Conservation of Intramembrane Proteolytic Activity and Substrate Specificity in Prokaryotic and Eukaryotic Rhomboids

AbstractRhomboid is an intramembrane serine protease responsible for the proteolytic activation of Drosophila epidermal growth factor receptor (EGFR) ligands [1]. Although nothing is known about the function of the ∼100 currently known rhomboid genes conserved throughout evolution, a recent analysis suggests that a Rhomboid from the pathogenic bacterium Providencia stuartii is involved in the production of a quorum-sensing factor [2]. This suggests that an intercellular signaling mechanism may have been conserved between prokaryotes and metazoans [3]. However, the function of prokaryotic Rhomboids is unknown. We have examined the ability of eight prokaryotic Rhomboids to cleave the three Drosophila EGFR ligands. Despite their striking sequence divergence, Rhomboids from one Gram-positive and four Gram-negative species, including Providencia, specifically cleaved Drosophila substrates, but not similar proteins such as Transforming Growth Factor α (TGFα) and Delta. Although the sequence similarity between these divergent Rhomboids is very limited, all contain the putative serine catalytic triad residues, and their specific mutation abolished protease activity. Therefore, despite low overall homology, the Rhomboids are a family of ancient, functionally conserved intramembrane serine proteases, some of which also have conserved substrate specificity. Moreover, a function for Rhomboids in activating intercellular signaling appears to have evolved early

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Electronic Implementation of Integrated End-of-life Care: A Local Approach

Introduction: The Liverpool Care Pathway for the Dying Patient is an instrument to deliver integrated care for patients in their last hours of life. Originally a paper-based system, this study investigates the feasibility of an electronic version.  Methods: An electronic Liverpool Care Pathway was implemented in a specialized palliative care unit of a German university hospital. Its use is exemplified by means of auditing and analysis of the proportion of recorded items.  Results: In the years 2013 and 2014 the electronic Liverpool Care Pathway was used for the care of 159 patients. The uptake of the instrument was high (67%). Most items were recorded. Apart from a high usability, the fast data retrieval allows fast analysis for auditing and research.  Conclusions and discussion: The electronic instrument is feasible in a computerized ward and has strong advantages for retrospective analysis.  Trial registration: Internal Clinical Trial Register of the Medical Faculty, Heinrich Heine University Düsseldorf, No. 2015124683 (7 December 2015)