The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients

Iron homeostasis is altered in Parkinson's disease (PD). The HFE protein is an important regulator of cellular iron homeostasis and variations within this gene can result in iron overload and the disorder known as hereditary haemochromatosis. We studied the Cys282Tyr single nucleotide polymorphism as a genetic risk factor for PD in two distinct and separately collected cohorts of Australian PD patients and controls. In the combined cohort comprising 438 PD patients and 485 control subjects, we revealed an odds ratio for possession of the 282Tyr allele of 0.61 (95% confidence interval, Cl = 0.42-0.90, P = 0.011) from univariate chi-squared and 0.59 (95% Cl = 0.39-0.90, P = 0.014) after logistic regression analyses (correcting for potential confounding factors). These results suggest that possession of the 282Tyr allele may offer some protection against the development of PD. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

The mitochondrial 12S gene is a suitable marker of populations of Sarcoptes scabiei from wombats, dogs and humans in Australia

We sequenced part of the mitochondrial 12S ribosomal RNA gene of 23 specimens of Sarcoptes scabiei from eight wombats, one dog and three humans. Twelve of the 326 nucleotide positions varied among these mites and there were nine haplotypes (sequences) that differed by 1-8 nucleotides. Phylogenetic analyses indicated that these mites were from two lineages: (1) mites from wombats from Victoria, Australia, and mites from the humans and dog from the Northern Territory, Australia (haplotypes 1-4, 9); and (2) mites from the humans and dog from the Northern Territory (haplotypes 5-8). Mites from the three different hosts (wombats, a dog and humans) had not diverged phylogenetically; rather, these mites had similar 12S sequences. Thus, we conclude that these mites from wombats, humans and a dog are closely related, and that they diverged from a common ancestor relatively recently. This conclusion is consistent with the argument that people and/or their dogs introduced to Australia the S. scabiei mites that infect wombats Australia. So, S. scabiei, which has been blamed for the extinction of populations of wombats in Australia, may be a parasitic mite that was introduced to Australia with people and/or their dogs. These data show that the mitochondrial 12S rRNA gene may be a suitable population marker of S. scabiei from wombats, dogs and humans in Australia.

A system for the heterologous expression of complex redox proteins in Rhodobacter capsulatus: characterisation of recombinant sulphite : cytochrome c oxidoreductase from Starkeya novella

The phototrophic purple non-sulfur bacterium Rhodobacter capsulatus expresses a wide variety of complex redox proteins in response to changing environmental conditions. Here we report the construction and evaluation of an expression system for recombinant proteins in that organism which makes use of the dor promoter from the same organism. A generic expression vector, pDorEX, was constructed and used to express sulphite:cytochrome c oxidoreductase from Starkeya novella, a heterodimeric protein containing both molybdenum and haem c. The recombinant protein was secreted to the periplasm and its biochemical properties were very similar to those of the native enzyme. The pDorEX system therefore seems to be potentially useful for heterologous expression of multi-subunit proteins containing complex redox cofactors. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.

Transformation processes, pathways, and possible sources of distinctive polychlorinated dibenzo-p-dioxin signatures in sink environments

In recent years, studies on environmental samples with unusual dibenzo-p-dioxin (PCDD) congener profiles were reported from a range of countries. These profiles, characterized by a dominance of octachlorinated dibenzodioxin (OCDD) and relatively low in dibenzofuran (PCDF) concentrations, could not be attributed to known sources or formation processes. In the present study, the processes that result in these unusual profiles were assessed using the concentrations and isomer signatures of PCDDs from dated estuarine sediment cores in Queensland, Australia. Increases in relative concentrations of lower chlorinated PODS and a relative decrease of OCDD were correlated with time of sediment deposition. Preferred lateral, anaerobic dechlorination of OCDD represents a likely pathway for these changes. In Queensland sediments, these transformations result in a distinct dominance of isomers fully chlorinated in the 1,4,6,9-positions (1,4-patterns), and similar 1,4-patterns were observed in sediments from elsewhere. Consequently, these environmental samples may not reflect the signatures of the original source, and a reevaluation of source inputs was undertaken. Natural formation of PCDDs, which has previously been suggested, is discussed; however, based on the present results and literature comparisons, we propose an alternative scenario. This scenario hypothesizes that an anthropogenic PCDD precursor input (e.g. pentachlorophenol) results in the contamination. These results and hypothesis imply further investigations are warrented into possible anthropogenic sources in areas where natural PCDD formation has been suggested.

