The Acidic Domains of the Toc159 Chloroplast Preprotein Receptor Family are Instrinsically Disordered Protein Domains

Background: The Toc159 family of proteins serve as receptors for chloroplast-destined preproteins. They directly bind to transit peptides, and exhibit preprotein substrate selectivity conferred by an unknown mechanism. The Toc159 receptors each include three domains: C-terminal membrane, central GTPase, and N-terminal acidic (A-) domains. Although the function(s) of the A-domain remains largely unknown, the amino acid sequences are most variable within these domains, suggesting they may contribute to the functional specificity of the receptors. Results: The physicochemical properties of the A-domains are characteristic of intrinsically disordered proteins (IDPs). Using CD spectroscopy we show that the A-domains of two Arabidopsis Toc159 family members (atToc132 and atToc159) are disordered at physiological pH and temperature and undergo conformational changes at temperature and pH extremes that are characteristic of IDPs. Conclusions: Identification of the A-domains as IDPs will be important for determining their precise function(s), and suggests a role in protein-protein interactions, which may explain how these proteins serve as receptors for such a wide variety of preprotein substrates

Lessons from the Canadian Cattle Industry for Developing the National Animal Identification System

The primary focus of animal identification programs, which are rapidly developing throughout the world, is to effectively respond to animal health emergencies that have the potential to cause devastating consequences to animal and public health. Additional benefits of an animal identification program include maintaining or expanding international trade, increased consumer confidence, and improved supply chain management. The primary objective of this paper is to provide a series of recommendations for the U.S. to consider as it continues to develop the National Animal Identification System. The secondary objective is to explain how some progressive operations, spanning all sectors of the live cattle and beef industry supply chain complex in Canada, have utilized the technology of the mandatory cattle identification program to improve management intensity.Animal Identification, Canadian Cattle Identification Agency, National Animal Identification System, Research and Development/Tech Change/Emerging Technologies, Q10, Q16,

Mechanisms of termination and prevention of atrial fibrillation by drug therapy

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I–IV drugs, namely Na+ channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca2+ channel blockers; the “upstream therapies”, e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as “atrial-selective” multiple ion channel blockers, gap junction-enhancers, and intracellular Ca2+-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms. Keywords: Atrial fibrillation; Cardiac arrhythmia mechanisms: reentry, afterdepolarisations; In-vivo animal models; Pathological electrical remodelling; Pharmacological treatment; Anti-arrhythmic drug mechanisms Abbreviations: ACE, angiotensin-converting enzyme; AF, atrial fibrillation; AFCL, AF cycle length; APD, action potential duration; DAD, delayed afterdepolarisation; EAD, early afterdepolarisation; ERP, effective refractory period; ICaL, L-type Ca2+ current; ICaT, T-type Ca2+ current; If, funny current; IK1, inward rectifier K+ current; IKACh, acetylcholine-activated K+ current; IKr, rapid delayed rectifier K+ current; IKS, slow delayed rectifier K+ current; IKur, ultra-rapid delayed rectifier K+ current; INa, Na+ current; INa/Ca, Na+-Ca2+ exchanger current; INa/H, Na+-H+ exchanger current; INaL, late INa; ISKCa, small conductance Ca2+-activated K+ current; ITO, transient outward K+ curren

A symmetric multivariate leakage correction for MEG connectomes

AbstractAmbiguities in the source reconstruction of magnetoencephalographic (MEG) measurements can cause spurious correlations between estimated source time-courses. In this paper, we propose a symmetric orthogonalisation method to correct for these artificial correlations between a set of multiple regions of interest (ROIs). This process enables the straightforward application of network modelling methods, including partial correlation or multivariate autoregressive modelling, to infer connectomes, or functional networks, from the corrected ROIs. Here, we apply the correction to simulated MEG recordings of simple networks and to a resting-state dataset collected from eight subjects, before computing the partial correlations between power envelopes of the corrected ROItime-courses. We show accurate reconstruction of our simulated networks, and in the analysis of real MEGresting-state connectivity, we find dense bilateral connections within the motor and visual networks, together with longer-range direct fronto-parietal connections

Formal Derivation of Concurrent Garbage Collectors

Concurrent garbage collectors are notoriously difficult to implement correctly. Previous approaches to the issue of producing correct collectors have mainly been based on posit-and-prove verification or on the application of domain-specific templates and transformations. We show how to derive the upper reaches of a family of concurrent garbage collectors by refinement from a formal specification, emphasizing the application of domain-independent design theories and transformations. A key contribution is an extension to the classical lattice-theoretic fixpoint theorems to account for the dynamics of concurrent mutation and collection.Comment: 38 pages, 21 figures. The short version of this paper appeared in the Proceedings of MPC 201

Interval training normalizes cCardiomyocyte function, diastolic Ca²⁺ control, and SR Ca²⁺ release synchronicity in a mouse model of diabetic cardiomyopathy

