A comprehensive analysis of sexual dimorphism in the midbrain dopamine system

Thesis (Ph.D.)--University of Washington, 2016-06

Molecular analysis of the pathway for the synthesis of thiol tripeptides in the model legume Lotus japonicus

The thiol tripeptides, glutathione (GSH) and homoglutathione (hGSH), perform multiple roles in legumes, including protection against toxicity of free radicals and heavy metals. The three genes involved in the synthesis of GSH and hGSH in the model legume, Lotus japonicus, have been fully characterized and appear to be present as single copies in the genome. The gamma-glutamylcysteine synthetase (gammaecs) gene was mapped on the long arm of chromosome 4 (70.0 centimorgans [cM]) and consists of 15 exons, whereas the glutathione synthetase (gshs) and homoglutathione synthetase (hgshs) genes were mapped on the long arm of chromosome 1 (81.3 cM) and found to be arranged in tandem, with a separation of approximately 8 kb. Both genes consist of 12 exons of exactly the same size (except exon 1, which is similar). Two types of transcripts were detected for the gshs gene, which putatively encode proteins localized in the plastids and cytosol. Promoter regions contain cis-acting regulatory elements that may be involved in the plant's response to light, hormones, and stress. Determination of transcript levels, enzyme activities, and thiol contents in nodules, roots, and leaves revealed that gammaecs and hgshs are expressed in all three plant organs, whereas gshs is significantly functional only in nodules. This strongly suggests an important role of GSH in the rhizobia-legume symbiosis.

Epidemiological analysis of electroconvulsive therapy in Victoria, Australia

Objective: To determine the population-based utilization rate of electroconvulsive therapy (ECT) in Victoria between 1998-1999, to examine the characteristics of the ECT treated group, and to identify patient factors independently associated with differential rates of ECT treatment. Method: Electroconvulsive therapy is reported under statute in Victoria, Australia. Crude, age-adjusted and age-sex specific utilization rates were calculated using this statutory data for the 1998-1999 financial year and estimated mid-year populations from the Australian Bureau of Statistics. Descriptive characteristics of those treated with ECT were derived from the statutory data. Patient factors associated with an increased likelihood of ECT in the public sector were explored with logistic regression analysis, using non-ECT treated mental health patients from the Victorian Psychiatric Case Register as the reference population. Results: The crude treated-person and age-adjusted rates for the State (both public and private sectors) were 39.9 and 44.0 persons per 100 000 resident population per annum, respectively. The crude and age-adjusted administration rates were 330.3 and 362.6 ECT administrations per 100 000 resident population per annum, respectively. Age-sex specific rates varied by age and sex, with rates generally increasing with age and female sex. Overall, 62.8% of the treated group were women, 32.9% aged over 64, and 75.2% had depression. Diagnosis, age and sex each independently predicted ECT in the public sector, with diagnosis the most important factor, followed by age then sex. Conclusions: Despite decades of use, the appropriate rate of ECT utilization is still unclear. Further research should be directed at exploring the factors, including provider variables, determining ECT treatment.

Structural, electrical, and optical analysis of ion implanted semi-insulating InP

Semi-insulating InP was implanted with MeV P, As, Ga, and In ions, and the resulting evolution of structural properties with increased annealing temperature was analyzed using double crystal x-ray diffractometry and cross sectional transmission electron microscopy. The types of damage identified are correlated with scanning spreading resistance and scanning capacitance measurements, as well as with previously measured Hall effect and time resolved photoluminescence results. We have identified multiple layers of conductivity in the samples which occur due to the nonuniform damage profile of a single implant. Our structural studies have shown that the amount and type of damage caused by implantation does not scale with implant ion atomic mass. (C) 2004 American Institute of Physics.

Analysis of Melanoma Onset: Assessing Familial Aggregation by Using Estimating Equations and Fitting Variance Components via Bayesian Random Effects Models

We investigate whether relative contributions of genetic and shared environmental factors are associated with an increased risk in melanoma. Data from the Queensland Familial Melanoma Project comprising 15,907 subjects arising from 1912 families were analyzed to estimate the additive genetic, common and unique environmental contributions to variation in the age at onset of melanoma. Two complementary approaches for analyzing correlated time-to-onset family data were considered: the generalized estimating equations (GEE) method in which one can estimate relationship-specific dependence simultaneously with regression coefficients that describe the average population response to changing covariates; and a subject-specific Bayesian mixed model in which heterogeneity in regression parameters is explicitly modeled and the different components of variation may be estimated directly. The proportional hazards and Weibull models were utilized, as both produce natural frameworks for estimating relative risks while adjusting for simultaneous effects of other covariates. A simple Markov Chain Monte Carlo method for covariate imputation of missing data was used and the actual implementation of the Bayesian model was based on Gibbs sampling using the free ware package BUGS. In addition, we also used a Bayesian model to investigate the relative contribution of genetic and environmental effects on the expression of naevi and freckles, which are known risk factors for melanoma.

