Enhancement of Gap Junction Function During Acute Myocardial Infarction Modifies Healing and Reduces Late Ventricular Arrhythmia Susceptibility

Objectives: To investigate the effects of enhancing gap junction (GJ) coupling during acute myocardial infarction (MI) on the healed infarct scar morphology and late post-MI arrhythmia susceptibility. Background: Increased heterogeneity of myocardial scarring after MI is associated with greater arrhythmia susceptibility. We hypothesized that short-term enhancement of GJ coupling during acute MI can produce more homogeneous infarct scars, reducing late susceptibility to post-MI arrhythmias. Methods: Following arrhythmic characterisation of the rat 4-week post-MI model (n=24), a further 27 Sprague-Dawley rats were randomised to receive rotigaptide to enhance GJ coupling (n=13) or saline control (n=14) by osmotic minipump immediately prior to, and for the first 7 days following surgical MI. At 4 weeks post-MI, hearts were explanted for ex vivo programmed electrical stimulation (PES) and optical mapping. Heterogeneity of infarct border zone (IBZ) scarring was quantified by histomorphometry. Results: Despite no detectable difference in infarct size at 4 weeks post-MI, rotigaptide-treated hearts had reduced arrhythmia susceptibility during PES (Inducibility score: rotigaptide 2.40.8, control 5.00.6, p=0.02) and less heterogeneous IBZ scarring (standard deviation of IBZ Complexity Score: rotigaptide 1.10.1, control 1.40.1, p=0.04), associated with an improvement in IBZ conduction velocity (rotigaptide 43.13.4 cm/s, control 34.82.0 cm/s, p=0.04). Conclusions: Enhancement of GJ coupling for only 7 days at the time of acute MI produced more homogeneous IBZ scarring and reduced arrhythmia susceptibility at 4 weeks post-MI. Short-term GJ modulation at the time of MI may represent a novel treatment strategy to modify the healed infarct scar morphology and reduce late post-MI arrhythmic risk

Distinct neural mechanisms underlie the success, precision, and vividness of episodic memory

A network of brain regions have been linked with episodic memory retrieval, but limited progress has been made in identifying the contributions of distinct parts of the network. Here, we utilized continuous measures of retrieval to dissociate three components of episodic memory: retrieval success, precision, and vividness. In the fMRI scanner, participants encoded objects that varied continuously on three features: color, orientation, and location. Participants' memory was tested by having them recreate the appearance of the object features using a continuous dial, and continuous vividness judgments were recorded. Retrieval success, precision, and vividness were dissociable both behaviorally and neurally: successful versus unsuccessful retrieval was associated with hippocampal activity, retrieval precision scaled with activity in the angular gyrus, and vividness judgments tracked activity in the precuneus. The ability to dissociate these components of episodic memory reveals the benefit afforded by measuring memory on a continuous scale, allowing functional parcellation of the retrieval network.James S McDonnell Foundation Scholar Award, Medical Research Council, Wellcome Trust, Economic and Social Research Counci

PacBio amplicon sequencing for metabarcoding of mixed DNA samples from lichen herbarium specimens.

The detection and identification of species of fungi in the environment using molecular methods heavily depends on reliable reference sequence databases. However, these databases are largely incomplete in terms of taxon coverage, and a significant effort is required from herbaria and living fungal collections for the mass-barcoding of well-identified and well-curated fungal specimens or strains. Here, a PacBio amplicon sequencing approach is applied to recent lichen herbarium specimens for the sequencing of the fungal ITS barcode, allowing a higher throughput sample processing than Sanger sequencing, which often required the use of cloning. Out of 96 multiplexed samples, a full-length ITS sequence of the target lichenised fungal species was recovered for 85 specimens. In addition, sequences obtained for co-amplified fungi gave an interesting insight into the diversity of endolichenic fungi. Challenges encountered at both the laboratory and bioinformatic stages are discussed, and cost and quality are compared with Sanger sequencing. With increasing data output and reducing sequencing cost, PacBio amplicon sequencing is seen as a promising approach for the generation of reference sequences for lichenised fungi as well as the characterisation of lichen-associated fungal communities

Challenges in Bridging Social Semantics and Formal Semantics on the Web

This paper describes several results of Wimmics, a research lab which names stands for: web-instrumented man-machine interactions, communities, and semantics. The approaches introduced here rely on graph-oriented knowledge representation, reasoning and operationalization to model and support actors, actions and interactions in web-based epistemic communities. The re-search results are applied to support and foster interactions in online communities and manage their resources

Emerging pathogenic links between microbiota and the gut-lung axis

© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. The microbiota is vital for the development of the immune system and homeostasis. Changes in microbial composition and function, termed dysbiosis, in the respiratory tract and the gut have recently been linked to alterations in immune responses and to disease development in the lungs. In this Opinion article, we review the microbial species that are usually found in healthy gastrointestinal and respiratory tracts, their dysbiosis in disease and interactions with the gut-lung axis. Although the gut-lung axis is only beginning to be understood, emerging evidence indicates that there is potential for manipulation of the gut microbiota in the treatment of lung diseases

