Stochastic chemical kinetics and the quasi-steady-state assumption : application to the stochastic simulation algorithm and chemical master equation

Recently the application of the quasi-steady-state approximation (QSSA) to the stochastic simulation algorithm (SSA) was suggested for the purpose of speeding up stochastic simulations of chemical systems that involve both relatively fast and slow chemical reactions [Rao and Arkin, J. Chem. Phys. 118, 4999 (2003)] and further work has led to the nested and slow-scale SSA. Improved numerical efficiency is obtained by respecting the vastly different time scales characterizing the system and then by advancing only the slow reactions exactly, based on a suitable approximation to the fast reactions. We considerably extend these works by applying the QSSA to numerical methods for the direct solution of the chemical master equation (CME) and, in particular, to the finite state projection algorithm [Munsky and Khammash, J. Chem. Phys. 124, 044104 (2006)], in conjunction with Krylov methods. In addition, we point out some important connections to the literature on the (deterministic) total QSSA (tQSSA) and place the stochastic analogue of the QSSA within the more general framework of aggregation of Markov processes. We demonstrate the new methods on four examples: Michaelis–Menten enzyme kinetics, double phosphorylation, the Goldbeter–Koshland switch, and the mitogen activated protein kinase cascade. Overall, we report dramatic improvements by applying the tQSSA to the CME solver.

A Krylov-based finite state projection algorithm for solving the chemical master equation arising in the discrete modelling of biological systems

Biochemical reactions underlying genetic regulation are often modelled as a continuous-time, discrete-state, Markov process, and the evolution of the associated probability density is described by the so-called chemical master equation (CME). However the CME is typically difficult to solve, since the state-space involved can be very large or even countably infinite. Recently a finite state projection method (FSP) that truncates the state-space was suggested and shown to be effective in an example of a model of the Pap-pili epigenetic switch. However in this example, both the model and the final time at which the solution was computed, were relatively small. Presented here is a Krylov FSP algorithm based on a combination of state-space truncation and inexact matrix-vector product routines. This allows larger-scale models to be studied and solutions for larger final times to be computed in a realistic execution time. Additionally the new method computes the solution at intermediate times at virtually no extra cost, since it is derived from Krylov-type methods for computing matrix exponentials. For the purpose of comparison the new algorithm is applied to the model of the Pap-pili epigenetic switch, where the original FSP was first demonstrated. Also the method is applied to a more sophisticated model of regulated transcription. Numerical results indicate that the new approach is significantly faster and extendable to larger biological models.

Charting the system : the integrated master schedule as a multi-level and poly-temporal boundary object in complex projects

This paper investigates the use of visual artifacts to represent a complex adaptive system (CAS). The integrated master schedule (IMS) is one of those visuals widely used in complex projects for scheduling, budgeting, and project management. In this paper, we discuss how the IMS outperforms the traditional timelines and acts as a ‘multi-level and poly-temporal boundary object’ that visually represents the CAS. We report the findings of a case study project on the way the IMS mapped interactions, interdependencies, constraints and fractal patterns in a complex project. Finally, we discuss how the IMS was utilised as a complex boundary object by eliciting commitment and development of shared mental models, and facilitating negotiation through the layers of multiple interpretations from stakeholders.

High-resolution DNA melt curve analysis of the clustered, regularly interspaced short-palindromic-repeat locus of Campylobacter jejuni

A novel method for genotyping the clustered, regularly interspaced short-palindromic-repeat (CRISPR) locus of Campylobacter jejuni is described. Following real-time PCR, CRISPR products were subjected to high-resolution melt (HRM) analysis, a new technology that allows precise melt profile determination of amplicons. This investigation shows that the CRISPR HRM assay provides a powerful addition to existing C. jejuni genotyping methods and emphasizes the potential of HRM for genotyping short sequence repeats in other species

Secondary curve behavior in Lenke Type 1C adolescent idiopathic scoliosis after thoracoscopic selective anterior thoracic fusion

