On a resampling approach for tests on the number of clusters with mixture model-based clustering of tissue samples

We consider the problem of assessing the number of clusters in a limited number of tissue samples containing gene expressions for possibly several thousands of genes. It is proposed to use a normal mixture model-based approach to the clustering of the tissue samples. One advantage of this approach is that the question on the number of clusters in the data can be formulated in terms of a test on the smallest number of components in the mixture model compatible with the data. This test can be carried out on the basis of the likelihood ratio test statistic, using resampling to assess its null distribution. The effectiveness of this approach is demonstrated on simulated data and on some microarray datasets, as considered previously in the bioinformatics literature. (C) 2004 Elsevier Inc. All rights reserved.

Potential yield and water-use effficiency benefits in sorghum from limited maximum transpiration rate

Limitations on maximum transpiration rates, which are commonly observed as midday stomatal closure, have been observed even under well-watered conditions. Such limitations may be caused by restricted hydraulic conductance in the plant or by limited supply of water to the plant from uptake by the roots. This behaviour would have the consequences of limiting photosynthetic rate, increasing transpiration efficiency, and conserving soil water. A key question is whether the conservation of water will be rewarded by sustained growth during seed fill and increased grain yield. This simulation analysis was undertaken to examine consequences on sorghum yield over several years when maximum transpiration rate was imposed in a model. Yields were simulated at four locations in the sorghum-growing area of Australia for 115 seasons at each location. Mean yield was increased slightly ( 5 - 7%) by setting maximum transpiration rate at 0.4 mm h(-1). However, the yield increase was mainly in the dry, low-yielding years in which growers may be more economically vulnerable. In years with yield less than similar to 450 g m(-2), the maximum transpiration rate trait resulted in yield increases of 9 - 13%. At higher yield levels, decreased yields were simulated. The yield responses to restricted maximum transpiration rate were associated with an increase in efficiency of water use. This arose because transpiration was reduced at times of the day when atmospheric demand was greatest. Depending on the risk attitude of growers, incorporation of a maximum transpiration rate trait in sorghum cultivars could be desirable to increase yields in dry years and improve water use efficiency and crop yield stability.

Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease

We have previously shown that complement factor 5a(C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(D-Cha) WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(D-Cha) WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(D-Cha) WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(D-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03 - 10 mg/kg/ day p.o.) in the 8-day rat TNBS- colitis model, against the comparator drug AcF-[OP(D-Cha) WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(D-Cha) WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP( D-Cha) WR], equiactive in vitro to AcF-[OP(D-Cha) WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(D-Cha) WR]. However, in the rat TNBS- colitis model, HC-[OP(D-Cha) WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30- fold lower oral doses than AcF-[OP( D-Cha) WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(D-Cha) WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(D-Cha) WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.

A simulation model of cereal-legume intercropping systems for semi-arid regions I. Model development

Cereal-legume intercropping plays an important role in subsistence food production in developing countries, especially in situations of limited water resources. Crop simulation can be used to assess risk for intercrop productivity over time and space. In this study, a simple model for intercropping was developed for cereal and legume growth and yield, under semi-arid conditions. The model is based on radiation interception and use, and incorporates a water stress factor. Total dry matter and yield are functions of photosynthetically active radiation (PAR), the fraction of radiation intercepted and radiation use efficiency (RUE). One of two PAR sub-models was used to estimate PAR from solar radiation; either PAR is 50% of solar radiation or the ratio of PAR to solar radiation (PAR/SR) is a function of the clearness index (K-T). The fraction of radiation intercepted was calculated either based on Beer's Law with crop extinction coefficients (K) from field experiments or from previous reports. RUE was calculated as a function of available soil water to a depth of 900 mm (ASW). Either the soil water balance method or the decay curve approach was used to determine ASW. Thus, two alternatives for each of three factors, i.e., PAR/SR, K and ASW, were considered, giving eight possible models (2 methods x 3 factors). The model calibration and validation were carried out with maize-bean intercropping systems using data collected in a semi-arid region (Bloemfontein, Free State, South Africa) during seven growing seasons (1996/1997-2002/2003). The combination of PAR estimated from the clearness index, a crop extinction coefficient from the field experiment and the decay curve model gave the most reasonable and acceptable result. The intercrop model developed in this study is simple, so this modelling approach can be employed to develop other cereal-legume intercrop models for semi-arid regions. (c) 2004 Elsevier B.V. All rights reserved.

