Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors

Traditional treatment of infectious diseases is based on compounds that kill or inhibit growth of bacteria. A major concern with this approach is the frequent development of resistance to antibiotics. The discovery of communication systems (quorum sensing systems) regulating bacterial virulence has afforded a novel opportunity to control infectious bacteria without interfering with growth. Compounds that can override communication signals have been found in the marine environment. Using Pseudomonas aeruginosa PAO1 as an example of an opportunistic human pathogen, we show that a synthetic derivate of natural furanone compounds can act as a potent antagonist of bacterial quorum sensing. We employed GeneChip((R)) microarray technology to identify furanone target genes and to map the quorum sensing regulon. The transcriptome analysis showed that the furanone drug specifically targeted quorum sensing systems and inhibited virulence factor expression. Application of the drug to P.aeruginosa biofilms increased bacterial susceptibility to tobramycin and SDS. In a mouse pulmonary infection model, the drug inhibited quorum sensing of the infecting bacteria and promoted their clearance by the mouse immune response.

Humans, dogs and parasitic zoonoses - Unravelling the relationships in a remote endemic community in Northeast India using molecular tools

Canine parasitic zoonoses pose a continuing public health problem, especially in developing countries and communities that are socioeconomically disadvantaged. Our study combined the use of conventional and molecular epidemic, logical tools to determine the role of dogs in transmission of gastrointestinal (GI) parasites such as hookworms, Giardia and Ascaris in a parasite endemic teagrowing community in northeast India. A highly sensitive and specific molecular tool was developed to detect and differentiate the zoonotic species of canine hookworm eggs directly from faeces. This allowed epidemiological screening of canine hookworm species in this community to be conducted with ease and accuracy. The zoonotic potential of canine Giardia was also investigated by characterising Giardia duodenalis recovered from humans and dogs living in the same locality and households at three different loci. Phylogenetic and epidemiological analysis provided compelling evidence to support the zoonotic transmission of canine Giardia. Molecular tools were also used to identify the species of Ascaris egg present in over 30% of dog faecal samples. The results demonstrated the role of dogs as a significant disseminator and environmental contaminator of Ascaris lumbricoides in communities where promiscuous defecation practices exist. Our study demonstrated the usefulness of combining conventional and molecular parasitological and epidemiological tools to help solve unresolved relationships with regards to parasitic zoonoses.

Is there an association between chronic lung disease and abdominal aortic aneurysm expansion?

Background: Although there is evidence demonstrating an association between chronic obstructive pulmonary disease (COPD) and abdominal aortic aneurysm (AAA), it is not clear whether COPD predicts greater rates of expansion of established aneurysms. We sought such an association in a cohort of men with aneurysms detected in a population-based study of screening for aneurysms. Methods: In addition to regular aortic ultrasound scans, 179 men with AAA underwent full lung function testing in order to identify the presence of COPD and its subgroups, emphysema and other obstructive ventilatory defects (OVD). The rate of expansion of each aneurysm was calculated and the men were divided into 'rapid expanders' (3 mm or more per year) and 'slow expanders' (less than 3 mm per year). Any association with the presence of COPD or smoking was tested using a multivariate model. Results: Over a median follow-up period of 36 months the mean rate of aortic expansion for the cohort of 179 men was 2.1 mm/year. There was no significant difference in prevalence of COPD (68% overall) or having ever been a smoker (87% overall) between the rapid expanders and the slow expanders. Conclusions: Although there was a high prevalence of COPD among men with an AAA, there was no association between the rate of expansion of AAA and the presence of any form of this disease.

Allergen databases

Allergies represent a significant medical and industrial problem. Molecular and clinical data on allergens are growing exponentially and in this article we have reviewed nine specialized allergen databases and identified data sources related to protein allergens contained in general purpose molecular databases. An analysis of allergens contained in public databases indicates a high level of redundancy of entries and a relatively low coverage of allergens by individual databases. From this analysis we identify current database needs for allergy research and, in particular, highlight the need for a centralized reference allergen database.

