Cell identity and nucleo-mitochondrial genetic context modulate OXPHOS performance and determine somatic heteroplasmy dynamics

Heteroplasmy, multiple variants of mitochondrial DNA (mtDNA) in the same cytoplasm, may be naturally generated by mutations but is counteracted by a genetic mtDNA bottleneck during oocyte development. Engineered heteroplasmic mice with nonpathological mtDNA variants reveal a nonrandom tissue-specific mtDNA segregation pattern, with few tissues that do not show segregation. The driving force for this dynamic complex pattern has remained unexplained for decades, challenging our understanding of this fundamental biological problem and hindering clinical planning for inherited diseases. Here, we demonstrate that the nonrandom mtDNA segregation is an intracellular process based on organelle selection. This cell type-specific decision arises jointly from the impact of mtDNA haplotypes on the oxidative phosphorylation (OXPHOS) system and the cell metabolic requirements and is strongly sensitive to the nuclear context and to environmental cues

Recursos para la integración de la investigación científica y profesional en la docencia de posgrado. El caso del máster oficial universitario en comunicación de las organizaciones de la UCM

Con la participación de todos los actores implicados, el proyecto registra, sistematiza e impulsa la integración de la investigación académica y profesional, produciendo recursos que ayudarán a consolidar el programa de posgrado Mást.CO. Se han producido 6 recursos: para llevar a cabo investigación académica y profesional en el ámbito de la comunicación de organizaciones, para utilizar las fuentes de la biblioteca, para realizar planes de comunicación de organizaciones, para realizar el informe ejecutivo ante un cliente, y para elaborar un plan e sesiones extraordinarias que acerque la academia y la profesión en el Máster de Comunicación de Organizaciones

Regulation of mother-to-offspring transmission of mtDNA heteroplasmy

mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood. Mouse studies led to contradictory models of random drift or haplotype selection for mother-to-offspring transmission of mtDNA heteroplasmy. Here, we show that mtDNA heteroplasmy affects embryo metabolism, cell fitness, and induced pluripotent stem cell (iPSC) generation. Thus, genetic and pharmacological interventions affecting oxidative phosphorylation (OXPHOS) modify competition among mtDNA haplotypes during oocyte development and/or at early embryonic stages. We show that heteroplasmy behavior can fall on a spectrum from random drift to strong selection, depending on mito-nuclear interactions and metabolic factors. Understanding heteroplasmy dynamics and its mechanisms provide novel knowledge of a fundamental biological process and enhance our ability to mitigate risks in clinical applications affecting mtDNA transmission

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Automatization of a multipurpose astronomical spectrograph

5 pages, 7 figures.This article deals with the study and fabrication of a system for the automation of a multipurpose spectrograph used in Astronomy. This system allows the 19 movements of the instrument to run by using high-level software, a "master" board, and 19 "slave" boards. The Astrophysique Lineal et BIdimensional par RÉseaux Optiques (ALBIREO) spectrograph has three working modes and is installed in the Observatorio de Sierra Nevada, Granada, Spain. We describe a low-cost system realized for the automatization of a multifunction spectrograph. It allows the control of a large number of motors: 19 for Albireo; the theoretical limit is 32 768! Another advantage of this architecture based on "slave" boards is to supply each motor with exactly the current it needs to reach the required torque (reliability and repetitivity of motions are obtained when the motor torque is at least twice the resistant torque). Thus, we can avoid unnecessary overheating which would be detrimental to the material as well as to the local image quality (seeing). The reliability of the system is obtained by software filtering the commands and also by using optocoupled electronics to avoid interference. For a complex instrument, the high-level software must be user friendly. The efficiency of the present software in this respect has been appreciated since first being used on the telescope. This system may be of interest to laboratories and observatories with similar needs for automation of motions. The adoption of this system will be supported by the IAA Laboratory, Granada, Spain.The development was financially supported by the Instituto de Astrofisica de Andalucia, from the CSIC, Granada, Spain.Peer reviewe

Transcriptional changes and oxidative stress associated with the synergistic interaction between Potato virus X and Potato virus Y and their relationship with symptom expresión

14 páginas, 7 figuras, 2 tablas -- PAGS nros. 1431-1444Many virus diseases of economic importance to agriculture result from mixtures of different pathogens invading the host at a given time. This contrasts with the latively scarce studies available on the molecular events associated with virus---host interactions in mixed infections. Compared with single infections, co-infection of Nicotiana benthamiana with Potato virus X (PVX) and Potato virus Y (PVY) resulted in increased systemic symptoms (synergism) that led to necrosis of the newly emerging leaves and death of the plant. A comparative transcriptional analysis was undertaken to identify quantitative and qualitative differences in gene expression during this synergistic infection and correlate these changes with the severe symptoms it caused. Global transcription rofiles of doubly infected leaves were compared with those from singly infected leaves using gene ontology enrichment analysis and metabolic pathway annotator software. Functional gene categories altered by the double infection comprise suites of genes regulated coordinately, which are associated with chloroplast functions (downregulated), protein synthesis and degradation (upregulated), carbohydrate metabolism (upregulated), and response to biotic stimulus and stress (upregulated). The expressions of reactive oxygen species–generating enzymes as well as several mitogen-activated protein kinases were also significantly induced. Accordingly, synergistic infection induced a severe oxidative stress in N. benthamiana leaves, as judged by increases in lipid peroxidation and by the generation of superoxide radicals in chloroplasts, which correlated with the misregulation of antioxidative genes in microarray data. Interestingly, expression of genes encoding oxylipin biosynthesis was uniquely upregulated by the synergistic infection. Virus-induced gene silencing of α-dioxygenase1 delayed cell death during PVX–PVY infectionThis work was supported by grant BIO2006-10944 from the Ministerio Educacione y Ciencia and by grant 200540M109 from the Comunidad Autónoma de MadridPeer reviewe

A CRO-species optimization scheme for robust global solar radiation statistical downscaling

This paper tackles the prediction of the global solar radiation (GSR) at a given point, using as predictive variables the outputs of a numerical weather model (the WRF meso-scale model) obtained at a different grid points. Prediction is obtained in this work using a Multilayer Perceptron (MLP) trained with Extreme Learning Machines (ELMs). Provided that the number of WRF outputs is vast, we propose the use of a Coral Reefs Optimization algorithm with species (CRO-SP) to obtain a reduced number of significant predictive variables, therefore improving the global solar radiation prediction attained without feature selection. The proposed system has been tested on real data from a radiometric station located at Toledo (Spain) and average best results of RMSE of 69.19 have been achieved, resulting in a 21.62% improvement over the average prediction without considering the CRO-SP for the feature selection.This work has been partially supported by the project TIN2014-54583-C2-2-R of the Spanish Ministerial Commission of Science and Technology (MICYT), and by the Comunidad Autónoma de Madrid, under project number S2013ICE-2933_02. We would like to thank as well AEMET for providing the observed atmospherical data used in this work.Peer reviewe