The martensitic transformation in ceramics - its role in transformation toughening

This paper reviews the current knowledge and understanding of martensitic transformations in ceramics - the tetragonal to monoclinic transformation in zirconia in particular. This martensitic transformation is the key to transformation toughening in zirconia ceramics. A very considerable body of experimental data on the characteristics of this transformation is now available. In addition, theoretical predictions can be made using the phenomenological theory of martensitic transformations. As the paper will illustrate, the phenomenological theory is capable of explaining all the reported microstructural and crystallographic features of the transformation in zirconia and in some other ceramic systems. Hence the theory, supported by experiment, can be used with considerable confidence to provide the quantitative data that is essential for developing a credible, comprehensive understanding of the transformation toughening process. A critical feature in transformation toughening is the shape strain that accompanies the transformation. This shape strain, or nucleation strain, determines whether or not the stress-induced martensitic transformation can occur at the tip of a potentially dangerous crack. If transformation does take place, then it is the net transformation strain left behind in the transformed region that provides toughening by hindering crack growth. The fracture mechanics based models for transformation toughening, therefore, depend on having a full understanding of the characteristics of the martensitic transformation and, in particular, on being able to specify both these strains. A review of the development of the models for transformation toughening shows that their refinement and improvement over the last couple of decades has been largely a result of the inclusion of more of the characteristics of the stress-induced martensitic transformation. The paper advances an improved model for the stress-induced martensitic transformation and the strains resulting from the transformation. This model, which separates the nucleation strain from the subsequent net transformation strain, is shown to be superior to any of the constitutive models currently available. (C) 2002 Elsevier Science Ltd. All rights reserved.

Relationship between stress-induced martensitic transformation and impact toughness in low carbon austenitic steels

The effect of test temperature, which controls the stability of austenite, on the impact toughness of a low carbon Fe-Ni-Mn-C austenitic steel and 304 stainless steel, has been investigated. Under impact conditions, stress-induced martensitic transformation occurred, in a region near the fracture surface, at test temperatures below 80degreesC for the Fe-Ni-Mn-C steel and below -25degreesC for 304 stainless steel. The former shows significant transformation toughening and the highest impact toughness was obtained at 10degreesC, which corresponds to the maximum amount of martensite formed by stress-induced transformation above the Ms temperature. The stress-induced martensitic transformation contributes negatively to the impact toughness in the 304 stainless steel. Increasing the amount of stress-induced transformation to martensite, lowered the impact toughness. The experimental results can be well explained by the Antolovich theory through the analysis of metallography and fractography. The different effect of stress-induced transformation on the impact toughness in Fe-Ni-Mn-C steel and 304 stainless steel has been further understood by applying the crystallographic model for stress-induced martensitic transformation to these two steels. (C) 2002 Kluwer Academic Publishers.

Genetic variability in cultivated common bean beyond the two major gene pools

It is generally accepted that two major gene pools exist in cultivated common bean (Phaseolus vulgaris L.), a Middle American and an Andean one. Some evidence, based on unique phaseolin morphotypes and AFLP analysis, suggests that at least one more gene pool exists in cultivated common bean. To investigate this hypothesis, 1072 accessions from a common bean core collection from the primary centres of origin, held at CIAT, were investigated. Various agronomic and morphological attributes (14 categorical and 11 quantitative) were measured. Multivariate analyses, consisting of homogeneity analysis and clustering for categorical data, clustering and ordination techniques for quantitative data and nonlinear principal component analysis for mixed data, were undertaken. The results of most analyses supported the existence of the two major gene pools. However, the analysis of categorical data of protein types showed an additional minor gene pool. The minor gene pool is designated North Andean and includes phaseolin types CH, S and T; lectin types 312, Pr, B and K; and mostly A5, A6 and A4 types alpha-amylase inhibitor. Analysis of the combined categorical data of protein types and some plant categorical data also suggested that some other germplasm with C type phaseolin are distinguished from the major gene pools.

Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a

Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximate to50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.

A case of myoepithelial carcinoma displaying biallelic inactivation of the tumour suppressor gene APC in a patient with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene. It is characterised by the appearance of hundreds to thousands of colorectal adenomas in adolescence and the subsequent development of colorectal cancer. Various extracolonic malignancies are associated with FAP, including desmoids and neoplasms of the stomach, duodenum, pancreas, liver, and brain. We present a family affected by FAP with an exon 14 APC mutation displaying two rare extracolonic lesions, a hepatoblastoma and a myoepithelial carcinoma. The hepatoblastoma was found in a male patient aged 2 years. The second lesion, a myoepithelial carcinoma of the right cheek, was found in a female patient aged 14 years. Inactivation of the normal APC allele was demonstrated in this lesion by loss of heterozygosity analysis, thus implicating APC in the initiation or progression of this neoplasm. This is the first reported case of this lesion in a family affected by FAP.

