ORCID Profile
0000-0002-5922-7643
Current Organisations
University of Melbourne
,
University of Sydney
,
University of Technology Sydney
,
Peter Doherty Institute
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Biochemistry and Cell Biology | Analytical Biochemistry | Computer Software not elsewhere classified | Systems Biology | Analytical Spectrometry | Cell Neurochemistry
Neurodegenerative Disorders Related to Ageing | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in the Chemical Sciences | Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified | Application Software Packages (excl. Computer Games) |
Publisher: Wiley
Date: 28-03-2019
DOI: 10.1111/JNC.14676
Abstract: Treatment with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson's disease pathogenesis has raised concern about potentiation of oxidative stress by l-DOPA. The rate of DA quinone formation increases in the presence of excess redox-active iron (Fe), which is a pathological hallmark of Parkinson's disease. Conversely, l-DOPA has pH-dependent Fe-chelating properties, and may act to 'redox silence' Fe and partially allay DA autoxidation. We examined the effects of l-DOPA in three murine models of parkinsonian neurodegeneration: early-life Fe overexposure in wild-type mice, transgenic human (h)A53T mutant α-synuclein (α-syn) over-expression, and a combined 'multi-hit' model of Fe-overload in hA53T mice. We found that l-DOPA was neuroprotective and prevented age-related Fe accumulation in the substantia nigra pars compacta (SNc), similar to the mild-affinity Fe chelator clioquinol. Chronic l-DOPA treatment showed no evidence of increased oxidative stress in wild-type midbrain and normalized motor performance, when excess Fe was present. Similarly, l-DOPA also did not exacerbate protein oxidation levels in hA53T mice, with or without excess nigral Fe, and showed evidence of neuroprotection. The effects of l-DOPA in Fe-fed hA53T mice were somewhat muted, suggesting that Fe-chelation alone is insufficient to attenuate neuron loss in an animal model also recapitulating altered DA metabolism. In summary, we found no evidence in any of our model systems that l-DOPA treatment accentuated neurodegeneration, suggesting DA replacement therapy does not contribute to oxidative stress in the Parkinson's disease brain.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6AY02545E
Abstract: Dried micro-droplets were used to characterise the formation of polyatomic interferences by LA-ICP-MS.
Publisher: Oxford University Press (OUP)
Date: 08-03-2016
DOI: 10.1093/BRAIN/AWW022
Abstract: Iron accumulation is a cardinal feature of degenerating regions in the Parkinson's disease brain. As a potent pro-oxidant, redox-active iron may be a key player in upstream mechanisms that precipitate cell death in this disorder. Although an elevation in brain iron levels is a normal feature of ageing, the increase is greater in Parkinson's disease on the other hand, the effects of the disease are most marked in the nigrostriatal dopaminergic system. In this Update, we explain that neurodegeneration in the affected regions may result from the potent redox couple formed by iron and dopamine itself, and discuss the clinical implications of this molecular trait in this dynamic and rapidly moving area of Parkinson's disease research.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C6MT00260A
Abstract: The biological transition metals iron (Fe), copper (Cu) and zinc (Zn) are thought to contribute to the neuronal pathologies that occur following traumatic brain injury (TBI), and indeed our previously published work in young (3 month-old) mice clearly demonstrates a significant spatiotemporal modulation of metals following TBI. Of note, however, is the literature observation that there is both an apparent detrimental effect of aging on TBI outcomes and an alteration in metals and their various transporters with normal advancing age. Therefore, to determine whether there was an interaction between aging, metals and TBI, we have utilised laser ablation-inductively coupled plasma-mass spectrometry to examine the spatial and temporal distribution of Fe, Zn and Cu following an acute controlled cortical impact brain injury in aged (24 months) rodents. The relative abundance of metals in corresponding regions within the ipsilateral and contralateral hemispheres as well as the hippoc us was assessed. Substantial region and time point specific alterations in Fe, Zn and Cu were identified immediately and up to 28 days post-TBI. The data from this follow-up study has also been compared to our previous data from young animals, and aged mice exhibit an appreciably enhanced and persistent elevation of all metals in every region surveyed, with in idual metal disparities at various time points observed post-injury. This may potentially contribute to the acceleration in the onset of cognitive decline and neurological disease that has been observed in the aged population following head trauma.
Publisher: American Chemical Society (ACS)
Date: 10-04-2012
DOI: 10.1021/AC300374X
Abstract: Atlases depicting molecular and functional features of the brain are becoming an integral part of modern neuroscience. In this study we used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICPMS) to quantitatively measure iron (Fe), copper (Cu), and zinc (Zn) levels in a serially sectioned C57BL/6 mouse brain (cerebrum and brainstem). Forty-six sections were analyzed in a single experiment of approximately 158 h in duration. We constructed a 46-plate reference atlas by aligning quantified images of metal distribution with corresponding coronal sections from the Allen Mouse Brain Reference Atlas. The 46 plates were also used to construct three-dimensional models of Fe, Cu, and Zn distribution. This atlas represents the first reconstruction of quantitative trace metal distribution through the brain by LA-ICPMS and will facilitate the study of trace metals in the brain and help to elucidate their role in neurobiology.
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.NUT.2015.05.005
Abstract: The Brazilian Amazon region has selenium (Se)-rich soil, which is associated with higher Se levels in populations fed locally grown produce. Brazil nuts are a major source of dietary Se and are included with meals offered to children enrolled in public preschool in Macapá. The aim of this study was to examine Se intake and status of these children. The Macapá group consisted of 41 children from a public preschool who received 15 to 30 g of Brazil nuts 3 d/wk. The control group included 88 children from the nearby city of Belém who did not receive Brazil nut-enriched meals. In both groups, school meals comprised ≥90% of the children's total food consumption. Selenium was assessed using hydride generation quartz tube atomic absorption spectroscopy in plasma, erythrocytes, nails, hair and urine. Dietary intakes (macronutrients and Se) were evaluated using the duplicate-portion method. Both groups received inadequate intakes of energy and macronutrients. Selenium intake was excessive in both groups (155.30 and 44.40 μg/d, in Macapá and Belém, respectively). Intake was potentially toxic in Macapá on days when Brazil nuts were added to meals. Although biomarkers of Se exposure exceeded reference levels in the Macapá group, no clinical symptoms of Se overload (selenosis) were observed. The inclusion of Brazil nuts in school meals provided to children with already high dietary Se intakes increased Se levels and may result in an increased risk for toxicity. As selenosis is associated with some chronic diseases, we recommend continued monitoring of Se intake and status in this population.
Publisher: Public Library of Science (PLoS)
Date: 28-02-2013
Publisher: Springer Science and Business Media LLC
Date: 22-05-2013
DOI: 10.1038/NATURE12169
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5SC02231B
Abstract: Studying the neuroanatomy of the mouse brain using imaging mass spectrometry and chemometric analysis.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.TINS.2018.04.005
Abstract: Interplay between genetic and environmental factors during critical time windows can have effects that span from neurodevelopment to neurodegeneration. We present the concept of the 'neuroexposome', emphasizing the brain's distinctive response to environmental exposure, and how current 'omics' sciences can inform on both disease pathogenesis and future public health policies.