Modelling of two-stage anaerobic digestion using the IWA Anaerobic Digestion Model No. 1 (ADM1)

The aim of the study presented was to implement a process model to simulate the dynamic behaviour of a pilot-scale process for anaerobic two-stage digestion of sewage sludge. The model implemented was initiated to support experimental investigations of the anaerobic two-stage digestion process. The model concept implemented in the simulation software package MATLAB(TM)/Simulink(R) is a derivative of the IWA Anaerobic Digestion Model No.1 (ADM1) that has been developed by the IWA task group for mathematical modelling of anaerobic processes. In the present study the original model concept has been adapted and applied to replicate a two-stage digestion process. Testing procedures, including balance checks and 'benchmarking' tests were carried out to verify the accuracy of the implementation. These combined measures ensured a faultless model implementation without numerical inconsistencies. Parameters for both, the thermophilic and the mesophilic process stage, have been estimated successfully using data from lab-scale experiments described in literature. Due to the high number of parameters in the structured model, it was necessary to develop a customised procedure that limited the range of parameters to be estimated. The accuracy of the optimised parameter sets has been assessed against experimental data from pilot-scale experiments. Under these conditions, the model predicted reasonably well the dynamic behaviour of a two-stage digestion process in pilot scale. (C) 2004 Elsevier Ltd. All rights reserved.

Stability and cycles in a cobweb model with heterogeneous expectations

We investigate the dynamics of a cobweb model with heterogeneous beliefs, generalizing the example of Brock and Hommes (1997). We examine situations where the agents form expectations by using either rational expectations, or a type of adaptive expectations with limited memory defined from the last two prices. We specify conditions that generate cycles. These conditions depend on a set of factors that includes the intensity of switching between beliefs and the adaption parameter. We show that both Flip bifurcation and Neimark-Sacker bifurcation can occur as primary bifurcation when the steady state is unstable.

Pig eye trabeculectomy - a wet-lab teaching model

Purpose A teaching model for trabeculectomy is described using pig eyes prepared in formalin. Method The model enables trainee surgeons to practice various aspects of tissue handling required for successful trabeculectomy including the construction of a fornix-based conjunctival flap, scleral flap with buried releasable sutures, and water-tight conjunctival closure. Results Exposure to the necessary skills required to perform trabeculectomy surgery can be improved by the use of wet laboratory practice. Conclusions Trabeculectomy surgery experience is becoming more limited as fewer procedures are being performed due to the efficacy of recent medications. Wet laboratories will become an increasingly important aspect of a comprehensive ophthalmology training programme.

An illustration of variable precision rough sets model:an analysis of the findings of the UK Monopolies and Mergers Commission

This paper introduces a new technique in the investigation of limited-dependent variable models. This paper illustrates that variable precision rough set theory (VPRS), allied with the use of a modern method of classification, or discretisation of data, can out-perform the more standard approaches that are employed in economics, such as a probit model. These approaches and certain inductive decision tree methods are compared (through a Monte Carlo simulation approach) in the analysis of the decisions reached by the UK Monopolies and Mergers Committee. We show that, particularly in small samples, the VPRS model can improve on more traditional models, both in-sample, and particularly in out-of-sample prediction. A similar improvement in out-of-sample prediction over the decision tree methods is also shown.

