Ditopic Aza-Scorpiand Ligands Interact Selectively with ds-RNA and Modulate the Interaction upon Formation of Zn2+ Complexes

Nucleic acids are essential biomolecules in living systems and represent one of the main targets of chemists, biophysics, biologists, and nanotechnologists. New small molecules are continuously developed to target the duplex (ds) structure of DNA and, most recently, RNA to be used as therapeutics and/or biological tools. Stimuli-triggered systems can promote and hamper the interaction to biomolecules through external stimuli such as light and metal coordination. In this work, we report on the interaction with ds-DNA and ds-RNA of two aza-macrocycles able to coordinate Zn2+ metal ions and form binuclear complexes. The interaction of the aza-macrocycles and the Zn2+ metal complexes with duplex DNA and RNA was studied using UV thermal and fluorescence indicator displacement assays in combination with theoretical studies. Both ligands show a high affinity for ds-DNA/RNA and selectivity for ds-RNA. The ability to interact with these duplexes is blocked upon Zn2+ coordination, which was confirmed by the low variation in the melting temperature and poor displacement of the fluorescent dye from the ds-DNA/RNA. Cell viability assays show a decrease in the cytotoxicity of the metal complexes in comparison with the free ligands, which can be associated with the observed binding to the nucleic acids

Assembly of Polyiodide Networks with Cu(II) Complexes of Pyridinol-Based Tetraaza Macrocycles

Polyiodide networks are currently of great practical interest for the preparation of new electronic materials. The participation of metals in the formation of these networks is believed to improve their mechanical performance and thermal stability. Here we report the results on the construction of polyiodide networks obtained using Cu(II) complexes of a series of pyridinol-based tetraazacyclophanes as countercations. The assembly of these crystalline polyiodides takes place from aqueous solutions on the basis of similar structural elements, the [CuL]2+ and [Cu(H-1L)]+ (L = L2, L2-Me, L2-Me3) complex cations, so that the peculiarities induced by the increase of N-methylation of ligands, the structural variable of ligands, can be highlighted. First, solution equilibria involving ligands and complexes were analyzed (potentiometry, NMR, UV-vis, ITC). Then, the appropriate conditions could be selected to prepare polyiodides based on the above complex cations. Single-crystal XRD analysis showed that the coordination of pyridinol units to two metal ions is a prime feature of these ligands, leading to polymeric coordination chains of general formula {[Cu(H-1L)]}nn+ (L = L2-Me, L2-Me3). In the presence of the I-/I2 couple, the polymerization tendency stops with the formation of [(CuL)(CuH-1L)]3+ (L = L2-Me, L2-Me3) dimers which are surrounded by polyiodide networks. Moreover, coordination of the pyridinol group to two metal ions transforms the surface charge of the ring from negative to markedly positive, generating a suitable environment for the assembly of polyiodide anions, while N-methylation shifts the directional control of the assembly from H-bonds to I···I interactions. In fact, an extended concatenation of iodine atoms occurs around the complex dimeric cations, the supramolecular I···I interactions become shorter and shorter, fading into stronger forces dominated by the orbital overlap, which is promising for effective electronic materials

TweetMT : a parallel microblog corpus

We introduce TweetMT, a parallel corpus of tweets in four language pairs that combine five languages (Spanish from/to Basque, Catalan, Galician and Portuguese), all of which have an official status in the Iberian Peninsula. The corpus has been created by combining automatic collection and crowdsourcing approaches, and it is publicly available. It is intended for the development and testing of microtext machine translation systems. In this paper we describe the methodology followed to build the corpus, and present the results of the shared task in which it was tested

Overview of TweetMT : a shared task on machine translation of tweets at SEPLN 2015

This article presents an overview of the shared task that took place as part of the TweetMT workshop held at SEPLN 2015. The task consisted in translating collections of tweets from and to several languages. The article outlines the data collection and annotation process, the development and evaluation of the shared task, as well as the results achieved by the participants. // Este artículo presenta un resumen de la tarea conjunta que tuvo lugar en el marco del taller TweetMT celebrado junto con SEPLN 2015, que consiste en traducir diversas colecciones de tweets en varios lenguajes. El artículo describe el proceso de recolección y anotación de datos, el desarrollo y evaluación de la tarea y los resultados obtenidos por los participantesPeer ReviewedPostprint (author’s final draft

DOR/Tp53inp2 and Tp53inp1 Constitute a Metazoan Gene Family Encoding Dual Regulators of Autophagy and Transcription

Human DOR/TP53INP2 displays a unique bifunctional role as a modulator of autophagy and gene transcription. However, the domains or regions of DOR that participate in those functions have not been identified. Here we have performed structure/function analyses of DOR guided by identification of conserved regions in the DOR gene family by phylogenetic reconstructions. We show that DOR is present in metazoan species. Invertebrates harbor only one gene, DOR/Tp53inp2, and in the common ancestor of vertebrates Tp53inp1 may have arisen by gene duplication. In keeping with these data, we show that human TP53INP1 regulates autophagy and that different DOR/TP53INP2 and TP53INP1 proteins display transcriptional activity. The use of molecular evolutionary information has been instrumental to determine the regions that participate in DOR functions. DOR and TP53INP1 proteins share two highly conserved regions (region 1, aa residues 28–42; region 2, 66–112 in human DOR). Mutation of conserved hydrophobic residues in region 1 of DOR (that are part of a nuclear export signal, NES) reduces transcriptional activity, and blocks nuclear exit and autophagic activity under autophagy-activated conditions. We also identify a functional and conserved LC3-interacting motif (LIR) in region 1 of DOR and TP53INP1 proteins. Mutation of conserved acidic residues in region 2 of DOR reduces transcriptional activity, impairs nuclear exit in response to autophagy activation, and disrupts autophagy. Taken together, our data reveal DOR and TP53INP1 as dual regulators of transcription and autophagy, and identify two conserved regions in the DOR family that concentrate multiple functions crucial for autophagy and transcription

