Estudios sobre la población X-frágil en Aragón

La enfermedad conocida como síndrome X frágil es una de las causas más habituales de discapacidad intelectual y autismo en las sociedades modernas. Este síndrome afecta a la regulación de la transcripción del mRNA de la proteína FMRP en las neuronas, un elemento fundamental en el control de la expresión de otros genes. Actualmente su origen se desconoce y no hay tratamiento, por lo que el diagnóstico temprano juega un papel crucial para mejor calidad de vida de los individuos afectos. En este estudio se han analizado los casos del Hospital Universitario Miguel Servet de Zaragoza con alteraciones genéticas relacionadas con dicho síndrome. Se ha llevado a cabo una comparativa de la metodología empleada para su diagnóstico entre los años 2011 y 2015, así como un estudio en profundidad de un caso particular en el que no hay una correlación entre el genotipo característico del síndrome de X frágil y el fenotipo que cabría esperar. Además se ha realizado una investigación para intentar demostrar la relación de esta alteración genética con el polimorfismo C667T de la metil tetrahidrofolato reductasa (MTHR) como apuntan algunos estudios recientes pero sin llegar a resultados concluyentes

Melatonin decreases glucose metabolism in prostate cancer cells: A 13C stable isotope-resolved metabolomic study

The pineal neuroindole melatonin exerts an exceptional variety of systemic functions. Some of them are exerted through its specific membrane receptors type 1 and type 2 (MT1 and MT2) while others are mediated by receptor-independent mechanisms. A potential transport of melatonin through facilitative glucose transporters (GLUT/SLC2A) was proposed in prostate cancer cells. The prostate cells have a particular metabolism that changes during tumor progression. During the first steps of carcinogenesis, oxidative phosphorylation is reactivated while the switch to the “Warburg effect” only occurs in advanced tumors and in the metastatic stage. Here, we investigated whether melatonin might change prostate cancer cell metabolism. To do so, 13C stable isotope-resolved metabolomics in androgen sensitive LNCaP and insensitive PC-3 prostate cancer cells were employed. In addition to metabolite 13C-labeling, ATP/AMP levels, and lactate dehydrogenase or pentose phosphate pathway activity were measured. Melatonin reduces lactate labeling in androgen-sensitive cells and it also lowers 13C-labeling of tricarboxylic acid cycle metabolites and ATP production. In addition, melatonin reduces lactate 13C-labeling in androgen insensitive prostate cancer cells. Results demonstrated that melatonin limits glycolysis as well as the tricarboxylic acid cycle and pentose phosphate pathway in prostate cancer cells, suggesting that the reduction of glucose uptake is a major target of the indole in this tumor type

Drought Sensitiveness on Forest Growth in Peninsular Spain and the Balearic Islands

Drought is one of the key natural hazards impacting net primary production and tree growth in forest ecosystems. Nonetheless, tree species show different responses to drought events, which make it difficult to adopt fixed tools for monitoring drought impacts under contrasting environmental and climatic conditions. In this study, we assess the response of forest growth and a satellite proxy of the net primary production (NPP) to drought in peninsular Spain and the Balearic Islands, a region characterized by complex climatological, topographical, and environmental characteristics. Herein, we employed three different indicators based on in situ measurements and satellite image-derived vegetation information (i.e., tree-ring width, maximum annual greenness, and an indicator of NPP). We used seven different climate drought indices to assess drought impacts on the tree variables analyzed. The selected drought indices include four versions of the Palmer Drought Severity Index (PDSI, Palmer Hydrological Drought Index (PHDI), Z-index, and Palmer Modified Drought Index (PMDI)) and three multi-scalar indices (Standardized Precipitation Evapotranspiration Index (SPEI), Standardized Precipitation Index (SPI), and Standardized Precipitation Drought Index (SPDI)). Our results suggest that—irrespective of drought index and tree species—tree-ring width shows a stronger response to interannual variability of drought, compared to the greenness and the NPP. In comparison to other drought indices (e.g., PDSI), and our results demonstrate that multi-scalar drought indices (e.g., SPI, SPEI) are more advantageous in monitoring drought impacts on tree-ring growth, maximum greenness, and NPP. This finding suggests that multi-scalar indices are more appropriate for monitoring and modelling forest drought in peninsular Spain and the Balearic Islands

Tree growth response to drought partially explains regional-scale growth and mortality patterns in Iberian forests