Seeing light vs dark lines: psychophysical performance is based on separate channels, limited by noise and uncertainty

Visual detection performance (d') is usually an accelerating function of stimulus contrast, which could imply a smooth, threshold-like nonlinearity in the sensory response. Alternatively, Pelli (1985 Journal of the Optical Society of America A 2 1508 - 1532) developed the 'uncertainty model' in which responses were linear with contrast, but the observer was uncertain about which of many noisy channels contained the signal. Such internal uncertainty effectively adds noise to weak signals, and predicts the nonlinear psychometric function. We re-examined these ideas by plotting psychometric functions (as z-scores) for two observers (SAW, PRM) with high precision. The task was to detect a single, vertical, blurred line at the fixation point, or identify its polarity (light vs dark). Detection of a known polarity was nearly linear for SAW but very nonlinear for PRM. Randomly interleaving light and dark trials reduced performance and rendered it non-linear for SAW, but had little effect for PRM. This occurred for both single-interval and 2AFC procedures. The whole pattern of results was well predicted by our Monte Carlo simulation of Pelli's model, with only two free parameters. SAW (highly practised) had very low uncertainty. PRM (with little prior practice) had much greater uncertainty, resulting in lower contrast sensitivity, nonlinear performance, and no effect of external (polarity) uncertainty. For SAW, identification was about v2 better than detection, implying statistically independent channels for stimuli of opposite polarity, rather than an opponent (light - dark) channel. These findings strongly suggest that noise and uncertainty, rather than sensory nonlinearity, limit visual detection.

Fast algorithms for automatic mapping with space-limited covariance functions

In this paper we discuss a fast Bayesian extension to kriging algorithms which has been used successfully for fast, automatic mapping in emergency conditions in the Spatial Interpolation Comparison 2004 (SIC2004) exercise. The application of kriging to automatic mapping raises several issues such as robustness, scalability, speed and parameter estimation. Various ad-hoc solutions have been proposed and used extensively but they lack a sound theoretical basis. In this paper we show how observations can be projected onto a representative subset of the data, without losing significant information. This allows the complexity of the algorithm to grow as O(n m 2), where n is the total number of observations and m is the size of the subset of the observations retained for prediction. The main contribution of this paper is to further extend this projective method through the application of space-limited covariance functions, which can be used as an alternative to the commonly used covariance models. In many real world applications the correlation between observations essentially vanishes beyond a certain separation distance. Thus it makes sense to use a covariance model that encompasses this belief since this leads to sparse covariance matrices for which optimised sparse matrix techniques can be used. In the presence of extreme values we show that space-limited covariance functions offer an additional benefit, they maintain the smoothness locally but at the same time lead to a more robust, and compact, global model. We show the performance of this technique coupled with the sparse extension to the kriging algorithm on synthetic data and outline a number of computational benefits such an approach brings. To test the relevance to automatic mapping we apply the method to the data used in a recent comparison of interpolation techniques (SIC2004) to map the levels of background ambient gamma radiation. © Springer-Verlag 2007.

Development of a co-culture model of the human lungs for toxicity testing and identification of biomarkers of inhalation toxicity

