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126 results on '"Hardwick, Simon A."'

1. Single-nuclei isoform RNA sequencing unlocks barcoded exon connectivity in frozen brain tissue

Author

Hardwick, Simon A., Hu, Wen, Joglekar, Anoushka, Fan, Li, Collier, Paul G., Foord, Careen, Balacco, Jennifer, Lanjewar, Samantha, Sampson, Maureen McGuirk, Koopmans, Frank, Prjibelski, Andrey D., Mikheenko, Alla, Belchikov, Natan, Jarroux, Julien, Lucas, Anne Bergstrom, Palkovits, Miklós, Luo, Wenjie, Milner, Teresa A., Ndhlovu, Lishomwa C., Smit, August B., Trojanowski, John Q., Lee, Virginia M. Y., Fedrigo, Olivier, Sloan, Steven A., Tombácz, Dóra, Ross, M. Elizabeth, Jarvis, Erich, Boldogkői, Zsolt, Gan, Li, and Tilgner, Hagen U.

Published
2022
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3. A spatially resolved brain region- and cell type-specific isoform atlas of the postnatal mouse brain

Author

Joglekar, Anoushka, Prjibelski, Andrey, Mahfouz, Ahmed, Collier, Paul, Lin, Susan, Schlusche, Anna Katharina, Marrocco, Jordan, Williams, Stephen R., Haase, Bettina, Hayes, Ashley, Chew, Jennifer G., Weisenfeld, Neil I., Wong, Man Ying, Stein, Alexander N., Hardwick, Simon A., Hunt, Toby, Wang, Qi, Dieterich, Christoph, Bent, Zachary, Fedrigo, Olivier, Sloan, Steven A., Risso, Davide, Jarvis, Erich D., Flicek, Paul, Luo, Wenjie, Pitt, Geoffrey S., Frankish, Adam, Smit, August B., Ross, M. Elizabeth, and Tilgner, Hagen U.

Published
2021
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5. The role of glutathione in the biochemical mechanism of paraquat toxicity and of other toxicants in the lung

Author

Hardwick, Simon J.

Subjects
615.9
Abstract

Paraquat and nitrofurantoin are proposed to exert their effects by redox cycling and oxidative stress. The aim of the studies presented in this thesis was to clarify the role of glutathione status in the toxicity of these agents. Mice and rats were treated with the glutathione reductase inhibitor 1,3 -bis (2-chloroethyl)-l-nitrosourea (BCNU). The lethality of paraquat was potentiated in both experimental species. BCNU was then employed in studies to develop a novel rat lung slice model with a compromised glutathione reductase activity but normal levels of ATP, NADP(H) and glucose oxidation along with a modest reduction in thiol levels in BCNU pretreated slices. The effects of paraquat, nitrofurantoin and 2, 3-dimethoxy-l, 4- naphthoquinone (a control compound, a 'pure' redox cycler) were assessed in the BCNU compromised model. From these studies it was concluded that, on the basis of biochemical (GSH and ATP levels) and functional assessments (oligoamine and 5-hydroxytryptamine uptake) of toxicity, the effects of paraquat, nitrofurantoin and the quinone were potentiated as a result of inhibition of glutathione reductase, thereby implicating GSH in the toxicity. In addition, it was concluded that paraquat selectively affected the alveolar type I and II cells, whereas nitrofurantoin and the quinone exerted effects throughout the lung slice. Furthermore, it was considered on the basis of these studies that much of the pulmonary GSH is in cell types distinct from the alveolar epithelium. The studies highlighted the insights which can be gained from use of theappropriate functional marker and underline the problems faced when investigating biochemical mechanisms of toxicity in a heterogeneous organ such as the lung. Adenosine uptake into rat lung slices was studied in an attempt to develop a method for assessing endothelial function, as an alternative to 5-hydroxytryptamine accumulation. Studies revealed that o< .-naphthylthiourea (ANTU), an endothelial damaging agent, reduced adenosine uptake, whereas paraquat failed to produce a loss of adenosine uptake, suggesting that adenosine uptake was specific for the endothelium. Studies of adenosine uptake into BCNU compromised lung slices confirmed previous studies with regard to the selectivity of paraquat and the quinone. Furthermore, incubation of lung slices with adenosine resulted in an elevation of pulmonary ATP levels, which may provide another exciting tool for toxicological studies, in vitro. In an attempt to raise pulmonary thiols, animals were treated with phorone which resulted in a significant elevation of GSH in lung and liver of rat and mouse after 48 h. Phorone pretreatment did not confer in vivo or inprotection against paraquat-induced lethality in mouse rat jin vivo or in vitro. Elevation of thiols did, however, confer protection against the endothelial damaging agent ANTU as evidenced by the abolition of mortality, hydrothorax and loss of functional markers. It wasj concluded that the lack of protection against paraquat may arise from a failure to elevate thiols in the cell types which constitute a target for paraquat. These studies implicate GSH in the toxicity of these agents whichexert their effects by oxidative stress and suggest that type I and II cells contain relatively small amounts of GSH. Furthermore, the work has established novel methods for investigating mechanisms of pulmonary toxicity.