Study Design. Analysis of a case series of 24 Lenke 1C adolescent idiopathic scoliosis (AIS) patients receiving selective thoracoscopic anterior scoliosis correction. Objective. To report the behaviour of the compensatory lumbar curve in a group of Lenke IC AIS patients following thoracoscopic anterior scoliosis correction, and to compare the results of this study with previously published data. Summary of Background Data. Several prior studies have reported spontaneous lumbar curve correction for both anterior and posterior selective fusion in Lenke 1C/King-Moe II patients; however to our knowledge no previous studies have reported outcomes of thoracoscopic anterior correction for this curve type. Methods. All AIS patients with a curve classification of Lenke 1C and a minimum of 24 months follow-up were retrieved from a consecutive series of 190 AIS patients who underwent thoracoscopic anterior instrumented fusion. Cobb angles of the major curve, instrumented levels, compensatory lumbar curve, and T5-T12 kyphosis were recorded, as well as coronal spinal balance, T1 tilt angle and shoulder balance. All radiographic parameters were measured before surgery and at 2, 6, 12 and 24 months after surgery. Results. Twenty-four female patients with right thoracic curves had a mean thoracic Cobb angle of 53.0° before surgery, decreasing to 24.9° two years after surgery. The mean lumbar compensatory Cobb angle was 43.5° before surgery, spontaneously correcting to 25.4° two years after surgery, indicating balance between the thoracic and lumbar scoliotic curves. The lumbar correction achieved (41.8%) compares favourably to previous studies. Conclusions. Selective thoracoscopic anterior fusion allows spontaneous lumbar curve correction and achieves coronal balance of main thoracic and compensatory lumbar curves, good cosmesis and patient satisfaction. Correction and balance are maintained 24 months after surgery.

CT and X-Ray analysis of sagittal curve changes following thoracoscopic anterior scoliosis surgery

Normal thoracic kyphosis Cobb angle for T5-T12 is most commonly reported as a range of 20-40º [1]. Patients with adolescent idiopathic scoliosis (AIS) exhibit a reduced thoracic kyphosis or hypokyphosis [2] accompanying the coronal and rotary distortion components. As a result, surgical restoration of the thoracic kyphosis while maintaining lumbar lordosis and overall sagittal balance is a critical aspect of achieving good clinical outcomes in AIS patients. Previous studies report an increase in thoracic kyphosis after anterior surgical approaches [3] and a flattening of sagittal contours following posterior approaches [4]. Difficulties with measuring sagittal parameters on radiographs are avoided with reformatted sagittal CT reconstructions due to the superior endplate clarity afforded by this imaging modality and are the subject of analysis in this study.

Temporal boundary objects in megaprojects : mapping the system with the integrated master schedule

Recently, a stream of project management research has recognized the critical role of boundary objects in the organization of projects. In this paper, we investigate how one advanced scheduling tool, the Integrated Master Schedule (IMS), is used as a temporal boundary object at various stages of complex projects. The IMS is critical to megaprojects which typically span long periods of time and face a high degree of complexity and uncertainty. In this paper, we conceptualize projects of this type as complex adaptive systems (CAS). We report the findings of four case projects on how the IMS mapped interactions, interdependencies, constraints, and fractal patterns of these emerging projects, and how the process of IMS visualization enabled communication and negotiation of project realities. This paper highlights that this advanced timeline tool acts as a boundary object and elicits shared understanding of complex projects from their stakeholders.

Vitronectin – master controller or micromanager?

The concept of the cellular glycoprotein vitronectin acts as a biological ‘glue’ and key controller of mammalian tissue repair and remodelling activity is emerging from nearly 50 years of experimental in vitro and in vivo data. Unexpectedly, the vitronectin-knock-out mouse was found to be viable and to have largely normal phenotype. However, diligent observation revealed that the VN-KO animal exhibits delayed coagulation and poor wound healing. This is interpreted to indicate that vitronectin occupies a role in the earliest events of thrombogenesis and tissue repair. That role is as a foundation upon which the thrombus grows in an organised structure. In addition to closing the wound, the thrombus also serves to protect the underlying tissue from oxidation, is a reservoir of mitogens and tissue repair mediators and provides a provisional scaffold for the repairing tissue. In the absence of vitronectin (e.g. VN-KO animal) this cascade is disrupted before it begins. Our data demonstrates that a wide variety of biologically active species associate with VN. While initial studies were focused on mitogens, other classes of bioactives (e.g. glycosaminoglycans, metalloproteinases) are now also known to specifically interact with VN. Many of these interactions are long-lived, often resulting in multi-protein complexes, while others are stable for prolonged periods. Multiprotein complexes provide several advantages: prolonging molecular interaction; sustaining local concentrations, facilitating co-stimulation of cell surface receptors and thereby enhancing cellular / biological responses. We contend that these, or equivalent, multi-protein complexes mediate vitronectin functionality in vivo. It is also likely that many of the species demonstrated to associate with vitronectin in vitro, also associate with vitronectin in vivo in similar multi-protein complexes. Thus the predominant biological function of vitronectin is that of a master controller of the extracellular environment; informing, and possibly instructing cells ‘where’ to behave, ‘when’ to behave, and ‘how’ to behave (i.e. appropriately for the current circumstance).

