the melas mutation m 3243a g promotes reactivation of fetal cardiac genes and an epithelial mesenchymal transition like program via dysregulation of mirnas

Abstract The pathomechanisms underlying oxidative phosphorylation (OXPHOS) diseases are not well-understood, but they involve maladaptive changes in mitochondria-nucleus communication. Many studies on the mitochondria-nucleus cross-talk triggered by mitochondrial dysfunction have focused on the role played by regulatory proteins, while the participation of miRNAs remains poorly explored. MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is mostly caused by mutation m.3243A>G in mitochondrial tRNALeu(UUR) gene. Adverse cardiac and neurological events are the commonest causes of early death in m.3243A>G patients. Notably, the incidence of major clinical features associated with this mutation has been correlated to the level of m.3243A>G mutant mitochondrial DNA (heteroplasmy) in skeletal muscle. In this work, we used a transmitochondrial cybrid model of MELAS (100% m.3243A>G mutant mitochondrial DNA) to investigate the participation of miRNAs in the mitochondria-nucleus cross-talk associated with OXPHOS dysfunction. High-throughput analysis of small-RNA-Seq data indicated that expression of 246 miRNAs was significantly altered in MELAS cybrids. Validation of selected miRNAs, including miR-4775 and miR-218-5p, in patient muscle samples revealed miRNAs whose expression declined with high levels of mutant heteroplasmy. We show that miR-218-5p and miR-4775 are direct regulators of fetal cardiac genes such as NODAL, RHOA, ISL1 and RXRB, which are up-regulated in MELAS cybrids and in patient muscle samples with heteroplasmy above 60%. Our data clearly indicate that TGF-β superfamily signaling and an epithelial-mesenchymal transition-like program are activated in MELAS cybrids, and suggest that down-regulation of miRNAs regulating fetal cardiac genes is a risk marker of heart failure in patients with OXPHOS diseases

La extensión universitaria en el diagnóstico, educación y prevención de las parasitosis infantiles

Una importante población de bajos recursos se asienta en las periferias de las ciudades con viviendas precarias, carentes de condiciones higienico-sanitarias adecuadas mínimas, conviviendo con mascotas sin desparasitar y expuestas a ambientes contaminados zoonóticamente que favorecen las parasitosis infantiles. Este escenario favorece la instalación de un grave problema de Salud Pública que vincula aspectos individuales, culturales, socioeconómicos y ambientales. El objetivo del trabajo es efectuar el diagnóstico enteroparasitológico, concientizar y educar a la población en la influencia de hábitos, suelo, agua y mascotas como fuentes de contaminación y diseminación de las parasitosis, incentivar a padres y docentes como agentes multiplicadores de prevención, transferir los resultados al equipo médico para tratamiento y seguimiento de individuos parasitados, hacer partícipes a los estudiantes de la problemática socio-ambiental y la realidad de las poblaciones vulnerables favoreciendo acciones solidarias.Facultad de Ciencias Veterinaria

La extensión universitaria en el diagnóstico, educación y prevención de las parasitosis infantiles

Una importante población de bajos recursos se asienta en las periferias de las ciudades con viviendas precarias, carentes de condiciones higienico-sanitarias adecuadas mínimas, conviviendo con mascotas sin desparasitar y expuestas a ambientes contaminados zoonóticamente que favorecen las parasitosis infantiles. Este escenario favorece la instalación de un grave problema de Salud Pública que vincula aspectos individuales, culturales, socioeconómicos y ambientales. El objetivo del trabajo es efectuar el diagnóstico enteroparasitológico, concientizar y educar a la población en la influencia de hábitos, suelo, agua y mascotas como fuentes de contaminación y diseminación de las parasitosis, incentivar a padres y docentes como agentes multiplicadores de prevención, transferir los resultados al equipo médico para tratamiento y seguimiento de individuos parasitados, hacer partícipes a los estudiantes de la problemática socio-ambiental y la realidad de las poblaciones vulnerables favoreciendo acciones solidarias.Facultad de Ciencias Veterinaria

