Building cross-scale models of epigenetic mechanisms

Epigenetic changes correspond to heritable modifications of the chromosome structure, which do not involve alteration of the DNA sequence but do affect gene expression. These mechanisms play an important role in normal cell differentiation, but aberration is associated also with several diseases, including cancer and neural disorders. In consequence, despite intensive studies in recent years, the contribution of modifications remains largely unquantified due to overall system complexity and insufficient data. Computational models can provide powerful auxiliary tools to experimentation, not least as scales from the sub-cellular through cell populations (or to networks of genes) can be spanned. In this paper, the challenges to development, of realistic cross-scale models, are discussed and illustrated with respect to current work.

Multi-parametric hydrogels support 3D in vitro bioengineered microenvironment models of tumour angiogenesis

Tumour microenvironment greatly influences the development and metastasis of cancer progression. The development of three dimensional (3D) culture models which mimic that displayed in vivo can improve cancer biology studies and accelerate novel anticancer drug screening. Inspired by a systems biology approach, we have formed 3D in vitro bioengineered tumour angiogenesis microenvironments within a glycosaminoglycan-based hydrogel culture system. This microenvironment model can routinely recreate breast and prostate tumour vascularisation. The multiple cell types cultured within this model were less sensitive to chemotherapy when compared with two dimensional (2D) cultures, and displayed comparative tumour regression to that displayed in vivo. These features highlight the use of our in vitro culture model as a complementary testing platform in conjunction with animal models, addressing key reduction and replacement goals of the future. We anticipate that this biomimetic model will provide a platform for the in-depth analysis of cancer development and the discovery of novel therapeutic targets.

Environmental conditions are important for establishing and evaluating pre-clinical models of GVHD

GVHD remains the major complication of allo-HSCT. Murine models are the primary system used to understand GVHD, and to develop potential therapies. Several factors are critical for GVHD in these models; including histo- compatibility, conditioning regimen, and T-cell number. We serendipitously found that environmental factors such as the caging system and bedding also significantly impact the kinetics of GVHD in these models. This is important because such factors may influence the experimental conditions required to cause GVHD and how mice respond to various treatments. Consequently, this is likely to alter interpretation of results between research groups, and the perceived effectiveness of experimental therapies.

Emergency department models of care in the context of care quality and cost: A systematic review

To identify current ED models of care and their impact on care quality, care effectiveness, and cost. A systematic search of key health databases (Medline, CINAHL, Cochrane, EMbase) was conducted to identify literature on ED models of care. Additionally, a focused review of the contents of 11 international and national emergency medicine, nursing and health economic journals (published between 2010 and 2013) was undertaken with snowball identification of references of the most recent and relevant papers. Articles published between 1998 and 2013 in the English language were included for initial review by three of the authors. Studies in underdeveloped countries and not addressing the objectives of the present study were excluded. Relevant details were extracted from the retrieved literature, and analysed for relevance and impact. The literature was synthesised around the study's main themes. Models described within the literature mainly focused on addressing issues at the input, throughput or output stages of ED care delivery. Models often varied to account for site specific characteristics (e.g. onsite inpatient units) or to suit staffing profiles (e.g. extended scope physiotherapist), ED geographical location (e.g. metropolitan or rural site), and patient demographic profile (e.g. paediatrics, older persons, ethnicity). Only a few studies conducted cost-effectiveness analysis of service models. Although various models of delivering emergency healthcare exist, further research is required in order to make accurate and reliable assessments of their safety, clinical effectiveness and cost-effectiveness.

Applying metaethical and normative claims of moral relativism to (shareholder and stakeholder) models of corporate governance

There has, in recent decades, been considerable scholarship regarding the moral aspects of corporate governance,and differences in corporate governance practices around the world have been widely documented and investigated. In such a context, the claims associated with moral relativism are relevant. The purpose of this paper is to provide a detailed consideration of how the metaethical and normative claims of moral relativism in particular can be applied to corporate governance. This objective is achieved, firstly, by reviewing what is meant by metaethical moral relativism and identifying two ways in which the metaethical claim can be assessed. The possibility of a single, morally superior model of corporate governance is subsequently considered through an analysis of prominent works justifying the shareholder and stakeholder approaches, together with a consideration of academic agreement in this area. The paper then draws on the work of Wong (Moral relativity, University of California Press, Berkeley, CA, 1984, A companion to ethics, Blackwell, Malden, 1993, Natural moralities: A defense of pluralistic relativism,Oxford University Press, Oxford, 2006), firstly in providing an argument supporting metaethical moral relativism and secondly regarding values of tolerance and/or accommodation that can contribute to the normative claim. The paper concludes by proposing an argument that it is morally wrong to impose a model of corporate governance where there are differences in moral judgements relevant to corporate governance, or to interfere with a model in similar circumstances, and closes with consideration of the argument’s implications.