Studios for the masses : can student colaboration replace the master-apprentice relationship in design instruction?

This action research project investigated the use of a collaborative learning approach for addressing issues associated with teaching urban design to large, diverse cohorts. As a case study, I observed two semesters of an urban design unit that I revised between 2011 and 2012 to incorporate collaborative learning activities. Data include instructional materials, participant observations, peer-reviews of collaborative learning activities, feedback from students and instructors and student projects. Themes that emerged through qualitative analysis include the challenge of removing inequalities inherent in the diverse cohort, the challenge of unifying project guidance and marking criteria, and the challenge of providing project guidance for a very large cohort. Most notably, the study revealed a need to clarify learning objectives relating to design principles in order to fully transition to and benefit from a collaborative learning model.

Sintering and densification mechanisms of Y2BaCuO5 pellets

The sintering and densification of Y2BaCuO5 (Y-211) pellets made from powders with different characteristics have been investigated in the temperature range 1000-1140°C. A pellet made from powder containing Ba-rich secondary phases shows very early liquid-assisted sintering and densification and clear evidence of exaggerated grain growth. The melting of BaCuO2 and YBa2Cu3O7-δ (Y-123) secondary phases increases the rate of densification of Y-211 pellets made from other powders at temperatures above 1025-1030°C. All the liquid produced by the melting of the latter phases recrystallizes as intergranular layers of Y-123. These intergranular layers account for the darker appearance and for measurable electrical conductivities at room temperature of the pellets sintered at the higher temperatures. The development of exaggerated grain growth within a uniform fine-grained matrix opens the possibility of using controlled secondary recrystallization to obtain large single domains of Y-211, provided that the trapping of porosity can be avoided or minimized. © 1999 Elsevier Science S.A.

Keep ahead of the workforce development curve through the establishment of standardised training for rail incident investigators

The Australasian rail industry lacks a consistently accepted standard of minimal training necessary to perform rail incident investigations. Current Australasian courses do not offer the breadth of development required for a comprehensive career pathway in incident investigation (Biggs, Banks & Dovan, 2012; Short, Kains & Harris, 2010).

New suburbs in the making? Locating master planned estates in a comparative analysis of suburbs in South-East Queensland

In urban scholarship Master Planned Estates (MPEs) are viewed as illustrative of broader changes to the urban environment and characterised as homogenous, affluent enclaves where community life is largely orchestrated by the developer. Yet no study has fully considered if, and to what extent, MPEs can be distinguished from other suburb types in terms of their residential composition and their levels of sociability and community attachment. In this article, we empirically test if MPEs are different from ‘conventional’ suburbs by examining them structurally in terms of their demographic and socio-economic characteristics, as well as in terms of their key community social processes. Using data from a 2008 study of 148 suburbs across Brisbane, Australia (which includes data from two MPEs), we undertake a comparative analysis of suburbs and examine the density of neighbour networks, residents' reports of place attachment and cohesion and neighbourly contact in MPEs compared to other residential suburbs. Our findings suggest that MPEs are not distinct in terms of their degree of homogeneity and socio-economic characteristics, but that connections among residents are lower than other suburbs despite—or perhaps because of—the active interventions of the developer.

Certified pseudonyms colligated with master secret key

A pseudonym provides anonymity by protecting the identity of a legitimate user. A user with a pseudonym can interact with an unknown entity and be confident that his/her identity is secret even if the other entity is dishonest. In this work, we present a system that allows users to create pseudonyms from a trusted master public-secret key pair. The proposed system is based on the intractability of factoring and finding square roots of a quadratic residue modulo a composite number, where the composite number is a product of two large primes. Our proposal is different from previously published pseudonym systems, as in addition to standard notion of protecting privacy of an user, our system offers colligation between seemingly independent pseudonyms. This new property when combined with a trusted platform that stores a master secret key is extremely beneficial to an user as it offers a convenient way to generate a large number of pseudonyms using relatively small storage.