D2 dopamine receptor gene polymorphism discriminates two kinds of novelty seeking

Cloninger's psychobiological model of personality as applied to substance misuse has received mixed support. Contrary to the model, recent data suggest that a combination of high novelty seeking (NS) and high harm avoidance (HA) represents a significant risk for the development of severe substance misuse. A genetic polymorphism previously implicated in severe substance dependence, the A1 allele of the D2 dopamine receptor (DRD2) gene, was examined in relation to NS and HA amongst 203 adolescent boys. Specifically, we hypothesized that subjects with the A1 + allele (A1/A1 and A1/A2 genotypes) would report stronger NS and would exhibit a more positive relationship between NS and HA than those with the A1-allele (A2/A2 genotypes). These predictions were supported. The correlation between NS and HA in 81 A1 + allelic boys (r = 0.27, P = 0.02), and that in the 122 A1- allelic boys (r = -0.15, P = 0.09), indicated that this relationship differed according to allelic status (F = 8.52, P < 0:004). Among those with the A1-allele, the present results are consistent with the traditional view that novelty seeking provides positive reinforcement, or the fulfillment of appetitive drives. In contrast, novelty seeking in those with the A1 + allele appears to include a negative reinforcement or self-medicating function. (C) 2002 Elsevier Science Ltd. All rights reserved.

The E(NK) model: extending the NK model to incorporate gene-by-environment interactions and epistasis for diploid genomes

The haploid NK model developed by Kauffman can be extended to diploid genomes and to incorporate gene-by-environment interaction effects in combination with epistasis. To provide the flexibility to include a wide range of forms of gene-by-environment interactions, a target population of environment types (TPE) is defined. The TPE consists of a set of E different environment types, each with their own frequency of occurrence. Each environment type conditions a different NK gene network structure or series of gene effects for a given network structure, providing the framework for defining gene-by-environment interactions. Thus, different NK models can be partially or completely nested within the E environment types of a TPE, giving rise to the E(NK) model for a biological system. With this model it is possible to examine how populations of genotypes evolve in context with properties of the environment that influence the contributions of genes to the fitness values of genotypes. We are using the E(NK) model to investigate how both epistasis and gene-by-environment interactions influence the genetic improvement of quantitative traits by plant breeding strategies applied to agricultural systems. © 2002 Wiley Periodicals, Inc.

The GP problem: quantifying gene-to-phenotype relationships

In this paper we refer to the gene-to-phenotype modeling challenge as the GP problem. Integrating information across levels of organization within a genotype-environment system is a major challenge in computational biology. However, resolving the GP problem is a fundamental requirement if we are to understand and predict phenotypes given knowledge of the genome and model dynamic properties of biological systems. Organisms are consequences of this integration, and it is a major property of biological systems that underlies the responses we observe. We discuss the E(NK) model as a framework for investigation of the GP problem and the prediction of system properties at different levels of organization. We apply this quantitative framework to an investigation of the processes involved in genetic improvement of plants for agriculture. In our analysis, N genes determine the genetic variation for a set of traits that are responsible for plant adaptation to E environment-types within a target population of environments. The N genes can interact in epistatic NK gene-networks through the way that they influence plant growth and development processes within a dynamic crop growth model. We use a sorghum crop growth model, available within the APSIM agricultural production systems simulation model, to integrate the gene-environment interactions that occur during growth and development and to predict genotype-to-phenotype relationships for a given E(NK) model. Directional selection is then applied to the population of genotypes, based on their predicted phenotypes, to simulate the dynamic aspects of genetic improvement by a plant-breeding program. The outcomes of the simulated breeding are evaluated across cycles of selection in terms of the changes in allele frequencies for the N genes and the genotypic and phenotypic values of the populations of genotypes.

Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells

Sonic Hedgehog is a secreted morphogen involved in patterning a wide range of structures in the developing embryo. Disruption of the Hedgehog signalling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. The identification of genes regulated by Hedgehog is crucial to understanding how disruption of this pathway leads to neoplastic transformation. We have used a Sonic Hedgehog (Shh) responsive mouse cell line, C3H/10T1/2, to provide a model system for hedgehog target gene discovery. Following activation of cell cultures with Shh, RNA was used to interrogate microarrays to investigate downstream transcriptional consequences of hedgehog stimulation. As a result 11 target genes have been identified, seven of which are induced (Thrombomodulin, GILZ, BF-2, Nr4a1, IGF2, PMP22, LASP1) and four of which are repressed (SFRP-1, SFRP-2, Mip1-gamma, Amh) by Shh. These targets have a diverse range of putative functions and include transcriptional regulators and molecules known to be involved in regulating cell growth or apoptosis. The corroboration of genes previously implicated in hedgehog signalling, along with the finding of novel targets, demonstrates both the validity and power of the C3H/10T1/2 system for Shh target gene discovery.