Age determination procedures on small and medium pelagic species in Spanish Institute of Oceanography (IEO)

This handbook presents a summary of the age estimation procedures used in Spanish Institute of Oceanography (IEO) for some of the main commercial small and medium pelagic species of the Spanish fleet: anchovy (Engraulis encrasicolus), sardine (Sardina pichardus), mackerel (Scomber scombrus), chuck mackerel (Scomber colias), horse mackerel (Trachurus trachurus), Mediterranean horse mackerel (Trachurus mediterraneus) and blue whiting (Micromesistius poutassou). It provides information about the sampling program, otolith extraction and preparation, and the age estimation criteria. A summary of the information related to the age accuracy, validation and corroboration of each species is also presented, as well as that related to the age precision, quality control and verification

Comparing the microstructure and photovoltaic performance of 3 perylene imide acceptors with similar energy levels but different packing tendencies

While it is widely recognized that microstructure plays an important role in the performance of organic photovoltaics (OPV), systematic studies are often challenging, as varying the molecular packing through typical chemical means (such as sidechain tuning) often affects the molecular energy levels, thus preventing a clear correlation. In this work we present the synthesis of three perylene imide (PI) based electron acceptors with almost identical energy levels, but distinct packing tendencies. We confirm our initial hypothesis by measuring solution and solid-state absorption, cyclic voltammetry as well as characterizing the films by grazing incident wide angle X-ray scattering (GIWAXS). In a second step, we repeat the characterization of the three materials in blends with two polymer donors, namely PCDTBT or PBDBT, whose energy levels are well aligned with those of the PI acceptors, and which, additionally, exhibit different degrees of structural order. We show how the initial strong difference between acceptors is partially blurred in blends, but still critical. Finally, we correlate our structural data with OPV devices made with the corresponding six blends. Our data suggest that a good donor acceptor marriage should ensure good energy alignment but also exhibit complementary crystallization tendencies of the two components.The authors acknowledge financial support from the Spanish Ministry of Science and Innovation through the Severo Ochoa” Program for Centers of Excellence in R&D (No. CEX2019-000917-S), and projects PGC2018-095411-B-I00, PID2019-106268GB-C33 and PID2019-110305GB-I00, as well as the European Commission through the Horizon 2020 Marie Sklodowska-Curie ITN Programme, SEPOMO, Grant Number: 722651, and the UCM (INV.GR.00.1819.10759). E.G. specially acknowledges Comunidad de Madrid and Universidad Complutense de Madrid for a post-doctoral contract (CT20/19- CT21/19/PEJD-2018-POST/IND-8661PAI). M.J.A.N. acknowledges URJC for a post-doctoral contract. R.P.O and A.H. also acknowledge support from Junta de Andalucía (projects UMA18-FEDERJA-080). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).Peer reviewe