Publisher: Oxford University Press (OUP)
Date: 2013
DOI: 10.1039/C2MT20151H
Abstract: Disturbances in brain copper result in rare and severe neurological disorders and may play a role in the pathogenesis and progression of multiple neurodegenerative diseases. Our current understanding of mammalian brain copper transport is based on model systems outside the central nervous system and no data are available regarding copper transport systems in the human brain. To address this deficit, we quantified regional copper concentrations and examined the distribution and cellular localization of the copper transport proteins Copper transporter 1, Atox1, ATP7A, and ATP7B in multiple regions of the human brain using inductively coupled plasma-mass spectrometry, Western blot and immunohistochemistry. We identified significant relationships between copper transporter levels and brain copper concentrations, supporting a role for these proteins in copper transport in the human brain. Interestingly, the substantia nigra contained twice as much copper than that in other brain regions, suggesting an important role for copper in this brain region. Furthermore, ATP7A levels were significantly greater in the cerebellum, compared with other brain regions, supporting an important role for ATP7A in cerebellar neuronal health. This study provides novel data regarding copper regulation in the human brain, critical to understand the mechanisms by which brain copper levels can be altered, leading to neurological disease.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.JDENT.2011.03.004
Abstract: In this study we present the application of a novel laboratory method that employs laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to construct two-dimensional maps of trace elements in teeth. Teeth were sectioned longitudinally, embedded in resin and polished to a smooth surface. Data were generated by laser ablating the entire sectioned tooth surface. Elemental images were constructed using custom-built software. Quantified images of (66)Zn, (88)Sr, (111)Cd and (208)Pb, with a spatial resolution of 30 μm(2), were generated from three teeth. Concentrations were determined by single-point calibration against NIST SRM 1486 (bone meal). Zn and Sr concentrations were determined in the μg g(-1) range and Cd and Pb in the ng g(-1) range. Concentrations of Pb, Zn and Cd were higher in dentine particularly in regions adjacent the pulp. Elemental bio-imaging employing LA-ICP-MS is a novel method for constructing μm-scale maps of trace elements in teeth. This simple imaging method displays the heterogeneity of trace elements throughout the tooth structure that correspond to specific structural and developmental features of teeth. As a preliminary study, this work demonstrates the capabilities of LA-ICP-MS imaging in dental research.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5RA23953B
Abstract: Elemental imaging using laser ablation inductively coupled plasma mass spectrometry was performed on whole leaves of the hyperaccumulating plant Noccaea caerulescens after treatments with either Ni, Zn or Cd.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5CS00055F
Abstract: A Tutorial Review to aid in designing the most comprehensive metal imaging experiments for biological s les.
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.CHEMBIOL.2018.05.004
Abstract: Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence of SOD1 mutations in PD highlights mounting evidence that SOD1 mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration.
Publisher: American Chemical Society (ACS)
Date: 10-03-2010
DOI: 10.1021/AC902650W
Abstract: Internal exposure from naturally occurring radionuclides (including the inhaled long-lived actinides (232)Th and (238)U) is a component of the ubiquitous background radiation dose (National Council on Radiation Protection and Measurements. Ionizing radiation exposure of the population of the United States NCRP Report No. 160 NCRP: Bethesda, MD, 2009). It is of interest to compare the concentration distribution of these natural alpha-emitters in the lungs and respiratory lymph nodes with those resulting from occupational exposure, including exposure to anthropogenic plutonium and depleted and enriched uranium. This study examines the application of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICPMS) to quantifying and visualizing the mass distribution of uranium and thorium isotopes from both occupational and natural background exposure in human respiratory tissues and, for the first time, extends this application to the direct imaging of plutonium isotopes. Sections of lymphatic and lung tissues taken from deceased former nuclear workers with a known history of occupational exposure to specific actinide elements (uranium, plutonium, or americium) were analyzed by LA-ICPMS. Using a previously developed LA-ICPMS protocol for elemental bio-imaging of trace elements in human tissue and a new software tool, we generated images of thorium ((232)Th), uranium ((235)U and (238)U), and plutonium ((239)Pu and (240)Pu) mass distributions in sections of tissue. We used a laboratory-produced matrix-matched standard to quantify the (232)Th, (235)U, and (238)U concentrations. The plutonium isotopes (239)Pu and (240)Pu were detected by LA-ICPMS in 65 mum diameter localized regions of both a paratracheal lymph node and a s le of lung tissue from a person who was occupationally exposed to refractory plutonium (plutonium dioxide). The average (overall) (239)Pu concentration in the lymph node was 39.2 ng/g, measured by high purity germanium (HPGe) gamma-spectrometry (Lynch, T. P. Tolmachev, S. Y. James, A. C. Radiat. Prot. Dosim. 2009, 134, 94-101). Localized mass concentrations of thorium ((232)Th) and uranium ((238)U) in lymph node tissue from a person not occupationally exposed to these elements (chronic natural background inhalation exposure) ranged up to 400 and 375 ng/g, respectively. In lung s les of occupationally nonexposed to thorium and uranium workers, (232)Th and (238)U concentrations ranged up to 200 and 170 ng/g, respectively. In a person occupationally exposed to air-oxidized uranium metal (Adley, F. E. Gill, W. E. Scott, R. H. Study of atmospheric contaminiation in the melt plant buiding. HW-23352(Rev.) United States Atomic Energy Commission: Oakridge, TN, 1952, p 1-97), the maximum (235)U and (238)U isotopic mass concentrations in a lymph node, measured at higher resolution (with a 30 mum laser spot diameter), were 70 and 8500 ng/g, respectively. The ratio of these simultaneously measured mass concentrations signifies natural uranium. The current technique was not sufficiently sensitive, even with a 65 mum laser spot diameter, to detect (241)Am (at an overall tissue concentration of 0.024 ng/g, i.e., 3 Bq/g).
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1186/S13643-019-1185-3
Abstract: Direct supplementation or food fortification with iron are two public health initiatives intended to reduce the prevalence of iron deficiency (ID) and iron deficiency anaemia (IDA) in 4–24-month-old infants. In most high-income countries where IDA prevalence is 15%, the recommended daily intake levels of iron from supplements and/or consumption of fortified food products are at odds with World Health Organisation (WHO) guidelines that recommend shorter-term (3 months/year) supplementation only in populations with IDA prevalence 40%. Emerging concerns about delayed neurological effects of early-life iron overexposure have raised questions as to whether recommended guidelines in high-income countries are unnecessarily excessive. This systematic review will gather evidence from supplementation/fortification trials, comparing health outcomes in studies where iron-replete children did or did not receive additional dietary iron and determine if replete children at study outset were not receiving additional iron show changes in haematological indices of ID/IDA over the trial duration. We will perform a systematic review of the literature, including all studies of iron supplementation and/or fortification, including study arms with confirmed iron-replete infants at the commencement of the trial. This includes both dietary iron intervention or placebo/average dietary intakes. One reviewer will conduct searches in electronic databases of published and ongoing trials (Medline, Web of Science, Scopus, CENTRAL, EBSCO [e.g. CINAHL Complete, Food Science and Technology Abstracts], Embase, ClinicalTrials.gov, ClinicalTrialsRegister.eu and who.it/trialsearch), digital theses and dissertations (WorldCat, Networked Digital Library of Theses and Dissertations, DART-Europe E-theses Portal, Australasian Digital Theses Program, Theses Canada Portal and ProQuest). For eligible studies, one reviewer will use a data extraction form, and a second reviewing entered data for accuracy. Both reviewers will independently perform quality assessments before qualitative and, if appropriate, quantitative synthesis as a meta-analysis. We will resolve any discrepancies through discussion or consult a third author to resolve discrepancies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement will be used as the basis for reporting. Recommended iron supplementation and food fortification practices in high-income countries have been criticised for being both excessive and based on outdated or underpowered studies. This systematic review will build a case for revisiting iron intake guidelines for infants through the design of new trials where health effects of additional iron intake in iron-replete infants are the primary outcome. PROSPERO CRD42018093744.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.TINS.2019.04.003
Abstract: The relationship between neurons and perineuronal nets (PNNs) is attracting attention as a central mechanism controlling brain plasticity. In the cortex, PNNs primarily surround inhibitory parvalbumin interneurons, playing roles as both a regulator of synaptic plasticity and a protective barrier. PNNs have a delayed developmental trajectory and are key components in the closure of critical periods of heightened neuroplasticity. In animal models, manipulating PNNs outside this critical window can enhance cognition, suggesting a potentially therapeutic approach for attenuating cognitive decline. However, the crucial role of PNNs in plasticity and protection means that such therapeutic modulation must strike a careful balance: manipulation of PNNs to promote plasticity may have unintended negative consequences resulting from excessive plasticity or from exposure of neurons to neurotoxins.
