Effects of Cardiac Structural Remodelling During Heart Failure on Cardiac Excitation – Insights from a Heterogeneous 3D Model of the Rabbit Atria

Heart failure is a leading cause of morbidity and mortality in the western world. One of the effects of heart failure is the structural remodelling of cardiac tissue, including tissue dilation and development of fibrosis. It is therefore important to study these changes and their effect on cardiac activity, in order to gain a better understanding of the underlying mechanisms in arrhythmogenesis, which will hopefully enable us to develop better treatments for heart failure. In this study we developed biophysically detailed models of the rabbit atria for normal and heart failure conditions. These models were used to study the effects of structural remodelling of heart failure on cardiac excitation wave conduction. Anatomical reconstructions of the control and heart failure hearts were based on contrast enhanced micro-CT imaging. Fibre orientation was extracted from the control and heart failure datasets. Effects of heart failure geometry on the activation pattern of atrial excitation waves were analyzed. It was found that atrial activation time increased from the control to the heart failure case in both isotropic and anisotropic conditions, which is attributed primarily to the dilation of tissue caused by heart failure

Artificial Metalloenzymes as Catalysts for Oxidative Lignin Degradation

We report novel artificial metalloenzymes (ArMs), containing tris­(pyridylmethyl)­amine (TPA), for the atom economic oxidation of lignin β-O-4 model compounds, using hydrogen peroxide. The protein scaffold alters the selectivity of the reaction from a low yielding cleavage reaction when using the parent Fe-tpa complex to a high yielding benzylic alcohol oxidation when using the complex incorporated into a protein scaffold, SCP-2L A100C. Engineering the protein scaffold to incorporate glutamic acid was found to improve the ArM activity, showing that rational design of the protein environment using metal binding amino acids can be a first step toward improving the overall activity of an artificial metalloenzyme

The novel design of an energy efficient superconductor-based series reactor for installation at a grid connected research site

This paper proposes the development of a superconducting series reactor (SSR) as an alternative to traditionally employed technologies and superconducting fault current limiters when managing fault levels on the electrical power grid. By utilizing superconducting tape, which has negligible resistance, in the construction of a series reactor, it is proposed that fault level mitigation could be achieved in a more energy efficient manner. Once constructed the SSR will be installed and tested at a grid-connected power engineering research site, and the proposed impact of this installation is firstly simulated using Reticmaster® power system simulation software. Design parameters for the prototype SSR are then calculated enabling the total cost of the modifications and prototype SSR to be determined. A desktop SSR was also constructed and tested as a pre-cursor to the prototype construction to confirm functionality and design and was found to be up to four times more energy efficient as the equivalent copper reactor. Finally, the calorimetric method of power loss determination was investigated and experimentally shown to be a viable alternative to the traditional electrical method of power loss determination. In the past, the relatively cheap cost of electricity in South Africa had favoured the installation of poor power efficiency devices that required a lower initial capital investment. With increasing energy costs and a focus on carbon emission reductions, the development of the SSR augurs a new era in power system engineering in which designs are proposed considering both total lifecycle costs and energy efficiency. Design proposal for the first superconducting power device in Africa Alternative to less efficient fault current management technologies currently employed Construction and testing of a desktop superconducting series reactor Verification of the calorimetric method for power loss determination

The Influence of Particle Concentration on the Formation of Settling-Driven Gravitational Instabilities at the Base of Volcanic Clouds

Settling-driven gravitational instabilities observed at the base of volcanic ash clouds have the potential to play a substantial role in volcanic ash sedimentation. They originate from a narrow, gravitationally unstable region called a Particle Boundary Layer (PBL) that forms at the lower cloud-atmosphere interface and generates downward-moving ash fingers that enhance the ash sedimentation rate. We use scaled laboratory experiments in combination with particle imaging and Planar Laser Induced Fluorescence (PLIF) techniques to investigate the effect of particle concentration on PBL and finger formation. Results show that, as particles settle across an initial density interface and are incorporated within the dense underlying fluid, the PBL grows below the interface as a narrow region of small excess density. This detaches upon reaching a critical thickness, that scales with (ν2/g′)1/3, where ν is the kinematic viscosity and g′ is the reduced gravity of the PBL, leading to the formation of fingers. During this process, the fluid above and below the interface remains poorly mixed, with only small quantities of the upper fluid phase being injected through fingers. In addition, our measurements confirm previous findings over a wider set of initial conditions that show that both the number of fingers and their velocity increase with particle concentration. We also quantify how the vertical particle mass flux below the particle suspension evolves with time and with the particle concentration. Finally, we identify a dimensionless number that depends on the measurable cloud mass-loading and thickness, which can be used to assess the potential for settling-driven gravitational instabilities to form. Our results suggest that fingers from volcanic clouds characterised by high ash concentrations not only are more likely to develop, but they are also expected to form more quickly and propagate at higher velocities than fingers associated with ash-poor clouds.</jats:p