Technical performance and diagnostic utility of the new Elecsys (R) neuron-specific enolase enzyme immunoassay

This international multicenter study was designed to evaluate the technical performance of the new double-monoclonal, single-step Elecsys neuron-specific enolase (NSE) enzyme immunoassay (EIA) and to assess its utility as a sensitive and specific test for the diagnosis of small-cell lung cancer (SCLC). Intra and interassay coefficients of variation, determined in five control or serum specimens in six laboratories, ranged from 0.7 to 5.3 (interlaboratory median: 1.3%) and from 1.3 to 8.5 (interlaboratory median: 3.4%), respectively. Laboratory-to-laboratory comparability was excellent with respect to recovery and interassay coefficients of variation. The test was linear between 0.0 and 320 ng/ml (highest measured concentration). There was a significant correlation between NSE concentrations measured using the Elecsys NSE and the established Cobas Core NSE EIA II in all subjects (n=723) and in patients with lung cancer (n=333). However, NSE concentrations were systematically lower (approximately 9%) with the Elecsys NSE than with the comparison test. Based on a specificity of 95% in comparison with the group suffering from benign lung diseases (n=183), the cutoff value for the discrimination between malignant and benign conditions was set at 21.6 ng/ml. NSE was raised in 73.4% of SCLC patients (n=188) and was significantly higher (p<0.01) in extensive (87.8%) as opposed to limited disease (56.7%). NSE was also elevated in 16.0% of the cases with non-small cell lung cancer (NSCLC, n=374). It is concluded that the Elecsys NSE EIA is a reliable and accurate diagnostic procedure for the measurement of NSE in serum samples. The special merits of this new assay are the wide measuring range (according to manufacturers declaration up to 370 ng/ml) and a short incubation time of 18 min

The electric dipole response of 76^{76}Se above 4 MeV

The dipole response of $^{76}_{34}$Se in the energy range 4 to 9 MeV has been analyzed using a $(\vec\gamma,{\gamma}')$ polarized photon scattering technique, performed at the High Intensity $\gamma$-Ray Source facility, to complement previous work performed using unpolarized photons. The results of this work offer both an enhanced sensitivity scan of the dipole response and an unambiguous determination of the parities of the observed J=1 states. The dipole response is found to be dominated by $E1$ excitations, and can reasonably be attributed to a pygmy dipole resonance. Evidence is presented to suggest that a significant amount of directly unobserved excitation strength is present in the region, due to unobserved branching transitions in the decays of resonantly excited states. The dipole response of the region is underestimated when considering only ground state decay branches. We investigate the electric dipole response theoretically, performing calculations in a 3D cartesian-basis time-dependent Skyrme-Hartree-Fock framework.Comment: 20 pages, 18 figures, to be submitted to PR

Characterisation of small molecule ligands 4CMTB and 2CTAP as modulators of human FFA2 receptor signalling

© 2018, The Author(s). Short chain fatty acids (SCFAs) are protective against inflammatory diseases. Free fatty acid receptor 2 (FFA2), is a target of SCFAs however, their selectivity for FFA2 over other FFA receptors is limited. This study aimed to functionally characterise 2-(4-chlorophenyl)-3-methyl-N-(thiazole-2-yl)butanamide (4CMTB) and 4-((4-(2-chlorophenyl)thiazole-2-yl)amino)-4oxo-3-phenylbutanoic acid (2CTAP), and their enantiomers, in modulating FFA2 activity. The racemic mixture (R/S) and its constituents (R-) and (S-) 4CMTB or 2CTAP were used to stimulate human (h)FFA2 in the absence or presence of acetate. Calcium ions (Ca2+), phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) and cyclic adenosine monophosphate (cAMP) were measured. R/S-4CMTB is a functionally selective ago-allosteric ligand that enhances Ca2+ response to acetate. Both R/S-4CMTB and S-4CMTB are more potent activators of pERK1/2 and inhibitors of forskolin-induced cAMP than acetate. S-4CMTB increased neutrophil infiltration in intestinal ischemia reperfusion injury (IRI). 2CTAP inhibited constitutive Ca2+ levels, antagonised acetate-induced pERK1/2 and prevented damage following IRI. This study characterises enantiomers of functionally selective ligands for FFA2 in cells stably expressing hFFA2. It highlights the novel roles of selective FFA2 enantiomers 4CMTB and 2CTAP on Ca2+, pERK1/2 and cAMP and their roles as allosteric modulators which, may assist in efforts to design novel therapeutic agents for FFA2-driven inflammatory diseases