Stromal upregulation of lateral epithelial adhesions : gene expression analysis of signalling pathways in prostate epithelium

BACKGROUND: Stromal signalling increases the lateral cell adhesions of prostate epithelial cells grown in 3D culture. The aim of this study was to use microarray analysis to identify significant epithelial signalling pathways and genes in this process. METHODS: Microarray analysis was used to identify genes that were differentially expressed when epithelial cells were grown in 3D Matrigel culture with stromal co-culture compared to without stroma. Two culture models were employed: primary epithelial cells (ten samples) and an epithelial cell line (three experiments). A separate microarray analysis was performed on each model system and then compared to identify tissue-relevant genes in a cell line model. RESULTS: TGF beta signalling was significantly ranked for both model systems and in both models the TGF beta signalling gene SOX4 was significantly down regulated. Analysis of all differentially expressed genes to identify genes that were common to both models found several morphology related gene clusters; actin binding (DIAPH2, FHOD3, ABLIM1, TMOD4, MYH10), GTPase activator activity (BCR, MYH10), cytoskeleton (MAP2, MYH10, TMOD4, FHOD3), protein binding (ITGA6, CD44), proteinaceous extracellular matrix (NID2, CILP2), ion channel/ ion transporter activity (CACNA1C, CACNB2, KCNH2, SLC8A1, SLC39A9) and genes associated with developmental pathways (POFUT1, FZD2, HOXA5, IRX2, FGF11, SOX4, SMARCC1). CONCLUSIONS: In 3D prostate cultures, stromal cells increase lateral epithelial cell adhesions. We show that this morphological effect is associated with gene expression changes to TGF beta signalling, cytoskeleton and anion activity.

mCOPA: analysis of heterogeneous features in cancer expression data

Background Cancer outlier profile analysis (COPA) has proven to be an effective approach to analyzing cancer expression data, leading to the discovery of the TMPRSS2 and ETS family gene fusion events in prostate cancer. However, the original COPA algorithm did not identify down-regulated outliers, and the currently available R package implementing the method is similarly restricted to the analysis of over-expressed outliers. Here we present a modified outlier detection method, mCOPA, which contains refinements to the outlier-detection algorithm, identifies both over- and under-expressed outliers, is freely available, and can be applied to any expression dataset. Results We compare our method to other feature-selection approaches, and demonstrate that mCOPA frequently selects more-informative features than do differential expression or variance-based feature selection approaches, and is able to recover observed clinical subtypes more consistently. We demonstrate the application of mCOPA to prostate cancer expression data, and explore the use of outliers in clustering, pathway analysis, and the identification of tumour suppressors. We analyse the under-expressed outliers to identify known and novel prostate cancer tumour suppressor genes, validating these against data in Oncomine and the Cancer Gene Index. We also demonstrate how a combination of outlier analysis and pathway analysis can identify molecular mechanisms disrupted in individual tumours. Conclusions We demonstrate that mCOPA offers advantages, compared to differential expression or variance, in selecting outlier features, and that the features so selected are better able to assign samples to clinically annotated subtypes. Further, we show that the biology explored by outlier analysis differs from that uncovered in differential expression or variance analysis. mCOPA is an important new tool for the exploration of cancer datasets and the discovery of new cancer subtypes, and can be combined with pathway and functional analysis approaches to discover mechanisms underpinning heterogeneity in cancers

Pulse dynamics in a three-component system : existence analysis

In this article, we analyze the three-component reaction-diffusion system originally developed by Schenk et al. (PRL 78:3781–3784, 1997). The system consists of bistable activator-inhibitor equations with an additional inhibitor that diffuses more rapidly than the standard inhibitor (or recovery variable). It has been used by several authors as a prototype three-component system that generates rich pulse dynamics and interactions, and this richness is the main motivation for the analysis we present. We demonstrate the existence of stationary one-pulse and two-pulse solutions, and travelling one-pulse solutions, on the real line, and we determine the parameter regimes in which they exist. Also, for one-pulse solutions, we analyze various bifurcations, including the saddle-node bifurcation in which they are created, as well as the bifurcation from a stationary to a travelling pulse, which we show can be either subcritical or supercritical. For two-pulse solutions, we show that the third component is essential, since the reduced bistable two-component system does not support them. We also analyze the saddle-node bifurcation in which two-pulse solutions are created. The analytical method used to construct all of these pulse solutions is geometric singular perturbation theory, which allows us to show that these solutions lie in the transverse intersections of invariant manifolds in the phase space of the associated six-dimensional travelling wave system. Finally, as we illustrate with numerical simulations, these solutions form the backbone of the rich pulse dynamics this system exhibits, including pulse replication, pulse annihilation, breathing pulses, and pulse scattering, among others.

