Rotating wave solutions of the FitzHugh–Nagumo equations

This paper will treat the bifurcation and numerical simulation of rotating wave (RW) solutions of the FitzHugh-Nagumo (FHN) equations. These equations are often used as a simple mathematical model of excitable media. The dependence of the solutions on a uniformly applied current, and also on the diffusion coefficients or domain size will be studied. Ranges of applied current and/or diffusion coefficients in which RW solutions are observed will be described using bifurcation theory and continuation methods. The bifurcation of time-periodic solutions of these FHN equations without diffusion is described first. Similar methods are then used to find RW solutions on a circular ring and numerical simulations are described. These results are then extended to investigate RW solutions on annular rings of finite cross-section. Scaling arguments are used to show how the existence of solutions depends on either the diffusion coefficient or on the size of the region.     

A blood based 12-miRNA signature of Alzheimer disease patients

Background

Alzheimer disease (AD) is the most common form of dementia but the identification of reliable, early and non-invasive biomarkers remains a major challenge. We present a novel miRNA-based signature for detecting AD from blood samples.

Results

We apply next-generation sequencing to miRNAs from blood samples of 48 AD patients and 22 unaffected controls, yielding a total of 140 unique mature miRNAs with significantly changed expression levels. Of these, 82 have higher and 58 have lower abundance in AD patient samples. We selected a panel of 12 miRNAs for an RT-qPCR analysis on a larger cohort of 202 samples, comprising not only AD patients and healthy controls but also patients with other CNS illnesses. These included mild cognitive impairment, which is assumed to represent a transitional period before the development of AD, as well as multiple sclerosis, Parkinson disease, major depression, bipolar disorder and schizophrenia. miRNA target enrichment analysis of the selected 12 miRNAs indicates an involvement of miRNAs in nervous system development, neuron projection, neuron projection development and neuron projection morphogenesis. Using this 12-miRNA signature, we differentiate between AD and controls with an accuracy of 93%, a specificity of 95% and a sensitivity of 92%. The differentiation of AD from other neurological diseases is possible with accuracies between 74% and 78%. The differentiation of the other CNS disorders from controls yields even higher accuracies.

Conclusions

The data indicate that deregulated miRNAs in blood might be used as biomarkers in the diagnosis of AD or other neurological diseases.     

Paramagnetic Beads and Magnetically Mediated Strain Enhance Cardiomyogenesis in Mouse Embryoid Bodies

Mechanical forces play an important role in proper embryologic development, and similarly such forces can directly impact pluripotency and differentiation of mouse embryonic stem cells (mESC) in vitro. In addition, manipulation of the embryoid body (EB) microenvironment, such as by incorporation of microspheres or microparticles, can similarly influence fate determination. In this study, we developed a mechanical stimulation regimen using permanent neodymium magnets to magnetically attract cells within an EB. Arginine-Glycine-Aspartic Acid (RGD)-conjugated paramagnetic beads were incorporated into the interior of the EBs during aggregation, allowing us to exert force on individual cells using short-term magnetization. EBs were stimulated for one hour at different magnetic field strengths, subsequently exerting a range of force intensity on the cells at different stages of early EB development. Our results demonstrated that following exposure to a 0.2 Tesla magnetic field, ESCs respond to magnetically mediated strain by activating Protein Kinase A (PKA) and increasing phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. The timing of stimulation can also be tailored to guide ESC differentiation: the combination of bone morphogenetic protein 4 (BMP4) supplementation with one hour of magnetic attraction on Day 3 enhances cardiomyogenesis by increasing contractile activity and the percentage of sarcomeric α-actin-expressing cells compared to control samples with BMP4 alone. Interestingly, we also observed that the beads alone had some impact on differentiation by increasingly slightly, albeit not significantly, the percentage of cardiomyocytes. Together these results suggest that magnetically mediated strain can be used to enhance the percentage of mouse ESC-derived cardiomyocytes over current differentiation protocols.     

Ovariectomy and overeating palatable, energy-dense food increase subcutaneous adipose tissue more than intra-abdominal adipose tissue in rats

Background

Men are at an increased risk of dying from heart failure caused by inflammatory heart diseases such as atherosclerosis, myocarditis and dilated cardiomyopathy (DCM). We previously showed that macrophages in the spleen are phenotypically distinct in male compared to female mice at 12 h after infection. This innate immune profile mirrors and predicts the cardiac immune response during acute myocarditis.

Methods

In order to study sex differences in the innate immune response, five male and female BALB/c mice were infected intraperitoneally with coxsackievirus B3 (CVB3) or phosphate buffered saline and their spleens were harvested 12 h later for microarray analysis. Gene expression was determined using an Affymetrix Mouse Gene 1.0 ST Array. Significant gene changes were verified by quantitative real-time polymerase chain reaction or ELISA.

Results

During the innate immune response to CVB3 infection, infected males had higher splenic expression of genes which are important in regulating the influx of cholesterol into macrophages, such as phospholipase A₂ (PLA₂) and the macrophage scavenger receptor compared to the infected females. We also observed a higher expression in infected males compared to infected females of squalene synthase, an enzyme used to generate cholesterol within cells, and Cyp2e1, an enzyme important in metabolizing cholesterol and steroids. Infected males also had decreased levels of the translocator protein 18 kDa (TSPO), which binds PLA₂ and is the rate-limiting step for steroidogenesis, as well as decreased expression of the androgen receptor (AR), which indicates receptor activation. Gene differences were not due to increased viral replication, which was unaltered between sexes.