Neurodevelopmental animal models of schizophrenia: Effects on prepulse inhibition

Epidemiological studies have shown increased incidence of schizophrenia in patients subjected to different forms of pre- or perinatal stress. However, as the onset of schizophrenic illness does not usually occur until adolescence or early adulthood, it is not yet fully understood how disruption of early brain development may ultimately lead to malfunction years later. In order to elucidate a possible role for neurodevelopmental factors in the pathogenesis of schizophrenia and to highlight potential new treatments, animal models are needed. Prepulse inhibition (PPI) is a model of sensorimotor gating mechanisms in the brain. It is disrupted in schizophrenia patients and the disruption can be reversed with atypical antipsychotics. It has been widely used in animal studies to explore central mechanisms possibly involved in schizophrenia. There has been a recent surge of behavioural and neurochemical animal studies on neurodevelopmental models, particularly on the effects of postweaning isolation, maternal separation and neonatal lesions of the hippocampus. In these models, long lasting alterations in behaviour and/or molecular changes in specific brain regions are observed, comparable to those seen in schizophrenia. The aim of this article is to critically review the available literature on such neurodevelopmental animal models with special focus on the effects on PPI and brain regions that are putatively involved in regulation of PPI.

Scoping study into wound management nurse practitioner models of practice

Objectives The primary objective of this research was to investigate wound management nurse practitioner (WMNP) models of service for the purposes of identifying parameters of practice and how patient outcomes are measured. Methods A scoping study was conducted with all authorised WMNPs in Australia from October to December 2012 using survey methodology. A questionnaire was developed to obtain data on the role and practice parameters of authorised WMNPs in Australia. The tool comprised seven sections and included a total of 59 questions. The questionnaire was distributed to all members of the WMNP Online Peer Review Group, to which it was anticipated the majority of WMNPs belonged. Results Twenty-one WMNPs responded (response rate 87%), with the results based on a subset of respondents who stated that, at the time of the questionnaire, they were employed as a WMNP, therefore yielding a response rate of 71% (n≤15). Most respondents (93%; n≤14) were employed in the public sector, with an average of 64 occasions of service per month. The typical length of a new case consultation was 60min, with 32min for follow ups. The most frequently performed activity was wound photography (83%; n≤12), patient, family or carer education (75%; n≤12), Doppler ankle-brachial pressure index assessment (58%; n≤12), conservative sharp wound debridement (58%; n≤12) and counselling (50%; n≤12). The most routinely prescribed medications were local anaesthetics (25%; n≤12) and oral antibiotics (25%; n≤12). Data were routinely collected by 91% of respondents on service-related and wound-related parameters to monitor patient outcomes, to justify and improve health services provided. Conclusion This study yielded important baseline information on this professional group, including data on patient problems managed, the types of interventions implemented, the resources used to accomplish outcomes and how outcomes are measured.

Effects of biodiesel chemical composition on the chemical and physical properties of the primary and secondary diesel particulate matter

This thesis improves our insight towards the effects of using biodiesels on the particulate matter emission of diesel engines and contributes to our understanding of their potential adverse health effects. The novelty of this project is the use of biodiesel fuel with controlled chemical composition that enables us to relate changes of physiochemical properties of particles to specific properties of the biodiesel. For the first time, the possibility of a correlation of the volatility and the Reactive Oxygen Species concentration of the particles is investigated versus the saturation, oxygen content and carbon chain length of the fuel.

Endogenous and exogenous effects in self-exciting process models of terrorist activity

A model based on the cluster process representation of the self-exciting process model in White and Porter 2013 and Ruggeri and Soyer 2008is derived to allow for variation in the excitation effects for terrorist events in a self-exciting or cluster process model. The details of the model derivation and implementation are given and applied to data from the Global Terrorism Database from 2000–2012. Results are discussed in terms of practical interpretation along with implications for a theoretical model paralleling existing criminological theory.

Study of surface evolution in the wheel-rail interface

This paper aims to trace surface evolution in the wheel-rail interface using data obtained from a twin-disc testing machine and the surface replication technique. Changes in the surface profile of the rail testing disc are explicitly analysed according to the wear mechanism, which helps elaborate a better understanding of the attrition of asperities during the wearing-in process of surface modification. The surface profile amplitude was seen to decrease during the initial running-in phase of the experiment cycle, and after reaching a saturation value, the profile amplitude then increased. Ultimately the results show that grinding will roughen the rail surface and the wheel-rail contact conditions will then remove this surface damage to some saturation value of the profile height. The variation in the rail surface profile beyond this point is then only dependant on the contact conditions which exist between the wheel and rail during normal operation.

Fractional diffusion models of cardiac electrical propagation: Role of structural heterogeneity in dispersion of repolarization

Impulse propagation in biological tissues is known to be modulated by structural heterogeneity. In cardiac muscle, improved understanding on how this heterogeneity influences electrical spread is key to advancing our interpretation of dispersion of repolarization. We propose fractional diffusion models as a novel mathematical description of structurally heterogeneous excitable media, as a means of representing the modulation of the total electric field by the secondary electrical sources associated with tissue inhomogeneities. Our results, analysed against in vivo human recordings and experimental data of different animal species, indicate that structural heterogeneity underlies relevant characteristics of cardiac electrical propagation at tissue level. These include conduction effects on action potential (AP) morphology, the shortening of AP duration along the activation pathway and the progressive modulation by premature beats of spatial patterns of dispersion of repolarization. The proposed approach may also have important implications in other research fields involving excitable complex media.