Published
1990

7. Single-nuclei isoform RNA sequencing reveals combination patterns of transcript elements across human brain cell types

Author

Hardwick, Simon A, primary, Hu, Wen, additional, Joglekar, Anoushka, additional, Fan, Li, additional, Collier, Paul G, additional, Foord, Careen, additional, Balacco, Jennifer, additional, Belchikov, Natan, additional, Jarroux, Julien, additional, Prjibelski, Andrey D, additional, Mikheenko, Alla, additional, Luo, Wenjie, additional, Milner, Teresa A, additional, Ndhlovu, Lishomwa, additional, Trojanowski, John Q, additional, Lee, Virginia MY, additional, Fedrigo, Olivier, additional, Tombacz, Dora, additional, Ross, Margaret Elizabeth, additional, Jarvis, Erich, additional, Boldogkoi, Zsolt, additional, Gan, Li, additional, and Tilgner, Hagen U, additional

Published
2021
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9. Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development

Author

Joglekar, Anoushka, primary, Prjibelski, Andrey, additional, Mahfouz, Ahmed, additional, Collier, Paul, additional, Lin, Susan, additional, Schlusche, Anna Katharina, additional, Marrocco, Jordan, additional, Williams, Stephen R., additional, Haase, Bettina, additional, Hayes, Ashley, additional, Chew, Jennifer G., additional, Weisenfeld, Neil I, additional, Wong, Man Ying, additional, Stein, Alexander N., additional, Hardwick, Simon, additional, Hunt, Toby, additional, Bent, Zachary, additional, Fedrigo, Olivier, additional, Sloan, Steven A., additional, Risso, Davide, additional, Jarvis, Erich D., additional, Flicek, Paul, additional, Luo, Wenjie, additional, Pitt, Geoffrey S., additional, Frankish, Adam, additional, Smit, August B., additional, Ross, M. Elizabeth, additional, and Tilgner, Hagen U., additional

Published
2020
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12. Designing synthetic spike-in controls for next-generation sequencing and beyond

Author

Hardwick, Simon

Subjects
RNA sequencing, Reference standards, Genomics, Metagenomics, DNA sequencing, Transcriptomics, Spike-in controls
Abstract

Next-generation sequencing (NGS) is a revolutionary tool that can be used for a myriad of applications, ranging from clinical genome sequencing, to gene expression profiling with RNA sequencing (RNA-seq), to the detection of microbes within environmental samples or isolates. However, significant analytical challenges remain with NGS data due to the complexity of genome architecture, as well as a range of biases introduced during library preparation, sequencing and analysis. These biases and challenges can be understood and mitigated through the use of spike-in controls – DNA or RNA oligonucleotides with known sequence and length that are added to samples prior to library preparation. While spike-in controls have previously been developed for transcriptomics, they were designed for technologies that predated the advent of NGS and consequently suffer from several limitations. In this thesis, I present a novel design framework for synthetic spike-in standards (‘sequins’) that can be applied to a range of NGS applications, and demonstrate how sequins can be used as internal controls to assist in the analysis of accompanying samples. In Chapter 1, I develop a set of spliced synthetic RNA standards that are encoded by artificial gene loci on an accompanying in silico chromosome. RNA sequins enable the assessment of important but previously intractable RNA-seq properties including split-read alignment, alternative splicing, isoform-level quantification and fusion gene detection. In Chapter 2, I present the design of a set of DNA sequins comprising a synthetic community of artificial microbial genomes, which can be used in metagenome sequencing and analysis. Importantly, DNA sequins facilitate the accurate resolution of microbial abundance shifts between samples, which are otherwise imperceptible with NGS. Finally, in Chapter 3, I show how RNA sequins can be used in the analysis of complex brain transcriptomes generated using targeted RNA-seq. This includes an assessment of capture efficiency, quantitative accuracy, and the setting of empirical thresholds to distinguish signal from noise. These transcriptomes are presented as an atlas that can be used to link gene expression with neurological phenotypes. The technologies, associated datasets and analytical methods developed herein provide a qualitative and quantitative reference with which to navigate the complexity of genome biology.