Conclusions

We found that, compared to females, male mice had a greater splenic expression of genes which are important for cholesterol metabolism and activation of the AR at 12 h after infection. Activation of the AR has been linked to increased cardiac hypertrophy, atherosclerosis, myocarditis/DCM and heart failure in male mice and humans.     

Effect of latitude and acclimation on the lethal temperatures of the peach‐potato aphid Myzus persicae

• 1 Aphids, similar to all insects, are ectothermic and, consequently, are greatly affected by environmental conditions. The peach potato aphid Myzus persicae (Sulzer) has a global distribution, although it is not known whether populations display regional adaptations to distinct climatic zones along its distribution and vary in their ability to withstand and acclimate to temperature extremes. In the present study, lethal temperatures were measured in nine anholocyclic clones of M. persicae collected along a latitudinal cline of its European distribution from Sweden to Spain. The effects of collection origin and intra‐ and intergenerational acclimation on cold and heat tolerance, as determined by upper and lower lethal temperatures (ULT₅₀ and LLT₅₀, respectively), were investigated.
• 2 Lethal temperatures of M. persicae were shown to be plastic and could be altered after acclimation over just one generation. Lower lethal temperatures were significantly depressed in eight of nine clones after acclimation for one generation at 10°C (range: ?13.3 to ?16.2°C) and raised after acclimation at 25°C (range: ?10.7 to ?11.6°C) compared with constant 20°C (range: ?11.9 to ?12.9°C). Upper lethal temperatures were less plastic, although significantly increased after one generation at 25°C (range: 41.8–42.4°C) and in five of nine clones after acclimation at 10°C. There was no evidence of intergenerational acclimation over three generations.
• 3 Thermal tolerance ranges were expanded after acclimation at 10 and 25°C compared with constant 20°C, resulting in aphids reared at 10°C surviving over a temperature range that was approximately 2–6°C greater than those reared at 25°C.
• 4 There was no clear relationship between lethal temperatures and latitude. Large scale mixing of clones may occur across Europe, thus limiting local adaption in thermal tolerance. Clonal type, as identified by microsatellite analysis, did show a relationship with thermal tolerance, notably with Type O clones being the most thermal tolerant. Clonal types may respond independently to climate change, affecting the relative proportions of clones within populations, with consequent implications for biodiversity and agriculture.

     

Ontogenetic shifts in a prey’s chemical defences influence feeding responses of a snake predator

Foraging theory suggests that predator responses to potential prey should be influenced by prey chemical defences, but the effects of ontogenetic variation in such defences on prey vulnerability to predators remain unclear. Cane toads (Rhinella marina) are toxic to anurophagous snakes, including the keelback (Tropidonophis mairii, a natricine colubrid that occurs within the toads' invasive range in Australia). Toxin levels and diversity change through toad ontogeny, decreasing from the egg stage to metamorphosis, then increasing in postmetamorphic toads. If the toxin content of a prey item influences predator responses, we predict that keelbacks should exhibit selective predation on toads close to metamorphosis. The results of our laboratory trials on adult (field-collected, and thus toad-experienced) and hatchling (laboratory-incubated, and thus toad-naive) keelbacks supported this prediction. The snakes selectively consumed later-stage rather than earlier-stage tadpoles, and earlier-stage rather than later-stage metamorphs. Our data are thus consistent with the hypothesis that ontogenetic changes in toxin content can affect individuals' vulnerability to predation.     

Prevalence of Batrachochytrium dendrobatidis infection is extremely low in direct-developing Australian microhylids

The emerging infectious disease chytridiomycosis has been implicated in declines and disappearances of amphibian populations around the world. However, susceptibility to infection and the extent of pathological effects of infection vary among hosts, and species with life histories that include parental care of direct-developing terrestrial eggs may tend to be less susceptible. We examined samples from a total of 595 individuals of 9 species of direct-developing Australian frogs in the family Microhylidae for the presence of infection by Batrachochytrium dendrobatidis (Bd). Between 1995 and 2004, 336 samples were collected; 102 of these were analysed histologically and 234 were tissues stored in alcohol, which were examined using diagnostic quantitative PCR (qPCR). Swab samples were collected from 259 frogs from 2005 to 2008 and were examined using qPCR. None of the 595 samples showed evidence of infection by Bd. If these data are regarded as a single sample representative of Australian microhylids, the upper 95% binomial confidence limit for the prevalence of infection in frogs of this family is 0.0062 (<1%). Even if only the data from the more powerful diagnostic qPCR tests are used, the upper 95% confidence limit for prevalence is 0.0075 (<1%). Our data suggest that Australian microhylids have a very low prevalence of infection by Bd in nature, and thus are either not susceptible, or are only slightly susceptible, to chytridiomycosis. This could be due solely to, or in combination with, low rates of transmission and to factors that promote resistance to infection, including ecological or behavioural characteristics, innate immune functions such as antimicrobial skin peptides, or antimicrobial symbionts in skin flora.