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(1998)Journal ArticleThe first results obtained using a SOI device for microdosimetry applications are presented. Microbeam and broadbeam spectroscopy methods are used for determining minority carrier lifetime and radiation damage constants. A spectroscopy model is presented which includes the majority of effects that impact spectral resolution. Charge collection statistics were found to substantially affect spectral resolution. Lateral diffusion effects significantly complicate charge collection
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(2013)Journal ArticleBackground and Objectives: Thought-action fusion (TAF), or maladaptive cognitions regarding the relationship between mental events and behaviours, has been implicated in the development and maintenance of obsessive-compulsive disorder (OCD). As some religions promote TAF-like appraisals, it has been proposed that religiosity may play a role in the transformation of normally occurring intrusive thoughts into clinically distressing obsessions. No research, however, has experimentally investigated the mediating role of TAF on the relationship between religiosity and OC symptoms. Methods: 85 Christian, Jewish, and Atheist/Agnostic participants were exposed to an experimental thought-induction protocol and reported on their associated levels of distress, guilt, feelings of responsibility, and urge to suppress target intrusions experienced during a 5-minute monitoring period. Participants also completed measures of obsessive-compulsive symptomatology, TAF beliefs, and general psychopathology. Results: Using PROCESS and bootstrapping analyses, a test of the conditional indirect effects of religiosity on obsessive-compulsive symptoms revealed that Christianity moderated the effects of religiosity on moral TAF beliefs, which in turn mediated the relationship between religiosity and obsessive-compulsive symptoms. Furthermore, in the Christian group, moral TAF beliefs mediated the relationship between religiosity and ratings of guilt and responsibility following the experimental protocol. Limitations: The use of university students with moderate levels of religiosity. Conclusions: Collectively the results suggest that obsessional thinking is not attributable to religion per se, but that teachings underlying certain religious doctrines may fuel TAF beliefs that are implicated in the maintenance of OCD.
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(2012)Journal ArticleThe CACCC-box binding protein erythroid Krüppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Krüppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119(+). Consistent with this, microarray analysis of both TER119(-) and TER119(+) erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis.
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(2009)Journal ArticleBACKGROUND: Circumcision status was examined as an independent risk factor for sexually transmissible infections (STIs) in the Health in Men cohort of homosexual men in Sydney. METHODS: From 2001 through 2004, 1427 initially human immunodeficiency virus (HIV)-negative men were enrolled and followed up until mid-2007. All participants were offered annual STI testing. The history of STIs was collected at baseline, and information on sexual risk behaviors was collected every 6 months. At annual face-to-face visits, participants reported STI diagnoses received during the previous year. RESULTS: Circumcision was not associated with prevalent or incident herpes simplex virus 1, herpes simplex virus 2, or self-reported genital warts. There was also no independent association of circumcision with incident urethral gonorrhea or chlamydia. Being circumcised was associated with a significantly reduced risk of incident (hazard ratio, 0.35 [95% confidence interval, 0.15-0.84]) but not prevalent (odds ratio, 0.71 [95% confidence interval, 0.35-1.44]) syphilis. The association was somewhat stronger among men who reported predominantly insertive unprotected anal intercourse (hazard ratio, 0.10 [95% confidence interval, 0.01-0.82]). CONCLUSIONS: These are the first prospective data obtained from homosexual men to assess circumcision status as a risk factor for STIs. Circumcised men were at reduced risk of incident syphilis but no other prevalent or incident STIs. Circumcision is unlikely to have a substantial public health impact in reducing acquisition of most STIs in homosexual men.
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(2020)ThesisPseudomonas aeruginosa causes both contact lens and non-contact lens-related keratitis (corneal infection). This opportunistic bacterium naturally has the ability to resist the mechanism of action of many antibiotics which are used for treatment. P. aeruginosa resistance patterns and the mechanism of resistance in isolates from keratitis are not well understood. This thesis described the phenotypic and genotypic patterns of antimicrobial resistance and compared these between ocular isolates of P. aeruginosa from Australia (contact lens) and India (non-contact lens). Changes in the antimicrobial susceptibility between isolates over time were also analysed. Susceptibility to antibiotics, multipurpose disinfecting solutions and disinfectants was analysed for twenty-seven Australian isolates from contact lens-related keratitis and forty non-contact lens-related isolated from India. The whole genomes of fourteen Australian (historical and recent) and twelve Indian isolates were sequenced using Illumina® MiSeq®. Computational analysis of the genomes was performed to analyse their core and pan genomes and these were examined for the presence of acquired resistance genes, virulence genes, gene mutations, and these compared to their phenotypic resistance to antibiotics. Indian isolates possessed large pan genomes with more acquired resistance (30) genes and larger numbers of genetic variations. The Indian isolates contained clones of three sequence types ST308, ST316 and ST491, whereas Australian isolates contained only one sequence type ST233. Isolates with larger gene variations had mutations in the DNA mismatch repair system. Most multi-drug resistant Indian (non-contact lens) isolates were exoU +. Indian isolates had large accessory genes compared to Australian isolates and this increased the pan genome size of the Indian isolates. The number of core genome mutations were larger in the Indian isolates a median of 50006 (IQR=26967-50600) compared to Australian isolates a median of 26317 (IQR=25681-33780). There were differences between isolates from Australia and India with respect to their antibiotic resistance and associated genes. Indian strains had more genetic diversity and were multi-drug resistant. However, there was no evidence of substantial genetic or phenotypic changes within isolates from their respective countries.
