A2A adenosine receptor deletion is protective in a mouse model of Tauopathy

© 2016 Macmillan Publishers Limited All rights reserved. This work is licensed under a Creative Commons Attribution- NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.This work was supported by grants from France Alzheimer (to DB) and LECMA/Alzheimer Forschung Initiative (to DB and CEM). DB and LVL got a Égide/Pessoa program EU exchange grant. Our laboratory is also supported by the LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), Inserm, CNRS, Université Lille 2, Lille Métropole Communauté Urbaine, Région Nord/Pas-de-Calais, FEDER, DN2M, ANR (ADONTAGE and ADORATAU, to DB) and FUI MEDIALZ. We thank the animal facility of IMPRT-IFR114 and M Besegher, I Brion, D Cappe, R Dehaynin, J Devassine, Y Lepage, C Meunier and D Taillieu for transgenic mouse production and animal care, as well as M Basquin, D Demeyer, S Eddarkaoui, H Obriot and M Schneider for support. CL holds a doctoral grant from Lille 2 University, and SB from Région Nord Pas de Calais and CHRU de Lille. VF holds a grant from Région Nord-Pas-de-Calais and Inserm. EF holds a post-doctoral grant from Région Nord-Pas-de-Calais (DN2M). LVL is an Investigator FCT (Fundação para a Ciência e Tecnologia, Portugal).info:eu-repo/semantics/publishedVersio

Technical note: automatic segmentation method of pelvic floor levator hiatus in ultrasound using a self-normalising neural network

Segmentation of the levator hiatus in ultrasound allows to extract biometrics which are of importance for pelvic floor disorder assessment. In this work, we present a fully automatic method using a convolutional neural network (CNN) to outline the levator hiatus in a 2D image extracted from a 3D ultrasound volume. In particular, our method uses a recently developed scaled exponential linear unit (SELU) as a nonlinear self-normalising activation function. SELU has important advantages such as being parameter-free and mini-batch independent. A dataset with 91 images from 35 patients all labelled by three operators, is used for training and evaluation in a leave-one-patient-out cross-validation. Results show a median Dice similarity coefficient of 0.90 with an interquartile range of 0.08, with equivalent performance to the three operators (with a Williams’ index of 1.03), and outperforming a U-Net architecture without the need for batch normalisation. We conclude that the proposed fully automatic method achieved equivalent accuracy in segmenting the pelvic floor levator hiatus compared to a previous semi-automatic approach

DMRN+18: Digital Music Research Network One-day Workshop 2023

DMRN+18: Digital Music Research Network One-day Workshop 2023 Queen Mary University of London Tuesday 19th December 2023 • Keynote speaker: Stefan Bilbao The Digital Music Research Network (DMRN) aims to promote research in the area of digital music, by bringing together researchers from UK and overseas universities, as well as industry, for its annual workshop. The workshop will include invited and contributed talks and posters. The workshop will be an ideal opportunity for networking with other people working in the area. Keynote speakers: Stefan Bilbao Tittle: Physics-based Audio: Sound Synthesis and Virtual Acoustics. Abstract: Any acoustically-produced sound produced must be the result of physical laws that describe the dynamics of a given system---always at least partly mechanical, and sometimes with an electronic element as well. One approach to the synthesis of natural acoustic timbres, thus, is through simulation, often referred to in this context as physical modelling, or physics-based audio. In this talk, the principles of physics-based audio, and the various different approaches to simulation are described, followed by a set of examples covering: various musical instrument types; the important related problem of the emulation of room acoustics or “virtual acoustics”; the embedding of instruments in a 3D virtual space; electromechanical effects; and also new modular instrument designs based on physical laws, but without a counterpart in the real world. Some more technical details follow, including the strengths, weaknesses and limitations of such methods, and pointers to some links to data-centred black-box approaches to sound generation and effects processing. The talk concludes with some musical examples and recent work on moving such algorithms to a real-time setting.. Bio: Stefan is a Professor (full) at Reid School of Music, University of Edinburgh, he is the Personal Chair of Acoustics and Audio Signal Processing, Music. He currently works on computational acoustics, for applications in sound synthesis and virtual acoustics. Special topics of interest include: Finite difference time domain methods, distributed nonlinear systems such as strings and plates, architectural acoustics, spatial audio in simulation, multichannel sound synthesis, and hardware and software realizations. More information on: https://www.acoustics.ed.ac.uk/group-members/dr-stefan-bilbao/ DMRN+18 is sponsored by The UKRI Centre for Doctoral Training in Artificial Intelligence and Music (AIM); a leading PhD research programme aimed at the Music/Audio Technology and Creative Industries, based at Queen Mary University of London