Publisher: Elsevier BV
Date: 02-2018
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5JA00293A
Abstract: Elemental bio-imaging using the technological advances of ICP-QQQ-MS.
Publisher: Oxford University Press (OUP)
Date: 2014
DOI: 10.1039/C4MT00060A
Abstract: Serum zinc decreases with age.
Publisher: Oxford University Press (OUP)
Date: 2013
DOI: 10.1039/C2MT20164J
Abstract: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a potent toxin used to selectively destroy dopaminergic neurons in the substantia nigra and induce parkinsonism. MPTP is metabolised to the 1-methyl-4-phenylpyridinium ion (MPP(+)) in glia, after which it enters the neuron via the dopamine transporter and results in elevated levels of oxidative stress. The mechanism through which MPP(+) causes cell death is thought to involve redox-active metals, particularly iron (Fe). This review will examine how cellular metal metabolism is altered following MPTP insult, and how this relates to metal dyshomeostasis in idiopathic Parkinson's disease. This includes both cell damage arising from increased metal concentration, and how metal-binding proteins respond to MPTP-induced neurotoxicity. Implications for using MPTP as a model for human Parkinson's disease will be discussed in terms of cell metallobiology.
Publisher: Oxford University Press (OUP)
Date: 2015
DOI: 10.1039/C4MT00258J
Abstract: Following acute brain injury ( hours post-event), cobalt levels in the brain are significantly elevated. This elevation may have important implications for positron emission tomography neuroimaging for assessing brain injury severity.
Publisher: Oxford University Press (OUP)
Date: 24-12-2020
DOI: 10.1039/C9MT00267G
Abstract: A dysregulation in the homeostasis of metals such as copper, iron and zinc is speculated to be involved in the pathogenesis of tauopathies, which includes Alzheimer's disease (AD). In particular, there is a growing body of evidence to support a role for iron in facilitating the hyperphosphorylation and aggregation of the tau protein into neurofibrillary tangles (NFTs) – a primary neuropathological hallmark of tauopathies. Therefore, the aim of this study was to characterize the spatial and temporal brain metallomic profile in a mouse model of tauopathy (rTg(tauP301L)4510), so as to provide some insight into the potential interaction between tau pathology and iron. Using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), our results revealed an age-dependent increase in brain iron levels in both WT and rTg(tauP301L)4510 mice. In addition, size exclusion chromatography-ICP-MS (SEC-ICP-MS) revealed significant age-related changes in iron bound to metalloproteins such as ferritin. The outcomes from this study may provide valuable insight into the inter-relationship between iron and tau in ageing and neurodegeneration.
Publisher: Springer Science and Business Media LLC
Date: 15-09-2018
DOI: 10.1007/S00216-018-1362-6
Abstract: Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) analysis of μ-droplets is becoming an attractive alternative for detecting and quantifying elements in biological s les. With minimal s le preparation required and detection limits comparable to solution nebulisation ICP-MS, μ-droplets have substantial advantages over traditional elemental detection, particularly for low volumes, such as aliquots taken from s les required for multiple independent biochemical assays, or fluids and tissues where elements of interest exist at native concentrations not suited to the necessary dilution steps required for solution nebulisation ICP-MS. However, the characteristics of μ-droplet residue deposition are heavily dependent on the matrix, and potential effects on signal suppression or enhancement have not been fully characterised. We present a validated and flexible high-throughput method for quantification of elements in μ-droplets using LA-ICP-MS imaging and matrix-matched external calibrants. Imaging the entire μ-droplet area removes analytical uncertainty arising from the often-heterogenous distribution when compared to radial or bisecting line scans that capture only a small portion of the droplet residue. We examined the effects of common matrices found in a standard biochemistry workflow, including native protein and salt contents, as well as reagents used in typical preparation steps for concurrent biochemical assays, such as total protein quantification and enzyme activity assays. We found that matrix composition results in systemic, concentration-dependent signal enhancement and suppression for carbon, whereas high sodium content has a specific space-charge-like suppression effect on high masses. We confirmed the accuracy of our method using both a certified serum standard (Seronorm™ L1) and independent measurements of analysed s les by solution nebulisation ICP-MS, then tested the specificity and reproducibility by examining spinal cord tissue homogenates from SOD1-G93A transgenic mice with a known molecular phenotype of increased copper- and zinc-binding superoxide dismutase-1 expression and altered copper-to-zinc stoichiometry. The method presented is rapid and transferable to multiple other biological matrices and allows high-throughput analysis of low-volume s les with sensitivity comparable to standard solution nebulisation ICP-MS protocols. Graphical Abstract ᅟ.
Publisher: Oxford University Press (OUP)
Date: 2009
DOI: 10.1039/B901310P
Publisher: Cold Spring Harbor Laboratory
Date: 29-04-2022
DOI: 10.1101/2022.04.28.489869
Abstract: Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). Finally, we utilised the SOD1 G37R mouse model of ALS and a novel CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo . We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Moreover, a molecular correlation between ferroptosis and neurotoxic astrocytes evident in ALS-affected spinal cord is recapitulated in the SOD1 G37R mouse model where treatment with the novel, CNS-permeant ferroptosis inhibitor, Cu II (atsm), ameliorated these markers and was neuroprotective. By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease.
Publisher: Springer Vienna
Date: 2012
Publisher: Springer New York
Date: 2017
Publisher: Royal Society of Chemistry (RSC)
Date: 2011
DOI: 10.1039/C0JA00267D
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/B911316A
Publisher: Oxford University Press (OUP)
Date: 10-2013
DOI: 10.5665/SLEEP.3038
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5AN02544C
Abstract: A comparison of complementary methods to quantify biometals per in idual for analytical biochemical studies using microscopic model organisms.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6RA22084C
Abstract: This paper describes a proof-of-concept study using SEC-ICP-MS to profile changes in metalloproteins during Caenorhabditis elegans development.
Publisher: American Chemical Society (ACS)
Date: 09-06-2015
DOI: 10.1021/ACS.ANALCHEM.5B01454
Abstract: Redox-active metals in the brain mediate numerous biochemical processes and are also implicated in a number of neurodegenerative diseases. A number of different approaches are available for quantitatively measuring the spatial distribution of biometals at an image resolution approaching the subcellular level. Measured biometal levels obtained using laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS spatial resolution 15 μm × 15 μm) were within the range of those obtained using X-ray fluorescence microscopy (XFM spatial resolution 2 μm × 7 μm) and regional changes in metal concentration across discrete brain regions were replicated to the same degree. Both techniques are well suited to profiling changes in regional biometal distribution between healthy and diseased brain tissues, but absolute quantitation of metal levels varied significantly between methods, depending on the metal of interest. Where all possible variables affect metal levels, independent of a treatment henotype are controlled, either method is suitable for examining differences between experimental groups, though, as with any method for imaging post mortem brain tissue, care should be taken when interpreting the total metal levels with regard to physiological concentrations.
Publisher: Springer Science and Business Media LLC
Date: 25-10-2016
DOI: 10.1038/MP.2016.196
Abstract: Glutathione peroxidase 4 (GPx4) is an antioxidant enzyme reported as an inhibitor of ferroptosis, a recently discovered non-apoptotic form of cell death. This pathway was initially described in cancer cells and has since been identified in hippoc al and renal cells. In this Perspective, we propose that inhibition of ferroptosis by GPx4 provides protective mechanisms against neurodegeneration. In addition, we suggest that selenium deficiency enhances susceptibility to ferroptotic processes, as well as other programmed cell death pathways due to a reduction in GPx4 activity. We review recent studies of GPx4 with an emphasis on neuronal protection, and discuss the relevance of selenium levels on its enzymatic activity.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2018
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5SC00233H
Abstract: Synchrotron-based X-ray fluorescence imaging and metalloproteomics reveals a loss of iron homeostasis in ageing Caenorhabditis elegans .