Impact fees and new housing cost: A comparative analysis of the empirical models

Developers and policy makers are consistently at odds over the debate as to whether impact fees increase house prices. This debate continues despite the extensive body of theoretical and empirical international literature that discusses the passing on to home buyers of impact fees, and the corresponding increase to housing prices. In attempting to quantify this impact, over a dozen empirical studies have been carried out in the US and Canada since the 1980’s. However the methodologies used vary greatly, as do the results. Despite similar infrastructure funding policies in numerous developed countries, no such empirical works exist outside of the US/Canada. The purpose of this research is to analyse the existing econometric models in order to identify, compare and contrast the theoretical bases, methodologies, key assumptions and findings of each. This research will assist in identifying if further model development is required and/or whether any of these models have external validity and are readily transferable outside of the US. The findings conclude that there is very little explicit rationale behind the various model selections and that significant model deficiencies appear still to exist.

A novel DRD2 single-nucleotide polymorphism associated with schizophrenia predicts age of onset : HapMap tag-single-nucleotide polymorphism analysis

Background: Dopamine D2 receptor (DRD2) is thought to be critical in regulating the dopaminergic pathway in the brain which is known to be important in the aetiology of schizophrenia. It is therefore not surprising that most antipsychotic medication acts on the Dopamine D2 receptor. DRD2 is widely expressed in brain, levels are reduced in brains of schizophrenia patients and DRD2 polymorphisms have been associated with reduced brain expression. We have previously identified a genetic variant in DRD2, rs6277 to be strongly implicated in schizophrenia susceptibility. Methods: To identity new associations in the DRD2 gene with disease status and clinical severity, we genotyped seven single nucleotide polymorphisms (SNPs) in DRD2 using a multiplex mass spectrometry method. SNPs were chosen using a haplotype block-based gene-tagging approach so the entire DRD2 gene was represented. Results: One polymorphism rs2734839 was found to be significantly associated with schizophrenia as well as late onset age. Individuals carrying the genetic variation were more than twice as likely to have schizophrenia compared to controls. Conclusions: Our results suggest that DRD2 genetic variation is a good indicator for schizophrenia risk and may also be used as a predictor age of onset.

Model development and dynamic load-sharing analysis of longitudinal-connected air suspensions

The objective of this research was to investigate the effect of suspension parameters on dynamic load-sharing of longitudinal-connected air suspensions of a tri-axle semi-trailer. A novel nonlinear model of a multi-axle semi-trailer with longitudinal-connected air suspension was formulated based on fluid mechanics and thermodynamics and was validated through test results. The effects of suspension parameters on dynamic load-sharing and road-friendliness of the semi-trailer were analyzed. Simulation results indicate that the road-friendliness metric DLC (Dynamic Load Coefficient), is generally in accordance with the load-sharing metric - DLSC (Dynamic Load Sharing Coefficient). When the static height or static pressure increases, the DLSC optimization ratio declines monotonically. The effect of employing larger air lines and connectors on the DLSC optimization ratio gives varying results as road roughness increases and as driving speed increases. The results also indicate that if the air line diameter is always assumed to be larger than the connector diameter, the influence of air line diameter on load-sharing is more significant than that of the connector.

