Transcriptional Regulation and Epigenetics in Cardiovascular Cells: Role of the Mineralocorticoid Receptor

The mineralocorticoid receptor (MR), a ligand-activated transcription factor, plays an important role in the pathophysiology of cardiovascular disease. Epigenetic mechanisms such as DNA methylation or histone modifications in addition to the DNA sequence are decisive regulators of cell type-specific transcriptional activity and gene expression by controlling chromatin accessibility. In this review, we summarise the current knowledge about the impact of MR on gene expression in cardiovascular cells. We discuss studies investigating the interaction of MR with epigenetic mechanisms or other transcription factors and their implications for the cardiovascular system. Finally, we compare mechanisms of transcriptional regulation by MR and other nuclear transcription factors. In conclusion, MR is an important regulator of gene expression in cardiovascular cells. Potential mechanisms of cell type-specific transcriptional regulation by MR include interaction with other transcription factors or co-regulators, tethering and post-translational modifications of the MR. Further studies will be needed to clarify the interplay of MR and epigenetic mechanisms

α2C-Adrenoceptor polymorphism is associated with improved event-free survival in patients with dilated cardiomyopathy

Aims The sympathetic nervous system plays a central role in cardiac growth but its overstimulation is associated with increased mortality in patients with chronic heart failure. Pre-synaptic α2-adrenoceptors are essential feedback regulators to control the release of norepinephrine from sympathetic nerves. In this study we tested whether a deletion polymorphism in the human α2C-adrenoceptor gene (α2CDel322-325) affects progression of heart failure in patients with dilated cardiomyopathy (DCM). Methods and results We genotyped and phenotyped 345 patients presenting with DCM in the heart transplant unit of the German Heart Institute, starting in 1994. Patients were treated according to guidelines (99% ACEI, 76% β-blockers) and were followed until December 2002 or until a first event [death, heart transplantation, or implantation of a left ventricular assist device (LVAD) for a life-threatening condition] occurred. Mean follow-up time was 249 weeks (4.9 years) in event-free patients and 104 weeks (2 years) in patients with events. During follow-up, 51% of the patients exhibited an event: death (18%), implantation of LVAD as bridging for transplantation (7%), or heart transplantation (25%). By Kaplan-Meier analysis, DCM patients with the deletion variant Del322-325 in the α2C-adrenoceptor showed significantly decreased event rates (P=0.0043). Cox regression analysis revealed that the presence of the deletion was associated with reduced death rate (relative risk: 0.129, 95% CI: 0.18-0.9441, P=0.044) and event rates (relative risk: 0.167, 95% CI: 0.041-0.685, P=0.012). Conclusion α2C-Adrenoceptor deletion may be a novel, strong, and independent predictor of reduced event rates in DCM patients treated according to guideline

Risikofaktoren für Probleme mit exzessiver Computer- und Internetnutzung von 14- bis 17-jährigen Jugendlichen in Deutschland: Ergebnisse einer deutschlandweiten Repräsentativerhebung

"In dem vorliegenden Artikel wird zunächst ein Modell vorgestellt, mit Hilfe dessen Probleme mit exzessiver Computer- und Internetnutzung von Jugendlichen aus drei Perspektiven abgebildet werden können: die wissenschaftlichobjektive Perspektive, die subjektive Perspektive der Eltern und die subjektive Perspektive der Jugendlichen. Datengrundlage bildet eine Repräsentativerhebung von 1744 Jugendlichen zwischen 14 und 17 Jahren in Deutschland sowie jeweils einem dazugehörigen Elternteil. Des Weiteren werden mit einer logistischen Regression Risikofaktoren wie Geschlecht, Sozialstatus, Familienklima und Nutzungszeiten dahingehend untersucht, inwieweit sie die Wahrscheinlichkeit erhöhen können, zur problematischsten Gruppe zu gehören." (Autorenreferat)"The article begins with the introduction of a model that intends to capture the problems resulting from excessive computer and internet use by adolescents. The model contains three perspectives: the scientific-objective perspective, the subjective perspective of parents and the subjective perspective of adolescents. The data basis for this is a representative survey of 1744 adolescents in Germany (aged 14 to 17) including one parent per adolescent. In addition, the article uses a logistic regression to investigate if riskfactors like gender, social state, emotional family environment and amount of adolescent’s internet use might enhance the probability of being part of the most problematic sub-group." (author's abstract

α2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment

Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine beta-hydroxylase knock-out (Dbh(-/-)) mice lacking norepinephrine, supporting a role for alpha(2)-heteroceptors on progenitor cells, rather than alpha(2)-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the alpha(2)-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of alpha(2)-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha(2)-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that alpha(2)-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants

Extraordinarily high biomass benthic community on Southern Ocean seamounts

We describe a previously unknown assemblage of seamount-associated megabenthos that has by far the highest peak biomass reported in the deep-sea outside of vent communities. The assemblage was found at depths of 2–2.5 km on rocky geomorphic features off the southeast coast of Australia, in an area near the Sub-Antarctic Zone characterised by high rates of surface productivity and carbon export to the deep-ocean. These conditions, and the taxa in the assemblage, are widely distributed around the Southern mid-latitudes, suggesting the high-biomass assemblage is also likely to be widespread. The role of this assemblage in regional ecosystem and carbon dynamics and its sensitivities to anthropogenic impacts are unknown. The discovery highlights the lack of information on deep-sea biota worldwide and the potential for unanticipated impacts of deep-sea exploitation

