Long-term miR-669a therapy alleviates chronic dilated cardiomyopathy in dystrophic mice.

BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of chronic morbidity and mortality in muscular dystrophy (MD) patients. Current pharmacological treatments are not yet able to counteract chronic myocardial wastage, thus novel therapies are being intensely explored. MicroRNAs have been implicated as fine regulators of cardiomyopathic progression. Previously, miR-669a downregulation has been linked to the severe DCM progression displayed by Sgcb-null dystrophic mice. However, the impact of long-term overexpression of miR-669a on muscle structure and functionality of the dystrophic heart is yet unknown. METHODS AND RESULTS: Here, we demonstrate that intraventricular delivery of adeno-associated viral (AAV) vectors induces long-term (18 months) miR-669a overexpression and improves survival of Sgcb-null mice. Treated hearts display significant decrease in hypertrophic remodeling, fibrosis, and cardiomyocyte apoptosis. Moreover, miR-669a treatment increases sarcomere organization, reduces ventricular atrial natriuretic peptide (ANP) levels, and ameliorates gene/miRNA profile of DCM markers. Furthermore, long-term miR-669a overexpression significantly reduces adverse remodeling and enhances systolic fractional shortening of the left ventricle in treated dystrophic mice, without significant detrimental consequences on skeletal muscle wastage. CONCLUSIONS: Our findings provide the first evidence of long-term beneficial impact of AAV-mediated miRNA therapy in a transgenic model of severe, chronic MD-associated DCM

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

Subtle behavioral changes and increased prefrontal-hippocampal network synchronicity in APPNL-G-F mice before prominent plaque deposition

Amyloid-β (Aβ) peptides occur in the brains of patients with Alzheimer's disease (AD), but their role in functional impairment is still debated. High levels of APP and APP fragments in mice that overexpress APP might confound their use in preclinical research. We examined the occurrence of behavioral, cognitive and neuroimaging changes in APPNL-G-F knock-in mice that display Aβ42 amyloidosis in the absence of APP overexpression. Female APPNL-G-F mice (carrying Swedish, Iberian and Arctic APP mutations) were compared to APPNL mice (APP Swedish) at 3, 7 and 10 months. Mice were subjected to a test battery that referred to clinical AD symptoms, comprising cage activity, open field, elevated plus maze, social preference and novelty test, and spatial learning, reversal learning and spatial reference memory performance. Our assessment confirmed that behavior at these early ages was largely unaffected in these mice in accordance with previous reports, with some subtle behavioral changes, mainly in social and anxiety-related test performance. Resting-state functional MRI (rsfMRI) assessed connectivity between hippocampal and prefrontal regions with an established role in flexibility, learning and memory. Increased prefrontal-hippocampal network synchronicity was found in 3-month-old APPNL-G-F mice. These functional changes occurred before prominent amyloid plaque deposition

Quinolinic acid injection in mouse medial prefrontal cortex affects reversal learning abilities, cortical connectivity and hippocampal synaptic plasticity.

Intracerebral injection of the excitotoxic, endogenous tryptophan metabolite, quinolinic acid (QA), constitutes a chemical model of neurodegenerative brain disease. Complementary techniques were combined to examine the consequences of QA injection into medial prefrontal cortex (mPFC) of C57BL6 mice. In accordance with the NMDAR-mediated synapto- and neurotoxic action of QA, we found an initial increase in excitability and an augmentation of hippocampal long-term potentiation, converting within two weeks into a reduction and impairment, respectively, of these processes. QA-induced mPFC excitotoxicity impaired behavioral flexibility in a reversal variant of the hidden-platform Morris water maze (MWM), whereas regular, extended MWM training was unaffected. QA-induced mPFC damage specifically affected the spatial-cognitive strategies that mice use to locate the platform during reversal learning. These behavioral and cognitive defects coincided with changes in cortical functional connectivity (FC) and hippocampal neuroplasticity. FC between various cortical regions was assessed by resting-state fMRI (rsfMRI) methodology, and mice that had received QA injection into mPFC showed increased FC between various cortical regions. mPFC and hippocampus (HC) are anatomically as well as functionally linked as part of a cortical network that controls higher-order cognitive functions. Together, these observations demonstrate the central functional importance of rodent mPFC as well as the validity of QA-induced mPFC damage as a preclinical rodent model of the early stages of neurodegeneration

Strain and strain rate parametric imaging. A new method for post processing to 3-/4-dimensional images from three standard apical planes. Preliminary data on feasibility, artefact and regional dyssynergy visualisation