A vulnerability analysis of the temperate forests of south central Chile A vulnerability analysis of the temperate forests of south central Chile. Biological Conservation, 122 2005: 9-21.

Areas of the landscape that are priorities for conservation should be those that are both vulnerable to threatening processes and that if lost or degraded, will result in conservation targets being compromised. While much attention is directed towards understanding the patterns of biodiversity, much less is given to determining the areas of the landscape most vulnerable to threats. We assessed the relative vulnerability of remaining areas of native forest to conversion to plantations in the ecologically significant temperate rainforest region of south central Chile. The area of the study region is 4.2 million ha and the extent of plantations is approximately 200000 ha. First, the spatial distribution of native forest conversion to plantations was determined. The variables related to the spatial distribution of this threatening process were identified through the development of a classification tree and the generation of a multivariate. spatially explicit, statistical model. The model of native forest conversion explained 43% of the deviance and the discrimination ability of the model was high. Predictions were made of where native forest conversion is likely to occur in the future. Due to patterns of climate, topography, soils and proximity to infrastructure and towns, remaining forest areas differ in their relative risk of being converted to plantations. Another factor that may increase the vulnerability of remaining native forest in a subset of the study region is the proposed construction of a highway. We found that 90% of the area of existing plantations within this region is within 2.5 km of roads. When the predictions of native forest conversion were recalculated accounting for the construction of this highway, it was found that: approximately 27000 ha of native forest had an increased probability of conversion. The areas of native forest identified to be vulnerable to conversion are outside of the existing reserve network. (C) 2004 Elsevier Ltd. All tights reserved.

Genetic analysis of complex demographic scenarios: Spatially expanding populations of the cane toad, Bufo marinus

Inferring the spatial expansion dynamics of invading species from molecular data is notoriously difficult due to the complexity of the processes involved. For these demographic scenarios, genetic data obtained from highly variable markers may be profitably combined with specific sampling schemes and information from other sources using a Bayesian approach. The geographic range of the introduced toad Bufo marinus is still expanding in eastern and northern Australia, in each case from isolates established around 1960. A large amount of demographic and historical information is available on both expansion areas. In each area, samples were collected along a transect representing populations of different ages and genotyped at 10 microsatellite loci. Five demographic models of expansion, differing in the dispersal pattern for migrants and founders and in the number of founders, were considered. Because the demographic history is complex, we used an approximate Bayesian method, based on a rejection-regression algorithm. to formally test the relative likelihoods of the five models of expansion and to infer demographic parameters. A stepwise migration-foundation model with founder events was statistically better supported than other four models in both expansion areas. Posterior distributions supported different dynamics of expansion in the studied areas. Populations in the eastern expansion area have a lower stable effective population size and have been founded by a smaller number of individuals than those in the northern expansion area. Once demographically stabilized, populations exchange a substantial number of effective migrants per generation in both expansion areas, and such exchanges are larger in northern than in eastern Australia. The effective number of migrants appears to be considerably lower than that of founders in both expansion areas. We found our inferences to be relatively robust to various assumptions on marker. demographic, and historical features. The method presented here is the only robust, model-based method available so far, which allows inferring complex population dynamics over a short time scale. It also provides the basis for investigating the interplay between population dynamics, drift, and selection in invasive species.

A comparative analysis of entrepreneurial approaches within public healthcare organisations

This article examines the development of two distinct models of organising allied health professionals within two public sector health service organisations in Australia. The first case illustrated a mode of organising that facilitated a culture that focused on asset protection and whose external orientation was threat oriented because its disparate multiple identities operated as a fractured, fragmented and competitive set of profession disciplines. In this milieu, there was no evidence of entrepreneurial approaches being used. In contrast, the second case study illustrated a mode of organising that facilitated an entrepreneurial culture that focused on asset growth and an external orientation that was opportunity oriented because of the evolution of a strong superordinate allied health identity that operated as a single united health services stakeholder. This evolution was coupled with the emergence of a corporate boardroom model of management that is consonant with Savage et al. (1997) IDS/N model of management. Once this structure and strategy were in place, corporate entrepreneur ship became the modus operandi. Consequently, because the case study was a situation where corporate entrepreneurship existed in the public sector, it was possible to compare the factors that stimulate corporate entrepreneurship in Sadler's (2000) study with factors that were observed in our study.

