Solving the heart mechanics equations with Newton and quasi Newton methods--a comparison

The non-linear elasticity equations of heart mechanics are solved while emulating the effects of a propagating activation wave. The dynamics of a 1 cm(3) slab of active cardiac tissue was simulated as the electrical wave traversed the muscular heart wall transmurally. The regular Newton (Newton-Raphson) method was compared to two modified Newton approaches, and also to a third approach that delayed update only of some selected Jacobian elements. In addition, the impact of changing the time step (0.01, 0.1 and 1 ms) and the relative non-linear convergence tolerance (10(-4), 10(-3) and 10(-2)) was investigated. Updating the Jacobian only when slow convergence occurred was by far the most efficient approach, giving time savings of 83-96%. For each of the four methods, CPU times were reduced by 48-90% when the time step was increased by a factor 10. Increasing the convergence tolerance by the same factor gave time savings of 3-71%. Different combinations of activation wave speed, stress rate and bulk modulus revealed that the fastest method became relatively even faster as stress rate and bulk modulus was decreased, while the activation speed had negligible influence in this respect.     

FRS 1000, an extract of red onion peel, strongly inhibits phosphodiesterase 5A (PDE 5A)

As part of our ongoing search for flavonoids that are bioactive in humans, it was determined that FRS 1000, a beverage containing flavonoids extracted from onion peel, showed unexpected improvement of male sexual function. An in vitro enzyme assay clearly showed that FRS 1000 has a strong phosphodiesterase 5A (PDE 5A) inhibitory activity, which is considered to be important for treatment of erectile dysfunction. Detailed assays of each major ingredient indicated that the antioxidative flavonoid quercetin was responsible for the activity. Results also suggested that PDE 5A inhibition is not directly related to the free radical scavenging activity of flavonoids.     

Chemical targeting of NEET proteins reveals their function in mitochondrial morphodynamics

Several human pathologies including neurological, cardiac, infectious, cancerous, and metabolic diseases have been associated with altered mitochondria morphodynamics. Here, we identify a small organic molecule, which we named Mito‐C. Mito‐C is targeted to mitochondria and rapidly provokes mitochondrial network fragmentation. Biochemical analyses reveal that Mito‐C is a member of a new class of heterocyclic compounds that target the NEET protein family, previously reported to regulate mitochondrial iron and ROS homeostasis. One of the NEET proteins, NAF‐1, is identified as an important regulator of mitochondria morphodynamics that facilitates recruitment of DRP1 to the ER–mitochondria interface. Consistent with the observation that certain viruses modulate mitochondrial morphogenesis as a necessary part of their replication cycle, Mito‐C counteracts dengue virus‐induced mitochondrial network hyperfusion and represses viral replication. The newly identified chemical class including Mito‐C is of therapeutic relevance for pathologies where altered mitochondria dynamics is part of disease etiology and NEET proteins are highlighted as important therapeutic targets in anti‐viral research.     

Wood production response to climate change will depend critically on forest composition and structure

Established forests currently function as a major carbon sink, sequestering as woody biomass about 26% of global fossil fuel emissions. Whether forests continue to act as a global sink will depend on many factors, including the response of aboveground wood production (AWP; MgC ha^?1 yr^?1) to climate change. Here, we explore how AWP in New Zealand's natural forests is likely to change. We start by statistically modelling the present‐day growth of 97 199 individual trees within 1070 permanently marked inventory plots as a function of tree size, competitive neighbourhood and climate. We then use these growth models to identify the factors that most influence present‐day AWP and to predict responses to medium‐term climate change under different assumptions. We find that if the composition and structure of New Zealand's forests were to remain unchanged over the next 30 years, then AWP would increase by 6–23%, primarily as a result of physiological responses to warmer temperatures (with no appreciable effect of changing rainfall). However, if warmth‐requiring trees were able to migrate into currently cooler areas and if denser canopies were able to form, then a different AWP response is likely: forests growing in the cool mountain environments would show a 30% increase in AWP, while those in the lowland would hardly respond (on average, ?3% when mean annual temperature exceeds 8.0 °C). We conclude that response of wood production to anthropogenic climate change is not only dependent on the physiological responses of individual trees, but is highly contingent on whether forests adjust in composition and structure.     