Potential mitigation and restoration actions in ecosystems impacted by seabed mining

Mining impacts will affect local populations to different degrees. Impacts range from removal of habitats and possible energy sources to pollution and smaller-scale alterations in local habitats that, depending on the degree of disturbance, can lead to extinction of local communities. While there is a shortage or even lack of studies investigating impacts that resemble those caused by actual mining activity, the information available on the potential long-lasting impacts of seabed mining emphasise the need for effective environmental management plans. These plans should include efforts to mitigate deep-sea mining impact such as avoidance, minimisation and potentially restoration actions, to maintain or encourage reinstatement of a resilient ecosystem. A wide range of mitigation and restoration actions for deep-sea ecosystems at risk were addressed. From an ecological point of view, the designation of set-aside areas (refuges) is of utmost importance as it appears to be the most comprehensive and precautionary approach, both for well-known and lesser studied areas. Other actions range from the deployment of artificial substrates to enhance faunal colonisation and survival to habitat recreation, artificial eutrophication, but also spatial and temporal management of mining operations, as well as optimising mining machine construction to minimise plume size on the sea floor, toxicity of the return plume and sediment compression. No single action will suffice to allow an ecosystem to recover, instead combined mitigation/restoration actions need to be considered, which will depend on the specific characteristics of the different mining habitats and the resources hosted (polymetallic sulphides, polymetallic nodules and cobalt-rich ferromanganese crusts). However, there is a lack of practical experience regarding mitigation and restoration actions following mining impacts, which severely hamper their predictability and estimation of their possible effect and success. We propose an extensive list of actions that could be considered as recommendations for best environmental practice. The list is not restricted and, depending on the characteristics of the site, additional actions can be considered. For all actions presented here, further research is necessary to fully encompass their potential and contribution to possible mitigation or restoration of the ecosystem.CT SFRH/BPD/110278/2015 IF/00029/2014/CP1230/CT0002 UID/MAR/00350/2013 EU Horizon 2020 project Marine Ecosystem Restoration in Changing European Seas (MERCES) 689518 PO ACORES 2020 project Acores-01-0145-Feder-000054_RECOinfo:eu-repo/semantics/publishedVersio

Real-time visualization of heterotrimeric G protein Gq activation in living cells

Contains fulltext : 97296.pdf (publisher's version ) (Open Access)BACKGROUND: Gq is a heterotrimeric G protein that plays an important role in numerous physiological processes. To delineate the molecular mechanisms and kinetics of signalling through this protein, its activation should be measurable in single living cells. Recently, fluorescence resonance energy transfer (FRET) sensors have been developed for this purpose. RESULTS: In this paper, we describe the development of an improved FRET-based Gq activity sensor that consists of a yellow fluorescent protein (YFP)-tagged Ggamma2 subunit and a Galphaq subunit with an inserted monomeric Turquoise (mTurquoise), the best cyan fluorescent protein variant currently available. This sensor enabled us to determine, for the first time, the kon (2/s) of Gq activation. In addition, we found that the guanine nucleotide exchange factor p63RhoGEF has a profound effect on the number of Gq proteins that become active upon stimulation of endogenous histamine H1 receptors. The sensor was also used to measure ligand-independent activation of the histamine H1 receptor (H1R) upon addition of a hypotonic stimulus. CONCLUSIONS: Our observations reveal that the application of a truncated mTurquoise as donor and a YFP-tagged Ggamma2 as acceptor in FRET-based Gq activity sensors substantially improves their dynamic range. This optimization enables the real-time single cell quantification of Gq signalling dynamics, the influence of accessory proteins and allows future drug screening applications by virtue of its sensitivity

Characterising and Predicting Benthic Biodiversity for Conservation Planning in Deepwater Environments

Understanding patterns of biodiversity in deep sea systems is increasingly important because human activities are extending further into these areas. However, obtaining data is difficult, limiting the ability of science to inform management decisions. We have used three different methods of quantifying biodiversity to describe patterns of biodiversity in an area that includes two marine reserves in deep water off southern Australia. We used biological data collected during a recent survey, combined with extensive physical data to model, predict and map three different attributes of biodiversity: distributions of common species, beta diversity and rank abundance distributions (RAD). The distribution of each of eight common species was unique, although all the species respond to a depth-correlated physical gradient. Changes in composition (beta diversity) were large, even between sites with very similar environmental conditions. Composition at any one site was highly uncertain, and the suite of species changed dramatically both across and down slope. In contrast, the distributions of the RAD components of biodiversity (community abundance, richness, and evenness) were relatively smooth across the study area, suggesting that assemblage structure (i.e. the distribution of abundances of species) is limited, irrespective of species composition. Seamounts had similar biodiversity based on metrics of species presence, beta diversity, total abundance, richness and evenness to the adjacent continental slope in the same depth ranges. These analyses suggest that conservation objectives need to clearly identify which aspects of biodiversity are valued, and employ an appropriate suite of methods to address these aspects, to ensure that conservation goals are met