Analysis of Object-Specific Authorization Protocol (OSAP) using coloured Petri nets

The use of Trusted Platform Module (TPM) is be- coming increasingly popular in many security sys- tems. To access objects protected by TPM (such as cryptographic keys), several cryptographic proto- cols, such as the Object Specific Authorization Pro- tocol (OSAP), can be used. Given the sensitivity and the importance of those objects protected by TPM, the security of this protocol is vital. Formal meth- ods allow a precise and complete analysis of crypto- graphic protocols such that their security properties can be asserted with high assurance. Unfortunately, formal verification of these protocols are limited, de- spite the abundance of formal tools that one can use. In this paper, we demonstrate the use of Coloured Petri Nets (CPN) - a type of formal technique, to formally model the OSAP. Using this model, we then verify the authentication property of this protocol us- ing the state space analysis technique. The results of analysis demonstrates that as reported by Chen and Ryan the authentication property of OSAP can be violated.

Geographical inquiry in Australian schools : a retrospective analysis

This paper explores the occurrence of geographical inquiry in the Australian curriculum since Geography became a high school subject in 1911. In this historical overview, I reflect upon my own experiences of undertaking geographical inquiry during the 1970’s and 1980’s. Primary school geographical inquiry experiences can be virtually non-existent despite being advocated in syllabus documents. High school geographical inquiry experiences do exist in some classrooms, but that geographic drive is also necessary to complete a meaningful inquiry experience. Although geographical inquiry is heavily advocated in Australia’s new Australian Curriculum: Geography, more work is needed in this area relating to teacher professional learning.

Content analysis of international research in geographical and environmental education : eighteen years of academic publishing

This paper examines the history of the IRGEE Journal in terms of its sustainable future. The development of geographical and environmental education is evaluated, as reflected from the articles published in the Journal “International Research in Geographical and Environmental Education” (IRGEE). A content analysis of all papers and forum sections which have appeared in the journal since Volume 1 Number 1 was published in 1992 has been conducted, examining the content of as many as 526 articles. The method was a content analysis, and revealed themes which have experienced an increasing or declining interest over the 18 years of publication of IRGEE (1992-2009), while other themes have remained current during this period. The main findings of this analysis are: a) the total number of articles has increased more than threefold, b) articles related to geographical education (sensu stricto) outweighed those related to environmental education, c) the themes “syllabi, textbooks, curricula” and “values, attitudes” attract the attention of researchers with increasing strength and d) emerging subjects, such as GIS and sustainability have appeared dynamically in the last years.

Statistical and scientometric analysis of international research in geographical and environmental education

Certain statistic and scientometric features of articles published in the journal “International Research in Geographical and Environmental Education” are examined in this paper, for the period 1992-2009, by applying nonparametric statistics and Shannon’s entropy (diversity) formula. The main findings of this analysis are: a) after 2004 the research priorities of researchers in geographical and environmental education seem to have changed, b) “teacher education” has been the most recurrent theme throughout these 18 years, followed by “values & attitudes” and “inquiry & problem solving” c) the themes “GIS” and “Sustainability” were the most “stable” throughout the 18 years, meaning that they maintained their ranks as publication priorities more than other themes, d) citations of IRGEE increase annually, e) the average thematic diversity of articles published during the period 1992-2009 is 82.7% of the maximum thematic diversity (very high), meaning that the Journal has the capacity to attract a wide readership for the 10 themes it has successfully covered throughout the 18 years of its publication.

Empirical analysis of the effect of dimension reduction and word order on semantic vectors

The aim of this paper is to provide a comparison of various algorithms and parameters to build reduced semantic spaces. The effect of dimension reduction, the stability of the representation and the effect of word order are examined in the context of the five algorithms bearing on semantic vectors: Random projection (RP), singular value decom- position (SVD), non-negative matrix factorization (NMF), permutations and holographic reduced representations (HRR). The quality of semantic representation was tested by means of synonym finding task using the TOEFL test on the TASA corpus. Dimension reduction was found to improve the quality of semantic representation but it is hard to find the optimal parameter settings. Even though dimension reduction by RP was found to be more generally applicable than SVD, the semantic vectors produced by RP are somewhat unstable. The effect of encoding word order into the semantic vector representation via HRR did not lead to any increase in scores over vectors constructed from word co-occurrence in context information. In this regard, very small context windows resulted in better semantic vectors for the TOEFL test.