Impact of Nitisinone on the Cerebrospinal Fluid Metabolome of a Murine Model of Alkaptonuria

BackgroundNitisinone-induced hypertyrosinaemia is well documented in Alkaptonuria (AKU), and there is uncertainty over whether it may contribute to a decline in cognitive function and/or mood by altering neurotransmitter metabolism. The aim of this work was to evaluate the impact of nitisinone on the cerebrospinal fluid (CSF) metabolome in a murine model of AKU, with a view to providing additional insight into metabolic changes that occur following treatment with nitisinone.Methods17 CSF samples were collected from BALB/c Hgd-/- mice (n = 8, treated with nitisinone-4 mg/L and n = 9, no treatment). Samples were diluted 1:1 with deionised water and analysed using a 1290 Infinity II liquid chromatography system coupled to a 6550 quadrupole time-of-flight mass spectrometry (Agilent, Cheadle, UK). Raw data were processed using a targeted feature extraction algorithm and an established in-house accurate mass retention time database. Matched entities (±10 ppm theoretical accurate mass and ±0.3 min retention time window) were filtered based on their frequency and variability. Experimental groups were compared using a moderated t-test with Benjamini-Hochberg false-discovery rate adjustment.ResultsL-Tyrosine, N-acetyl-L-tyrosine, γ-glutamyl-L-tyrosine, p-hydroxyphenylacetic acid, and 3-(4-hydroxyphenyl)lactic acid were shown to increase in abundance (log2 fold change 2.6-6.9, 3/5 were significant p &lt; 0.05) in the mice that received nitisinone. Several other metabolites of interest were matched, but no significant differences were observed, including the aromatic amino acids phenylalanine and tryptophan, and monoamine metabolites adrenaline, 3-methoxy-4-hydroxyphenylglycol, and octopamine.ConclusionsEvaluation of the CSF metabolome of a murine model of AKU revealed a significant increase in the abundance of a limited number of metabolites following treatment with nitisinone. Further work is required to understand the significance of these findings and the mechanisms by which the altered metabolite abundances occur

Metabolomic studies in the inborn error of metabolism alkaptonuria reveal new biotransformations in tyrosine metabolism

Alkaptonuria (AKU) is an inherited disorder of tyrosine metabolism caused by lack of active enzyme homogentisate 1,2-dioxygenase (HGD). The primary consequence of HGD deficiency is increased circulating homogentisic acid (HGA), the main agent in the pathology of AKU disease. Here we report the first metabolomic analysis of AKU homozygous Hgd knockout (Hgd(−/−)) mice to model the wider metabolic effects of Hgd deletion and the implication for AKU in humans. Untargeted metabolic profiling was performed on urine from Hgd(−/−) AKU (n = 15) and Hgd(+/−) non-AKU control (n = 14) mice by liquid chromatography high-resolution time-of-flight mass spectrometry (Experiment 1). The metabolites showing alteration in Hgd(−/−) were further investigated in AKU mice (n = 18) and patients from the UK National AKU Centre (n = 25) at baseline and after treatment with the HGA-lowering agent nitisinone (Experiment 2). A metabolic flux experiment was carried out after administration of (13)C-labelled HGA to Hgd(−/−)(n = 4) and Hgd(+/−)(n = 4) mice (Experiment 3) to confirm direct association with HGA. Hgd(−/−) mice showed the expected increase in HGA, together with unexpected alterations in tyrosine, purine and TCA-cycle pathways. Metabolites with the greatest abundance increases in Hgd(−/−) were HGA and previously unreported sulfate and glucuronide HGA conjugates, these were decreased in mice and patients on nitisinone and shown to be products from HGA by the (13)C-labelled HGA tracer. Our findings reveal that increased HGA in AKU undergoes further metabolism by mainly phase II biotransformations. The data advance our understanding of overall tyrosine metabolism, demonstrating how specific metabolic conditions can elucidate hitherto undiscovered pathways in biochemistry and metabolism

