Efficient simulation of stochastic chemical kinetics with the Stochastic Bulirsch-Stoer extrapolation method

Background Biochemical systems with relatively low numbers of components must be simulated stochastically in order to capture their inherent noise. Although there has recently been considerable work on discrete stochastic solvers, there is still a need for numerical methods that are both fast and accurate. The Bulirsch-Stoer method is an established method for solving ordinary differential equations that possesses both of these qualities. Results In this paper, we present the Stochastic Bulirsch-Stoer method, a new numerical method for simulating discrete chemical reaction systems, inspired by its deterministic counterpart. It is able to achieve an excellent efficiency due to the fact that it is based on an approach with high deterministic order, allowing for larger stepsizes and leading to fast simulations. We compare it to the Euler τ-leap, as well as two more recent τ-leap methods, on a number of example problems, and find that as well as being very accurate, our method is the most robust, in terms of efficiency, of all the methods considered in this paper. The problems it is most suited for are those with increased populations that would be too slow to simulate using Gillespie’s stochastic simulation algorithm. For such problems, it is likely to achieve higher weak order in the moments. Conclusions The Stochastic Bulirsch-Stoer method is a novel stochastic solver that can be used for fast and accurate simulations. Crucially, compared to other similar methods, it better retains its high accuracy when the timesteps are increased. Thus the Stochastic Bulirsch-Stoer method is both computationally efficient and robust. These are key properties for any stochastic numerical method, as they must typically run many thousands of simulations.

Stochastic dynamics of interacting haematopoietic stem cell niche lineages

Since we still know very little about stem cells in their natural environment, it is useful to explore their dynamics through modelling and simulation, as well as experimentally. Most models of stem cell systems are based on deterministic differential equations that ignore the natural heterogeneity of stem cell populations. This is not appropriate at the level of individual cells and niches, when randomness is more likely to affect dynamics. In this paper, we introduce a fast stochastic method for simulating a metapopulation of stem cell niche lineages, that is, many sub-populations that together form a heterogeneous metapopulation, over time. By selecting the common limiting timestep, our method ensures that the entire metapopulation is simulated synchronously. This is important, as it allows us to introduce interactions between separate niche lineages, which would otherwise be impossible. We expand our method to enable the coupling of many lineages into niche groups, where differentiated cells are pooled within each niche group. Using this method, we explore the dynamics of the haematopoietic system from a demand control system perspective. We find that coupling together niche lineages allows the organism to regulate blood cell numbers as closely as possible to the homeostatic optimum. Furthermore, coupled lineages respond better than uncoupled ones to random perturbations, here the loss of some myeloid cells. This could imply that it is advantageous for an organism to connect together its niche lineages into groups. Our results suggest that a potential fruitful empirical direction will be to understand how stem cell descendants communicate with the niche and how cancer may arise as a result of a failure of such communication.

Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Characteristics of on-road driving by persons with central vision loss: Learning to drive with a bioptic telescope

There is limited research on the driving performance and safety of bioptic drivers and even less regarding the driving skills that are most challenging for those learning to drive with bioptic telescopes. This research consisted of case studies of five trainee bioptic drivers whose driving skills were compared with those of a group of licensed bioptic drivers (n = 23) while they drove along city, suburban, and controlled-access highways in an instrumented dual-brake vehicle. A certified driver rehabilitation specialist was positioned in the front passenger seat to monitor safety and two backseat evaluators independently rated driving using a standardized scoring system. Other aspects of performance were assessed through vehicle instrumentation and video recordings. Results demonstrate that while sign recognition, lane keeping, steering steadiness, gap judgments and speed choices were significantly worse in trainees, some driving behaviors and skills, including pedestrian detection and traffic light recognition were not significantly different to those of the licensed drivers. These data provide useful insights into the skill challenges encountered by a small sample of trainee bioptic drivers which, while not generalizable because of the small sample size, provide valuable insights beyond that of previous studies and can be used as a basis to guide training strategies.

Exact solutions of coupled multispecies linear reaction–diffusion equations on a uniformly growing domain

Embryonic development involves diffusion and proliferation of cells, as well as diffusion and reaction of molecules, within growing tissues. Mathematical models of these processes often involve reaction–diffusion equations on growing domains that have been primarily studied using approximate numerical solutions. Recently, we have shown how to obtain an exact solution to a single, uncoupled, linear reaction–diffusion equation on a growing domain, 0 < x < L(t), where L(t) is the domain length. The present work is an extension of our previous study, and we illustrate how to solve a system of coupled reaction–diffusion equations on a growing domain. This system of equations can be used to study the spatial and temporal distributions of different generations of cells within a population that diffuses and proliferates within a growing tissue. The exact solution is obtained by applying an uncoupling transformation, and the uncoupled equations are solved separately before applying the inverse uncoupling transformation to give the coupled solution. We present several example calculations to illustrate different types of behaviour. The first example calculation corresponds to a situation where the initially–confined population diffuses sufficiently slowly that it is unable to reach the moving boundary at x = L(t). In contrast, the second example calculation corresponds to a situation where the initially–confined population is able to overcome the domain growth and reach the moving boundary at x = L(t). In its basic format, the uncoupling transformation at first appears to be restricted to deal only with the case where each generation of cells has a distinct proliferation rate. However, we also demonstrate how the uncoupling transformation can be used when each generation has the same proliferation rate by evaluating the exact solutions as an appropriate limit.

