Clinical considerations on the posology of direct oral anticoagulants

Los anticoagulantes dicumarínicos han demostrado su eficacia en pacientes con fibrilación auricular no valvular. Sin embargo, presentan desventajas como la necesidad de ajustar la dosis y la interacción con fármacos y alimentos. Por su parte, los anticoagulantes orales de acción directa se presentan como una alternativa eficaz y segura con un manejo clínico menos complejo. Existe un considerable debate sobre los criterios de selección de las pautas posológicas de los anticoagulantes orales de acción directa. Las diferencias entre ellos y sus pautas de administración han despertado dudas sobre los criterios de selección clínicos, farmacocinéticos y farmacodinámicos que avalan dicha posología. Esta revisión analiza de forma crítica las evidencias disponibles y su impacto en la selección final del esquema posológic

Deciphering a multi-event in a non-complex set of detrital zircon U-Pb ages from Carboniferous graywackes of SW Iberia

The determination of U–Pb ages from detrital zircons of sedimentary rocks using LA-ICP-MS has been widely used for the purpose of provenance analysis. One problem that frequently arises is finding a population that appears to be non-complex despite several perceptible age peaks in its spectrum. These peaks are qualitatively defined by means of relative probability diagrams, or PDFs, but it is difficult to quantify their statistical significance relative to a zircon forming multi-event. Thus, can a multi-event in a non-complex set of detrital zircon U–Pb ages be deciphered and characterized? The aim of this study is to attempt to provide an answer to this question by means of statistical analysis. Its objectives are: a) to determine the best minimum number of zircon age populations (peaks), BmPs, b) for the characterization of each peak in terms of age and event duration; c) to compare the results obtained from two datasets showing similar zircon ages; and d) to demonstrate the usefulness of deciphering these BmPs. First, cluster analysis is carried out, aimed at grouping zircon ages into a set of consistent clusters. A Gaussian Kernel function is then fitted to each cluster and summed to obtain a theoretical PDFm (modeled probability density function). Finally, the selected modeled PDFm (that built on the BmPs) is that which reports the lowest number of peaks for which the difference as compared with the original gPDF (global probability density function) is equal to or below 5%. Deciphered BmP peaks can be characterized and used for characterizing and providing an understanding of related event(s). A geological interpretation, based on the results obtained, is attempted. This includes a robust measure for maximum age of deposition for both Cabrela and Mértola graywackes

Insights from the felsic volcanic rocks hosting the sulphide ore of the giant Aljustrel deposit, Iberian Pyrite Belt

This is a contribution to the research project PetroGeo (LNEG)A geochronological study using SHRIMP U-Pb analysis of zircon grains has been conducted to date felsic volcanic rocks hosting the six massive sulphide deposits of the giant Aljustrel mining district in the Iberian Pyrite Belt. A multiple method age calculation approach was used to validate and ponder calculated Concordia ages (emplacement and inherited), which included weighted average, probability density peak(s), Tuff Zirc and Unmix functions. This approach was particularly useful to interpret the wide continuous single U-Pb ages (320–405 Ma) recorded in the Aljustrel volcanic rocks. The volcanic pile (>250 m) that hosts the Aljustrel deposits was emplaced between 359 and 353 Ma. Upper Devonian inheritance, representing subvolcanic activity, is well-represented in the volcanic rocks of Aljustrel (373–365 Ma). Older Devonian inherited zircon ages at 405 Ma, 388 Ma and 380 Ma were retrieved, hypothetically representing deep plutonism or other melting episodes, which suggests a long-lasting (~50 Ma) magmatic activity in the Aljustrel district. Older pre-Devonian inherited ages, uppermost Silurian and early to late Cambrian, and post-emplacement ages (~330–345 Ma) were also detected, with the latter reflecting Pb loss most likely driven by the main Variscan orogenic event. Maximum ages obtained for the volcanic rocks in the different deposits open the possibility that the last pulses of volcanic activity and subsequent deposition of the massive sulphides were diachronic in the different Aljustrel sub-basins. Additionally, results imply that, contrary to previously assumed, Gavião and São João-Moinho deposits are probably not the same ore lens disrupted by tardi-Variscan faults. This opens new opportunities for mining exploration and targeting in the Aljustrel district and points out the importance of high-resolution geochronological studies in mining and brownfield areas.info:eu-repo/semantics/publishedVersio

Time span of the volcanic setting of the Neves-Corvo VHMS deposit

Resumo alargad

Physical and mathematical modeling of wave propagation in the Ariane 5 VEB structure

The separation of the lower stage of the ARIANE 5 Vehicle Equipment Bay (VEB) Structure is to be done using a pyrotechnic device. The wave propagation effects produced by the explosion can affect the electronic equipment, so it was decided to analyze, using both physical and numerical modeling, a small piece of the structure to determine the distribution of the accelerations and the relative importance of damping, stiffness, connections, etc. on the response of the equipment

Apoptosis-associated microRNAs are modulated in mouse, rat and human neural differentiation