In the present study we explored the mechanisms behind excitation-contraction (EC)-coupling defects in cardiomyocytes from mice with type-2 diabetes (db/db), and determined whether 13-weeks of aerobic interval training could restore cardiomyocyte Ca2+ cycling and EC-coupling. Reduced contractility in cardiomyocytes isolated from sedentary db/db was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca2+ leak, reduced synchrony of Ca2+ release, reduced transverse (T)-tubule density, and lower peak systolic and diastolic Ca2+ and caffeine-induced Ca2+ release. Additionally, the rate of SR Ca2+ ATPase (SERCA2a)-mediated Ca2+ uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca2+ release indicated increased Na+/Ca2+- exchanger (NCX) activity. The increased SR-Ca2+ leak was attributed to increased Ca2+-calmodulindependent protein kinase (CaMKIIδ) phosphorylation, supported by the normalization of SR-Ca2+ leak upon inhibition of CaMKIIδ (AIP). Exercise training restored contractile function associated with restored SR Ca2+ release synchronicity, T-tubule density, twitch Ca2+ amplitude, SERCA2a and NCX activities, and SR-Ca2+ leak. The latter was associated with reduced phosphorylation of cytosolic CaMKIIδ. Despite normal contractile function and Ca2+ handling after the training period, phospholamban was hyperphosphorylated at Serine-16. Protein kinase A (PKA) inhibition (H-89) in cardiomyocytes from the exercised db/db group abolished the differences in SR-Ca2+ load when compared with the sedentary db/db mice. EC-coupling changes were observed without changes in serum insulin or glucose levels, suggesting that the exercise training-induced effects are not via normalization of the diabetic condition. These data demonstrate that aerobic interval training almost completely restored the contractile function of the diabetic cardiomyocyte to levels close to sedentary wild type (WT)

Control strategies for coal dust and methane explosions in underground coal mines : current South African research and development initiatives

Please read abstract in article.http://www.saimm.co.za/journal-papersam2017Mining Engineerin

The use of ratiometric fluorescence measurements of the voltage sensitive dye Di-4-ANEPPS to examine action potential characteristics and drug effects on human induced pluripotent stem cell-derived cardiomyocytes

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and higher throughput platforms have emerged as potential tools to advance cardiac drug safety screening. This study evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in cardiomyocytes (CMC) from both sources though the mean and variance differed significantly (APD90: 229 ± 15 ms vs 427 ± 49 ms [mean ± SD, P < 0.01]; average spontaneous cycle length: 0.99 ± 0.02 s vs 1.47 ± 0.35 s [mean ± SD, P < 0.01], Cor.4U vs iCell CMC, respectively). The 10–90% rise time of the AP (Trise) was ∼6 ms and was normally distributed when expressed as 1/T2riseTrise2 in both cell preparations. Both cell types showed a rate dependence analogous to that of adult human cardiac cells. Furthermore, nifedipine, ranolazine, and E4031 had similar effects on cardiomyocyte electrophysiology in both cell types. However, ranolazine and E4031 induced early after depolarization-like events and high intrinsic firing rates at lower concentrations in iCell CMC. These data show that VSDs provide a minimally invasive, quantitative, and accurate method to assess hiPSC-CM electrophysiology and detect subtle drug-induced effects for drug safety screening while highlighting a need to standardize experimental protocols across preparations

How should I treat a patient with significant angina and a severe left anterior descending artery stenosis beyond the insertion of a left internal mammary artery jump graft (diagonal to LAD)?

BACKGROUND: A 60-year-old man with a history of previous coronary artery bypass grafting (saphenous vein grafting [SVG] to native right coronary artery [RCA] and sequential left internal mammary artery [LIMA] jump grafting to his native first diagonal [D1] and left anterior descending [LAD] arteries), who had developed a previous ischaemic cerebrovascular accident following femoral angiography, re-presented with further ischaemic cardiac symptoms.\ud \ud INVESTIGATIONS: Physical examination, electrocardiography, biochemistry including high-sensitive troponin, echocardiography, and trans-radial angiography.\ud \ud DIAGNOSIS: Severe native 3 vessel disease including ostial occlusion of the LAD, distal left circumflex and obtuse marginal (LCX/OM) disease and proximal RCA occlusion; occluded SVG to RCA, and evidence of a critical stenosis in the mid LAD distal to the insertion of the tortuous LIMA jump graft (diagonal to LAD).\ud \ud TREATMENT: PCI to mid LAD lesion via LIMA jump graft from left trans-radial approach

Spin-Polarized Electron Transport at Ferromagnet/Semiconductor Schottky Contacts

We theoretically investigate electron spin injection and spin-polarization sensitive current detection at Schottky contacts between a ferromagnetic metal and an n-type or p-type semiconductor. We use spin-dependent continuity equations and transport equations at the drift-diffusion level of approximation. Spin-polarized electron current and density in the semiconductor are described for four scenarios corresponding to the injection or the collection of spin polarized electrons at Schottky contacts to n-type or p-type semiconductors. The transport properties of the interface are described by a spin-dependent interface resistance, resulting from an interfacial tunneling region. The spin-dependent interface resistance is crucial for achieving spin injection or spin polarization sensitivity in these configurations. We find that the depletion region resulting from Schottky barrier formation at a metal/semiconductor interface is detrimental to both spin injection and spin detection. However, the depletion region can be tailored using a doping density profile to minimize these deleterious effects. For example, a heavily doped region near the interface, such as a delta-doped layer, can be used to form a sharp potential profile through which electrons tunnel to reduce the effective Schottky energy barrier that determines the magnitude of the depletion region. The model results indicate that efficient spin-injection and spin-polarization detection can be achieved in properly designed structures and can serve as a guide for the structure design.Comment: RevTex