Survival probability for a diffusive process on a growing domain

We consider the motion of a diffusive population on a growing domain, 0 < x < L(t ), which is motivated by various applications in developmental biology. Individuals in the diffusing population, which could represent molecules or cells in a developmental scenario, undergo two different kinds of motion: (i) undirected movement, characterized by a diffusion coefficient, D, and (ii) directed movement, associated with the underlying domain growth. For a general class of problems with a reflecting boundary at x = 0, and an absorbing boundary at x = L(t ), we provide an exact solution to the partial differential equation describing the evolution of the population density function, C(x,t ). Using this solution, we derive an exact expression for the survival probability, S(t ), and an accurate approximation for the long-time limit, S = limt→∞ S(t ). Unlike traditional analyses on a nongrowing domain, where S ≡ 0, we show that domain growth leads to a very different situation where S can be positive. The theoretical tools developed and validated in this study allow us to distinguish between situations where the diffusive population reaches the moving boundary at x = L(t ) from other situations where the diffusive population never reaches the moving boundary at x = L(t ). Making this distinction is relevant to certain applications in developmental biology, such as the development of the enteric nervous system (ENS). All theoretical predictions are verified by implementing a discrete stochastic model.

Genome-wide mapping of cystitis due to Streptococcus agalactiae and Escherichia coli in mice identifies a unique bladder transcriptome that signifies pathogen-specific antimicrobial defense against urinary tract infection

The most common causes of urinary tract infections (UTIs) are Gram-negative pathogens such as Escherichia coli; however, Gram-positive organisms including Streptococcus agalactiae, or group B streptococcus (GBS), also cause UTI. In GBS infection, UTI progresses to cystitis once the bacteria colonize bladder, but the host responses triggered in the bladder immediately following infection are largely unknown. Here, we used genome-wide expression profiling to map the bladder transcriptome of GBS UTI in mice infected transurethrally with uropathogenic GBS that was cultured from a 35 year-old women with cystitis. RNA from bladders was applied to Affymetrix Gene-1.0ST microarrays; qRT-PCR was used to analyze selected gene responses identified in array datasets. A surprisingly small significant gene list of 172 genes was identified at 24h; this compared to 2507 genes identified in a side-by-side comparison with uropathogenic E. coli (UPEC). No genes exhibited significantly altered expression at 2h in GBS-infected mice according to arrays despite high bladder bacterial loads at this early time point. The absence of a marked early host response to GBS juxtaposed with broad-based bladder responses activated by UPEC at 2h. Bioinformatics analyses including integrative systems-level network mapping revealed multiple activated biological pathways in the GBS cystitis transcriptome that regulate leukocyte activation, inflammation, apoptosis, and cytokine-chemokine biosynthesis. These findings define a novel, minimalistic type of bladder host response triggered by GBS UTI, which comprises collective antimicrobial pathways that differ dramatically from those activated by UPEC. Overall, this study emphasizes the unique nature of bladder immune activation mechanisms triggered by distinct uropathogens.

Freedom ride... I have a dream

A play in two parts on the subject of racism. Part One presents the story of the Montgomery bus boycott arising from the refusal of Rosa Parkes to give up her seat on a bus and leading to the rise of Martin Luther King, Jr. Part Two is set in contemporary Australia, in the household of a group of young people who re-create the sixties' Freedom Ride in order to heal the spirit of Auntie, an Aboriginal woman, who is the centre of their world.