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(2020)ThesisSirtuins (SIRTs) comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, capable of affecting health-span and DNA expression. In cell-culture and peripheral-tissue models, researchers have identified that SIRT1 and SIRT2 are also capable of changing enzymatic activity in glycolysis and Krebs cycle. In brain, the impact of SIRT1 and SIRT2 deacetylase activity on metabolism is poorly understood. The aim of this project was to determine if metabolic pathways in brain could be regulated by SIRT1 and SIRT2-mediated deacetylation in mammalian systems. An established ex vivo reductionist model of brain metabolism was used to test the hypothesis that direct inhibition, activation or ablation of SIRT1 or SIRT2 deacetylase activity would result in significant changes in brain metabolism. Alterations in brain metabolism were assessed by examining changes in 13C-enriched substrates, and metabolite pools with 13C and 1H nuclear magnetic resonance spectroscopy. Chapter three provides evidence that approximately 30% of the GABA synthesized from [1,2-13C]acetate was made directly in neurons. Activation of neuronal specific SIRT1 caused an increase in the incorporation of [1,2-13C]acetate into brain, while activation of astrocytes with potassium depolarization caused a decrease in [1,2-13C]acetate incorporation. These results indicate that acetate is not a reliable marker, nor exclusively metabolised in astrocytes. Further, brain metabolism of acetate is modulated through enzyme acetylation regulated by SIRT1 deacetylase activity. Results in chapter four posit that activation of SIRT1 with SRT 1720 directly stimulated incorporation of 13C into Krebs cycle intermediates and reduced incorporation into lactate. Several off-target effects were observed for SIRT1 activator resveratrol and SIRT1 inhibitory EX-527 that questions their suitability for study of SIRT1 activity. Chapter five concludes that inhibition of SIRT deacetylase activity by AGK2 produced an effect consistent with glutamatergic AMPA receptor activation, in keeping with known SIRT2 targets. Potent SIRT2 inhibitor C64 increased 13C label incorporation into GABA from [1-13C]D-glucose in guinea pigs, and glutamine from [1,2-13C]acetate in WT mice, an effect that was also observed in SIRT2 KO mice. These results indicate that SIRT2 deacetylase activity may impact neurotransmitter systems. This thesis supports the theory that SIRT1 and SIRT2 deacetylase activity can influence brain metabolism in mammalian systems.
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(2023)ThesisPluripotent stem cell-derived cardiomyocytes (hPSC–CM) have great importance for predicting safety parameters for pharmaceutical compounds and models of healthy versus disease states of the human heart. In recent years, there has been an insistence that all new pharmaceutical products are tested on in vitro models for potential proarrhythmic effects and the increased demand for improved biomimetic hPSC-CM in pharmaceutical safety assays such as the Comprehensive in vitro Proarrhythmic Assay (CiPA). In addition, hPSC-CM are being utilised in cell therapies to treat and reverse the effects of ischaemic heart disease, offering potential cures for cardiovascular diseases instead of treatments for delaying progressive heart failure. In the first part of this thesis, I will examine how purified extracellular matrix proteins (ECMPs) can influence pluripotent stem cell (PSC) behaviour and how we may use this to precondition cardiac progenitor lineage specifications. I use array-based techniques to investigate how protein combinations affect proliferation, pluripotency, germ layer, and cardiac progenitors. This method allows us to visualise how individual proteins can affect cells' behaviour in a larger array whilst highlighting how specific combinations can precondition pluripotent cells towards a cardiomyocyte lineage. This combinatorial approach led to the identification of several unique matrices that promote differentiation, which will aid efforts at producing therapeutically useful cell types with greater efficiency. In the second part of this thesis, I demonstrate a novel bioreactor that attenuates a magnetic field to dynamically modulate the stiffness of magnetoactive hydrogel to look at how biomimetic dynamic stiffening of a substrate can influence cardiomyocyte lineage specification. We investigate how biomimetic in vivo mechanics may influence cell fate by following the expression profiles of cells in different dynamic environments. Non-invasive electromagnetic signals affect substrate stiffness when combined with magnetic particles and magnetic fibres and how this can help direct cell orientation and accompanying lineage specification Finally, I investigate how variability in cell phenotypes and expression patterns are influenced by biomimetic cues and how these variabilities could be utilised in future safety assessment protocols and cell therapy treatments for cardiovascular disease.