Bioinformatics analysis of mutations in SARSCoV- 2 and clinical phenotypes

1 p.-1 fig.-8 tab.Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially reported in Wuhan (China) hasspread worldwide. Like other viruses, SARS-CoV-2 accumulates mutations with each cycle of replication by continuously evolving a viral strain with one or more single nucleotide variants (SNVs). However, SNVs that cause severe COVID-19 or lead to immune escape or vaccine failure are not well understood. We aim to identify SNVs associated with severe clinical phenotypes.Methods: In this study, 27429 whole-genome aligned consensus sequences of SARS-CoV-2 were collected from genomic epidemiology of SARS-CoV-2 project in Spain (SeqCOVID) [1]. These samples were obtained from patients who required hospitalization and/or intensive care unit admission (ICU), excluding those registered in the first pandemic wave.Besides, 248 SARS-CoV-2 genomes were isolated from COVID-19 hospitalized patients from Gregorio Marañon General University Hospital (GMH) of which 142 were fully vaccinated. Bioinformatics tools using R and Python programming languages were developed and implemented comparing those to SARS-CoV-2 Wuhan-Hu-1 (reference genome).Results: Using a selection threshold mutational frequency 10%, 27 SNVs were expected to have association with hospitalization and ICU risk. The reference haplotype differing at the SNV coding for lysine at the residue 203 (N:R203K) was found to have negative association with COVID-19 hospitalization risk (p = 5.37 x 10-04). Similarly, a negative association was observed when the residue at 501 is replaced by tyrosine (S:N501Y) (p = 1.33 x 10-02). The application of a Chi-square test suggested that SNV-haplotypes coding for mutants residues such as (S:A222V, N:A220V, ORF10:V30L) and (ORF1a:T1001I, ORF1a:I2230T, S:N501Y, S:T716S, S:S982A, ORF8:Q27*, N:R203K, N:S235F) have negative associations with COVID-19 hospitalization risk (p = 6.58 x 10-07 and p = 2.27 x 10-16, respectively) and COVID-19 ICU risk (p = 1.15 x 10-02 and p = 2.51 x 10-02, respectively). Focusing on the SNV-haplotype coding the mutations (S:A222V, N:A220V, N:D377Y, ORF10:V30L) were observed to increase the risk of COVID-19 hospitalization (p = 2.71 x 10-04). Results from SARS-CoV-2 genomes analysis from GMH showed 63 coding SNVs which met the established threshold value. Applying a Chi-square test, the SNV-haplotype carrying coding variants for mutant residues in 5 ORF proteins and surface and membrane glycoprotein and nucleocapsid phosphoprotein was significantly associated with vaccine failure in hospitalized COVID-19 patients (p = 7.91 x 10-04).Conclusions: SNV-haplotypes carrying variants lead to non-synonymous mutations located along SARS-CoV-2 wholeproteome may influence COVID-19 severity and vaccine failure suggesting a functional role in the clinical outcome for COVID-19 patients.This research work was funded by the European Commission-NextGenerationEU (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global)Peer reviewe

HIV-1 Vpu Protein Mediates the Transport of Potassium in Saccharomyces cerevisiae

Human immunodeficiency virus type 1 (HIV-1) Vpu is an integral membrane protein that belongs to the viroporin family. Viroporins interact with cell membranes, triggering membrane permeabilization and promoting release of viral particles. In vitro electrophysiological methods have revealed changes in membrane ion currents when Vpu is present; however, in vivo the molecular mechanism of Vpu at the plasma membrane is still uncertain. We used the yeast Saccharomyces cerevisiae as a genetic model system to analyze how Vpu ion channel impacts cellular homeostasis. Inducible expression of Vpu impaired cell growth, suggesting that this viral protein is toxic to yeast cultures. This toxicity decreased with extracellular acidic pH. Also, Vpu toxicity diminished as the extracellular K(+) concentration was increased. However, expression of the Vpu protein suppresses the growth defect of K(+) uptake-deficient yeast (Δtrk1,2). The phenotype rescue of these highly hyperpolarized cells was almost total when they were grown in medium supplemented with high concentrations of KCl (100 mM) at pH 7.0 but was significantly reduced when the extracellular K(+) concentration or pH was decreased. These results indicate that Vpu has the ability to modify K(+) transport in both yeast strains. Here, we show also that Vpu confers tolerance to the aminoglycoside antibiotic hygromycin B in Δtrk1,2 yeast. Our results suggest that Vpu interferes with cell growth of wild-type yeast but improves proliferation of the hyperpolarized trk1,2 mutant by inducing plasma membrane depolarization. Furthermore, evaluation of the ion channel activity of the Vpu protein in Δtrk1,2 yeast could aid in the development of a high-throughput screening assay for molecules that target the retroviral protein.This study was supported by Grants PI PI05/00013 and PI08/0912 from Fondo de Investigación Sanitaria. L.H. and N.M. were holders of Predoctoral Fellowships from Instituto de Salud Carlos III.S

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series