52 research outputs found
Rate-dependent Ca2+ signalling underlying the force-frequency response in rat ventricular myocytes: A coupled electromechanical modeling study
Rate-dependent effects on the Ca2+ sub-system in a rat ventricular myocyte are investigated. Here,
we employ a deterministic mathematical model describing various Ca2+ signalling pathways under
voltage clamp (VC) conditions, to better understand the important role of calmodulin (CaM) in modulating
the key control variables Ca2+/calmodulin-dependent protein kinase-II (CaMKII), calcineurin
(CaN), and cyclic adenosine monophosphate (cAMP) as they affect various intracellular targets. In
particular, we study the frequency dependence of the peak force generated by the myofilaments, the
force-frequency response (FFR). Our cell model incorporates frequency-dependent CaM-mediated spatially heterogenous interaction
of CaMKII and CaN with their principal targets (dihydropyridine (DHPR) and ryanodine (RyR) receptors
and the SERCA pump). It also accounts for the rate-dependent effects of phospholamban
(PLB) on the SERCA pump; the rate-dependent role of cAMP in up-regulation of the L-type Ca2+
channel (ICa;L); and the enhancement in SERCA pump activity via phosphorylation of PLB.Our model reproduces positive peak FFR observed in rat ventricular myocytes during voltage-clamp
studies both in the presence/absence of cAMP mediated -adrenergic stimulation. This study provides
quantitative insight into the rate-dependence of Ca2+-induced Ca2+-release (CICR) by investigating
the frequency-dependence of the trigger current (ICa;L) and RyR-release. It also highlights the relative
role of the sodium-calcium exchanger (NCX) and the SERCA pump at higher frequencies, as well
as the rate-dependence of sarcoplasmic reticulum (SR) Ca2+ content. A rigorous Ca2+ balance
imposed on our investigation of these Ca2+ signalling pathways clarifies their individual roles. Here,
we present a coupled electromechanical study emphasizing the rate-dependence of isometric force
developed and also investigate the temperature-dependence of FFR. Our model provides mechanistic biophysically based explanations for the rate-dependence of CICR,
generating useful and testable hypotheses. Although rat ventricular myocytes exhibit a positive peak
FFR in the presence/absence of beta-adrenergic stimulation, they show a characteristic increase in the
positive slope in FFR due to the presence of Norepinephrine or Isoproterenol. Our study identifies
cAMP-mediated stimulation, and rate-dependent CaMKII-mediated up-regulation of ICa;L as the key
mechanisms underlying the aforementioned positive FFR
The Role of the Frank–Starling Law in the Transduction of Cellular Work to Whole Organ Pump Function: A Computational Modeling Analysis
We have developed a multi-scale biophysical electromechanics model of the rat left ventricle at room temperature. This model has been applied to investigate the relative roles of cellular scale length dependent regulators of tension generation on the transduction of work from the cell to whole organ pump function. Specifically, the role of the length dependent Ca2+ sensitivity of tension (Ca50), filament overlap tension dependence, velocity dependence of tension, and tension dependent binding of Ca2+ to Troponin C on metrics of efficient transduction of work and stress and strain homogeneity were predicted by performing simulations in the absence of each of these feedback mechanisms. The length dependent Ca50 and the filament overlap, which make up the Frank-Starling Law, were found to be the two dominant regulators of the efficient transduction of work. Analyzing the fiber velocity field in the absence of the Frank-Starling mechanisms showed that the decreased efficiency in the transduction of work in the absence of filament overlap effects was caused by increased post systolic shortening, whereas the decreased efficiency in the absence of length dependent Ca50 was caused by an inversion in the regional distribution of strain
Choice of Tax Base Revisited: Cash Flow vs. Prepayment Approaches to Consumption Taxation
Tractable consumer choice
We derive a rational model of separable consumer choice which can also serve as a
behavioral model. The central construct is [lambda] , the marginal utility of money, derived
from the consumer's rest-of-life problem. We present a robust approximation of [lambda],
and show how to incorporate liquidity constraints, indivisibilities and adaptation to
a changing environment. We fi nd connections with numerous historical and recent
constructs, both behavioral and neoclassical, and draw contrasts with standard partial
equilibrium analysis. The result is a better grounded, more
flexible and more intuitive description of consumer choice
The mammals of Angola
Scientific investigations on the mammals of Angola started over 150 years
ago, but information remains scarce and scattered, with only one recent published
account. Here we provide a synthesis of the mammals of Angola based on a thorough
survey of primary and grey literature, as well as recent unpublished records. We present
a short history of mammal research, and provide brief information on each species
known to occur in the country. Particular attention is given to endemic and near endemic
species. We also provide a zoogeographic outline and information on the conservation
of Angolan mammals. We found confirmed records for 291 native species, most of
which from the orders Rodentia (85), Chiroptera (73), Carnivora (39), and
Cetartiodactyla (33). There is a large number of endemic and near endemic species,
most of which are rodents or bats. The large diversity of species is favoured by the wide range of habitats with contrasting environmental conditions, while endemism tends to
be associated with unique physiographic settings such as the Angolan Escarpment. The
mammal fauna of Angola includes 2 Critically Endangered, 2 Endangered, 11
Vulnerable, and 14 Near-Threatened species at the global scale. There are also 12 data
deficient species, most of which are endemics or near endemics to the countryinfo:eu-repo/semantics/publishedVersio
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