Published
2018
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14. Targeted, High-Resolution RNA Sequencing of Non-coding Genomic Regions Associated With Neuropsychiatric Functions

Author

Hardwick, Simon A., primary, Bassett, Samuel D., additional, Kaczorowski, Dominik, additional, Blackburn, James, additional, Barton, Kirston, additional, Bartonicek, Nenad, additional, Carswell, Shaun L., additional, Tilgner, Hagen U., additional, Loy, Clement, additional, Halliday, Glenda, additional, Mercer, Tim R., additional, Smith, Martin A., additional, and Mattick, John S., additional

Published
2019
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16. Designing synthetic spike-in controls for next-generation sequencing and beyond

Author

Mercer, Tim, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, Mattick, John, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, Smith, Martin, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, Hardwick, Simon, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, Mercer, Tim, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, Mattick, John, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, Smith, Martin, Garvan Institute of Medical Research, Faculty of Medicine, UNSW, and Hardwick, Simon, Garvan Institute of Medical Research, Faculty of Medicine, UNSW

Abstract

Next-generation sequencing (NGS) is a revolutionary tool that can be used for a myriad of applications, ranging from clinical genome sequencing, to gene expression profiling with RNA sequencing (RNA-seq), to the detection of microbes within environmental samples or isolates. However, significant analytical challenges remain with NGS data due to the complexity of genome architecture, as well as a range of biases introduced during library preparation, sequencing and analysis. These biases and challenges can be understood and mitigated through the use of spike-in controls – DNA or RNA oligonucleotides with known sequence and length that are added to samples prior to library preparation. While spike-in controls have previously been developed for transcriptomics, they were designed for technologies that predated the advent of NGS and consequently suffer from several limitations. In this thesis, I present a novel design framework for synthetic spike-in standards (‘sequins’) that can be applied to a range of NGS applications, and demonstrate how sequins can be used as internal controls to assist in the analysis of accompanying samples. In Chapter 1, I develop a set of spliced synthetic RNA standards that are encoded by artificial gene loci on an accompanying in silico chromosome. RNA sequins enable the assessment of important but previously intractable RNA-seq properties including split-read alignment, alternative splicing, isoform-level quantification and fusion gene detection. In Chapter 2, I present the design of a set of DNA sequins comprising a synthetic community of artificial microbial genomes, which can be used in metagenome sequencing and analysis. Importantly, DNA sequins facilitate the accurate resolution of microbial abundance shifts between samples, which are otherwise imperceptible with NGS. Finally, in Chapter 3, I show how RNA sequins can be used in the analysis of complex brain transcriptomes generated using targeted RNA-seq. This includes an assessment of

Published
2018

29. Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband

Author

Hardwick, Simon A, primary, Reuter, Kirsten, additional, Williamson, Sarah L, additional, Vasudevan, Vidya, additional, Donald, Jennifer, additional, Slater, Katrina, additional, Bennetts, Bruce, additional, Bebbington, Ami, additional, Leonard, Helen, additional, Williams, Simon R, additional, Smith, Robert L, additional, Cloosterman, Desiree, additional, and Christodoulou, John, additional

Published
2007
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31. Sintering Performance of Magnetite–Hematite–Goethite and Hematite–Goethite Iron Ore Blends and Microstructure of Products of Sintering.

Author

Ooi, TzeChean, Campbell-Hardwick, Simon, Zhu, Deqing, and Pan, Jian

Subjects
*SINTERING, *MAGNETITE, *IRON ores, *MICROSTRUCTURE, *HEMATITE, *CHEMICAL kinetics
Abstract

Parallel experimentation allowing comparison of magnetite–hematite–goethite inland and hematite–goethite coastal mill blends in terms of sintering performance is reported. Magnetite–hematite–goethite blend affords slightly lower productivity, tumble index, and yield than hematite–goethite blend. However, magnetite–hematite–goethite blend required 9.2 kg · t−1lower solid fuel rate than the hematite–goethite blend. The lower sintering temperature of the magnetite–hematite–goethite blend than that of the hematite–goethite blend contributed to higher reducibility and lower low temperature degradation under reduction. Its sinter product also contained lower proportions of columnar silico-ferrite of calcium and alumina, magnetite, and fayalite. [ABSTRACT FROM PUBLISHER]

Published
2014
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42. Gene cassettes encoding resistance to quaternary ammonium compounds: a role in the origin of clinical class 1 integrons?

Author

Gillings, Michael R., Xuejun, Duan, Hardwick, Simon A., Holley, Marita P., and Stokes, H. W.

