University General - Research Publications
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ItemA multilevel study of neighborhood disadvantage, individual socioeconomic position, and body mass index: Exploring cross-level interaction effects(ELSEVIER, 2019-06)This study examined associations between neighborhood disadvantage and body mass index (BMI), and tested whether this differed by level of individual socioeconomic position (SEP). Data were from 9953 residents living in 200 neighborhoods in Brisbane, Australia in 2007. Multilevel linear regression analyses were undertaken by gender to determine associations between neighborhood disadvantage, individual SEP (education, occupation and household income) and BMI (from self-reported height and weight); with cross-level interactions testing whether the relationship between neighborhood disadvantage and BMI differed by level of individual SEP. Both men (Quintile 4, where Quintile 5 is the most disadvantaged β = 0.66 95%CI 0.20, 1.12) and women (Quintile 5 β = 1.32 95%CI 0.76, 1.87) from more disadvantaged neighborhoods had a higher BMI. BMI was significantly higher for those with lower educational attainment (men β = 0.71 95%CI 0.36, 1.07 and women β = 1.66 95%CI 0.78, 1.54), and significantly lower for those in blue collar occupations (men β = -0.67 95%CI -1.09, -0.25 and women β = -0.71 95%CI -1.40, -0.01). Among men, those with a lower income had a significantly lower BMI, while the opposite was found among women. None of the interaction models had a significantly better fit than the random intercept models. The relationship between neighborhood disadvantage and BMI did not differ by level of education, occupation, or household income. This suggests that individual SEP is unlikely to be an effector modifier of the relationship between neighborhood disadvantage and BMI. Further research is required to assist policy-makers to make more informed decisions about where to intervene to counteract BMI-inequalities.
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ItemHuman papillomavirus vaccination and genital warts in young Indigenous Australians: national sentinel surveillance data(Australasian Medical Publishing Company, 2017-03-20)OBJECTIVES: To examine the impact of the national human papillomavirus (HPV) vaccination program (available to girls and women [12-26 years] since 2007 and to boys [12-15 years] since 2013) on the number of diagnoses of genital warts in Australian Aboriginal and Torres Strait Islander (Indigenous) people. DESIGN, SETTING, PARTICIPANTS: Analysis of routinely collected data from patients attending 39 sexual health clinics (SHCs) in the Genital Warts Surveillance Network for the first time.Major outcome: The average annual proportion of Indigenous and non-Indigenous SHC patients diagnosed with genital warts during the pre-vaccination (2004-2007) and vaccination periods (2008-2014), stratified by age group and sex. RESULTS: 7.3% of the 215 599 Australian-born patients with known Indigenous status and seen for the first time at participating SHCs during 2004-2014 were Indigenous Australians. The average proportion of female Indigenous patients diagnosed with warts was lower during the vaccination period than during the pre-vaccination period (in those under 21, summary rate ratio [SRR], 0.12; 95% CI, 0.07-0.21; P < 0.001); in 21-30-year olds: SRR, 0.41; 95% CI, 0.27-0.61; P < 0.001); there was no significant difference for women over 30 (SRR, 0.84; 95% CI, 0.51-1.36; P = 0.47). The proportion of male Indigenous heterosexual SHC patients under 21 diagnosed with warts was also lower during the vaccination period (SRR, 0.25; 95% CI, 0.12-0.49; P < 0.001), with no significant changes among older Indigenous men over 30. CONCLUSIONS: There were marked declines in the proportions of diagnoses of genital warts in young Indigenous women and men attending SHCs after the introduction of the HPV vaccination program. If high levels of HPV vaccine coverage are sustained, HPV-related cancer rates should also decline.
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ItemNovel 1-Methyl-1H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity(American Chemical Society, 2019-03-15)A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure–activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.
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ItemStructure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development(AMER CHEMICAL SOC, 2019-01-24)Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.
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ItemOptimization of Novel 1-Methyl-1H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm(AMER CHEMICAL SOC, 2018-12-13)A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 μM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 μM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 μM.
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ItemDeguelin exerts potent nematocidal activity via the mitochondrial respiratory chain(WILEY, 2017-10)As a result of limited classes of anthelmintics and an over-reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant-derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real-time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic (Haemonchus contortus) and free-living (Caenorhabditis elegans) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.-Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B. C. H., Gijs, M. A. M., Sternberg, P. W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R. B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain.
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ItemScreening of a small, well-curated natural product-based library identifies two rotenoids with potent nematocidal activity against Haemonchus contortus(ELSEVIER SCIENCE BV, 2017-09-15)The control of parasitic roundworms (nematodes) is heavily reliant on the use of a limited number of anthelmintic drugs. However, drug resistance is now very widespread and no vaccines are available, such that the discovery of new chemical entities is crucial. Within this context, we screened a library of pure natural products (n=400) against exsheathed third-stage (xL3) larvae of the parasitic nematode Haemonchus contortus using a whole-organism screening method. We identified two plant-derived rotenoids, deguelin and rotenone, with inhibitory activity on xL3 motility. Rotenone was not investigated further, because of its toxicity to some vertebrates. The dose response and cytotoxicity studies showed potent and selective inhibitory activity of deguelin on motility of xL3 larvae of H. contortus. Detailed future work needs to be conducted to explore the mode of action of this compound on H. contortus and related nematodes, and to assess its potential as an anthelmintic candidate.
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ItemReal-Time Urban Microclimate Analysis Using Internet of Things(IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC, 2018-04)Real-time environment monitoring and analysis is an important research area of Internet of Things (IoT). Understanding the behavior of the complex ecosystem requires analysis of detailed observations of an environment over a range of different conditions. One such example in urban areas includes the study of tree canopy cover over the microclimate environment using heterogeneous sensor data. There are several challenges that need to be addressed, such as obtaining reliable and detailed observations over monitoring area, detecting unusual events from data, and visualizing events in real-time in a way that is easily understandable by the end users (e.g., city councils). In this regard, we propose an integrated geovisualization framework, built for real-time wireless sensor network data on the synergy of computational intelligence and visual methods, to analyze complex patterns of urban microclimate. A Bayesian maximum entropy-based method and a hyperellipsoidal model-based algorithm have been build in our integrated framework to address above challenges. The proposed integrated framework was verified using the dataset from an indoor and two outdoor network of IoT devices deployed at two strategically selected locations in Melbourne, Australia. The data from these deployments are used for evaluation and demonstration of these components' functionality along with the designed interactive visualization components.
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ItemMid-infrared Magnetic Mirror Based on a Hybrid Metal/Dielectric Metasurface(IEEE, 2018)We propose a hybrid metal/dielectric metasurface that functions as a mid-infrared magnetic mirror. It consists amorphous silicon cuboids on gold. The physical mechanism is explained by image theory. Measured reflection spectra agree with simulations.