Publisher: Society for Neuroscience
Date: 18-02-2015
DOI: 10.1523/JNEUROSCI.2912-14.2015
Abstract: The extracellular accumulation of amyloid β (Aβ) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Aβ, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from Aβ:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Aβ fibrillar polymerization and direct depolymerization of existing Aβ fibrils. In the present study, we find that CQ and PBT2 can interact directly with Aβ and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Aβ associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Aβ with an affinity of 1–10 μ m and suppress the formation of large ( kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Aβ toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Aβ oligomer formation through stabilization of small (dimeric) nontoxic Aβ conformers.
Publisher: Oxford University Press (OUP)
Date: 2018
DOI: 10.1039/C8MT00068A
Abstract: Zinc (Zn) deficiency is a clinical consequence of brain injury that can result in neuropathological outcomes that are exacerbated with age.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.CHEMBIOL.2017.10.006
Abstract: A picture may speak a thousand words, but if those words fail to form a coherent sentence there is little to be learned. As cutting-edge imaging technology now provides us the tools to decipher the multitude of roles played by metals and metalloids in molecular, cellular, and developmental biology, as well as health and disease, it is time to reflect on the advances made in imaging, the limitations discovered, and the future of a burgeoning field. In this Perspective, the current state of the art is discussed from a self-imposed contrarian position, as we not only highlight the major advances made over the years but use them as teachable moments to zoom in on challenges that remain to be overcome. We also describe the steps being taken toward being able to paint a completely undisturbed picture of cellular metal metabolism, which is, metaphorically speaking, the Holy Grail of the discipline.
Publisher: Springer Science and Business Media LLC
Date: 23-06-2015
DOI: 10.1038/NRNEUROL.2015.100
Abstract: The effects of iron deficiency are well documented, but relatively little is known about the long-term implications of iron overload during development. High levels of redox-active iron in the brain have been associated with neurodegenerative disorders, most notably Parkinson disease, yet a gradual increase in brain iron seems to be a feature of normal ageing. Increased brain iron levels might result from intake of infant formula that is excessively fortified with iron, thereby altering the trajectory of brain iron uptake and lifying the risk of iron-associated neurodegeneration in later life. In this Perspectives article, we discuss the potential long-term implications of excessive iron intake in early life, propose the analysis of iron deposits in teeth as a method for retrospective determination of iron exposure during critical developmental windows, and call for evidence-based optimization of the chemical composition of infant dietary supplements.
Publisher: Oxford University Press (OUP)
Date: 2013
DOI: 10.1039/C3MT00227F
Abstract: Metals often determine the chemical reactivity of the proteins to which they are bound. Each cell in the body tightly maintains a unique metalloproteomic profile, mostly dependent on function. This paper describes an analytical online flow injection quantitative size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) method, which was applied to profiling the metal-binding proteins found in primary cultures of neurons and astrocytes. This method can be conducted using similar amounts of s le to those used for Western blotting (20-150 μg protein), and has a turnaround time of <15 minutes. Metalloprotein standards for Fe (as ferritin), Cu and Zn (as superoxide dismutase-1) were used to construct multi-point calibration curves for online quantification of metalloproteins by SEC-ICP-MS. Homogenates of primary neuron and astrocyte cultures were analysed by SEC-ICP-MS. Online quantification by external calibration with metalloprotein standards determined the mass of metal eluting from the column relative to time (as pg s(-1)). Total on-column Fe, Cu and Zn detection limits ranged from 0.825 ± 0.005 ng to 13.6 ± 0.7 pg. Neurons and astrocytes exhibited distinct metalloprotein profiles, featuring both ubiquitous and unique metalloprotein species. Separation and detection by SEC-ICP-MS allows appraisal of these metalloproteins in their native state, and online quantification was achieved using this relatively simple external calibration process.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C7MT90013A
Publisher: Society for Neuroscience
Date: 04-06-2014
Publisher: Springer Science and Business Media LLC
Date: 05-01-2017
DOI: 10.1038/S41531-016-0004-Y
Abstract: Iron accumulates gradually in the ageing brain. In Parkinson’s disease, iron deposition within the substantia nigra is further increased, contributing to a heightened pro-oxidant environment in dopaminergic neurons. We hypothesise that in iduals in high-income countries, where cereals and infant formulae have historically been fortified with iron, experience increased early-life iron exposure that predisposes them to age-related iron accumulation in the brain. Combined with genetic factors that limit iron regulatory capacity and/or dopamine metabolism, this may increase the risk of Parkinson’s diseases. We propose to (a) validate a retrospective biomarker of iron exposure in children (b) translate this biomarker to adults (c) integrate it with in vivo brain iron in Parkinson’s disease and (d) longitudinally examine the relationships between early-life iron exposure and metabolism, brain iron deposition and Parkinson’s disease risk. This approach will provide empirical evidence to support therapeutically addressing brain iron deposition in Parkinson’s diseases and produce a potential biomarker of Parkinson’s disease risk in preclinical in iduals.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C5FO01270H
Abstract: Selenoproteins play important roles in antioxidant mechanisms, but it is hypothesised that single polymorphism nucleotides (SNPs) may affect their function.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.SCITOTENV.2016.07.054
Abstract: Mercury is potent toxicant element, but its toxicity can be reduced by forming a complex with selenium for safe excretion. Considering the impact of mercury exposure in the Amazon region and the possible interaction between these two elements, we aimed to assess the effects of Pro198Leu polymorphism to GPX1 and GSTM1 deletion, on mercury levels in a population from Porto Velho, an urban locality in the Brazilian Amazon region. Two hundred women from the capital city of Rondônia state were recruited for this study with 149 deemed suitable to participate. We assessed dietary intake using 24-hour recall. Selenium levels in plasma and erythrocytes were measured using hydride generation quartz tube atomic absorption spectroscopy and total hair mercury using cold vapor atomic absorption spectrometry. Oxidative stress parameters (GPx activity, oxygen radical absorbency capacity [ORAC] and malondialdehyde [MDA]) were also analyzed. All participants were genotyped for Pro198Leu polymorphism and GSTM1 deletion. We observed that this population presented high prevalence of selenium deficiency, and also low levels of mercury, likely due to food habits that did not include selenium-rich food sources or significant consumption of fish (mercury biomagnifiers) regularly. Univariate statistical analysis showed that Pro198Leu and GSTM1 genotypes did not affect selenium and mercury levels in this population. Pro198Leu polymorphism and GSTM1 deletion had no effect on mercury levels in mildly exposed people, suggesting these genetic variants impact mercury levels only in highly exposed populations.
Publisher: Springer Science and Business Media LLC
Date: 21-03-2016
DOI: 10.1038/SREP22684
Abstract: Scientific Reports 6: Article number: 20350 published online: 10 February 2016 updated: 21 March 2016 In this Article, the online methods were omitted. The online methods should read: Strains Wild type C. elegans (strain N2) were obtained from the Caenorhabditis Genetics Center (University of Minnesota), and ftn-2(ok404) and the ferritin null ftn-2(ok404) ftn-1(ok3625) (strain GMC005) have been previously described 1 .