Event-related FMRI analysis with maximum correlation modelling

Functional magnetic resonance imaging (FMRI) analysis methods can be quite generally divided into hypothesis-driven and data-driven approaches. The former are utilised in the majority of FMRI studies, where a specific haemodynamic response is modelled utilising knowledge of event timing during the scan, and is tested against the data using a t test or a correlation analysis. These approaches often lack the flexibility to account for variability in haemodynamic response across subjects and brain regions which is of specific interest in high-temporal resolution event-related studies. Current data-driven approaches attempt to identify components of interest in the data, but currently do not utilise any physiological information for the discrimination of these components. Here we present a hypothesis-driven approach that is an extension of Friman's maximum correlation modelling method (Neurolmage 16, 454-464, 2002) specifically focused on discriminating the temporal characteristics of event-related haemodynamic activity. Test analyses, on both simulated and real event-related FMRI data, will be presented.

Mental rotation processes in mathematically gifted boys: An fMRI investigation

The functional brain organisation of mathematically gifted adolescents may be different from those of average mathematical ability. In this study we used fMRI to examine the neural circuitry that mediates the performance of mathematically gifted boys and average ability controls while engaged in mental rotation. Eight math gifted male adolescents and five average ability male adolescents were presented 18 control and 18 mental rotation trials in two separate blocks. Participants selected one of four test stimuli to match the target stimulus by pressing one of four fibreoptic buttons. The control task required a simple 'best match' for the target stimulus. EPI scans were acquired on a 3-T MR scanner and a fixed effects statistical analysis (SPM99) was used to identify areas of significant activation in the rotation tasks, for the two groups. The results indicate that during mental rotation both groups activate the parietal lobes bilaterally, though to different levels. Moreover, the math gifted are uniformly bilateral in their pattern of activation, and engage some anterior regions not found in those of average ability. These regions include bilateral prefrontal cortex and the right anterior cingulate, which may serve to heighten concentration, and to optimise the pre-planning of purposeful actions.

Identification of "pathologs" (disease-related genes) from the RIKEN mouse cDNA dataset using human curation plus FACTS, a new biological information extraction system

Background: A major goal in the post-genomic era is to identify and characterise disease susceptibility genes and to apply this knowledge to disease prevention and treatment. Rodents and humans have remarkably similar genomes and share closely related biochemical, physiological and pathological pathways. In this work we utilised the latest information on the mouse transcriptome as revealed by the RIKEN FANTOM2 project to identify novel human disease-related candidate genes. We define a new term patholog to mean a homolog of a human disease-related gene encoding a product ( transcript, anti-sense or protein) potentially relevant to disease. Rather than just focus on Mendelian inheritance, we applied the analysis to all potential pathologs regardless of their inheritance pattern. Results: Bioinformatic analysis and human curation of 60,770 RIKEN full-length mouse cDNA clones produced 2,578 sequences that showed similarity ( 70 - 85% identity) to known human-disease genes. Using a newly developed biological information extraction and annotation tool ( FACTS) in parallel with human expert analysis of 17,051 MEDLINE scientific abstracts we identified 182 novel potential pathologs. Of these, 36 were identified by computational tools only, 49 by human expert analysis only and 97 by both methods. These pathologs were related to neoplastic ( 53%), hereditary ( 24%), immunological ( 5%), cardio-vascular (4%), or other (14%), disorders. Conclusions: Large scale genome projects continue to produce a vast amount of data with potential application to the study of human disease. For this potential to be realised we need intelligent strategies for data categorisation and the ability to link sequence data with relevant literature. This paper demonstrates the power of combining human expert annotation with FACTS, a newly developed bioinformatics tool, to identify novel pathologs from within large-scale mouse transcript datasets.