Subjects
PATHOGENIC microorganisms, DRUG resistance in microorganisms, BIOLOGICAL evolution, GENETICS, BACTERIAL transformation, TRANSPOSONS, QUATERNARY ammonium salts, MICROBIAL genetics
Abstract

DNA sequencing, phylogenetic and mapping studies suggest that the class 1 integron found in pathogens arose when one member of the diverse family of environmental class 1 integrons became embedded into a Tn402 transposon. However, the timing of this event and the selective forces that first fixed the newly formed element in a bacterial lineage are still unknown. Biocides have a longer use in clinical practice than antibiotics, and a qac (quaternary ammonium compound) resistance gene, or remnant thereof, is a normal feature of class 1 integrons recovered from clinical isolates. Consequently, it is possible that the initial selective advantage was conferred by resistance to biocides, mediated by qac. Here, we show that diverse qac gene cassettes are a dominant feature of cassette arrays from environmental class 1 integrons, and that they occur in the absence of any antibiotic resistance gene cassettes. They are present in arrays that are dynamic, acquiring and rearranging gene cassettes within the arrays. The abundance of qac gene cassettes makes them a likely candidate for participation in the original insertion into Tn402, and as a source of a readily selectable phenotype. More broadly, the increasing use of qac and other biocides at the present time seems likely to promote the fixation of further novel genetic elements, with unpredictable and potentially adverse consequences for human health and agriculture.The ISME Journal (2009) 3, 209–215; doi:10.1038/ismej.2008.98; published online 16 October 2008 [ABSTRACT FROM AUTHOR]

Published
2009
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44. Administrative aspects of the Uganda election--December 1980: a comparison with Zimbabwe.

Author

Hardwick, Simon

Subjects
ELECTIONS, LEGITIMACY of governments, POLITICAL science
Abstract

Since international observers were used to give legitimacy both to the Uganda and Zimbabwe elections in 1980 there is an obvious point of comparison between them. Despite this initial similarity comparing the administration of the elections in the two emphasizes the differences and draws attention to the administrative problems in Uganda resulting from the use of a law and procedures which derived from different circumstances in the country and which assumed an experience in operating elections which was largely lacking. This article explains problems encountered and points to lessons to be learnt. [ABSTRACT FROM AUTHOR]

Published
1982
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45. Changes in elemental concentrations are associated with early stages of apoptosis in human monocyte–macrophages exposed to oxidized low-density lipoprotein: an X-ray microanalytical study

Author

Skepper, Jeremy N., Karydis, Ioannis, Garnett, Matthew R., Hegyi, Laszlo, Hardwick, Simon J., Warley, Alice, Mitchinson, Malcolm J., and Cary, Nat R. B.

Abstract

This study examines ion homeostasis in monocyte–macrophages committed to death by apoptosis. X-ray microanalysis has been used to demonstrate that intracellular concentrations of potassium decreased whilst those of sodium increased following 3 h of exposure to 100 µg/ml of oxidized low-density lipoprotein (LDL) in vitro. In contrast, the maximal incidence of cell death, as determined by the inability to exclude trypan blue, was not seen until 24 h of exposure. At 12 h, less than 1 per cent of cells were stained using terminal transferase-mediated DNA nick-end labelling, which is generally accepted as a marker of late stages in the apoptotic pathway. This is the first demonstration of early perturbations of ion homeostasis in monocyte–macrophages exposed to concentrations of oxidized LDL known to cause apoptosis. Copyright © 1999 John Wiley & Sons, Ltd.

Published
1999

47. Tablet patent wars Down Under.

Author

Tyacke, Nicholas, Collins, John, and Hardwick, Simon

Subjects
PATENT infringement, INJUNCTIONS, ACTIONS & defenses (Law)
Abstract

The article discusses the court case Apple Inc. v Samsung Electronics Co. Ltd. on granting of preliminary injunctions by the Australia courts. The case focuses on the war of Apple over smartphone and Android tablet manufacturers alleged to infringe its patents. The court rules on the unwillingness of Samsung to accept an early hearing date in November 2011 for the balance of convenience.

Published
2011

50. Funds' day out.

Author

Hardwick, Simon and Small, Elizabeth

Subjects
*REAL estate investment, *INVESTORS, *RATE of return, *CAPITAL investments, *REAL estate development
Abstract

The article examines the potential of property investment funds as an alternative for investors in Great Britain. The author explains that these funds could be the perfect product where investors can find an adequate return on their capital without assuming an unacceptable degree of risk. Moreover, investors in these funds will be able to enjoy substantial tax breaks.

Published
2007

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