Many cells use oscillations in calcium concentration to transmit messages. The oscillations largely result from an influx of calcium into the cytosol from the endoplasmic reticulum (ER), followed by an efflux of calcium from the cytosol back into the ER. The sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump pumps calcium into the ER. It binds calcium on the cytosolic side and releases it on the ER side and in the delay between binding and release, calcium is buffered by the pump. We developed a model of a buffering SERCA pump and investigated whether including this in a model of calcium oscillations has any significant effects. We found that the oscillations produced when using the SERCA pump, which does not buffer calcium, have a larger amplitude and a slightly smaller period than when using the buffering SERCA pump. We show that the buffering SERCA pump shows adaptation to a stimulus, and we demonstrate that, by using a bidirectional SERCA pump, we are able to eliminate futile cycling of calcium between the cytosol and ER when the cell is at rest.

Atherosclerosis is a chronic cardiovascular disease which increases risk of major cardiovascular events including myocardial infarction and stroke. Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) have long been recognised as a hallmark of cardiovascular disease and are associated with cardiovascular risk factors including hypertension, obesity and hypertriglyceridemia. In this review, we discuss the clinical literature that link ADMA concentrations to increased risk of the development of atherosclerosis. The formation of atherosclerotic lesions relies on the interplay between vascular dysfunction, leading to endothelial activation and the accumulation of inflammatory cells, particularly macrophages, within the vessel wall. Here, we review the mechanisms through which elevated ADMA contributes to endothelial dysfunction, activation and reactive oxygen species (ROS) production; how ADMA may affect vascular smooth muscle phenotype; and finally whether ADMA plays a regulatory role in the inflammatory processes occurring within the vessel wall.

Inositol 1,4,5-trisphosphate (IP(3)R) receptor channels control release of Ca(2+) from the endoplasmic reticulum into the cytosol of a cell. The binding of both 1,4,5-trisphosphate (IP(3)) and activating Ca(2+) is required for the channel to open. At high Ca(2+) concentrations, IP(3)Rs are inhibited. IP(3)Rs are composed of four identical subunits and form in clusters. Many models have been proposed to describe how the binding of IP(3) and Ca(2+) to subunits results in the opening and closing of IP(3)Rs. Here we compare the opening and closing probability distributions for clusters of IP(3)Rs, resulting from three different models. The distributions are calculated both analytically, using a method we have developed, and with simulations. We found significant differences in the behavior of the three models as the Ca(2+) and IP(3) concentrations are varied.

Microdomains of calcium (i.e., areas on the nanometer scale that have qualitatively different calcium concentrations from that in the bulk cytosol) are known to be important in many situations. In cardiac cells, for instance, a calcium microdomain between the L-type channels and the ryanodine receptors, the so-called diadic cleft, is where the majority of the control of calcium release occurs. In other cell types that exhibit calcium oscillations and waves, the importance of microdomains in the vicinity of clusters of inositol trisphosphate receptors, or between the endoplasmic reticulum (ER) and other internal organelles or the plasma membrane, is clear.Given the limits of computational power, it is not currently realistic to model an entire cellular cytoplasm by incorporating detailed structural information about the ER throughout the entire cytoplasm. Hence, most models use a homogenised approach, assuming that both cytoplasm and ER coexist at each point of the domain. Conversely, microdomain models can be constructed, in which detailed structural information can be incorporated, but, until now, methods have not been developed for linking such a microdomain model to a model at the level of the entire cell.Using the homogenisation approach we developed in an earlier paper (Goel P., A. Friedman and J. Sneyd. 2006. Homogenization of the cell cytoplasm: the calcium bidomain equations. SIAM J. on Multiscale Modeling and Simulation, in press) we show how a multiscale model of a calcium microdomain can be constructed. In this model a detailed model of the microdomain (in which the ER and the cytoplasm are separate compartments) is coupled to a homogenised model of the entire cell in a rigorous way. Our method is illustrated by a simple model of the diadic cleft of a cardiac half-sarcomere.

Classical Wolf-Rayet (WR) stars mark an important stage in the late evolution of massive stars. As hydrogen-poor massive stars, these objects have lost their outer layers, while still losing further mass through strong winds indicated by their prominent emission line spectra. Wolf-Rayet stars have been detected in a variety of different galaxies. Their strong winds are a major ingredient of stellar evolution and population synthesis models. Yet, a coherent theoretical picture of their strong mass-loss is only starting to emerge. In particular, the occurrence of WR stars as a function of metallicity (Z) is still far from being understood.To uncover the nature of the complex and dense winds of Wolf-Rayet stars, we employ a new generation of model atmospheres including a consistent solution of the wind hydrodynamics in an expanding non-LTE situation. With this technique, we can dissect the ingredients driving the wind and predict the resulting mass-loss for hydrogen-depleted massive stars. Our modelling efforts reveal a complex picture with strong, non-linear dependencies on the luminosity-to-mass ratio and Z with a steep, but not totally abrupt onset for WR-type winds in helium stars. With our findings, we provide a theoretical motivation for a population of helium stars at low Z, which cannot be detected via WR-type spectral features. Our study of massive He-star atmosphere models yields the very first mass-loss recipe derived from first principles in this regime. Implementing our first findings in stellar evolution models, we demonstrate how traditional approaches tend to overpredict WR-type mass loss in the young Universe.

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The most massive stars dominate the chemical enrichment, mechanical and radiative feedback, and energy budget of their host environments. Yet how massive stars initially form and how they evolve throughout their lives is ambiguous. The mass loss of the most massive stars remains a key unknown in stellar physics, with consequences for stellar feedback and populations. In this work, we compare grids of very massive star (VMS) models with masses ranging from 80-1000 M , for a range of input physics. We include enhanced winds close to the Eddington limit as a comparison to standard O-star winds, with consequences for present-day observations of ∼50-100 M stars. We probe the relevant surface H abundances (𝑋 s ) to determine the key traits of VMS evolution compared to O stars. We find fundamental differences in the behaviour of our models with the enhanced-wind prescription, with a convergence on the stellar mass at 1.6 Myr, regardless of the initial mass. It turns out that 𝑋 s is an important tool in deciphering the initial mass due to the chemically homogeneous nature of VMS above a mass threshold. We use 𝑋 s to break the degeneracy of the initial masses of both components of a detached binary, and a sample of WNh stars in the Tarantula nebula. We find that for some objects, the initial masses are unrestricted and, as such, even initial masses of the order 1000 M are not excluded. Coupled with the mass turnover at 1.6 Myr, 𝑋 s can be used as a 'clock' to determine the upper stellar mass.

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