Anogenital gland secretions of Lemur catta and Propithecus verreauxi coquereli: A preliminary chemical examination

Although prosimians are greatly olfaction-oriented, little is known about the specifics of how they use scent to communicate. In this preliminary study we attempted to delineate intra- and interspecific differences among the anogenital gland secretions of two lemur species (Lemur catta and Propithecus verreauxi coquereli) using gas chromatography-mass spectrometry (GC-MS). The results indicate that the two species are discernible through scent. Furthermore, we were able to identify reproductive status using this technique. The anogenital secretions of the different sexes in L. catta, though perhaps not P. v. coquereli, are chemically distinguishable. Given this information, it appears that at least some lemur species can use scent marks to determine species, sex, and reproductive status. (C) 2004 Wiley-Liss, Inc.

Investment prioritization based on broadscale spatial budgeting to meet downstream targets for suspended sediment loads

On the basis of a spatially distributed sediment budget across a large basin, costs of achieving certain sediment reduction targets in rivers were estimated. A range of investment prioritization scenarios were tested to identify the most cost-effective strategy to control suspended sediment loads. The scenarios were based on successively introducing more information from the sediment budget. The relationship between spatial heterogeneity of contributing sediment sources on cost effectiveness of prioritization was investigated. Cost effectiveness was shown to increase with sequential introduction of sediment budget terms. The solution which most decreased cost was achieved by including spatial information linking sediment sources to the downstream target location. This solution produced cost curves similar to those derived using a genetic algorithm formulation. Appropriate investment prioritization can offer large cost savings because the magnitude of the costs can vary by several times depending on what type of erosion source or sediment delivery mechanism is targeted. Target settings which only consider the erosion source rates can potentially result in spending more money than random management intervention for achieving downstream targets. Coherent spatial patterns of contributing sediment emerge from the budget model and its many inputs. The heterogeneity in these patterns can be summarized in a succinct form. This summary was shown to be consistent with the cost difference between local and regional prioritization for three of four test catchments. To explain the effect for the fourth catchment, the detail of the individual sediment sources needed to be taken into account.

Familial partial epilepsy with variable foci: Clinical features and linkage to chromosome 22q12

Background: Familial partial epilepsy with variable foci (FPEVF) is an autosomal dominant syndrome characterized by partial seizures originating from different brain regions in different family members in the absence of detectable structural abnormalities. A gene for FPEVF was mapped to chromosome 22q12 in two distantly related French-Canadian families. Methods: We describe the clinical features and performed a linkage analysis in a Spanish kindred and in a third French-Canadian family distantly related to the original pedigrees. Results: Onset of seizures was typically in middle childhood, and attacks were usually easy to control. Seizure semiology varied among family members but was constant for each individual. In some, a pattern of nocturnal frontal lobe seizures led to consideration of the diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The Spanish family was mapped to chromosome 22q (multipoint lod score, 3.4), and the new French-Canadian family had a multipoint lod score of 2.97 and shared the haplotype of the original French-Canadian families. Conclusions: Identification of the various forms of familial partial epilepsy is challenging, particularly in small families, in which insufficient individuals exist to identify a specific pattern. We provide clinical guidelines for this task, which will eventually be supplanted by specific molecular diagnosis. We confirmed linkage of FPEVF to chromosome 22q 12 and redefined the region to a 5.2-Mb segment of DNA.

Mapping cortical change in Alzheimer's disease, brain development, and schizophrenia

