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Kingsbury J.M.,Duke University | Kingsbury J.M.,The Institute of Environmental Science and Research | Shamaprasad N.,Duke University | Billmyre R.B.,Duke University | And 2 more authors.
Human Molecular Genetics | Year: 2015

Amajor advance in understanding the progression and prognostic outcome of certain cancers, such as low-grade gliomas, acute myeloid leukaemia, and chondrosarcomas, has been the identification of early-occurring mutations in the NADP+-dependent isocitrate dehydrogenase genes IDH1 and IDH2. These mutations result in the production of the onco-metabolite D-2-hydroxyglutarate (2HG), thought to contribute to disease progression. To better understand the mechanisms of 2HG pathophysiology, we introduced the analogous glioma-associated mutations into the NADP+isocitrate dehydrogenase genes (IDP1, IDP2, IDP3) inSaccharomyces cerevisiae. Intriguingly, expression of themitochondrial IDP1R148H mutant allele results in high levels of 2HG production as well as extensivemtDNA loss and respiration defects. We find no evidence for a reactive oxygen-mediatedmechanism mediating this mtDNA loss. Instead, we show that 2HG production perturbs the iron sensingmechanisms as indicated by upregulation of the Aft1-controlled iron regulon and a concomitant increase in iron levels. Accordingly, iron chelation, or overexpression of a truncated AFT1 allele that dampens transcription of the iron regulon, suppresses the loss of respirative capacity. Additional suppressing factors include overexpression of themitochondrial aldehyde dehydrogenase gene ALD5 or disruption of the retrograde response transcription factor RTG1. Furthermore, elevated α-ketoglutarate levels also suppress 2HG-mediated respiration loss; consistent with a mechanism by which 2HG contributes to mtDNA loss by acting as a toxic α-ketoglutarate analog. Our findings provide insight into themechanisms thatmay contribute to 2HG oncogenicity in glioma and acutemyeloid leukaemia progression, with the promise for innovative diagnostic and prognostic strategies and novel therapeuticmodalities. © The Author 2016. Published by Oxford University Press. All rights reserved.


Stotesbury T.,Trent University | Illes M.,Trent University | Jermy M.,University of Canterbury | Taylor M.,The Institute of Environmental Science and Research | And 2 more authors.
Forensic Science International | Year: 2016

This research uses high-speed video analysis of bloodstain impact events to investigate the influence of impact velocity, fluid depth and free-space on the characteristics of the mechanism. We focus on the changes in the crown growth over time. This work demonstrates qualitative differences in the impact mechanism under a range of impact conditions. These differences are further explained quantitatively as a function of measured crown width and height lengths over time. Fluid dynamic explanations of this growth are featured in the results and discussion. A comparison to water dynamics is reported. Our image analysis demonstrates that droplets are consistently formed at points which are different from the impactor/fluid interface and that this difference is fluid dependent. This fluid dependency demonstrates the importance of accurately modeling fluid dynamics of blood when designing and deploying blood substitutes in forensics applications. © 2016 Elsevier Ireland Ltd


PubMed | The Institute of Environmental Science and Research and Community and Public Health
Type: Journal Article | Journal: Journal of water and health | Year: 2014

Outbreaks of waterborne gastroenteritis continue to occur in developed countries. Darfield, a rural town in the South Island of New Zealand experienced an outbreak of campylobacteriosis following a transgression of Escherichia coli on 16 August 2012. A descriptive outbreak investigation was performed. As a result, 29 cases had a laboratory-confirmed diagnosis of campylobacteriosis and 138 were identified as probable cases. Heavy rains, contamination of water with animal effluent from nearby paddocks and failures in the treatment of drinking water led to pathogens being distributed through the towns water supply. A multi-barrier approach is advocated to ensure the quality of water and many countries have legislation or programmes to address this. Although legislation for water safety plans based on a multi-barrier approach is in place in New Zealand, at the time of the outbreak it was not a requirement for the Darfield water supply. In addition, despite the awareness of the importance of a multi-barrier approach, competing interests, including those from the agricultural industry and financial restraints on water suppliers, can prevent it from being implemented. Governments need to be more willing to enforce legislation and standards to protect the public from waterborne disease.


Peacey M.,The Institute of Environmental Science and Research | Hall R.J.,The Institute of Environmental Science and Research | Wang J.,The Institute of Environmental Science and Research | Todd A.K.,The Institute of Environmental Science and Research | And 5 more authors.
PLoS ONE | Year: 2013

Enterovirus 74 (EV74) is a rarely detected viral infection of children. In 2010, EV74 was identified in New Zealand in a 2 year old child with acute flaccid paralysis (AFP) through routine polio AFP surveillance. A further three cases of EV74 were identified in children within six months. These cases are the first report of EV74 in New Zealand. In this study we describe the near complete genome sequence of four EV74 isolates from New Zealand, which shows only limited sequence identity in the non-structural proteins when compared to the other two known EV74 sequences. As is typical of enteroviruses multiple recombination events were evident, particularly in the P2 region and P3 regions. This is the first complete EV74 genome sequenced from a patient with acute flaccid paralysis. © 2013 Peacey et al.


Peacey M.,The Institute of Environmental Science and Research | Hall R.J.,The Institute of Environmental Science and Research | Sonnberg S.,The Institute of Environmental Science and Research | Sonnberg S.,Stjude Childrens Research Hospital | And 10 more authors.
Emerging Infectious Diseases | Year: 2010

Co-infection with seasonal infl uenza A (H1N1) and pandemic (H1N1) 2009 could result in reassortant viruses that may acquire new characteristics of transmission, virulence, and oseltamivir susceptibility. Results from oseltamivir-sensitivity testing on viral culture suggested the possibility of co-infections with oseltamivir-resistant (seasonal A [H1N1]) and -susceptible (pandemic [H1N1] 2009) viruses.


PubMed | The Institute of Environmental Science and Research
Type: Journal Article | Journal: Emerging infectious diseases | Year: 2010

Co-infection with seasonal influenza A (H1N1) and pandemic (H1N1) 2009 could result in reassortant viruses that may acquire new characteristics of transmission, virulence, and oseltamivir susceptibility. Results from oseltamivir-sensitivity testing on viral culture suggested the possibility of co-infections with oseltamivir-resistant (seasonal A [H1N1]) and -susceptible (pandemic [H1N1] 2009) viruses.


PubMed | The Institute of Environmental Science and Research
Type: Journal Article | Journal: PloS one | Year: 2013

Enterovirus 74 (EV74) is a rarely detected viral infection of children. In 2010, EV74 was identified in New Zealand in a 2 year old child with acute flaccid paralysis (AFP) through routine polio AFP surveillance. A further three cases of EV74 were identified in children within six months. These cases are the first report of EV74 in New Zealand. In this study we describe the near complete genome sequence of four EV74 isolates from New Zealand, which shows only limited sequence identity in the non-structural proteins when compared to the other two known EV74 sequences. As is typical of enteroviruses multiple recombination events were evident, particularly in the P2 region and P3 regions. This is the first complete EV74 genome sequenced from a patient with acute flaccid paralysis.

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