BACKGROUND: We describe a method for 3-/4D reconstruction of tissue Doppler data from three standard apical planes, post processing to derived data of strain rate / strain and parametric colour imaging of the data. The data can be displayed as M-mode arrays from all six walls, Bull's eye projection and a 3D surface figure that can be scrolled and rotated. Numerical data and waveforms can be re-extracted. METHODS: Feasibility was tested by Strain Rate Imaging in 6 normal subjects and 6 patients with acute myocardial infarction. Reverberation artefacts and dyssynergy was identified by colour images. End systolic strain, peak systolic and mid systolic strain rate were measured. RESULTS: Infarcts were visualised in all patients by colour imaging of mid systolic strain rate, end systolic strain and post systolic shortening by strain rate. Reverberation artefacts were visible in 3 of 6 normals, and 2 of 6 patients, and were identified both on bull's eye and M-mode display, but influenced quantitative measurement. Peak systolic strain rate was in controls minimum -1.11, maximum -0.89 and in patients minimum -1.66, maximum 0.02 (p = 0.04). Mid systolic strain rate and end systolic strain did not separate the groups significantly. CONCLUSION: 3-/4D reconstruction and colour display is feasible, allowing quick visual identification of infarcts and artefacts, as well as extension of area of post systolic shortening. Strain rate is better suited to colour parametric display than strain

Increased Cardiac Myocyte PDE5 Levels in Human and Murine Pressure Overload Hypertrophy Contribute to Adverse LV Remodeling

Background: The intracellular second messenger cGMP protects the heart under pathological conditions. We examined expression of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cGMP, in human and mouse hearts subjected to sustained left ventricular (LV) pressure overload. We also determined the role of cardiac myocyte-specific PDE5 expression in adverse LV remodeling in mice after transverse aortic constriction (TAC). Methodology/Principal Findings: In patients with severe aortic stenosis (AS) undergoing valve replacement, we detected greater myocardial PDE5 expression than in control hearts. We observed robust expression in scattered cardiac myocytes of those AS patients with higher LV filling pressures and BNP serum levels. Following TAC, we detected similar, focal PDE5 expression in cardiac myocytes of C57BL/6NTac mice exhibiting the most pronounced LV remodeling. To examine the effect of cell-specific PDE5 expression, we subjected transgenic mice with cardiac myocyte-specific PDE5 overexpression (PDE5-TG) to TAC. LV hypertrophy and fibrosis were similar as in WT, but PDE5-TG had increased cardiac dimensions, and decreased dP/dtmax and dP/dtmin with prolonged tau (P<0.05 for all). Greater cardiac dysfunction in PDE5-TG was associated with reduced myocardial cGMP and SERCA2 levels, and higher passive force in cardiac myocytes in vitro. Conclusions/Significance: Myocardial PDE5 expression is increased in the hearts of humans and mice with chronic pressure overload. Increased cardiac myocyte-specific PDE5 expression is a molecular hallmark in hypertrophic hearts with contractile failure, and represents an important therapeutic target

Proton nuclear magnetic resonance spectroscopic detection of oligomannosidic n glycans in alpha-mannosidosis: a method of monitoring treatment

In Alpha-mannosidosis (MIM 248500) the patients accumulate mainly unbranched oligosaccharide chains in the lysosomes in all body tissues, including the brain. With ensuing therapeutic modalities in man (BMT and ERT) non-invasive methods of monitoring the effect of treatment are needed. Paramount is the possible effect of the treatment on the brain, since this organ is regarded as difficult to reach because of the blood-brain barrier. We therefore performed proton nuclear magnetic resonance spectroscopy (MRS) of the brain in two untreated patients, and a 16-year-old patient treated with BMT at the age of 10 to assess whether this non-invasive method could be applied in the monitoring of the accumulation of abnormal chemicals in the brain of patients. We found an abnormal peak that was not present in the treated patient. A similar pattern was also found in MRS of urine from patients, reflecting the concentration of oligosaccharides in serum and tissues. We therefore conclude that MRS can be a useful method to monitor the effect of treatment for Alpha-Mannosidosis

High fat diet treatment impairs hippocampal long-term potentiation without alterations of the core neuropathological features of Alzheimer disease

Type 2 diabetes (T2DM) and obesity might increase the risk for AD by 2-fold. Different attempts to model the effect of diet-induced diabetes on AD pathology in transgenic animal models, resulted in opposite conclusions. Here, we used a novel knock-in mouse model for AD, which, differently from other models, does not overexpress any proteins. Long-term high fat diet treatment triggers a reduction in hippocampal N-acetyl-aspartate/myo-inositol metabolites ratio and impairs long term potentiation in hippocampal acute slices. Interestingly, these alterations do not correlate with changes in the core neuropathological features of AD, i.e. amyloidosis and Tau hyperphosphorylation. The data suggest that AD phenotypes associated with high fat diet treatment seen in other models for AD might be exacerbated because of the overexpressing systems used to study the effects of familial AD mutations. Our work supports the increasing insight that knock-in mice might be more relevant models to study the link between metabolic disorders and AD