Growing Graphs with Hyperedge Replacement Graph Grammars

Discovering the underlying structures present in large real world graphs is a fundamental scientific problem. In this paper we show that a graph's clique tree can be used to extract a hyperedge replacement grammar. If we store an ordering from the extraction process, the extracted graph grammar is guaranteed to generate an isomorphic copy of the original graph. Or, a stochastic application of the graph grammar rules can be used to quickly create random graphs. In experiments on large real world networks, we show that random graphs, generated from extracted graph grammars, exhibit a wide range of properties that are very similar to the original graphs. In addition to graph properties like degree or eigenvector centrality, what a graph "looks like" ultimately depends on small details in local graph substructures that are difficult to define at a global level. We show that our generative graph model is able to preserve these local substructures when generating new graphs and performs well on new and difficult tests of model robustness.Comment: 18 pages, 19 figures, accepted to CIKM 2016 in Indianapolis, I

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes

Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal–regulated kinases (ERK1/2), β-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB or CB, or CB-CB heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to the orthosteric center of either receptor, was measured. From the huge amount of generated data, we would like to highlight that the two psychotropic molecules (Δ-tetrahydrocannabinol/THC and CP-55940) showed similar bias in CBR and that the bias of THC was particularly relevant toward MAPK pathway. Furthermore, THC did not activate the G protein coupled to CBR. Interestingly, the biased agonism was reduced when assays were performed in cells expressing the two receptors, thus suggesting that the heteromer allows less functional selectivity. In terms of cannabidiol action, the phytocannabinoid altered the functional responses, likely by allosteric means, and modified potency, agonist IC/EC values and biased agonism in qualitative and/or quantitative different ways depending on the agonist. The effect of cannabidiol on anandamide actions on both cannabinoid receptors was particularly noteworthy as was significantly different from that of other compounds. Results are a compendium of data on biased agonism on cannabinoid receptors in the absence and presence of cannabidiol. In addition, for the first time, GPCR biased agonism is characterized in an heteromeric context.This work was partially supported by grants from the Spanish Ministry of Economy and Competitiveness (Ref. no. BFU2015-64405-R and SAF2017-84117-R; they may include FEDER funds) and by grant 201413-30 from: Fundació la Marató de TV3Peer Reviewe

International study of perceived neighbourhood environmental attributes and Body Mass Index: IPEN Adult study in 12 countries

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Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

HRS/EHRA/APHRS/LAHRS/ACC/AHA worldwide practice update for telehealth and arrhythmia monitoring during and after a pandemic

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), started in the city of Wuhan late in 2019. Within a few months, the disease spread toward all parts of the world and was declared a pandemic on March 11, 2020. The current health care dilemma worldwide is how to sustain the capacity for quality services not only for those suffering from COVID-19 but also for non-COVID-19 patients, all while protecting physicians, nurses, and other allied health care workers

World Heart Federation Roadmap on Atrial Fibrillation - A 2020 Update

The World Heart Federation (WHF) commenced a Roadmap initiative in 2015 to reduce the global burden of cardiovascular disease and resultant burgeoning of healthcare costs. Roadmaps provide a blueprint for implementation of priority solutions for the principal cardiovascular diseases leading to death and disability. Atrial fibrillation (AF) is one of these conditions and is an increasing problem due to ageing of the world’s population and an increase in cardiovascular risk factors that predispose to AF. The goal of the AF roadmap was to provide guidance on priority interventions that are feasible in multiple countries, and to identify roadblocks and potential strategies to overcome them. Since publication of the AF Roadmap in 2017, there have been many technological advances including devices and artificial intelligence for identification and prediction of unknown AF, better methods to achieve rhythm control, and widespread uptake of smartphones and apps that could facilitate new approaches to healthcare delivery and increasing community AF awareness. In addition, the World Health Organisation added the non-vitamin K antagonist oral anticoagulants (NOACs) to the Essential Medicines List, making it possible to increase advocacy for their widespread adoption as therapy to prevent stroke. These advances motivated the WHF to commission a 2020 AF Roadmap update. Three years after the original Roadmap publication, the identified barriers and solutions were judged still relevant, and progress has been slow. This 2020 Roadmap update reviews the significant changes since 2017 and identifies priority areas for achieving the goals of reducing death and disability related to AF, particularly targeted at low-middle income countries. These include advocacy to increase appreciation of the scope of the problem; plugging gaps in guideline management and prevention through physician education, increasing patient health literacy, and novel ways to increase access to integrated healthcare including mHealth and digital transformations; and greater emphasis on achieving practical solutions to national and regional entrenched barriers. Despite the advances reviewed in this update, the task will not be easy, but the health rewards of implementing solutions that are both innovative and practical will be great

HEMOPHAGOCYTOSIS SECONDARY TO PHARYNGEAL ABSCESS IN AN IMMUNOCOMPETENT PATIENT (case report)

Background. Hemophagocytosis is a rare, potentially fatal disorder, comprising pancytopenia, liver dysfunction, hepatosplenomegaly, hypertriglyceridemia, and hyperferritinemia presenting as fever, lympha­denopathy and skin rashes. Objective. To attract the clinicians’ attention to a problem of hemophagocytosis in Critical Care management. Methods. Hemophagocytosis secondary to pharyngeal abscess in a 58 year old male is being reported. Results. A 58-year-old immunocompetent patient presenting with hemophagocytosis secondary to pharyngeal abscess, was managed on ventilator and inotropic support, when he developed heathcare-associated urinary tract infection by Escherichia coli and ventilator-associated pneumonia by Acinetobacter baumanii. He developed neutropenic septic shock and multi-organ dysfunction and went through a downhill course leading to demise. Conclusions. Hemophagocytosis remains a sinister entity in modern intensive care despite astute clinical management. Secondary superinfections with opportunistic multidrug resistant pathogens are difficult to treat. A high index of clinical suspicion, aggressive diagnosis and prompt treatment for hemophagocytosis and polymicrobial opportunistic superinfections with multidrug-resistant healthcare-associated pathogens needs to be addressed upfront