Study protocol: a randomised controlled trial investigating the effect of exercise training on peripheral blood gene expression in patients with stable angina

Background: Exercise training has been shown to reduce angina and promote collateral vessel development in patients with coronary artery disease. However, the mechanism whereby exercise exerts these beneficial effects is unclear. There has been increasing interest in the use of whole genome peripheral blood gene expression in a wide range of conditions to attempt to identify both novel mechanisms of disease and transcriptional biomarkers. This protocol describes a study in which we will assess the effect of a structured exercise programme on peripheral blood gene expression in patients with stable angina, and correlate this with changes in angina level, anxiety, depression, and exercise capacity. Methods/Design: Sixty patients with stable angina will be recruited and randomised 1: 1 to exercise training or conventional care. Patients randomised to exercise training will attend an exercise physiology laboratory up to three times weekly for supervised aerobic interval training sessions of one hour in total duration. Patients will undergo assessments of angina, anxiety, depression, and peripheral blood gene expression at baseline, after six and twelve weeks of training, and twelve weeks after formal exercise training ceases. Discussion: This study will provide comprehensive data on the effect of exercise training on peripheral blood gene expression in patients with angina. By correlating this with improvement in angina status we will identify candidate peripheral blood transcriptional markers predictive of improvements in angina level in response to exercise training

Explicit Stabilised Gradient Descent for Faster Strongly Convex Optimisation

This paper introduces the Runge-Kutta Chebyshev descent method (RKCD) for strongly convex optimisation problems. This new algorithm is based on explicit stabilised integrators for stiff differential equations, a powerful class of numerical schemes that avoid the severe step size restriction faced by standard explicit integrators. For optimising quadratic and strongly convex functions, this paper proves that RKCD nearly achieves the optimal convergence rate of the conjugate gradient algorithm, and the suboptimality of RKCD diminishes as the condition number of the quadratic function worsens. It is established that this optimal rate is obtained also for a partitioned variant of RKCD applied to perturbations of quadratic functions. In addition, numerical experiments on general strongly convex problems show that RKCD outperforms Nesterov's accelerated gradient descent

Biochemical indices and life traits of loggerhead turtles (Caretta caretta) from Cape Verde Islands

The loggerhead turtle (Caretta caretta) is an endangered marine reptile for whom assessing population health requires knowledge of demographic parameters such as individual growth rate. In Cape Verde, as within several populations, adult female loggerhead sea turtles show a size-related behavioral and trophic dichotomy. While smaller females are associated with oceanic habitats, larger females tend to feed in neritic habitats, which is reflected in their physiological condition and in their offspring. The ratio of RNA/DNA provides a measure of cellular protein synthesis capacity, which varies depending on changes in environmental conditions such as temperature and food availability. The purpose of this study was to evaluate the combined use of morphometric data and biochemical indices as predictors of the physiological condition of the females of distinct sizes and hatchlings during their nesting season and how temperature may influence the physiological condition on the offspring. Here we employed biochemical indices based on nucleic acid derived indices (standardized RNA/DNA ratio-sRD, RNA concentration and DNA concentration) in skin tissue as a potential predictor of recent growth rate in nesting females and hatchling loggerhead turtles. Our major findings were that the physiological condition of all nesting females (sRD) decreased during the nesting season, but that females associated with neritic habitats had a higher physiological condition than females associated with oceanic habitats. In addition, the amount of time required for a hatchling to right itself was negatively correlated with its physiological condition (sRD) and shaded nests produced hatchlings with lower sRD. Overall, our results showed that nucleic acid concentrations and ratios of RNA to DNA are an important tool as potential biomarkers of recent growth in marine turtles. Hence, as biochemical indices of instantaneous growth are likely temperature-, size- and age-dependent, the utility and validation of these indices on marine turtles stocks deserves further study.The authors thank the Cape Verde Ministry of Environment (General Direction for the Environment), INDP (National Fisheries Institution), the Canary Islands Government (D.G. Africa and D.G. Research and Universities), ICCM (Canarian Institution for Marine Sciences), the Andalusian Government (Andalusian Environmental Office) and AEGINA PROJECT (INTERREG IIIB) for funding and hosting them during this study. The authors also thank the European Regional Development Fund (ERDF) through the COMPETE - Operational Competitiveness Programme, and national funds through FCT - PEst-C/MAR/LA0015/2011 for supporting the biochemical analysis