Population effects on individual systolic blood pressure: A multilevel analysis of the World Health Organization MONICA project

Individuals from the same population share a number of contextual circumstances that may condition a common level of blood pressure over and above individual characteristics. Understanding this population effect is relevant for both etiologic research and prevention strategies. Using multilevel regression analyses, the authors quantified the extent to which individual differences in systolic blood pressure (SBP) could be attributed to the population level. They also investigated possible cross-level interactions between the population in which a person lived and pharmacological (antihypertensive medication) and nonpharmacological (body mass index) effects on individual SBP. They analyzed data on 23,796 men and 24,986 women aged 35-64 years from 39 worldwide Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) study populations participating in the final survey of this World Health Organization project (1989-1997). SBP was positively associated with low educational achievement, high body mass index, and use of antihypertensive medication and, for women, was negatively associated with smoking. About 7-8% of all SBP differences between subjects were attributed to the population level. However, this population effect was particularly strong (i.e., 20%) in antihypertensive medication users and overweight women. This empirical evidence of a population effect on individual SBP emphasizes the importance of developing population-wide strategies to reduce individual risk of hypertension.

Violence against young Australian women and association with reproductive events: a cross-sectional analysis of a national population sample

Objective: This study aimed to investigate associations between violence and younger women's reproductive events using Survey 1 (1996) data of the Younger cohort of the Australian Longitudinal Study of Women's Health (ALSWH). Methods: Multinomial regression, using composite variables for both violence and reproductive events, adjusting for socioeconomic variables and weighted for rural and remote areas. Results: 23.8% of 14,784 women aged 18 to 23 years reported violence; 12.6% reported non-partner violence in the previous year; and 11.2% reported ever having had a violent relationship with a partner. Of the latter group, 43% (4.8% overall) also reported violence in the past year. Compared with women reporting no violence, women reporting partner but not recent violence (OR 2.55, 95% Cl 2.10-3.09) or partner and recent violence (OR 3.96, 95% Cl 3.18-4.93) were significantly more likely to have had one or more pregnancies. Conversely, having had a pregnancy (2,561) was associated with an 80% increase in prevalence of any violence and a 230% increase in partner violence. Among women who had a pregnancy, having had a miscarriage or termination was associated with violence. Partner and recent violence is strongly associated with having had a miscarriage, whether alone (OR = 2.85, 95% Cl 1.74-4.66), with a termination (OR = 4.60, 2.26-9.35), or with birth, miscarriage and a termination (OR 4.12, 1.89-9.00). Conclusions and implications: Violence among young women of childbearing age is a factor for which doctors should be vigilant, well-trained and supported to identify and manage effectively.

Maintaining and updating semantic context in schizophrenia: an investigation of the effects of multiple remote primes

Conflicting findings regarding the ability of people with schizophrenia to maintain and update semantic contexts have been due, arguably, to vagaries within the experimental design employed (e.g. whether strongly or remotely associated prime-target pairs have been used, what delay between the prime and the target was employed, and what proportion of related prime-target pairs appeared) or to characteristics of the participant cohort (e.g. medication status, chronicity of illness). The aim of the present study was to examine how people with schizophrenia maintain and update contextual information over an extended temporal window by using multiple primes that were either remotely associated or unrelated to the target. Fourteen participants with schizophrenia and 12 healthy matched controls were compared across two stimulus onset asynchronies (SOAs) (short and long) and two relatedness proportions (RP) (high and low) in a crossed design. Analysis of variance statistics revealed significant two- and three-way interactions between Group and SOA, Group and Condition, SOA and RP, and Group, SOA and RP. The participants with schizophrenia showed evidence of enhanced remote priming at the short SOA and low RP, combined with a reduction in the time course over which context could be maintained. There was some sensitivity to biasing contextual information at the short SOA, although the mechanism over which context served to update information appeared to be different from that in the controls. The participants with schizophrenia showed marked performance decrements at the long SOA (both low and high RP). Indices of remote priming at the short (but not the long) SOA correlated with both clinical ratings of thought disorder and with increasing length of illness. The results support and extend the hypothesis that schizophrenia is associated with concurrent increases in tonic dopamine activity and decreases in phasic dopamine activity. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Comparative analysis of CNS populations in knockout mice with altered growth hormone responsiveness

Recently we have shown that growth hormone (GH) inhibits neuronal differentiation and that this process is blocked by suppressor of cytokine signalling-2 (SOCS2). Here we examine several cortical and subcortical neuronal populations in GH hyper-responsive SOCS2 null (-/-) mice and GH non-responsive GH receptor null (GHR-/-) mice. While SOCS2-/- mice showed a 30% decrease in density of NeuN positive neurons in cortex compared to wildtype, GHR-/- mice showed a 25% increase even though brain size was decreased. Interneuron sub-populations were variably affected, with a slight decrease in cortical parvalbumin expressing interneurons in SOCS2-/- mice and an increase in cortical calbindin and calretinin and striatal cholinergic neuron density in GHR-/- mice. Analysis of glial cell numbers in cresyl violet or glial fibrillary acidic protein (GFAP) stained sections of cortex showed that the neuron: glia ratio was increased in GHR-/- mice and decreased in SOCS2-/- mice. The astrocytes in GHR-/- mice appeared smaller, while they were larger in SOCS2-/- mice. Neuronal soma size also varied in the different genotypes, with smaller striatal cholinergic neurons in GHR-/- mice. While the size of layer 5 pyramidal neurons was not significantly different from wildtype, SOCS2-/- neurons were larger than GHR-/- neurons. In addition, primary dendritic length was similar in all genotypes but dendritic branching of pyramidal neurons in the cortex appeared sparser in GHR-/- and SOCS2-/- mice. These results suggest that GH, possibly regulated by SOCS2, has multiple effects on central nervous system (CNS) development and maturation, regulating the number and size of multiple neuronal and glial cell types.