Stochastic binding of Ca2+ ions in the dyadic cleft; continuous versus random walk description of diffusion

Ca²⁺ signaling in the dyadic cleft in ventricular myocytes is fundamentally discrete and stochastic. We study the stochastic binding of single Ca²⁺ ions to receptors in the cleft using two different models of diffusion: a stochastic and discrete Random Walk (RW) model, and a deterministic continuous model. We investigate whether the latter model, together with a stochastic receptor model, can reproduce binding events registered in fully stochastic RW simulations. By evaluating the continuous model goodness-of-fit for a large range of parameters, we present evidence that it can. Further, we show that the large fluctuations in binding rate observed at the level of single time-steps are integrated and smoothed at the larger timescale of binding events, which explains the continuous model goodness-of-fit. With these results we demonstrate that the stochasticity and discreteness of the Ca²⁺ signaling in the dyadic cleft, determined by single binding events, can be described using a deterministic model of Ca²⁺ diffusion together with a stochastic model of the binding events, for a specific range of physiological relevant parameters. Time-consuming RW simulations can thus be avoided. We also present a new analytical model of bimolecular binding probabilities, which we use in the RW simulations and the statistical analysis.     

Multi-country field trials comparing wash-resistance of PermaNet and conventional insecticide-treated nets against anopheline and culicine mosquitoes

Insecticide-treated bednets (ITNs) are commonly used as a means of personal protection from malaria transmission by anopheline mosquitoes (Diptera: Culicidae). Long-lasting insecticidal nets (LLINs) have special treatments intended to remain effective after many washes. The present trials assessed the efficacy and wash-resistance of several production batches of PermaNet (polyester net coated with polymer resin containing pyrethroid insecticide deltamethrin 55 mg ai/m2) against malaria vectors in Pakistan, Iran and Tanzania compared to ITNs conventionally treated with alphacypermethrin 15 or 20 mg ai/m2, or deltamethrin 25 or 50 mg ai/m2. Insecticidal efficacy of the nets before and after repeated washing (using W.H.O. recommended and traditional local washing procedures) was monitored through contact bioassays with Anopheles and by experimental hut and outdoor platform tests. Local washing regimes gradually reduced the insecticidal efficacy of conventionally treated nets, but they were not exhausted, even after 21 washes. Using a more rigorous laboratory washing method, insecticide was more readily stripped from conventionally treated nets. PermaNet retained high efficacy after 21 washes, giving more than 97% mortality of Anopheles in contact bioassays with 3-min exposure. Using the more sensitive bioassay criterion of 'median time to knockdown', PermaNet showed no loss of insecticidal activity against Anopheles after washing repeatedly in 2 out of 6 trials; whereas in a further three trials knockdown activity of PermaNet and conventional ITNs declined at comparable rates. Higher mortality levels of Anopheles in contact bioassays did not always translate to superiority in experimental hut or enclosed platform trials. In only one of four comparative field trials did PermaNet out-perform conventional ITNs after washing: this was in the trial of PermaNet 2.0--the product with improved quality assurance. Because PermaNet and conventionally treated nets were both quite tolerant of local washing procedures, it is important in field trials to compare LLINs with conventional ITNs washed an equivalent number of times. Our comparison of PermaNet 2.0 against conventionally treated deltamethrin nets (CTDN) in Pakistan demonstrated superior performance of the LLIN after 20 washes in phase I and phase II bioassays, and this was corroborated by chemical assays of residual deltamethrin. Although PermaNet 2.0 has received WHOPES interim recommendation for malaria control purposes, its performance should be monitored in everyday use throughout its lifespan in various cultural settings to assess its durability and long-term effectiveness for malaria prevention and control. As many millions of conventionally treated nets are already in routine use, and these will require regular re-treatment, programme strategies should be careful to preserve the effectiveness of ITNS before and after establishing the reliability of LLINs in long-term use.     