Publisher: Frontiers Media SA
Date: 26-11-2018
Publisher: Wiley
Date: 06-03-2022
DOI: 10.1002/JCSM.12950
Abstract: Oxidative stress is implicated in the pathophysiology of Duchenne muscular dystrophy (DMD, caused by mutations in the dystrophin gene), which is the most common and severe of the muscular dystrophies. To our knowledge, the distribution of iron, an important modulator of oxidative stress, has not been assessed in DMD. We tested the hypotheses that iron accumulation occurs in mouse models of DMD and that modulation of iron through the diet or chelation could modify disease severity. We assessed iron distribution and total elemental iron using LA‐ICP‐MS on skeletal muscle cross‐sections of 8‐week‐old Bl10 control mice and dystrophic mdx mice (with moderate dystrophy) and dystrophin/utrophin‐null mice ( dko , with severe dystrophy). In addition, mdx mice (4 weeks) were treated with either an iron chelator (deferiprone 150 mg/kg/day) or iron‐enriched feed (containing 1% added iron as carbonyl iron). Immunoblotting was used to determine the abundance of iron‐ and mitochondria‐related proteins. (Immuno)histochemical and mRNA assessments of fibrosis and inflammation were also performed. We observed a significant increase in total elemental iron in hindlimb muscles of dko mice (+50%, P 0.05) and in the diaphragm of mdx mice (+80%, P 0.05), with both tissues exhibiting severe pathology. Iron dyshomeostasis was further evidenced by an increase in the storage protein ferritin ( dko : +39%, P 0.05) and ferroportin compared with Bl10 control mice ( mdx : +152% and dko : +175%, P 0.05). Despite having features of iron overload, dystrophic muscles had lower protein expression of ALAS‐1, the rate‐limiting enzyme for haem synthesis ( dko −44%, P 0.05), and the haem‐containing protein myoglobin ( dko −54%, P 0.05). Deferiprone treatment tended to decrease muscle iron levels in mdx mice (−30%, P 0.1), which was associated with lower oxidative stress and fibrosis, but suppressed haem‐containing proteins and mitochondrial content. Increasing iron via dietary intervention elevated total muscle iron (+25%, P 0.05) but did not aggravate the pathology. Muscles from dystrophic mice have increased iron levels and dysregulated iron‐related proteins that are associated with dystrophic pathology. Muscle iron levels were manipulated by iron chelation and iron enriched feed. Iron chelation reduced fibrosis and reactive oxygen species (ROS) but also suppressed haem‐containing proteins and mitochondrial activity. Conversely, iron supplementation increased ferritin and haem‐containing proteins but did not alter ROS, fibrosis, or mitochondrial activity. Further studies are required to investigate the contribution of impaired ferritin breakdown in the dysregulation of iron homeostasis in DMD.
Publisher: MDPI AG
Date: 13-08-2021
DOI: 10.3390/IJMS22168715
Abstract: Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C7MT00047B
Abstract: There are numerous blood-based biomarkers for assessing iron stores, but all come with certain limitations. Hepcidin is a hormone primarily produced in the liver that has been proposed as the 'master regulator' of dietary uptake and iron metabolism, and has enormous potential to provide a 'real time' indicator of body iron levels. In this Minireview, the biochemical function of hepcidin in regulating iron levels will be discussed, with a specific focus on how hepcidin can aid in the assessment of iron stores and clinical diagnosis of iron deficiency, iron deficiency anaemia and other iron-related disorders. The role hepcidin itself plays in diseases of iron metabolism will be examined, and current efforts to translate hepcidin assays into the clinic will be critically appraised. Potential limitations of hepcidin as a marker of iron need will also be addressed, as well as the development of new therapies that directly target the hormone that sits atop the hierarchy of systemic iron metabolism.
Publisher: Elsevier
Date: 2017
Publisher: Elsevier BV
Date: 06-2017
Publisher: American Chemical Society (ACS)
Date: 03-05-2017
DOI: 10.1021/ACSCHEMNEURO.7B00014
Abstract: The antioxidant activity of selenium, which is mainly conferred by its incorporation into dedicated selenoproteins, has been suggested as a possible neuroprotective approach for mitigating neuronal loss in Alzheimer's disease. However, there is inconsistent information with respect to selenium levels in the Alzheimer's disease brain. We examined the concentration and cellular compartmentalization of selenium in the temporal cortex of Alzheimer's disease and control brain tissue. We found that Alzheimer's disease was associated with decreased selenium concentration in both soluble (i.e., cytosolic) and insoluble (i.e., plaques and tangles) fractions of brain homogenates. The presence of the APOE ε4 allele correlated with lower total selenium levels in the temporal cortex and a higher concentration of soluble selenium. Additionally, we found that age significantly contributed to lower selenium concentrations in the peripheral membrane-bound and vesicular fractions. Our findings suggest a relevant interaction between APOE ε4 and selenium delivery into brain, and show changes in cellular selenium distribution in the Alzheimer's disease brain.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.NBD.2014.12.012
Abstract: Zinc transporter-3 (ZnT3) protein is responsible for loading zinc into presynaptic vesicles and consequently controls the availability of zinc at the glutamatergic synapse. ZnT3 has been shown to decline with age and in Alzheimer's disease (AD) and is crucially involved in learning and memory. In this study, we utilised whole animal behavioural analyses in the ZnT3 KO mouse line, together with electrophysiological analysis of long-term potentiation in brain slices from ZnT3 KO mice, to show that metal chaperones (clioquinol, 30 mg/kg/day for 6weeks) can prevent the age-dependent cognitive phenotype that characterises these animals. This likely occurs as a result of a homeostatic restoration of synaptic protein expression, as clioquinol significantly restored levels of various pre- and postsynaptic proteins that are critical for normal cognition, including PSD-95 AMPAR and NMDAR2b. We hypothesised that this clioquinol-mediated restoration of synaptic health resulted from a selective increase in synaptic zinc content within the hippoc us. While we demonstrated a small regional increase in hippoc al zinc content using synchrotron x-ray fluorescence microscopy, further sub-region analyses are required to determine whether this effect is seen in other regions of the hippoc al formation that are more closely linked to the synaptic plasticity effects observed in this study. These data support our recent report on the use of a different metal chaperone (PBT2) to prevent normal age-related cognitive decline and demonstrate that metal chaperones are efficacious in preventing the zinc-mediated cognitive decline that characterises ageing and disease.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C5MT00234F
Abstract: A LA-ICP-MS time course study of changing metal concentrations following traumatic brain injury in mice.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C7MT00012J
Abstract: Despite the importance of transition metals for normal brain function, relatively little is known about the distribution of these elemental species across the different tissue compartments of the primate brain. In this study, we employed laser ablation-inductively coupled plasma-mass spectrometry on PFA-fixed brain sections obtained from two adult common marmosets. Concurrent cytoarchitectonic, myeloarchitectonic, and chemoarchitectonic measurements allowed for identification of the major neocortical, archaecortical, and subcortical isions of the brain, and precise localisation of iron, manganese, and zinc concentrations within each ision. Major findings across tissue compartments included: (1) differentiation of white matter tracts from grey matter based on manganese and zinc distribution (2) high iron concentrations in the basal ganglia, cortex, and substantia nigra (3) co-localization of high concentrations of iron and manganese in the primary sensory areas of the cerebral cortex and (4) high manganese in the hippoc us. The marmoset has become a model species of choice for connectomic, aging, and transgenic studies in primates, and the application of metallomics to these disciplines has the potential to yield high translational and basic science value.
Publisher: American Chemical Society (ACS)
Date: 21-05-2021
DOI: 10.1021/ACS.CHEMREV.0C01219
Abstract: Elemental imaging gives insight into the fundamental chemical makeup of living organisms. Every cell on Earth is comprised of a complex and dynamic mixture of the chemical elements that define structure and function. Many disease states feature a disturbance in elemental homeostasis, and understanding how, and most importantly where, has driven the development of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) as the principal elemental imaging technique for biologists. This review provides an outline of ICP-MS technology, laser ablation cell designs, imaging workflows, and methods of quantification. Detailed ex les of imaging applications including analyses of cancers, elemental uptake and accumulation, plant bioimaging, nanomaterials in the environment, and exposure science and neuroscience are presented and discussed. Recent incorporation of immunohistochemical workflows for imaging biomolecules, complementary and multimodal imaging techniques, and image processing methods is also reviewed.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8FO02118J
Abstract: A hypercaloric diet given to adolescent rats induces social memory deficits and reduced neurochemical markers of normal social development.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1016/J.SCITOTENV.2014.05.115
Abstract: Microchemical analysis of otolith (calcified 'ear stones' used for balance and orientation) of fishes is an important tool for studying their environmental history and management. However, the spatial resolution achieved is often too coarse to examine short-term events occurring in early life. Current methods rely on single points or transects across the otolith surface, which may provide a limited view of elemental distributions, a matter that has not previously been investigated. Imaging by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) permits microchemical analyses of short-term events in early life with high ( 97% was achieved using a multi-point non matrix-matched calibration of National Institute of Standards and Technology (NIST) 610 and 612 (trace elements in glass) using Longerich's calculation method against the matrix-matched standard FEBS-1 (powdered red snapper [Lutjanus c echanus] otolith). The spatial resolution achieved in the otolith corresponded to a time period of 2 ± 1 days during the larval phase, and 4 ± 1 days during the post-settlement juvenile phase. This method has the potential to improve interpretations of early life-history events at scales corresponding to specific events. While the images showed gradients in Sr and Ba across the larval settlement zone more clearly than single transects, the method proved s le homogeneity throughout the structure demonstrating that 2D scanning has no significant advantage over line scans.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1AN00546D
Abstract: ATR–FTIR with a machine learning model predicts ESBL genotype of unknown E. coli strains with 86.5% AUC.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.CHEMOSPHERE.2019.124631
Abstract: There is an interdisciplinary interface between analytical chemistry and epidemiology studies with respect to the design, execution, and analysis of environmental epidemiology cohorts and studies. Extracting meaningful results linking chemical exposure to human health outcomes begins at study design and spans the entire workflow. Here we discuss analytical experimental design from an exposure science perspective, and propose a reporting checklist for the design of human biomonitoring studies. We explain key analytical chemistry concepts of blanks and limits of reporting and present a case series of plastic product chemical exposure in prenatal urine specimens from the Barwon Infant Study.