A flexible hierarchical approach for facial age estimation based on multiple features

Age estimation from facial images is increasingly receiving attention to solve age-based access control, age-adaptive targeted marketing, amongst other applications. Since even humans can be induced in error due to the complex biological processes involved, finding a robust method remains a research challenge today. In this paper, we propose a new framework for the integration of Active Appearance Models (AAM), Local Binary Patterns (LBP), Gabor wavelets (GW) and Local Phase Quantization (LPQ) in order to obtain a highly discriminative feature representation which is able to model shape, appearance, wrinkles and skin spots. In addition, this paper proposes a novel flexible hierarchical age estimation approach consisting of a multi-class Support Vector Machine (SVM) to classify a subject into an age group followed by a Support Vector Regression (SVR) to estimate a specific age. The errors that may happen in the classification step, caused by the hard boundaries between age classes, are compensated in the specific age estimation by a flexible overlapping of the age ranges. The performance of the proposed approach was evaluated on FG-NET Aging and MORPH Album 2 datasets and a mean absolute error (MAE) of 4.50 and 5.86 years was achieved respectively. The robustness of the proposed approach was also evaluated on a merge of both datasets and a MAE of 5.20 years was achieved. Furthermore, we have also compared the age estimation made by humans with the proposed approach and it has shown that the machine outperforms humans. The proposed approach is competitive with current state-of-the-art and it provides an additional robustness to blur, lighting and expression variance brought about by the local phase features.

Complexity of collaborative work in residential aged care facilities: An analysis of information exchange for medication management

Information exchange (IE) is a critical component of the complex collaborative medication process in residential aged care facilities (RACFs). Designing information and communication technology (ICT) to support complex processes requires a profound understanding of the IE that underpins their execution. There is little existing research that investigates the complexity of IE in RACFs and its impact on ICT design. The aim of this study was thus to undertake an in-depth exploration of the IE process involved in medication management to identify its implications for the design of ICT. The study was undertaken at a large metropolitan facility in NSW, Australia. A total of three focus groups, eleven interviews and two observation sessions were conducted between July to August 2010. Process modelling was undertaken by translating the qualitative data via in-depth iterative inductive analysis. The findings highlight the complexity and collaborative nature of IE in RACF medication management. These models emphasize the need to: a) deal with temporal complexity; b) rely on an interdependent set of coordinative artefacts; and c) use synchronous communication channels for coordination. Taken together these are crucial aspects of the IE process in RACF medication management that need to be catered for when designing ICT in this critical area. This study provides important new evidence of the advantages of viewing process as a part of a system rather than as segregated tasks as a means of identifying the latent requirements for ICT design and that is able to support complex collaborative processes like medication management in RACFs. © 2012 IEEE.

Worldwide outdoor round robin study of organic photovoltaic devices and modules

Accurate characterization and reporting of organic photovoltaic (OPV) device performance remains one of the important challenges in the field. The large spread among the efficiencies of devices with the same structure reported by different groups is significantly caused by different procedures and equipment used during testing. The presented article addresses this issue by offering a new method of device testing using “suitcase sample” approach combined with outdoor testing that limits the diversity of the equipment, and a strict measurement protocol. A round robin outdoor characterization of roll-to-roll coated OPV cells and modules conducted among 46 laboratories worldwide is presented, where the samples and the testing equipment were integrated in a compact suitcase that served both as a sample transportation tool and as a holder and test equipment during testing. In addition, an internet based coordination was used via plasticphotovoltaics.org that allowed fast and efficient communication among participants and provided a controlled reporting format for the results that eased the analysis of the data. The reported deviations among the laboratories were limited to 5% when compared to the Si reference device integrated in the suitcase and were up to 8% when calculated using the local irradiance data. Therefore, this method offers a fast, cheap and efficient tool for sample sharing and testing that allows conducting outdoor measurements of OPV devices in a reproducible manner.

Proteomic identification of putative microRNA394 target genes in Arabidopsis thaliana identifies MLP family members critical for normal development

Expression of the F-Box protein Leaf Curling Responsiveness (LCR) is regulated by microRNA, miR394, and alterations to this interplay in Arabidopsis thaliana produce defects in leaf polarity and shoot apical meristem (SAM) organisation. Although the miR394-LCR node has been documented in Arabidopsis, the identification of proteins targeted by LCR F-box itself has proven problematic. Here, a proteomic analysis of shoot apices from plants with altered LCR levels identified a member of the Major Latex Protein (MLP) family gene as a potential LCR F-box target. Bioinformatic and molecular analyses also suggested that other MLP family members are likely to be targets for this post-translational regulation. Direct interaction between LCR F-Box and MLP423 was validated. Additional MLP members had reduction in protein accumulation, in varying degrees, mediated by LCR F-Box. Transgenic Arabidopsis lines, in which MLP28 expression was reduced through an artificial miRNA technology, displayed severe developmental defects, including changes in leaf patterning and morphology, shoot apex defects, and eventual premature death. These phenotypic characteristics resemble those of Arabidopsis plants modified to over-express LCR. Taken together, the results demonstrate that MLPs are driven to degradation by LCR, and indicate that MLP gene family is target of miR394-LCR regulatory node, representing potential targets for directly post-translational regulation mediated by LCR F-Box. In addition, MLP28 family member is associated with the LCR regulation that is critical for normal Arabidopsis development.