Capturing juvenile tree dynamics from count data using Approximate Bayesian Computation

The juvenile life stage is a crucial determinant of forest dynamics and a first indicator of changes to species' ranges under climate change. However, paucity of detailed re-measurement data of seedlings, saplings and small trees means that their demography is not well understood at large scales, and rarely represented in forest models in detail. In this study we quantify the effects of climate and density dependence on recruitment and juvenile growth and mortality rates of thirteen species measured in the Spanish Forest Inventory. Single-census sapling count data is used to constrain demographic parameters of a simple forest juvenile dynamics model based on the perfect plasticity approximation model (PPA) within a likelihood-free parameterisation method, Approximate Bayesian Computation. Our results highlight marked differences between species, and the important role of climate and stand structure, in controlling juvenile dynamics. Recruitment had a hump-shaped relationship with conspecific density, and for most species conspecific competition had a stronger negative effect than heterospecific competition. Mediterranean species showed on average higher mortality and lower growth rates than temperate species, and in low density stands recruitment and mortality rates were positively correlated. Under climate change our model predicted declines in recruitment rates for almost all species. Reliable predictive models of forest dynamics should include realistic representation of critical early life-stage processes and our approach demonstrates that existing coarse count data can be used to parameterise such models. Approximate Bayesian Computation may have wide application in many fields of ecology to unlock information about past processes from single survey observations.     

Existence of excitation waves for a collection of cardiomyocytes electrically coupled to fibroblasts

We consider mathematical models of a collection of cardiomyocytes (myocardial tissue) coupled to a varying number of fibroblasts. Our aim is to understand how conductivity (δ) and fibroblast density (η) affect the stability of the collection. We provide mathematical and computational arguments indicating that there is a region of instability in the η-δ space. Mathematical arguments, based on a simplified model of the coupled myocyte-fibroblast system, show that for certain parameter choices, a stationary solution cannot exist. Numerical experiments (1D, 2D) are based on a recently developed model of electro-chemical coupling between a human atrial myocyte and a number of associated atrial fibroblasts. The numerical experiments demonstrate that there is a region of instability of the form observed in the simplified model analysis.     

Predictable changes in aboveground allometry of trees along gradients of temperature,aridity and competition

Aim Trees are often observed to get shorter and more narrowly crowned in dry regions and at high elevations. We explore how this pattern is driven by two opposing factors: competition for light makes it advantageous to extend branches to their biomechanical limit, whereas under cold or arid conditions it is advantageous to have shorter branches, thereby reducing the length of the hydraulic transport system and embolism risk. Using data from 700,000 trees of 26 species, we quantify how environmental conditions influence the scaling of height and crown diameter (CD) with stem diameter (d.b.h.). We compare our predictions with those of metabolic scaling theory (MST), which suggests that allometry is invariant of environment. Location 48,000 inventory plots that systematically sample mainland Spain, a region in which climate varies strongly. Methods We fit d.b.h.–height and d.b.h.–CD functions using Bayesian methods, allowing comparison of within‐ and across‐species trends in allometry along gradients of temperature, precipitation, drought and competition for light (i.e. the basal area of taller trees). Results The competitive environment had a strong influence on aboveground allometry, but all trees were far shorter than predicted by biomechanical models, suggesting that factors other than biomechanics are important. Species that dominate in arid and cold habitats were much shorter (for a given diameter) than those from benign conditions; but within‐species heights did not vary strongly across climatic gradients. Main conclusions Our results do not support the MST prediction that d.b.h.–height and d.b.h.–CD allometries are invariant, or that biomechanical constraints determine height allometry. Rather, we highlight the role of hydraulic limitations in this region. The fact that intra‐specific adjustment in d.b.h.–CD – height allometry along environmental gradients was far weaker than across‐species changes may indicate genetic constraints on allometry which might contribute to niche differentiation among species.