Evaluation of stochastic effects on biomolecular networks using the generalised Nyquist stability criterion

Abstract—Stochastic differential equations are now commonly used to model biomolecular networks in systems biology, and much recent research has been devoted to the development of methods to analyse their stability properties. Stability analysis of such systems may be performed using the Laplace transform, which requires the calculation of the exponential matrix involving time symbolically. However, the calculation of the symbolic exponential matrix is not feasible for problems of even moderate size, as the required computation time increases exponentially with the matrix order. To address this issue, we present a novel method for approximating the Laplace transform which does not require the exponential matrix to be calculated explicitly. The calculation time associated with the proposed method does not increase exponentially with the size of the system, and the approximation error is shown to be of the same order as existing methods. Using this approximation method, we show how a straightforward application of the generalized Nyquist stability criterion provides necessary and sufficient conditions for the stability of stochastic biomolecular networks. The usefulness and computational efficiency of the proposed method is illustrated through its application to the problem of analysing a model for limit-cycle oscillations in cAMP during aggregation of Dictyostelium cells

Robustness analysis of magnetic torquer controlled spacecraft attitude dynamics

This paper describes a systematic approach to the robustness analysis of linear periodically time-varying (LPTV) systems. The method uses the technique known as Lifting to transform the original time-varying uncertain system into linear fractional transformation (LFT) form. The stability and performance robustness of the system to structured parametric uncertainty can then be analysed non-conservatively using the structured singular value μ. The method is applied to analyse the stability robustness of an attitude control law for a spacecraft controlled by magnetic torquer bars, whose linearised dynamics can naturally be written in linear periodically time-varying form. The proposed method allows maximum allowable levels of uncertainty, as well as worst-case uncertainty combinations to be computed. The destabilising effect of these uncertain parameter combinations is verified in time-domain simulations

Thick film silicon growth techniques

Thick film silicon ribbons were produced by means of the edge-defined, film-fed growth (EFG) technique. EFG is a process by which single crystals may be grown having a shape controlled by the outside dimensions of a die, the growth taking place from an extremely thin film of liquid fed by capillary action from a crucible below. The principal problem to be overcome in the application of this process to the growth of thick film silicon ribbon relates to the material, such as the shaping die. For the method to operate, this die material must be wet by the liquid silicon. To preserve semiconductor quality, the liquid silicon must not react significantly with the die material. The most promising die material for this application appears to be SiC and SiC-SiO2 admixture. In this case good wetting occurs between the molten silicon and the SiC. C is a relatively unharmful contaminant of Si and additions of quartz to SiC are found to decrease the extent of reaction

Thick silicon growth techniques

Hall mobility measurements on a number of single crystal silicon ribbons grown from graphite dies have shown some ribbons to have mobilities consistent with their resistivities. The behavior of other ribbons appears to be explained by the introduction of impurities of the opposite sign. Growth of a small single crystal silicon ribbon has been achieved from a beryllia dia. Residual internal stresses of the order of 7 to 18,000 psi have been determined to exist in some silicon ribbon, particularly those grown at rates in excess of 1 in./min. Growth experiments have continued toward definition of a configuration and parameters to provide a reasonable yield of single crystal ribbons. High vacuum outgassing of graphite dies and evacuation and backfilling of growth chambers have provided significant improvements in surface quality of ribbons grown from graphite dies

Toroidal Vortices in Resistive Magnetohydrodynamic Equilibria

Resistive steady states in toroidal magnetohydrodynamics (MHD), where Ohm's law must be taken into account, differ considerably from ideal ones. Only for special (and probably unphysical) resistivity profiles can the Lorentz force, in the static force-balance equation, be expressed as the gradient of a scalar and thus cancel the gradient of a scalar pressure. In general, the Lorentz force has a curl directed so as to generate toroidal vorticity. Here, we calculate, for a collisional, highly viscous magnetofluid, the flows that are required for an axisymmetric toroidal steady state, assuming uniform scalar resistivity and viscosity. The flows originate from paired toroidal vortices (in what might be called a ``double smoke ring'' configuration), and are thought likely to be ubiquitous in the interior of toroidally driven magnetofluids of this type. The existence of such vortices is conjectured to characterize magnetofluids beyond the high-viscosity limit in which they are readily calculable.Comment: 17 pages, 4 figure

Least-squares methods for identifying biochemical regulatory networks from noisy measurements

<b>Background</b>: We consider the problem of identifying the dynamic interactions in biochemical networks from noisy experimental data. Typically, approaches for solving this problem make use of an estimation algorithm such as the well-known linear Least-Squares (LS) estimation technique. We demonstrate that when time-series measurements are corrupted by white noise and/or drift noise, more accurate and reliable identification of network interactions can be achieved by employing an estimation algorithm known as Constrained Total Least Squares (CTLS). The Total Least Squares (TLS) technique is a generalised least squares method to solve an overdetermined set of equations whose coefficients are noisy. The CTLS is a natural extension of TLS to the case where the noise components of the coefficients are correlated, as is usually the case with time-series measurements of concentrations and expression profiles in gene networks. <b>Results</b>: The superior performance of the CTLS method in identifying network interactions is demonstrated on three examples: a genetic network containing four genes, a network describing p53 activity and <i>mdm2</i> messenger RNA interactions, and a recently proposed kinetic model for interleukin (IL)-6 and (IL)-12b messenger RNA expression as a function of ATF3 and NF-κB promoter binding. For the first example, the CTLS significantly reduces the errors in the estimation of the Jacobian for the gene network. For the second, the CTLS reduces the errors from the measurements that are corrupted by white noise and the effect of neglected kinetics. For the third, it allows the correct identification, from noisy data, of the negative regulation of (IL)-6 and (IL)-12b by ATF3. <b>Conclusion</b>: The significant improvements in performance demonstrated by the CTLS method under the wide range of conditions tested here, including different levels and types of measurement noise and different numbers of data points, suggests that its application will enable more accurate and reliable identification and modelling of biochemical networks