Tree-ring data has been widely used to inform about tree growth responses to drought at the individual scale, but less is known about how tree growth sensitivity to drought scales up driving changes in forest dynamics. Here, we related tree-ring growth chronologies and stand-level forest changes in basal area from two independent data sets to test if tree-ring responses to drought match stand forest dynamics (stand basal area growth, ingrowth, and mortality). We assessed if tree growth and changes in forest basal area covary as a function of spatial scale and tree taxa (gymnosperm or angiosperm). To this end, we compared a tree-ring network with stand data from the Spanish National Forest Inventory. We focused on the cumulative impact of drought on tree growth and demography in the period 1981–2005. Drought years were identified by the Standardized Precipitation Evapotranspiration Index, and their impacts on tree growth by quantifying tree-ring width reductions. We hypothesized that forests with greater drought impacts on tree growth will also show reduced stand basal area growth and ingrowth and enhanced mortality. This is expected to occur in forests dominated by gymnosperms on drought-prone regions. Cumulative growth reductions during dry years were higher in forests dominated by gymnosperms and presented a greater magnitude and spatial autocorrelation than for angiosperms. Cumulative drought-induced tree growth reductions and changes in forest basal area were related, but initial stand density and basal area were the main factors driving changes in basal area. In drought-prone gymnosperm forests, we observed that sites with greater growth reductions had lower stand basal area growth and greater mortality. Consequently, stand basal area, forest growth, and ingrowth in regions with large drought impacts was significantly lower than in regions less impacted by drought. Tree growth sensitivity to drought can be used as a predictor of gymnosperm demographic rates in terms of stand basal area growth and ingrowth at regional scales, but further studies may try to disentangle how initial stand density modulates such relationships. Drought-induced growth reductions and their cumulative impacts have strong potential to be used as early-warning indicators of regional forest vulnerability.This study was financially supported by Xunta de Galicia, Grant/Award Number PGIDIT06PXIB502262PR, GRC GI-1809; INIA, Grant/Award Number RTA2006-00117; CANOPEE, 2014-2020-FEDER funds, Spanish Science Ministry RTI2018-096884-B-C31, RTI2018-096884-B-C33, AGL2017-83828-C2-2R, RTI2018-096884-B-C3,1 and RTI2018-096884-B-C32 projects. Gabriel Sangüesa-Barreda was supported by a “Juan de la Cierva-Formación” grant from MINECO (FJCI 2016-30121). Antonio Gazol and Paloma Ruiz-Benito were supported by a project “2018 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation.” Ana-Maria Hereş was supported by the project PN-III-P1-1.1-TE-2019-1099 financed by the Romanian Ministry of Education and Research through UEFISCDI. Raúl Sánchez-Salguero was supported by VULBOS project (UPO-1263216, FEDER Funds, Andalusia Regional Government, Consejería de Economía, Conocimiento, Empresas y Universidad 2014-2020). Paloma Ruiz-Benito was supported by the Community of Madrid Region under the framework of the multi-year Agreement with the University of Alcalá (Stimulus to Excellence for Permanent University Professors, EPU-INV/2020/010) and the University of Alcalá “Ayudas para la realización de Proyectos para potenciar la Creación y Consolidación de Grupos de Investigación.” Andrea Hevia was supported by PinCaR project (UHU-1266324, FEDER Funds, Andalusia Regional Government, Consejería de Economía, Conocimiento, Empresas y Universidad 2014-2020).Peer reviewe

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

Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited heart disease. Next-generation sequencing (NGS) is the preferred genetic test, but the diagnostic value of screening for minor and candidate genes, and the role of copy number variants (CNVs) deserves further evaluation.Three hundred and eighty-seven consecutive unrelated patients with HCM were screened for genetic variants in the 5 most frequent genes (MYBPC3, MYH7, TNNT2, TNNI3 and TPM1) using Sanger sequencing (N = 84) or NGS (N = 303). In the NGS cohort we analyzed 20 additional minor or candidate genes, and applied a proprietary bioinformatics algorithm for detecting CNVs. Additionally, the rate and classification of TTN variants in HCM were compared with 427 patients without structural heart disease.The percentage of patients with pathogenic/likely pathogenic (P/LP) variants in the main genes was 33.3%, without significant differences between the Sanger sequencing and NGS cohorts. The screening for 20 additional genes revealed LP variants in ACTC1, MYL2, MYL3, TNNC1, GLA and PRKAG2 in 12 patients. This approach resulted in more inconclusive tests (36.0% vs. 9.6%, p<0.001), mostly due to variants of unknown significance (VUS) in TTN. The detection rate of rare variants in TTN was not significantly different to that found in the group of patients without structural heart disease. In the NGS cohort, 4 patients (1.3%) had pathogenic CNVs: 2 deletions in MYBPC3 and 2 deletions involving the complete coding region of PLN.A small percentage of HCM cases without point mutations in the 5 main genes are explained by P/LP variants in minor or candidate genes and CNVs. Screening for variants in TTN in HCM patients drastically increases the number of inconclusive tests, and shows a rate of VUS that is similar to patients without structural heart disease, suggesting that this gene should not be analyzed for clinical purposes in HCM