Analysis of the Ush2a Gene in Medaka Fish (Oryzias latipes)

Patients suffering from Usher syndrome (USH) exhibit sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. USH is the most common genetic disorder affecting hearing and vision and is included in a group of hereditary pathologies associated with defects in ciliary function known as ciliopathies. This syndrome is clinically classified into three types: USH1, USH2 and USH3. USH2 accounts for well over one-half of all Usher cases and mutations in the USH2A gene are responsible for the majority of USH2 cases, but also for atypical Usher syndrome and recessive non-syndromic RP. Because medaka fish (Oryzias latypes) is an attractive model organism for genetic-based studies in biomedical research, we investigated the expression and function of the USH2A ortholog in this teleost species. Ol-Ush2a encodes a protein of 5.445 aa codons, containing the same motif arrangement as the human USH2A. Ol-Ush2a is expressed during early stages of medaka fish development and persists into adulthood. Temporal Ol-Ush2a expression analysis using whole mount in situ hybridization (WMISH) on embryos at different embryonic stages showed restricted expression to otoliths and retina, suggesting that Ol-Ush2a might play a conserved role in the development and/or maintenance of retinal photoreceptors and cochlear hair cells. Knockdown of Ol-Ush2a in medaka fish caused embryonic developmental defects (small eyes and heads, otolith malformations and shortened bodies with curved tails) resulting in late embryo lethality. These embryonic defects, observed in our study and in other ciliary disorders, are associated with defective cell movement specifically implicated in left-right (LR) axis determination and planar cell polarity (PCP)

Intron Evolution: Testing Hypotheses of Intron Evolution Using the Phylogenomics of Tetraspanins

BACKGROUND: Although large scale informatics studies on introns can be useful in making broad inferences concerning patterns of intron gain and loss, more specific questions about intron evolution at a finer scale can be addressed using a gene family where structure and function are well known. Genome wide surveys of tetraspanins from a broad array of organisms with fully sequenced genomes are an excellent means to understand specifics of intron evolution. Our approach incorporated several new fully sequenced genomes that cover the major lineages of the animal kingdom as well as plants, protists and fungi. The analysis of exon/intron gene structure in such an evolutionary broad set of genomes allowed us to identify ancestral intron structure in tetraspanins throughout the eukaryotic tree of life. METHODOLOGY/PRINCIPAL FINDINGS: We performed a phylogenomic analysis of the intron/exon structure of the tetraspanin protein family. In addition, to the already characterized tetraspanin introns numbered 1 through 6 found in animals, three additional ancient, phase 0 introns we call 4a, 4b and 4c were found. These three novel introns in combination with the ancestral introns 1 to 6, define three basic tetraspanin gene structures which have been conserved throughout the animal kingdom. Our phylogenomic approach also allows the estimation of the time at which the introns of the 33 human tetraspanin paralogs appeared, which in many cases coincides with the concomitant acquisition of new introns. On the other hand, we observed that new introns (introns other than 1-6, 4a, b and c) were not randomly inserted into the tetraspanin gene structure. The region of tetraspanin genes corresponding to the small extracellular loop (SEL) accounts for only 10.5% of the total sequence length but had 46% of the new animal intron insertions. CONCLUSIONS/SIGNIFICANCE: Our results indicate that tests of intron evolution are strengthened by the phylogenomic approach with specific gene families like tetraspanins. These tests add to our understanding of genomic innovation coupled to major evolutionary divergence events, functional constraints and the timing of the appearance of evolutionary novelty

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Phosphotyrosine phosphatase R3 receptors: Origin, evolution and structural diversification

DOI: 10.1371/journal.pone.0172887 URL: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172887 Filiació URV: SI Paraules en blancLimited data exists on the interrelationships between physical activity (PA), sedentary behaviors and sleep concerning cardiometabolic risk factors in aged adults at high cardiovascular disease risk. Our aim was to examine independent and joint associations between time spent in leisure-time PA, sedentary behaviors and sleep on the prevalence of obesity, type 2 diabetes (T2D) and components of the metabolic syndrome (MetS) in Mediterranean individuals at high cardiovascular risk. Cross-sectional analyses were performed on baseline data from 5776 Spanish adults (aged 55-75y in men; 60-75y in women) with overweight/ obesity and MetS, from October 2013 to October 2016, in the PREDIMED-PLUS trial. Employing multivariable-adjusted Cox regression with robust variance and constant time (given the cross-sectional design), higher prevalence of obesity, T2D and abdominal obesity as component of the MetS were associated with greater time in TV-viewing (Relative Risk, RR: 1.02, 95%CI: 1.01, 1.03; RR:1.04, 95%CI: 1.02, 1.06 and RR: 1.01 95%CI: 1.00, 1.02; respectively, all P < .01). Conversely, greater time in moderate-vigorous PA (MVPA) was associated with lower prevalence of obesity, T2D, abdominal obesity and low HDL-cholesterol (RR: 0.95, 95%CI: 0.93, 0.97; RR: 0.94, 95%CI: 0.89, 0.99; RR: 0.97, 95%CI: 0.96, 0.98; and RR: 0.95, 95%CI: 0.91, 0.99, respectively, all P < .05). For these outcomes, theoretically substituting 1-h/day of MVPA for 1-h/day TV-viewing was also significantly associated with lower prevalence (RR 0.91 to 0.97, all P < .05). Similar lower RR in these outcomes was observed when substituting 1-h/day of MVPA for 1-h/day of sleeping. Longer time watching TV and not meeting MVPA recommendations were jointly associated with higher RR of the pr