleep. However, only a few studies verified its potential in older adults, especially with vulnerable populations such as migrants. This article presents the protocol of the MEDITAGING study, which is the first to investigate the MBSR effects in migrants aged ≥55 in comparison to a health promotion program. METHODS: MEDITAGING is a two-arm randomized, double-blinded, controlled study, which will include older Portuguese-speaking migrants (n = 90). Participants are randomized to the MBSR or a health promotion program. Both interventions are conducted in groups over a total of 8 weeks, incorporating weekly meetings, an additional 4-hour class, and extra at-home tasks. The health promotion program has the same structure as the MBSR but comprises different activities related to dementia prevention, healthy habits, cognitive stimulation, sleeping, nutrition, watercolor painting, and physical activity. The assessment of executive functioning, physiological stress measures, self-reported questionnaires, and qualitative interviews are conducted at baseline, after 8 weeks (post-intervention), and at a follow-up session (from one to 3 months thereafter). Analyzes will be conducted using a modified intention-to-treat approach (all participants with at least 3 days of participation in the group-sessions and one post-intervention observation). DISCUSSION: This study will test effects of a mindfulness-based intervention against an active control condition in older adult migrants, which few studies have addressed. TRIAL REGISTRATION: ClinicalTrials.gov NCT05615337 (date of registration: 27 September 2022; date of record verification: 14 November 2022).U-AGR-7039 - Meditaging - part UL (01/06/2021 - 31/05/2023) - LEIST Anj