Leucine-enriched protein feeding does not impair exercise-induced free fatty acid availability and lipid oxidation: beneficial implications for training in carbohydrate-restricted states

Given that the enhanced oxidative adaptations observed when training in carbohydrate (CHO) restricted states are potentially regulated through free fatty acid (FFA) mediated signalling and that leucine rich protein elevates muscle protein synthesis, the present study aimed to test the hypothesis that leucine enriched protein feeding enhances circulating leucine concentration but does not impair FFA availability nor whole body lipid oxidation 56 during exercise. Nine males cycled for 2 h at 70% VO2peak when fasted (PLACEBO) or having consumed a whey protein solution (WHEY) or a leucine enriched whey protein gel (GEL), administered as 22 g 1 hour pre-exercise, 11 g/h during and 22 g thirty minutes post-exercise. Total leucine administration was 14.4 g and 6.3 in GEL and WHEY, respectively. Mean plasma leucine concentrations were elevated in GEL (P= 0.001) compared 60 with WHEY and PLACEBO (375 ± 100, 272 ± 51, 146 ± 14 μmol.L-1 respectively). No differences (P= 0.153) in plasma FFA (WHEY 0.53 ± 0.30, GEL 0.45 ± 0.25, PLACEBO 0.65 ± 0.30, mmol.L-1) or whole body lipid oxidation during exercise (WHEY 0.37 ± 0.26, GEL 0.36 ± 0.24, PLACEBO 0.34 ± 0.24 g/min) were apparent between trials, despite elevated (P= 0.001) insulin in WHEY and GEL compared with PLACEBO (38 ± 16, 35 ± 16, 22 ± 11 pmol.L-1 respectively). We conclude that leucine enriched protein feeding does not impair FFA availability nor whole body lipid oxidation during exercise, thus having practical applications for athletes who deliberately train in CHO restricted states to promote skeletal muscle adaptations

Within- and Among-Population Variation in Chytridiomycosis-Induced Mortality in the Toad Alytes obstetricans

Background Chytridiomycosis is a fungal disease linked to local and global extinctions of amphibians. Susceptibility to chytridiomycosis varies greatly between amphibian species, but little is known about between- and within-population variability. However, this kind of variability is the basis for the evolution of tolerance and resistance evolution to disease. Methodology/Principal Findings In a common garden experiment, we measured mortality after metamorphosis of Alytes obstetricans naturally infected with Batrachochytrium dendrobatidis. Mortality rates differed significantly among populations and ranged from 27 to 90%. Within populations, mortality strongly depended on mass at and time through metamorphosis. Conclusions/Significance Although we cannot rule out that the differences observed resulted from differences in skin microbiota, different pathogen strains or environmental effects experienced by the host or the pathogen prior to the start of the experiment, we argue that genetic differences between populations are a likely source of at least part of this variation. To our knowledge, this is the first study showing differences in survival between and within populations under constant laboratory conditions. Assuming that some of this intraspecific variation has a genetic basis, this may suggest that there is the potential for the evolution of resistance or tolerance, which might allow population persistence

Stable Isotope Tracking of Endangered Sea Turtles: Validation with Satellite Telemetry and δ15N Analysis of Amino Acids