The airway epithelium is the first point of contact in the lung for inhaled material, including infectious pathogens and particulate matter, and protects against toxicity from these substances by trapping and clearance via the mucociliary escalator, presence of a protective barrier with tight junctions and initiation of a local inflammatory response. The inflammatory response involves recruitment of phagocytic cells to neutralise and remove and invading materials and is oftern modelled using rodents. However, development of valid in vitro airway epithelial models is of great importance due to the restrictions on animal studies for cosmetic compound testing implicit in the 7th amendment to the European Union Cosmetics Directive. Further, rodent innate immune responses have fundamental differences to human. Pulmonary endothelial cells and leukocytes are also involved in the innate response initiated during pulmonary inflammation. Co-culture models of the airways, in particular where epithelial cells are cultured at air liquid interface with the presence of tight junctions and differentiated mucociliary cells, offer a solution to this problem. Ideally validated models will allow for detection of early biomarkers of response to exposure and investigation into inflammatory response during exposure. This thesis describes the approaches taken towards developing an in vitro epithelial/endothelial cell model of the human airways and identification biomarkers of response to exposure to xenobiotics. The model comprised normal human primary microvascular endothelial cells and the bronchial epithelial cell line BEAS-2B or normal human bronchial epithelial cells. BEAS-2B were chosen as their characterisation at air liquid interface is limited but they are robust in culture, thereby predicted to provide a more reliable test system. Proteomics analysis was undertaken on challenged cells to investigate biomarkers of exposure. BEAS-2B morphology was characterised at air liquid interface compared with normal human bronchial epithelial cells. The results indicate that BEAS-2B cells at an air liquid interface form tight junctions as shown by expression of the tight junction protein zonula occludens-1. To this author’s knowledge this is the first time this result has been reported. The inflammatory response of BEAS-2B (measured as secretion of the inflammatory mediators interleukin-8 and -6) air liquid interface mono-cultures to Escherichia coli lipopolysaccharide or particulate matter (fine and ultrafine titanium dioxide) was comparable to published data for epithelial cells. Cells were also exposed to polymers of “commercial interest” which were in the nanoparticle range (and referred to particles hereafter). BEAS-2B mono-cultures showed an increased secretion of inflammatory mediators after challenge. Inclusion of microvascular endothelial cells resulted in protection against LPS- and particle- induced epithelial toxicity, measured as cell viability and inflammatory response, indicating the importance of co-cultures for investigations into toxicity. Two-dimensional proteomic analysis of lysates from particle-challenged cells failed to identify biomarkers of toxicity due to assay interference and experimental variability. Separately, decreased plasma concentrations of serine protease inhibitors, and the negative acute phase proteins transthyretin, histidine-rich glycoprotein and alpha2-HS glycoprotein were identified as potential biomarkers of methyl methacrylate/ethyl methacrylate/butylacrylate treatment in rats.

Unified model for performance analysis of IEEE 802.11 ad hoc networks in unsaturated conditions

IEEE 802.11 standard has achieved huge success in the past decade and is still under development to provide higher physical data rate and better quality of service (QoS). An important problem for the development and optimization of IEEE 802.11 networks is the modeling of the MAC layer channel access protocol. Although there are already many theoretic analysis for the 802.11 MAC protocol in the literature, most of the models focus on the saturated traffic and assume infinite buffer at the MAC layer. In this paper we develop a unified analytical model for IEEE 802.11 MAC protocol in ad hoc networks. The impacts of channel access parameters, traffic rate and buffer size at the MAC layer are modeled with the assistance of a generalized Markov chain and an M/G/1/K queue model. The performance of throughput, packet delivery delay and dropping probability can be achieved. Extensive simulations show the analytical model is highly accurate. From the analytical model it is shown that for practical buffer configuration (e.g. buffer size larger than one), we can maximize the total throughput and reduce the packet blocking probability (due to limited buffer size) and the average queuing delay to zero by effectively controlling the offered load. The average MAC layer service delay as well as its standard deviation, is also much lower than that in saturated conditions and has an upper bound. It is also observed that the optimal load is very close to the maximum achievable throughput regardless of the number of stations or buffer size. Moreover, the model is scalable for performance analysis of 802.11e in unsaturated conditions and 802.11 ad hoc networks with heterogenous traffic flows. © 2012 KSI.

A new DEA model for technology selection in the presence of ordinal data

This paper suggests a data envelopment analysis (DEA) model for selecting the most efficient alternative in advanced manufacturing technology in the presence of both cardinal and ordinal data. The paper explains the problem of using an iterative method for finding the most efficient alternative and proposes a new DEA model without the need of solving a series of LPs. A numerical example illustrates the model, and an application in technology selection with multi-inputs/multi-outputs shows the usefulness of the proposed approach. © 2012 Springer-Verlag London Limited.

