Probability density methods for modeling local and global aspects of intracellular calcium signaling

Considerable insight into intracellular calcium (Ca) responses has been obtained through the development of whole cell models that are based on molecular mechanisms, e.g., the kinetics of intracellular Ca channels and the feedback of Ca upon these channels. However, a limitation of most deterministic whole cell models to date is the assumption that channels are globally coupled by a single [Ca], when in fact channels experience localized domain Ca concentrations. More realistic stochastic Monte Carlo simulations are capable of representing individual domain Ca concentrations but suffer from increased computational demand. This dissertation introduces a novel probability approach which captures important aspects of local Ca signaling while improving computational efficiency.;In many cell types calcium release is mediated by diffusely distributed 1,4,5-trisphosphate receptors (IP3Rs). In Chapter 2 a Monte Carlo whole cell model is presented where each IP3R has a local cytosolic and luminal domain [Ca]. The Monte Carlo model is used to validate a probability density approach where local cytosolic and luminal domains Ca concentrations are represented as bivariate probability densities jointly distributed with IP3R state. Using this probability density approach, analysis shows that the time scale of Ca domain formation and collapse (both cytosolic and luminal) influences global Ca oscillations. Additionally, two reduced models of Ca signaling are derived that are valid when there is a separation of time scales between the stochastic gating of IP3Rs and the dynamics of domain Ca. These reduced whole cell models account for the influence of local Ca signaling on global Ca dynamics and are therefore more realistic than other conventional deterministic whole cell models.;In cardiac myocytes, Ca influx through voltage gated channels causes the release of intracellular Ca, a process known as Ca-induced Ca release (CICR). In Chapter 3 a probability density approach to CICR is derived from advection-reaction equations relating the time-dependent probability density of subsarcolemmal subspace and junctional sarcoplasmic reticulum [Ca] conditioned on Ca release unit state. When these equations are coupled to ordinary differential equations for the bulk myoplasmic and sarcoplasmic reticulum [Ca], a realistic but minimal whole cell model is produced. Modeling Ca release unit activity using this probability density approach avoids the computationally demanding task of resolving spatial aspects of global Ca signaling, while accurately representing heterogeneous local Ca signals in a population of diadic subspaces and junctional sarcoplasmic reticulum domains. The probability density approach is validated and benchmarked for computational efficiency by comparison to traditional Monte Carlo simulations. However, a probability density calculation can be significantly faster than the corresponding Monte Carlo simulation, especially when cellular parameters are such that univariate rather than multivariate probability densities may be employed.;Expanding upon the computational advantages of the probability density approach, a moment closure technique is introduced in Chapter 4 which facilitates whole cell modeling of cardiac myocytes when the dynamics of subspace [Ca] are much faster than those of junctional SR [Ca]. The method begins with the derivation of a system of ODEs describing the time-evolution of the moments of the univariate probability density functions for junctional SR [Ca] jointly distributed with CaRU state. This open system of ODEs is then closed using an algebraic relationship that expresses the third moment of junctional SR [Ca] in terms of the first and second moments. Benchmark simulations indicate that the moment closure approach is nearly 10,000-times more computationally efficient than corresponding Monte Carlo simulations while leading to nearly identical results

Observation of enhanced optical spring damping in a macroscopic mechanical resonator and application for parametric instability control in advanced gravitational-wave detectors

We show that optical spring damping in an optomechanical resonator can be enhanced by injecting a phase delay in the laser frequency-locking servo to rotate the real and imaginary components of the optical spring constant. This enhances damping at the expense of optical rigidity. We demonstrate enhanced parametric damping which reduces the Q factor of a 0.1-kg-scale resonator from 1.3×10^5 to 6.5×10^3. By using this technique adequate optical spring damping can be obtained to damp parametric instability predicted for advanced laser interferometer gravitational-wave detectors

Strategies for Agile Leadership in a Challenging Environment

The post pandemic environment has provided many significant challenges for all forms of organisations. The requirement for good leadership in this context is vital. This research considers the features of such leadership and how their application can affect organisations and their required outputs. The need for agility in this sphere is proposed, in order to accommodate the environmental challenges, globally and within the different sectors. There should be an emphasis on creativity in order to provide solutions to the many issues for organisations in the prevailing environment. Recruitment and retention are viewed as critical activities for sustaining these entities by ensuring the supply of the requisite standard of personnel at all levels. The latter should have suitable qualifications or the aptitude to acquire them. These staff should be given appropriate training then empowered, including being given the scope to utilise their own leadership style, as appropriate. The form of the post pandemic environment and its effects on leadership are noted. The principal factors identified here include the economic challenges, hybrid working patterns and the use of agency staff to supplement the permanent resource. The proactive development of leaders is emphasised as a critical activity for organisations, enabling them to address the issues prevalent in their environment. Research into this area occurred, using qualitative techniques. A literature review and interview with a current practitioner were performed, in order to glean the data for an inductive analysis. A template to assist organisations in creating a strategy for ‘Agile Leadership’ was then formulated.How to cite this article: Blair, G., Barratt, S., & Pagano, R., (2023). Strategies for Agile Leadership in a Challenging Environment. GS Spark: Journal of Applied Academic Discourse. 1(1), 55-66. https://doi.org/10.5281/zenodo.837211

Isotopic composition of Murchison organic compounds: Intramolecular carbon isotope fractionation of acetic acid. Simulation studies of cosmochemical organic syntheses

Recently, in our laboratories, samples of Murchison acetic acid were decarboxylated successfully and the carbon isotopic composition was measured for the methane released by this procedure. These analyses showed significant differences in C-13/C-12 ratios for the methyl and carboxyl carbons of the acetic acid molecule, strongly suggesting that more than one carbon source may be involved in the synthesis of the Murchison organic compounds. On the basis of this finding, laboratory model systems simulating cosmochemical synthesis are being studied, especially those processes capable of involving two or more starting carbon sources

Reconstruction of Fundamental SUSY Parameters

We summarize methods and expected accuracies in determining the basic low-energy SUSY parameters from experiments at future e$^+$e$^-$ linear colliders in the TeV energy range, combined with results from LHC. In a second step we demonstrate how, based on this set of parameters, the fundamental supersymmetric theory can be reconstructed at high scales near the grand unification or Planck scale. These analyses have been carried out for minimal supergravity [confronted with GMSB for comparison], and for a string effective theory.Comment: 8 pages, latex, 7 figures, expanded version of contributions to the proceedings of ICHEP.2002 (Amstersdam) and LCWS.2002 (Jeju Island