Effective conservation strategies for highly migratory species must incorporate information about long-distance movements and locations of high-use foraging areas. However, the inherent challenges of directly monitoring these factors call for creative research approaches and innovative application of existing tools. Highly migratory marine species, such as marine turtles, regularly travel hundreds or thousands of kilometers between breeding and feeding areas, but identification of migratory routes and habitat use patterns remains elusive. Here we use satellite telemetry in combination with compound-specific isotope analysis of amino acids to confirm that insights from bulk tissue stable isotope analysis can reveal divergent migratory strategies and within-population segregation of foraging groups of critically endangered leatherback sea turtles (Dermochelys coriacea) across the Pacific Ocean. Among the 78 turtles studied, we found a distinct dichotomy in δ15N values of bulk skin, with distinct “low δ15N” and “high δ15N” groups. δ15N analysis of amino acids confirmed that this disparity resulted from isotopic differences at the base of the food chain and not from differences in trophic position between the two groups. Satellite tracking of 13 individuals indicated that their bulk skin δ15N value was linked to the particular foraging region of each turtle. These findings confirm that prevailing marine isoscapes of foraging areas can be reflected in the isotopic compositions of marine turtle body tissues sampled at nesting beaches. We use a Bayesian mixture model to show that between 82 and 100% of the 78 skin-sampled turtles could be assigned with confidence to either the eastern Pacific or western Pacific, with 33 to 66% of all turtles foraging in the eastern Pacific. Our forensic approach validates the use of stable isotopes to depict leatherback turtle movements over broad spatial ranges and is timely for establishing wise conservation efforts in light of this species’ imminent risk of extinction in the Pacific

Collateral circulation: Past and present

Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors

Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation?

Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other proteins coalesce together. SGs assembly is crucial for cell survival, since SGs are implicated in the regulation of translation, mRNA storage and stabilization and cell signalling, during stress. One defining feature of SGs is their dynamism, as they are quickly assembled upon stress and then rapidly dispersed after the stress source is no longer present. Recently, SGs dynamics, their components and their functions have begun to be studied in the context of human diseases. Interestingly, the regulated protein self-assembly that mediates SG formation contrasts with the pathological protein aggregation that is a feature of several neurodegenerative diseases. In particular, aberrant protein coalescence is a key feature of polyglutamine (PolyQ) diseases, a group of nine disorders that are caused by an abnormal expansion of PolyQ tract-bearing proteins, which increases the propensity of those proteins to aggregate. Available data concerning the abnormal properties of the mutant PolyQ disease-causing proteins and their involvement in stress response dysregulation strongly suggests an important role for SGs in the pathogenesis of PolyQ disorders. This review aims at discussing the evidence supporting the existence of a link between SGs functionality and PolyQ disorders, by focusing on the biology of SGs and on the way it can be altered in a PolyQ disease context.ALG-01-0145-FEDER-29480, SFRH/BD/133192/2017, SFRH/BD/133192/2017, SFRH/BD/148533/2019info:eu-repo/semantics/publishedVersio

Earth: Atmospheric Evolution of a Habitable Planet

Our present-day atmosphere is often used as an analog for potentially habitable exoplanets, but Earth's atmosphere has changed dramatically throughout its 4.5 billion year history. For example, molecular oxygen is abundant in the atmosphere today but was absent on the early Earth. Meanwhile, the physical and chemical evolution of Earth's atmosphere has also resulted in major swings in surface temperature, at times resulting in extreme glaciation or warm greenhouse climates. Despite this dynamic and occasionally dramatic history, the Earth has been persistently habitable--and, in fact, inhabited--for roughly 4 billion years. Understanding Earth's momentous changes and its enduring habitability is essential as a guide to the diversity of habitable planetary environments that may exist beyond our solar system and for ultimately recognizing spectroscopic fingerprints of life elsewhere in the Universe. Here, we review long-term trends in the composition of Earth's atmosphere as it relates to both planetary habitability and inhabitation. We focus on gases that may serve as habitability markers (CO2, N2) or biosignatures (CH4, O2), especially as related to the redox evolution of the atmosphere and the coupled evolution of Earth's climate system. We emphasize that in the search for Earth-like planets we must be mindful that the example provided by the modern atmosphere merely represents a single snapshot of Earth's long-term evolution. In exploring the many former states of our own planet, we emphasize Earth's atmospheric evolution during the Archean, Proterozoic, and Phanerozoic eons, but we conclude with a brief discussion of potential atmospheric trajectories into the distant future, many millions to billions of years from now. All of these 'Alternative Earth' scenarios provide insight to the potential diversity of Earth-like, habitable, and inhabited worlds.Comment: 34 pages, 4 figures, 4 tables. Review chapter to appear in Handbook of Exoplanet