Astrocronología y evolución de la sedimentación marina del margen Atlántico del Corredor Bético y su relación con la crisis de salinidad del Mesiniense

[EN] This thesis gives an overview in understanding the Late Miocene evolution of Mediterranean-Atlantic gateways in general and new results and insights for the Betic Corridor in particular. Betic Corridor research was done in two ways: • By constructing a high-resolution age model for the Atlantic side of the corridor and linking changes in depositional environment to basin or corridor evolution and events in the Late Miocene Atlantic or Mediterranean region. • By improving the chronostratigraphic framework of Upper Miocene sediments in the western Betics and relating changes in depositional environment to corridor evolution. During the Late Miocene, when the strait of Gibraltar probably did not exist yet, the Betic Corridor through southern Spain formed, together with the Rifian corridor through northern Morocco, the marine connection between the Atlantic Ocean and the Mediterranean Sea. Progressive restriction and finally closure of these marine gateways led to catastrophic changes in both Mediterranean sea-level and salinity. This event is known as the Messinian Salinity Crisis (MSC). Despite decades of research, the exact timing of closure, the geometry of the corridors, and the patterns of exchange through them still remain uncertain.[ES] Esta Tesis Doctoral brinda una visión general y plantea nuevas consideraciones para entender la evolución de los canales interoceánicos Atlántico-Mediterráneo durante el Mioceno tardío, se enfoca particularmente en la evolución del corredor Bético. La investigación se adelantó en dos etapas: • Inicialmente, se construyó un modelo de edad de alta resolución para el margen Atlántico del corredor Bético y se relacionaron los cambios en el ambiente de sedimentación de la cuenca del Guadalquivir con la evolución del corredor, y con los eventos regionales ocurridos durante el Mioceno tardío en el Atlántico Norte y en el Mediterráneo. • Adicionalmente, se mejoró el marco cronoestratigráfico para los sedimentos acumulados durante el Mioceno tardío en la región Bética occidental, y se correlacionaron los cambios en el ambiente de depósito con la evolución del corredor. Durante el Mioceno tardío, cuando el Estrecho de Gibraltar posiblemente aún no existía, la conexión entre el océano Atlántico y el mar Mediterráneo se estableció a través de dos canales: el corredor Bético a lo largo del sur de España, y el corredor Rifeño en el norte de Marruecos. La restricción progresiva y finalmente el cierre de dichos canales interoceánicos produjo importantes cambios tanto en la salinidad como en el nivel del Mediterráneo. Este evento se conoce como la Crisis de Salinidad del Mesiniense (CSM). A pesar de décadas de investigación enfocadas en entender la evolución geológica de los corredores, el momento exacto del cierre, su geometría y los patrones de interconexión de aguas aún son inciertos

The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy

Phospholamban (PLN) plays a role in cardiomyocyte calcium handling as primary inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The p.(Arg14del) pathogenic variant in the PLN gene results in a high risk of developing dilated or arrhythmogenic cardiomyopathy with heart failure. There is no established treatment other than standard heart failure therapy or heart transplantation. In this study, we generated a novel mouse model with the PLN-R14del pathogenic variant, performed detailed phenotyping, and tested the efficacy of established heart failure therapies eplerenone or metoprolol. Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion. Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality. Neither eplerenone nor metoprolol administration improved cardiac function or survival. In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease. Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy. This model provides a great opportunity to study the pathophysiology, and to screen for potential therapeutic treatments

Author Correction:The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy (Scientific Reports, (2020), 10, 1, (9819), 10.1038/s41598-020-66656-9)

The title in the original version of this Article contained a typographical error of ‘unresponsive’. The error has now been corrected in the PDF and HTML versions of the Article

DNA methylation signatures of aggression and closely related constructs : A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 x 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.Peer reviewe

Author Correction: The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy (vol 10, 9819, 2020): The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics

Next-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFPE) tissue is increasingly used to also identify actionable copy number gains (gene amplifications) in addition to sequence variants. While guidelines for the reporting of sequence variants are available, guidance with respect to reporting copy number gains from gene-panel NGS data is limited. Here, we report on Dutch consensus recommendations obtained in the context of the national Predictive Analysis for THerapy (PATH) project, which aims to optimize and harmonize routine diagnostics in molecular pathology. We briefly discuss two common approaches to detect gene copy number gains from NGS data, i.e., the relative coverage and B-allele frequencies. In addition, we provide recommendations for reporting gene copy gains for clinical purposes. In addition to general QC metrics associated with NGS in routine diagnostics, it is recommended to include clinically relevant quantitative parameters of copy number gains in the clinical report, such as (i) relative coverage and estimated copy numbers in neoplastic cells, (ii) statistical scores to show significance (e.g., z-scores), and (iii) the sensitivity of the assay and restrictions of NGS-based detection of copy number gains. Collectively, this information can guide clinical and analytical decisions such as the reliable detection of high-level gene amplifications and the requirement for additional in situ assays in case of borderline results or limited sensitivity

Recommendations for the clinical interpretation and reporting of copy number gains using gene panel NGS analysis in routine diagnostics

Next-generation sequencing (NGS) panel analysis on DNA from formalin-fixed paraffin-embedded (FFPE) tissue is increasingly used to also identify actionable copy number gains (gene amplifications) in addition to sequence variants. While guidelines for the reporting of sequence variants are available, guidance with respect to reporting copy number gains from gene-panel NGS data is limited. Here, we report on Dutch consensus recommendations obtained in the context of the national Predictive Analysis for THerapy (PATH) project, which aims to optimize and harmonize routine diagnostics in molecular pathology. We briefly discuss two common approaches to detect gene copy number gains from NGS data, i.e., the relative coverage and B-allele frequencies. In addition, we provide recommendations for reporting gene copy gains for clinical purposes. In addition to general QC metrics associated with NGS in routine diagnostics, it is recommended to include clinically relevant quantitative parameters of copy number gains in the clinical report, such as (i) relative coverage and estimated copy numbers in neoplastic cells, (ii) statistical scores to show significance (e.g., z-scores), and (iii) the sensitivity of the assay and restrictions of NGS-based detection of copy number gains. Collectively, this information can guide clinical and analytical decisions such as the reliable detection of high-level gene amplifications and the requirement for additional in situ assays in case of borderline results or limited sensitivity