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRs or miRNAs) regulate several biological processes in the cell. However, evidence for miRNAs that control the differentiation program of specific neural cell types has been elusive. Recently, we have shown that apoptosis-associated factors, such as p53 and caspases participate in the differentiation process of mouse neural stem (NS) cells. To identify apoptosis-associated miRNAs that might play a role in neuronal development, we performed global miRNA expression profiling experiments in NS cells. Next, we characterized the expression of proapoptotic miRNAs, including miR-16, let-7a and miR-34a in distinct models of neural differentiation, including mouse embryonic stem cells, PC12 and NT2N cells. In addition, the expression of antiapoptotic miR-19a and 20a was also evaluated.</p> <p>Results</p> <p>The expression of miR-16, let-7a and miR-34a was consistently upregulated in neural differentiation models. In contrast, expression of miR-19a and miR-20a was downregulated in mouse NS cell differentiation. Importantly, differential expression of specific apoptosis-related miRNAs was not associated with increased cell death. Overexpression of miR-34a increased the proportion of postmitotic neurons of mouse NS cells.</p> <p>Conclusions</p> <p>In conclusion, the identification of miR-16, let-7a and miR-34a, whose expression patterns are conserved in mouse, rat and human neural differentiation, implicates these specific miRNAs in mammalian neuronal development. The results provide new insights into the regulation of neuronal differentiation by apoptosis-associated miRNAs.</p

Altered expression of the immunoregulatory ligand-receptor pair CD200-CD200R1 in the brain of Parkinson's disease patients

Neuroinflammation, in which activated microglia are involved, appears to contribute to the development of Parkinson's disease (PD). However, the role of microglial activation and the mechanisms governing this process remain uncertain. We focused on one inhibitory mechanism involved in the control of microglial activation, the microglia inhibitory receptor CD200R1, and its ligand CD200, mainly expressed by neurons. The human CD200R1 gene encodes two membrane-associated and two soluble protein isoforms and the human CD200 gene encodes full-length proteins (CD200full) but also truncated (CD200tr) proteins which act as CD200R1 antagonists. Little is known about their expression in the human brain under pathological conditions. We used human peripheral blood monocytes and monocyte-derived microglia-like cells from control subjects to characterize the expression of the CD200R1 mRNA variants, which showed stimulus-specific responses. We provide evidence of increased CD200R1 (mRNA variants and protein isoforms) and CD200 expression (CD200tr mRNA) in brain tissue of PD patients, mainly in the hippocampus, as well as increased CD200 expression (CD200full and CD200tr mRNAs) in iPSCs-derived dopaminergic neurons generated from skin fibroblasts of PD patients. Our results suggest that CD200-CD200R1 signalling is altered in PD, which may affect the microglial function and constitute a potential target in therapeutic strategies for PD.© 2022. The Author(s)

Dengue virus targets RBM10 deregulating host cell splicing and innate immune response

© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] experiments previously performed by our laboratories showed enrichment in intronic sequences and alterations in alternative splicing in dengue-infected human cells. The transcript of the SAT1 gene, of well-known antiviral action, displayed higher inclusion of exon 4 in infected cells, leading to an mRNA isoform that is degraded by non-sense mediated decay. SAT1 is a spermidine/spermine acetyl-transferase enzyme that decreases the reservoir of cellular polyamines, limiting viral replication. Delving into the molecular mechanism underlying SAT1 pre-mRNA splicing changes upon viral infection, we observed lower protein levels of RBM10, a splicing factor responsible for SAT1 exon 4 skipping. We found that the dengue polymerase NS5 interacts with RBM10 and its sole expression triggers RBM10 proteasome-mediated degradation. RBM10 over-expression in infected cells prevents SAT1 splicing changes and limits viral replication, while its knock-down enhances the splicing switch and also benefits viral replication, revealing an anti-viral role for RBM10. Consistently, RBM10 depletion attenuates expression of interferon and pro-inflammatory cytokines. In particular, we found that RBM10 interacts with viral RNA and RIG-I, and even promotes the ubiquitination of the latter, a crucial step for its activation. We propose RBM10 fulfills diverse pro-inflammatory, anti-viral tasks, besides its well-documented role in splicing regulation of apoptotic genes.Agencia Nacional de Promoción Científica y Tecnológica de Argentina (ANPCyT) [2014-2888, 2015-1731, 2017-0111 to A.S. and 2015-2555, 2017-1717 to A.V.G.]; Universidad de Buenos Aires, Argentina (UBACyT) [20020170100045BA to A.S.]; NIH (NIAID) [R01.AI095175 to A.V.G.]; Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina (CONICET) [PIP 11220170100171CO to C.C.G]; B.P. has been a postdoctoral fellow from CONICET from 2017 to 2019 and is currently a postdoctoral fellow at the Institute of Cell Biology in the University of Bern, Switzerland; L.B. and M.E.G.S. are recipients of doctoral fellowships from CONICET; M.F.T. is a doctoral fellowship recipient from ANPCyT; N.G. has been an undergraduate fellowship recipient from the University of Buenos Aires (2018–2020); P.M. has been a doctoral fellow from CONICET (2015–2019) and is currently a postdoctoral fellow supported by H2020-Marie Sklodowska-Curie Research and Innovation Staff Exchanges [734825-LysoMod]; R.V.D. has been a visiting post-doctoral fellow at the Srebrow lab from IMM (Lisbon, Portugal) supported by the same program. A.S., A.V.G., C.C.G., N.G.I. and L.G.G. are career investigators from CONICET.info:eu-repo/semantics/publishedVersio