This paper describes algorithms that can identify patterns of brain structure and function associated with Alzheimer's disease, schizophrenia, normal aging, and abnormal brain development based on imaging data collected in large human populations. Extraordinary information can be discovered with these techniques: dynamic brain maps reveal how the brain grows in childhood, how it changes in disease, and how it responds to medication. Genetic brain maps can reveal genetic influences on brain structure, shedding light on the nature-nurture debate, and the mechanisms underlying inherited neurobehavioral disorders. Recently, we created time-lapse movies of brain structure for a variety of diseases. These identify complex, shifting patterns of brain structural deficits, revealing where, and at what rate, the path of brain deterioration in illness deviates from normal. Statistical criteria can then identify situations in which these changes are abnormally accelerated, or when medication or other interventions slow them. In this paper, we focus on describing our approaches to map structural changes in the cortex. These methods have already been used to reveal the profile of brain anomalies in studies of dementia, epilepsy, depression, childhood and adult-onset schizophrenia, bipolar disorder, attention-deficit/ hyperactivity disorder, fetal alcohol syndrome, Tourette syndrome, Williams syndrome, and in methamphetamine abusers. Specifically, we describe an image analysis pipeline known as cortical pattern matching that helps compare and pool cortical data over time and across subjects. Statistics are then defined to identify brain structural differences between groups, including localized alterations in cortical thickness, gray matter density (GMD), and asymmetries in cortical organization. Subtle features, not seen in individual brain scans, often emerge when population-based brain data are averaged in this way. Illustrative examples are presented to show the profound effects of development and various diseases on the human cortex. Dynamically spreading waves of gray matter loss are tracked in dementia and schizophrenia, and these sequences are related to normally occurring changes in healthy subjects of various ages. (C) 2004 Published by Elsevier Inc.

Virtual models of the HLA class I antigen processing pathway

Antigen recognition by cytotoxic CD8 T cells is dependent upon a number of critical steps in MHC class I antigen processing including proteosomal cleavage, TAP transport into the endoplasmic reticulum, and MHC class 1 binding. Based on extensive experimental data relating to each of these steps there is now the capacity to model individual antigen processing steps with a high degree of accuracy. This paper demonstrates the potential to bring together models of individual antigen processing steps, for example proteosome cleavage, TAP transport, and MHC binding, to build highly informative models of functional pathways. In particular, we demonstrate how an artificial neural network model of TAP transport was used to mine a HLA-binding database so as to identify H LA-binding peptides transported by TAP. This integrated model of antigen processing provided the unique insight that HLA class I alleles apparently constitute two separate classes: those that are TAP-efficient for peptide loading (HLA-B27, -A3, and -A24) and those that are TAP-inefficient (HLA-A2, -B7, and -B8). Hence, using this integrated model we were able to generate novel hypotheses regarding antigen processing, and these hypotheses are now capable of being tested experimentally. This model confirms the feasibility of constructing a virtual immune system, whereby each additional step in antigen processing is incorporated into a single modular model. Accurate models of antigen processing have implications for the study of basic immunology as well as for the design of peptide-based vaccines and other immunotherapies. (C) 2004 Elsevier Inc. All rights reserved.

The Australian Universities Teaching Committee project in 'Learning Outcomes and Curriculum Development in Psychology'

The Australian Universities Teaching Committee (AUTC) funds projects intended to improve the quality of teaching and learning in specific disciplinary areas. The project brief for 'Learning Outcomes and Curriculum Development in Psychology' for 2004/2005 was to 'produce an evaluative overview of courses ... with a focus on the specification and assessment of learning outcomes and ... identify strategic directions for universities to enhance teaching and learning'. This project was awarded to a consortium from The University of Queensland, University of Tasmania, and Southern Cross University. The starting point for this project is an analysis of the scientist-practitioner model and its role in curriculum design, a review of current challenges at a conceptual level, and consideration of the implications of recent changes to universities relating to such things as intemationalisation of programs and technological advances. The project will seek to bring together stakeholders from around the country in order to survey the widest possible range of perspectives on the project brief requirements. It is hoped also to establish mechanisms for fiiture scholarly discussion of these issues, including the establishment of an Australian Society for the Teaching of Psychology and an annual conference.

A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping

Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.

A study of the interaction between operator style and machine capability for a hydraulic mining excavator

This paper presents a case study that explores how operator digging style juxtaposes with mechanical capability for a class of hydraulic mining excavators. The relationships between actuator and digging forces are developed and these are used to identify the excavator's capability to apply forces in various directions. Two distinct modes of operation are examined to see how they relate to the mechanical capabilities of the linkage and to establish if one has merit over the other. It is found that one of these styles results in lower loading of the machine.