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2AN15792F
Abstract: This review provides analysts with critical insights of current approaches for quantification by laser ablation-inductively coupled plasma-mass spectrometry in the field of elemental imaging. This encompasses both calibration strategies that have been used with success in imaging biological s les, as well as those with potential to improve analytical accuracy and precision if applied to imaging. Methods reviewed include the use of CRMs, laboratory prepared matrix matched standards, internal standardisation, online standard addition and a variety of novel approaches that makes elemental imaging accessible to a wider base of analysts. The importance of quantification and factors affecting its use in imaging will also be considered.
Publisher: Oxford University Press (OUP)
Date: 2009
DOI: 10.1039/B816188G
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0SC02844D
Abstract: Structural and chemical characterisation of microfeatures in unadulterated Parkinson's disease brain tissue using synchrotron nanoscale XFM and ptychography.
Publisher: Elsevier BV
Date: 06-2019
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5RA11241A
Abstract: Accurate assessment of early life lead exposure requires an accessible and reliable biomarker.
Publisher: American Chemical Society (ACS)
Date: 31-10-2017
DOI: 10.1021/ACS.ANALCHEM.7B02817
Abstract: Analytical approaches that preserve the endogenous state of the examined system are essential for the in vivo study of bioinorganics. X-ray fluorescence microscopy of biological s les can map elements in vivo at subcellular resolutions in tissue s les and multicellular organisms. However, X-ray irradiation induces modifications that accumulate with dose. Consequently, the utility of X-ray fluorescence microscopy is intrinsically limited by the radiation damage it causes and the degree to which it alters the target features of interest. Identification of the dose threshold, below which the integrity of the specimen and its elemental distribution is preserved, is required to ensure valid interpretation of concentrations. Here we use the nematode, Caenorhabditis elegans, to explore these issues using three chemical-free specimen preparations: lyophilization, cryofixation, and live. We develop quantitative methods for investigating damage and present dose limits for each preparation pertaining to the micrometer-scale spatial distribution of specific analytes (potassium, calcium, manganese, iron, and zinc), and discuss dose-appropriate guidelines for X-ray fluorescence microscopy of microscale biological s les.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3SC53461H
Abstract: Imaging of iron and dopamine by laser ablation-inductively coupled plasma-mass spectrometry reveals a risk index for parkinsonian neurodegeneration
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C1JA10301F
Publisher: Public Library of Science (PLoS)
Date: 24-08-2017
Publisher: Wiley
Date: 06-10-2023
DOI: 10.1111/JNC.15978
Publisher: American Chemical Society (ACS)
Date: 09-07-2012
DOI: 10.1021/AC301156F
Abstract: Imaging of trace metal distribution in tissue sections by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) is typically performed using spatial resolutions of 30 μm(2) and above. Higher resolution imaging is desirable for many biological applications in order to approach the dimensions of a single cell. The limiting factor for increasing resolution is sensitivity, where signal-to-noise ratios are poor due to inherent background spectral interferences and reduced s le volume with decreasing laser beam diameter. Several prominent spectral interferences are present for a number of biologically relevant isotopes, including the (40)Ar(16)O(+) spectral interference on (56)Fe(+). We examined if H(2) as a reaction gas could improve the analytical performance of imaging experiments for a range of masses with spectral interferences. At low (<1 mL min(-1)) H(2) flow rates, greater spectral interference due to H(+) adducts was observed for (55)Mn, (57)Fe, and (59)Co. At higher flow rates of up to 3 mL H(2) per minute, the spectral interferences were reduced leading to improvement in limits of analysis for masses with O- and N-based polyatomic interferences. Enhanced sensitivity with the reaction cell allowed construction of high resolution (6 μm(2)) imaging of (56)Fe in the mouse brain that approached the dimensions of single cells.
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9JA00423H
Abstract: Integration of quantitative elemental distributions with structural information, allowing novel insights into how tissue development is associated with a dynamic chemical environment.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C6MT00019C
Abstract: We examined serum and erythrocyte lead and manganese levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), which contains over 1000 registrants including over 200 cases of Alzheimer's disease (AD) and 100 mildly cognitively impaired (MCI) in iduals. After correcting for confounding effects of age, collection site and sex, we found a significant decrease in serum manganese levels in AD subjects compared to healthy controls. Analysis of smaller subset of erythrocytes revealed no difference in either lead or manganese levels in AD. Although lead and manganese have neurotoxic effects and may be involved in AD pathology, our results showed that neither metal in serum nor erythrocytes are suitable biomarkers in our cohort. However, prospective studies might reveal whether the burden of either metal modifies disease outcomes.
Publisher: Baishideng Publishing Group Inc.
Date: 21-05-2015
Publisher: American Chemical Society (ACS)
Date: 07-01-2016
DOI: 10.1021/ACSCHEMNEURO.5B00305
Abstract: Increased nigral iron (Fe) is a cardinal feature of Parkinson's disease, as is the accumulation of aggregates comprising α-synuclein. We used wild-type mice and transgenic mice overexpressing the human A53T mutation to α-synuclein to examine the influence of increased Fe (days 10-17 postpartum) on the parkinsonian development phenotype of these animals (including abnormal nigral Fe levels and deficits in both cell numbers and locomotor activity), and to explore the impact of the Fe chelator clioquinol in the model. Both untreated and Fe-loaded A53T mice showed similar levels of nigral cell loss, though 5 months of clioquinol treatment was only able to prevent the loss in the non-Fe-loaded A53T group. Iron levels in the Fe-loaded A53T mice returned to normal at 8 months, though effects of dopamine denervation remained, demonstrated by limited locomotor activity and sustained neuron loss. These data suggest that Fe exposure during a critical developmental window, combined with the overexpression mutant α-synuclein, presents a disease phenotype resistant to intervention using clioquinol later in life.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2016
Publisher: American Chemical Society (ACS)
Date: 23-01-2015
DOI: 10.1021/CN5003557
Abstract: Plasma iron levels are decreased in Alzheimer's disease (AD) and associated with an idiopathic anemia. We examined iron-binding plasma proteins from AD patients and healthy controls from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing using size exclusion chromatography-inductively coupled plasma-mass spectrometry. Peak area corresponding to transferrin (Tf) saturation was directly compared to routine pathological testing. We found a significant decrease in transferrin-associated iron in AD that was missed by routine pathological tests of transferrin saturation, and that was able to discriminate between AD and controls. The AD cases showed no significant difference in transferrin concentration, only a decrease in total transferrin-bound iron. These findings support that a previously identified decrease in plasma iron levels in AD patients within the AIBL study is attributable to decreased loading of iron into transferrin, and that this subtle but discriminatory change is not observed through routine pathological testing.