Mixture models of nucleotide sequence evolution that account for heterogeneity in the substitution process across sites and across lineages

Molecular phylogenetic studies of homologous sequences of nucleotides often assume that the underlying evolutionary process was globally stationary, reversible, and homogeneous (SRH), and that a model of evolution with one or more site-specific and time-reversible rate matrices (e.g., the GTR rate matrix) is enough to accurately model the evolution of data over the whole tree. However, an increasing body of data suggests that evolution under these conditions is an exception, rather than the norm. To address this issue, several non-SRH models of molecular evolution have been proposed, but they either ignore heterogeneity in the substitution process across sites (HAS) or assume it can be modeled accurately using the distribution. As an alternative to these models of evolution, we introduce a family of mixture models that approximate HAS without the assumption of an underlying predefined statistical distribution. This family of mixture models is combined with non-SRH models of evolution that account for heterogeneity in the substitution process across lineages (HAL). We also present two algorithms for searching model space and identifying an optimal model of evolution that is less likely to over- or underparameterize the data. The performance of the two new algorithms was evaluated using alignments of nucleotides with 10 000 sites simulated under complex non-SRH conditions on a 25-tipped tree. The algorithms were found to be very successful, identifying the correct HAL model with a 75% success rate (the average success rate for assigning rate matrices to the tree's 48 edges was 99.25%) and, for the correct HAL model, identifying the correct HAS model with a 98% success rate. Finally, parameter estimates obtained under the correct HAL-HAS model were found to be accurate and precise. The merits of our new algorithms were illustrated with an analysis of 42 337 second codon sites extracted from a concatenation of 106 alignments of orthologous genes encoded by the nuclear genomes of Saccharomyces cerevisiae, S. paradoxus, S. mikatae, S. kudriavzevii, S. castellii, S. kluyveri, S. bayanus, and Candida albicans. Our results show that second codon sites in the ancestral genome of these species contained 49.1% invariable sites, 39.6% variable sites belonging to one rate category (V1), and 11.3% variable sites belonging to a second rate category (V2). The ancestral nucleotide content was found to differ markedly across these three sets of sites, and the evolutionary processes operating at the variable sites were found to be non-SRH and best modeled by a combination of eight edge-specific rate matrices (four for V1 and four for V2). The number of substitutions per site at the variable sites also differed markedly, with sites belonging to V1 evolving slower than those belonging to V2 along the lineages separating the seven species of Saccharomyces. Finally, sites belonging to V1 appeared to have ceased evolving along the lineages separating S. cerevisiae, S. paradoxus, S. mikatae, S. kudriavzevii, and S. bayanus, implying that they might have become so selectively constrained that they could be considered invariable sites in these species.

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.

Optimal management of the critically Ill: Anaesthesia, monitoring, data capture, and point-of-care technological practices in ovine models of critical care

Animal models of critical illness are vital in biomedical research. They provide possibilities for the investigation of pathophysiological processes that may not otherwise be possible in humans. In order to be clinically applicable, the model should simulate the critical care situation realistically, including anaesthesia, monitoring, sampling, utilising appropriate personnel skill mix, and therapeutic interventions. There are limited data documenting the constitution of ideal technologically advanced large animal critical care practices and all the processes of the animal model. In this paper, we describe the procedure of animal preparation, anaesthesia induction and maintenance, physiologic monitoring, data capture, point-of-care technology, and animal aftercare that has been successfully used to study several novel ovine models of critical illness. The relevant investigations are on respiratory failure due to smoke inhalation, transfusion related acute lung injury, endotoxin-induced proteogenomic alterations, haemorrhagic shock, septic shock, brain death, cerebral microcirculation, and artificial heart studies. We have demonstrated the functionality of monitoring practices during anaesthesia required to provide a platform for undertaking systematic investigations in complex ovine models of critical illness.

A novel near-infrared spectroscopy and chemometrics method for rapid analysis of several chemical components and antioxidant activity of mint (mentha haplocalyx briq.) samples

A novel near-infrared spectroscopy (NIRS) method has been researched and developed for the simultaneous analyses of the chemical components and associated properties of mint (Mentha haplocalyx Briq.) tea samples. The common analytes were: total polysaccharide content, total flavonoid content, total phenolic content, and total antioxidant activity. To resolve the NIRS data matrix for such analyses, least squares support vector machines was found to be the best chemometrics method for prediction, although it was closely followed by the radial basis function/partial least squares model. Interestingly, the commonly used partial least squares was unsatisfactory in this case. Additionally, principal component analysis and hierarchical cluster analysis were able to distinguish the mint samples according to their four geographical provinces of origin, and this was further facilitated with the use of the chemometrics classification methods-K-nearest neighbors, linear discriminant analysis, and partial least squares discriminant analysis. In general, given the potential savings with sampling and analysis time as well as with the costs of special analytical reagents required for the standard individual methods, NIRS offered a very attractive alternative for the simultaneous analysis of mint samples.