Reducing the number of accepted species in Aspergillus series Nigri

The Aspergillus series Nigri contains biotechnologically and medically important species. They can produce hazardous mycotoxins, which is relevant due to the frequent occurrence of these species on foodstuffs and in the indoor environment. The taxonomy of the series has undergone numerous rearrangements, and currently, there are 14 species accepted in the series, most of which are considered cryptic. Species-level identifications are, however, problematic or impossible for many isolates even when using DNA sequencing or MALDI-TOF mass spectrometry, indicating a possible problem in the definition of species limits or the presence of undescribed species diversity. To re-examine the species boundaries, we collected DNA sequences from three phylogenetic markers (benA, CaM and RPB2) for 276 strains from series Nigri and generated 18 new whole-genome sequences. With the three-gene dataset, we employed phylogenetic methods based on the multispecies coalescence model, including four single-locus methods (GMYC, bGMYC, PTP and bPTP) and one multilocus method (STACEY). From a total of 15 methods and their various settings, 11 supported the recognition of only three species corresponding to the three main phylogenetic lineages: A. niger, A. tubingensis and A. brasiliensis. Similarly, recognition of these three species was supported by the GCPSR approach (Genealogical Concordance Phylogenetic Species Recognition) and analysis in DELINEATE software. We also showed that the phylogeny based on benA, CaM and RPB2 is suboptimal and displays significant differences from a phylogeny constructed using 5 752 single-copy orthologous proteins; therefore, the results of the delimitation methods may be subject to a higher than usual level of uncertainty. To overcome this, we randomly selected 200 genes from these genomes and performed ten independent STACEY analyses, each with 20 genes. All analyses supported the recognition of only one species in the A. niger and A. brasiliensis lineages, while one to four species were inconsistently delimited in the A. tubingensis lineage. After considering all of these results and their practical implications, we propose that the revised series Nigri includes six species: A. brasiliensis, A. eucalypticola, A. luchuensis (syn. A. piperis), A. niger (syn. A. vinaceus and A. welwitschiae), A. tubingensis (syn. A. chiangmaiensis, A. costaricensis, A. neoniger and A. pseudopiperis) and A. vadensis. We also showed that the intraspecific genetic variability in the redefined A. niger and A. tubingensis does not deviate from that commonly found in other aspergilli. We supplemented the study with a list of accepted species, synonyms and unresolved names, some of which may threaten the stability of the current taxonomy.The Czech Ministry of Health, the Charles University Research Centre program, the Czech Academy of Sciences Long-term Research Development Project, the project of Charles University Grant Agency, JST SPRING, the Foundational Biodiversity Information Programme (FBIP) of the National Research Foundation of South Africa, the Japan Society for the Promotion of Science - Postdoctoral Fellowships for Research in Japan and Grant-in-aid for a JSPS research fellow.https://www.journals.elsevier.com/studies-in-mycologyam2023BiochemistryGeneticsMicrobiology and Plant Patholog

Progressive leukoencephalopathy impairs neurobehavioral development in sialin-deficient mice

Slc17a5−/− mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10–p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5−/− mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5−/− mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders

Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction

The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell–matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor β (TGF)–mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-β rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI

A new 2D-based method for myocardial velocity strain and strain rate quantification in a normal adult and paediatric population: assessment of reference values

<p>Abstract</p> <p>Background</p> <p>Recent advances in technology have provided the opportunity for off-line analysis of digital video-clips of two-dimensional (2-D) echocardiographic images.</p> <p>Commercially available software that follows the motion of cardiac structures during cardiac cycle computes both regional and global velocity, strain, and strain rate (SR).</p> <p>The present study aims to evaluate the clinical applicability of the software based on the tracking algorithm feature (studied for cardiology purposes) and to derive the reference values for longitudinal and circumferential strain and SR of the left ventricle in a normal population of children and young adults.</p> <p>Methods</p> <p>45 healthy volunteers (30 adults: 19 male, 11 female, mean age 37 ± 6 years; 15 children: 8 male, 7 female, mean age 8 ± 2 years) underwent transthoracic echocardiographic examination; 2D cine-loops recordings of apical 4-four 4-chamber (4C) and 2-chamber (2C) views and short axis views were stored for off-line analysis.</p> <p>Computer analyses were performed using specific software relying on the algorithm of optical flow analysis, specifically designed to track the endocardial border, installed on a Windows™ based computer workstation. Inter and intra-observer variability was assessed.</p> <p>Results</p> <p>The feasibility of measurements obtained with tissue tracking system was higher in apical view (100% for systolic events; 64% for diastolic events) than in short axis view (70% for systolic events; 52% for diastolic events). Longitudinal systolic velocity decreased from base to apex in all subjects (5.22 ± 1.01 vs. 1.20 ± 0.88; p < 0.0001). Longitudinal strain and SR significantly increased from base to apex in all subjects (-12.95 ± 6.79 vs. -14.87 ± 6.78; p = 0.002; -0.72 ± 0.39 vs. -0.94 ± 0.48, p = 0.0001, respectively). Similarly, circumferential strain and SR increased from base to apex (-21.32 ± 5.15 vs. -27.02 ± 5.88, p = 0.002; -1.51 ± 0.37 vs. -1.95 ± 0.57, p = 0.003, respectively).</p> <p>Values of global systolic SR, both longitudinal and circumferential, were significantly higher in children than in adults (-1.3 ± 0.2, vs. -1.11 ± 0.2, p = 0.006; -1.9 ± 0.6 vs. -1.6 ± 0.5, p = 0.0265, respectively). No significant differences in longitudinal and circumferential systolic velocities were identified for any segment when comparing adults with children.</p> <p>Conclusion</p> <p>This 2D based tissue tracking system used for computation is reliable and applicable in adults and children particularly for systolic events. Measured with this technology, we have established reference values for myocardial velocity, Strain and SR for both young adults and children.</p