Publisher: Hindawi Limited
Date: 2013
DOI: 10.1155/2013/623241
Abstract: Alzheimer’s disease (AD) is the leading cause of dementia and represents a significant burden on the global economy and society. The role of transition metals, in particular copper (Cu), in AD has become of significant interest due to the dyshomeostasis of these essential elements, which can impart profound effects on cell viability and neuronal function. We tested the hypothesis that there is a systemic perturbation in Cu compartmentalization in AD, within the brain as well as in the periphery, specifically within erythrocytes. Our results showed that the previously reported decrease in Cu within the human frontal cortex was confined to the soluble ( P 0.05 ) and total homogenate ( P 0.05 ) fractions. No differences were observed in Cu concentration in erythrocytes. Our data indicate that there is a brain specific alteration in Cu levels in AD localized to the soluble extracted material, which is not reflected in erythrocytes. Further studies using metalloproteomics approaches will be able to elucidate the metabolic mechanism(s) that results in the decreased brain Cu levels during the progression of AD.
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1SC02237G
Abstract: Digital pathology and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging reveals a unique elemental signature of colorectal cancer.
Publisher: Oxford University Press (OUP)
Date: 2017
DOI: 10.1039/C7MT00244K
Abstract: Altered iron and copper levels in the Parkinson's disease substantia nigra are confined to the cytosolic compartment of the cell.
Publisher: Wiley
Date: 20-08-2019
DOI: 10.1111/ACEL.13031
Abstract: Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady‐state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.
Publisher: Oxford University Press (OUP)
Date: 2016
DOI: 10.1039/C5MT00288E
Abstract: A unified approach to chemical imaging was used to spatially profile essential bio-elements in Caenorhabditis elegans .
Publisher: Springer Science and Business Media LLC
Date: 28-06-2017
DOI: 10.1186/S40478-017-0456-2
Abstract: Elevated iron in the SNpc may play a key role in Parkinson’s disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology . In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C4AN02283A
Abstract: Triple–quadrupole ICP-MS using O 2 mass-shift technology is superior for removing gadolinium interference on selenium in serum.
Publisher: American Chemical Society (ACS)
Date: 22-12-2017
DOI: 10.1021/ACSCHEMNEURO.6B00362
Abstract: The metal ions of iron, copper, and zinc have long been associated with the aggregation of β-amyloid (Aβ) plaques in Alzheimer's disease an interaction that has been suggested to promote increased oxidative stress and neuronal dysfunction. We examined plaque metal load in the hippoc us of APP/PS1 mice using X-ray fluorescence microscopy to assess how the anatomical location of Aβ plaques was influenced by the metal content of surrounding tissue. Immunohistochemical staining of Aβ plaques colocalized with areas of increased X-ray scattering power in unstained tissue sections, allowing direct X-ray based-assessment of plaque metal levels in sections subjected to minimal chemical fixation. We identified and mapped 48 in idual plaques in four subregions of the hippoc us from four biological replicates. Iron, Cu, and Zn areal concentrations (ng cm
Publisher: Springer New York
Date: 2016
DOI: 10.1007/978-1-4939-2627-5_22
Abstract: Metals are increasingly recognized to have an important role in molecular processes underlying Alzheimer's disease (AD). This chapter discusses the current role of metals in AD and expands on the development of metalloproteomics and how the recent advances in analytical technology will allow detailed investigation of metalloproteins. Investigation of in idual metalloproteins will yield new mechanistic details about the role of metals in AD.
Publisher: Elsevier BV
Date: 07-2018
Publisher: MyJove Corporation
Date: 22-01-2017
DOI: 10.3791/55042
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7CS00610A
Abstract: A ‘how-to’ guide for designing chemical imaging experiments using antibodies and immunohistochemistry.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.NEUROIMAGE.2016.05.057
Abstract: Iron deposition in the brain is a feature of normal aging, though in several neurodegenerative disorders, including Alzheimer's disease, the rate of iron accumulation is more advanced than in age-matched controls. Using laser ablation-inductively coupled plasma-mass spectrometry imaging we present here a pilot study that quantitatively assessed the iron content of white and gray matter in paraffin-embedded sections from the frontal cortex of Alzheimer's and control subjects. Using the phosphorus image as a confirmed proxy for the white/gray matter boundary, we found that increased intrusion of iron into gray matter occurs in the Alzheimer's brain compared to controls, which may be indicative of either a loss of iron homeostasis in this vulnerable brain region, or provide evidence of increased inflammatory processes as a response to chronic neurodegeneration. We also observed a trend of increasing iron within the white matter of the frontal cortex, potentially indicative of disrupted iron metabolism preceding loss of myelin integrity. Considering the known potential toxicity of excessive iron in the brain, our results provide supporting evidence for the continuous development of novel magnetic resonance imaging approaches for assessing white and gray matter iron accumulation in Alzheimer's disease.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.NEUROBIOLAGING.2013.09.034
Abstract: Synchrotron-based x-ray fluorescence microscopy, immunofluorescence, and Western blotting were used to investigate changes in copper (Cu) and Cu-associated pathways in the vulnerable substantia nigra (SN) and locus coeruleus (LC) and in nondegenerating brain regions in cases of Parkinson's disease (PD) and appropriate healthy and disease controls. In PD and incidental Lewy body disease, levels of Cu and Cu transporter protein 1, were significantly reduced in surviving neurons in the SN and LC. Specific activity of the cuproprotein superoxide dismutase 1 was unchanged in the SN in PD but was enhanced in the parkinsonian anterior cingulate cortex, a region with α-synuclein pathology, normal Cu, and limited cell loss. These data suggest that regions affected by α-synuclein pathology may display enhanced vulnerability and cell loss if Cu-dependent protective mechanisms are compromised. Additional investigation of copper pathology in PD may identify novel targets for the development of protective therapies for this disorder.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3JA50281C
Publisher: Oxford University Press (OUP)
Date: 2019
DOI: 10.1039/C8MT00242H
Abstract: Detailed quantitative in situ imaging of embryonic mice reveals overt Cu redistribution associated with SOD1-overexpression.
Publisher: Radiological Society of North America (RSNA)
Date: 09-2014
Abstract: To evaluate the use of 5-aminolevulinic acid (5-ALA) for the noninvasive detection of malignant gliomas by using in vivo magnetic resonance (MR) imaging in a mouse brain tumor model. The experiments were animal care committee approved. U-87 glioblastoma cells were exposed to 5-ALA (500 µmol/L) for 6 hours, cells were harvested, and intracellular concentrations of iron, heme, protoporphyrin IX, and ferrochelatase were measured (six in each group). BALB/c nude mice (n = 10) were inoculated with U-87 glioma cells to produce orthotopic brain tumors. T2-weighted imaging was performed 3 weeks after inoculation, and T2* maps were created with a 7-T MR imager before and 24 hours after oral administration of 5-ALA (0.1 mg/g of body weight n = 6) or normal saline (n = 4). Intratumoral iron concentrations were measured with laser ablation inductively coupled plasma mass spectrometry. For in vitro experiments, differences in the measured data were assessed by using the Mann-Whitney U test with Bonferroni correction. For the in vivo studies, differences in T2* values and iron concentrations of the tumors in the 5-ALA and control groups were assessed by using the Mann-Whitney U test. The intracellular concentration of heme and iron was increased at both 24 and 48 hours after 5-ALA exposure (P = .004). 5-ALA promoted expression of ferrochelatase in glioblastoma cells at both 24 and 48 hours after 5-ALA exposure compared with that at 1 hour (P = .004). In vivo MR imaging revealed a lower median T2* value in glioblastomas treated with 5-ALA compared with those in control mice (14.0 msec [interquartile range, 13.0-14.5 msec] vs 21.9 msec [interquartile range, 19.6-23.2 msec] P = .011), and laser ablation inductively coupled plasma mass spectrometry revealed that iron concentrations were increased in glioblastomas from the 5-ALA group. Administration of 5-ALA increased the intracellular iron concentration of glioblastomas by promoting the synthesis of heme, which is the metabolite of 5-ALA. Because intracellular iron can be detected at MR imaging, 5-ALA may aid in the identification of high-grade foci in gliomas.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1016/J.SCITOTENV.2010.12.018
Abstract: Emerging evidence indicates that excessive exposure to manganese (Mn) during the prenatal period and early childhood may result in neurodevelopmental deficits. However, accurate exposure biomarkers are not well established, limiting our understanding of exposure-response relationships over these susceptible periods of development. Naturally shed deciduous teeth are potentially a useful biomarker of environmental exposure to Mn. However, the uptake and distribution of Mn in human teeth has not been studied in detail. Mn distribution was measured at high resolution (~20 μm) in eight human primary teeth using laser ablation-inductively coupled plasma-mass spectrometry. A bio-imaging methodology was applied to construct detailed elemental maps of three incisors, and bone meal (NIST SRM 1486) was used to validate the analyses. The distribution of Mn in enamel and coronal dentine showed a distinct and reproducible pattern. In enamel, the ⁵⁵Mn:⁴³Ca ratio was highest at the outer edge of enamel (range=0.57 to 4.74) for approximately 20-40 μm but was substantially lower in deeper layers (range=0.005 to 0.013). The highest levels of Mn were observed in dentine immediately adjacent the pulpal margin (⁵⁵Mn:⁴³Ca range=2.27 to 6.95). Importantly, a clearly demarcated high Mn zone was observed in dentine at the incisal end of the teeth. Using confocal laser scanning microscopy to visualize the neonatal line, this region was identified as being in the prenatally formed dentine. The high-resolution map of the spatial distribution of Mn in human primary teeth highlighted specific reproducible patterns of Mn distribution in enamel and coronal dentine.