The phasevarion: A genetic system controlling coordinated, random switching of expression of multiple genes

Several host-adapted bacterial pathogens contain methyltransferases associated with type III restriction-modification (R-M) systems that are subject to reversible, high-frequency on/off switching of expression (phase variation). To investigate the role of phase-variable expression of R-M systems, we made a mutant strain lacking the methyltransferase (mod) associated with a type III R-M system of Haemophilus influenzae and analyzed its phenotype. By microarray analysis, we identified a number of genes that were either up- or down-regulated in the mod mutant strain. This system reports the coordinated random switching of a set of genes in a bacterial pathogen and may represent a widely used mechanism.

Differences in mail and telephone responses to self-rated health: use of multiple imputation in correcting for response bias

Objectives: To estimate differences in self-rated health by mode of administration and to assess the value of multiple imputation to make self-rated health comparable for telephone and mail. Methods: In 1996, Survey 1 of the Australian Longitudinal Study on Women's Health was answered by mail. In 1998, 706 and 11,595 mid-age women answered Survey 2 by telephone and mail respectively. Self-rated health was measured by the physical and mental health scores of the SF-36. Mean change in SF-36 scores between Surveys 1 and 2 were compared for telephone and mail respondents to Survey 2, before and after adjustment for socio-demographic and health characteristics. Missing values and SF-36 scores for telephone respondents at Survey 2 were imputed from SF-36 mail responses and telephone and mail responses to socio-demographic and health questions. Results: At Survey 2, self-rated health improved for telephone respondents but not mail respondents. After adjustment, mean changes in physical health and mental health scores remained higher (0.4 and 1.6 respectively) for telephone respondents compared with mail respondents (-1.2 and 0.1 respectively). Multiple imputation yielded adjusted changes in SF-36 scores that were similar for telephone and mail respondents. Conclusions and Implications: The effect of mode of administration on the change in mental health is important given that a difference of two points in SF-36 scores is accepted as clinically meaningful. Health evaluators should be aware of and adjust for the effects of mode of administration on self-rated health. Multiple imputation is one method that may be used to adjust SF-36 scores for mode of administration bias.

Analysis of distinct tartrate-resistant acid phosphatase promoter regions in transgenic mice

The tartrate-resistant acid phosphatase (TRAP) is present in multiple tissues, including kidney, liver, lung, spleen, and bone. Recent study of (TRAP) gene expression has provided evidence for distinct promoters within the (TRAP) gene, suggesting that the gene has alternative, tissue-preferred mRNA transcripts. Examination of endogenous (TRAP) exon 1B and 1C mRNA transcripts revealed tissue-preferred transcript abundance with increased exon 1B transcripts detected in liver and kidney and increased exon 1C transcripts detected in bone and spleen. In this investigation, we have made transgenic mice that express a marker gene driven by two candidate promoters, designated BC and C, within the (TRAP) gene. The BC and C promoters are 2.2 and 1.6 kb, respectively, measured from the translation initiation site. Evaluation of BC transgenic lines demonstrated robust expression in multiple tissues. In contrast, significant transgene expression was not detected in C transgenic lines. Evaluation of transgene mRNAs in BC transgenic lines revealed that virtually all expression was in the form of B transcripts, suggesting that the tissue-preferred pattern of endogenous (TRAP) was not replicated in the BC transgenic line. Likewise, osteoclastogenic cultures from BC, but not C, transgenic bone marrow cells expressed the transgene following receptor activator of NFkappaB ligand/macrophage colony-stimulating factor stimulation. In conclusion, when compared with the 2.2-kb BC portion of the (TRAP) promoter region, the 1.6-kb C portion does not account for significant gene expression in vivo or in vitro; production of the bone- and spleen-preferred (TRAP) C transcript must depend on regulatory elements outside of the 2.2-kb promoter. As the majority of currently investigated transcription factors that influence transcriptional regulation of osteoclast gene expression bind within the 1.6-kb C portion of the (TRAP) promoter, it is likely that transcription binding sites outside of the 2.2-kb region will have profound effects on regulation of the gene in vivo and in vitro.