Diffuse Stellar Light at 100 kpc Scales in M87

In a new survey of nearby galaxies from stacked photographic images, M87 shows a diffuse fan of stellar material which extends along the projected SE (major) axis out to about 100 kpc at a limiting (B) surface brightness of $28 \hbox{mag arcsec}^{-2}$. We suggest that disruption of a small spheroidal galaxy within a larger potential is the most likely explanation for the diffuse structure. Our simulations include a rigid primary potential with characteristics similar to those derived for M87 and a populated intruder. The orbit is required to pass close to the center of the potential to produce a fan which nearly aligns with the major axis and has a large opening angle, as seen in M87. The structure of the dark matter at large galactic radii is investigated by representing M87 with different potentials. The morphology and luminosity of the fan and the kinematics of debris in the center of the primary potential are analyzed and compared with substructure in M87. The short lifetimes (t_fan < 5 10^8 years) of the simulated diffuse fans indicate that several accretion events could be hidden in galaxies.Comment: 24 pages, Latex (aaspp4.sty), with 15 figures. Accepted for publication in Ap

Transcriptomic and Epigenetic Regulation of Disuse Atrophy and the Return to Activity in Skeletal Muscle

Physical inactivity and disuse are major contributors to age-related muscle loss. Denervation of skeletal muscle has been previously used as a model with which to investigate muscle atrophy following disuse. Although gene regulatory networks that control skeletal muscle atrophy after denervation have been established, the transcriptome in response to the recovery of muscle after disuse and the associated epigenetic mechanisms that may function to modulate gene expression during skeletal muscle atrophy or recovery have yet to be investigated. We report that silencing the tibialis anterior muscle in rats with tetrodotoxin (TTX)—administered to the common peroneal nerve—resulted in reductions in muscle mass of 7, 29, and 51% with corresponding reductions in muscle fiber cross-sectional area of 18, 42, and 69% after 3, 7, and 14 d of TTX, respectively. Of importance, 7 d of recovery, during which rodents resumed habitual physical activity, restored muscle mass from a reduction of 51% after 14 d TTX to a reduction of only 24% compared with sham control. Returning muscle mass to levels observed at 7 d TTX administration (29% reduction). Transcriptome-wide analysis demonstrated that 3714 genes were differentially expressed across all conditions at a significance of P ≤ 0.001 after disuse-induced atrophy. Of interest, after 7 d of recovery, the expression of genes that were most changed during TTX had returned to that of the sham control. The 20 most differentially expressed genes after microarray analysis were identified across all conditions and were cross-referenced with the most frequently occurring differentially expressed genes between conditions. This gene subset included myogenin (MyoG), Hdac4, Ampd3, Trim63 (MuRF1), and acetylcholine receptor subunit α1 (Chrna1). Transcript expression of these genes and Fboxo32 (MAFbx), because of its previously identified role in disuse atrophy together with Trim63 (MuRF1), were confirmed by real-time quantitative RT-PCR, and DNA methylation of their promoter regions was analyzed by PCR and pyrosequencing. MyoG, Trim63 (MuRF1), Fbxo32 (MAFbx), and Chrna1 demonstrated significantly decreased DNA methylation at key time points after disuse-induced atrophy that corresponded with significantly increased gene expression. Of importance, after TTX cessation and 7 d of recovery, there was a marked increase in the DNA methylation profiles of Trim63 (MuRF1) and Chrna1 back to control levels. This also corresponded with the return of gene expression in the recovery group back to baseline expression observed in sham-operated controls. To our knowledge, this is the first study to demonstrate that skeletal muscle atrophy in response to disuse is accompanied by dynamic epigenetic modifications that are associated with alterations in gene expression, and that these epigenetic modifications and gene expression profiles are reversible after skeletal muscle returns to normal activity