An overview of current pharmacy impact on immunisation: A global report

The role of pharmacists in immunisation and vaccination varies across the world; in some countries pharmacists are primarily involved in ensuring the safe supply and dispensing of vaccines, as well as advocating for immunisation, while in other countries they are empowered to play a more active role, as they are legally authorised to administer vaccinations, manage patients’ vaccination schedules and/or organise vaccinations activities and campaigns. It is estimated that ten million lives per year could be saved by increasing access to medicines and vaccinations. Community pharmacists are therefore in a strong position to provide a major contribution to public health due to their accessibility, distribution and available medicines expertise. Pharmacists are also highly trusted healthcare professionals and can therefore significantly improve communication channels and provide public reassurance on product quality. We conducted a survey, disseminated to 137 FIP member organisations, to gather a better understanding of the current role of pharmacists in immunisation across the world and the impact of these activities. We also provide here a closer look at the immunisation activities undertaken in eleven different countries and territories presented as case studies. Vaccination policies vary across the world; the legal authority to perform immunisation activities currently varies significantly across countries and the integration of community pharmacies and pharmacists in national vaccination policies tends to develop as a gradual process over time. Strategic and integrated partnerships between healthcare professionals are increasingly common and the role of pharmacists as educators, facilitators and immunisers is becoming more readily recognised. Several countries authorise vaccination in pharmacies and/or by pharmacists (for example in Argentina, Australia, Philippines, South Africa, UK and USA); this practice has been initiated, in the majority of the cases, with pharmacy-based vaccinations against influenza and then expanded to include other vaccines from the immunisation schedule. In most cases, it is associated with specific requirements such as pharmacist training, management of vaccination records and specifications on premises, equipment and waste management. Based on the sample of countries presented in this report, 940 million people live in countries where over 193,000 community-pharmacies can potentially offer access to vaccination services. In this sample alone, we further estimate that currently, pharmacist-administered vaccination services have the potential to reach a total global population of 655 million. These estimates are based on our sample of 45 countries and territories; the potential in health gain to have pharmacy-led outreach to global populations is clear and this report suggests that community-based pharmacies are safe and high quality vaccination centres. Providing direct administration of vaccines, using pharmacists and pharmacies, is a highly effective public health strategy for health systems and healthcare planners, complementing the existing service offerings for immunisation. Pharmacists are trusted healthcare professionals and as such can offer strong advocacy for building societal trust in vaccines as essential medicines. Added to this is the pharmacy-based opportunity for promoting immunisation in communities linked with the easy access to vaccination that community pharmacies bring and the outreach opportunities for healthcare planners. On the technical side, and highly significant, is the medicines expertise embedded in the vaccination supply chain and storage of cold-chain products; the safety and quality assurance that society demands of vaccines also has significant input from pharmacists. Pharmacists offer convenience, product safety, advocacy support and an overall highly impactful contribution to the public health challenges of immunisation and vaccination policies. The continuing trend to authorise pharmacists to provide direct access to immunisation allows policy makers to ensure additional resilience for national public health systems. Unexpected outbreaks of preventable communicable disease (from influenza to events such as H1N1) will happen again, somewhere, at some time, and pharmacists should be considered as invaluable contributors, together with our healthcare professional colleagues, in the delivery, access and administration of vaccines also during emergencies

Global Pharmacy Workforce Intelligence: Trends Report 2015

The aspiration of many countries towards establishing universal health coverage will require an enhanced health workforce, including pharmacists that can meet the need for pharmaceutical expertise in the population it serves. It is important to monitor trends in the workforce over time. The countries identified as having data for each of the time points 2006, 2009 and 2012 were present in all WHO regions, with Europe having the most countries with data available and South East Asia the fewest. All WHO regions have experienced an increase in the density of pharmacists (measured as number of pharmacists per 10,000 population) over the period 2006–12. However, some countries indicate a reduction in the density of pharmacists. African countries show large relative increases in acceleration of capacity building, but remain significantly behind in terms of absolute capacity per capita. South East Asian and Middle Eastern countries also show large proportional changes in pharmacist workforce. The global trend is an increase in workforce across all nations and regions, and this is a move in the right direction towards improved access to, and availability of, pharmaceutical expertise. However, there is still much to be done, with some regions and low-income countries still displaying a disproportionately low number of pharmacists on small overall capacity for delivering pharmacy services

Advanced Practice and Specialisation in Pharmacy: Global Report 2015

This report is the most comprehensive collection of data and evidence that relates to practitioner advancement of practice and policy, and maps out a wide range of national initiatives worldwide. This report should be viewed as a first attempt to map out global trends and will stimulate further reportage and analysis as engagement in this practice continues to progress

Validation of a model of regulation in the tryptophan operon against multiple experiment data using global optimisation

This paper is concerned with validating a mathematical model of regulation in the tryptophan operon using global optimization. Although a number of models for this biochemical network are proposed, in many cases only qualitative agreement between the model output and experimental data was demonstrated, since very little information is currently available to guide the selection of parameter values for the models. This paper presents a model validating method using both multiple experimental data and global optimization