Monocyte urokinase-type plasminogen activator up-regulation reduces thrombus size in a model of venous thrombosis

Background - Our previous studies showed that the direct injection of an adenovirus construct expressing urokinase-type plasminogen activator (uPA) into experimental venous thrombi significantly reduces thrombus weight. The systemic use of adenovirus vectors is limited by inherent hepatic tropism and inflammatory response. As macrophages are recruited into venous thrombi, it is reasonable to speculate that these cells could be used to target the adenovirus uPA (ad-uPA) gene construct to the thrombus. The aims of this study were to determine whether macrophages transduced with ad-uPA have increased fibrinolytic activity and whether systemic injection of transduced cells could be used to target uPA expression to the thrombus and reduce its size. Methods - The effect of up-regulating uPA was examined in an immortalized macrophage cell line (MM6) and macrophages differentiated from human blood monocyte-derived macrophages (HBMMs). Cells were infected with ad-uPA or blank control virus (ad-blank). Fibrinolytic mediator expression, cell viability, and cytokine expression were measured by activity assays and enzyme-linked immunosorbent assays. Monocyte migration was measured using a modified Boyden chamber assay. A model of venous thrombosis was developed and characterized in mice with severe combined immunodeficiency (SCID). This model was used to study whether systemically administered macrophages over-expressing uPA reduced thrombus size. Uptake of HBMMs into the thrombus induced in these mice was confirmed by a combination of PKH2-labeled cell tracking and colocalization with human leukocyte antigen (HLA) by immunohistology. Results - Compared with ad-blank, treated HBMMs transduction with ad-uPA increased uPA production by >1000-fold (P = .003), uPA activity by 150-fold (P = .0001), and soluble uPA receptor (uPAR) by almost twofold (P = .043). Expression of plasminogen activator inhibitor (PAI-1) and PAI-2 was decreased by about twofold (P = .011) and threefold (P = .005), respectively. Up-regulation of uPA had no effect on cell viability or inflammatory cytokine production compared with ad-blank or untreated cells. Ad-uPA transduction increased the migration rate of HBMMs (about 20%, P = .03) and MM6 cells (>twofold, P = .005) compared with ad-blank treated controls. Human macrophage recruitment into the mouse thrombus was confirmed by the colocalization of HLA with the PKH2-marked cells. Systemic injection of uPA-up-regulated HBMMs reduced thrombus weight by approximately 20% compared with ad-blank (P = .038) or sham-treated controls (P = .0028). Conclusion - Transduction of HBBM with ad-uPA increases their fibrinolytic activity. Systemic administration of uPA up-regulated HBBMs reduced thrombus size in an experimental model of venous thrombosis. Alternative methods of delivering fibrinolytic agents are worth exploring.

Managing enterprises and ERP systems:a contingency model for the enterprization of operations

Purpose: The purpose of this paper is to investigate enterprise resource planning (ERP) systems development and emerging practices in the management of enterprises (i.e. parts of companies working with parts of other companies to deliver a complex product and/or service) and identify any apparent correlations. Suitable a priori contingency frameworks are then used and extended to explain apparent correlations. Discussion is given to provide guidance for researchers and practitioners to deliver better strategic, structural and operational competitive advantage through this approach; coined here as the "enterprization of operations". Design/methodology/approach: Theoretical induction uses a new empirical longitudinal case study from Zoomlion (a Chinese manufacturing company) built using an adapted form of template analysis to produce a new contingency framework. Findings: Three main types of enterprises and the three main types of ERP systems are defined and correlations between them are explained. Two relevant a priori frameworks are used to induct a new contingency model to support the enterprization of operations; known as the dynamic enterprise reference grid for ERP (DERG-ERP). Research limitations/implications: The findings are based on one longitudinal case study. Further case studies are currently being conducted in the UK and China. Practical implications: The new contingency model, the DERG-ERP, serves as a guide for ERP vendors, information systems management and operations managers hoping to grow and sustain their competitive advantage with respect to effective enterprise strategy, enterprise structure and ERP systems. Originality/value: This research explains how ERP systems and the effective management of enterprises should develop in order to sustain competitive advantage with respect to enterprise strategy, enterprise structure and ERP systems use. © Emerald Group Publishing Limited.