Publisher: Springer Science and Business Media LLC
Date: 09-2009
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7JA00033B
Abstract: A new graphite furnace atomic absorption spectrometry method is presented for the analysis of zinc in small volume biological s les.
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6CC00128A
Abstract: Analytical chemistry has much to offer to an improved understanding of biological systems.
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5AY00555H
Abstract: A rapid, simple isotope dilution method for detecting organotins in sediment s les.
Publisher: Wiley
Date: 31-12-2019
DOI: 10.1002/MDS.27947
Abstract: Variations in study quality and design complicate interpretation of the clinical significance of consistently reported changes in copper and iron levels in human Parkinson's disease brain and biofluids. We systematically searched literature databases for quantitative reports of biometal levels in the degenerating substantia nigra (SN), CSF, serum, and plasma in Parkinson's disease compared with healthy age‐matched controls and assessed the quality of these publications. The primary outcomes of our analysis confirmed SN copper and iron levels are decreased and increased, respectively, in the Parkinson's disease brain. We applied a novel Quality Assessment Scale for Human Tissue to categorize the quality of in idual studies and investigated the effects of study quality on our outcomes. We undertook a random‐effects meta‐analysis and meta‐regression subgroup analysis. In the 18 eligible studies identified (211 Parkinson's disease, 215 control cases), SN copper levels were significantly lower ( d, ‐2.00 95% CI, ‐2.81 to ‐1.19 P 0.001), and iron levels were significantly higher (d , 1.31 95% CI, 0.38–2.24 P 0.01) in Parkinson's disease. No changes were detected in CSF, serum, or plasma for any metals (29 studies 2443 Parkinson's disease and 2183 control cases) except serum iron, which was lower in Parkinson's disease (14 studies 1177 Parkinson's disease and 1447 control cases). Reductions in copper levels and elevations in iron were confirmed as characteristic of the degenerating SN of Parkinson's disease. Iron in serum was also changed, but in the opposite direction to that in the SN and to a lesser extent. © 2019 International Parkinson and Movement Disorder Society
Publisher: Wiley
Date: 04-12-2014
DOI: 10.1111/ACEL.12178
Publisher: Society for Neuroscience
Date: 25-02-2015
DOI: 10.1523/JNEUROSCI.3439-14.2015
Abstract: Elevation of both neuronal iron and nitric oxide (NO) in the substantia nigra are associated with Parkinson's disease (PD) pathogenesis. We reported previously that the Alzheimer-associated β-amyloid precursor protein (APP) facilitates neuronal iron export. Here we report markedly decreased APP expression in dopaminergic neurons of human PD nigra and that APP −/− mice develop iron-dependent nigral cell loss. Conversely, APP-overexpressing mice are protected in the MPTP PD model. NO suppresses APP translation in mouse MPTP models, explaining how elevated NO causes iron-dependent neurodegeneration in PD.
Publisher: Oxford University Press (OUP)
Date: 13-05-2015
DOI: 10.1039/C5MT00075K
Abstract: It is unsurprising that our understanding of the role of selenium in neurological function is somewhat immature, considering its relatively recent discovery as an essential element to human health. Selenocysteine, the 21st amino acid, is the defining feature of the 25 selenoprotein-encoding genes so far discovered within the human genome. The low abundance of these proteins in the brain belies the integral role they play in normal neurological function, from well-characterised antioxidant activity in the periphery to poorly understood mechanisms that modulate mitochondrial function and response to brain pathology. Selenium has been identified as playing a role in several neurodegenerative disorders, including Alzheimer's and Parkinson's disease, though its function as a ‘cause or effect’ of disease process remains unclear. This review discusses selenium metabolism in detail, specifically with regard to the role it plays within the central nervous system, and examines the most current literature investigating how selenium may be involved in chronic diseases of the central nervous system.
Publisher: Oxford University Press (OUP)
Date: 2010
DOI: 10.1039/C0MT00039F
Abstract: Three dimensional maps of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn) and phosphorous (P) in a 6-hydroxydopamine (6-OHDA) lesioned mouse brain were constructed employing a novel quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method known as elemental bio-imaging. The 3D maps were produced by ablating serial consecutive sections taken from the same animal. Each section was quantified against tissue standards resulting in a three dimensional map that represents the variation of trace element concentrations of the mouse brain in the area surrounding the substantia nigra (SN). Damage caused by the needle or the toxin did not alter the distribution of Zn, and Cu but significantly altered Fe in and around the SN and both Mn and Fe around the needle track. A 20% increase in nigral Fe concentration was observed within the lesioned hemisphere. This technique clearly shows the natural heterogeneous distributions of these elements throughout the brain and the perturbations that occur following trauma or intoxication. The method may applied to three-dimensional modelling of trace elements in a wide range of tissue s les.
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8CC09664C
Abstract: Accurately locating biologically relevant elements at high resolution: simultaneous ptychography and fluorescence imaging of large specimens comes of age.
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3AY26248K
Publisher: Springer Science and Business Media LLC
Date: 19-10-2017
Publisher: Springer Science and Business Media LLC
Date: 13-09-2012
DOI: 10.1007/S00702-012-0898-4
Abstract: Redox-active iron is considered to be an important factor in the pathology and progression of several neurodegenerative disorders, including Parkinson's disease. The various roles of iron in normal physiology and its prevalence in the wider environment present numerous challenges to both accurate measurement and interpretation of brain iron levels. This review will discuss considerations for the analysis of iron in post-mortem s les, including how contamination, s le preparation and methods of analysis may influence results. In addition, several important factors influencing interpretation of iron levels will be considered.
Location: Australia
Location: United States of America
Start Date: 2018
End Date: 2020
Funder: Australian Research Council
View Funded ActivityStart Date: 2014
End Date: 2017
Funder: Australian Research Council
View Funded ActivityStart Date: 2012
End Date: 2015
Funder: Australian Research Council
View Funded ActivityStart Date: 2010
End Date: 2013
Funder: Australian Research Council
View Funded ActivityStart Date: 06-2013
End Date: 12-2017
Amount: $259,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 07-2014
End Date: 12-2017
Amount: $229,960.00
Funder: Australian Research Council
View Funded ActivityStart Date: 11-2011
End Date: 12-2014
Amount: $343,000.00
Funder: Australian Research Council
View Funded Activity