Metallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity

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. © 2013 The Royal Society of Chemistry

A novel laboratory scale method for studying heat treatment of cake flour

A lab-scale method for replicating the time–temperature history experienced by cake flours undergoing heat treatment was developed based on a packed bed configuration. The performance of heat-treated flours was compared with untreated and commercially heat-treated flour by test baking a high ratio cake formulation. Both cake volume and AACC shape measures were optimal after 15 min treatment at 130 °C, though their values varied between harvests. Separate oscillatory rheometry tests of cake batter at 80–100 °C exhibited similar behaviour to the baking tests. The gel strength parameter in the weak gel model, measured at 100 °C, was shown to correlate with flour quality and was identified as a possible alternative to test baking as a means of assessing flour quality after heat treatment.A CASE Ph.D. Studentship for AKSC from the Food Processing Faraday and support from Premier Foods are all gratefully acknowledged.This is the accepted manuscript version. The final version is available from Elsevier at http://www.sciencedirect.com/science/article/pii/S0260877414003112

Age modulates the injury-induced metallomic profile in the brain

© 2017 The Royal Society of Chemistry. 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 hippocampus 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 individual 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

A time-course analysis of changes in cerebral metal levels following a controlled cortical impact

© 2016 The Royal Society of Chemistry. Traumatic brain injury (TBI) is complicated by a sudden and dramatic change in brain metal levels, including iron (Fe), copper (Cu) and zinc (Zn). Specific 'metallo-pathological' features of TBI include increased non-heme bound Fe and the liberation of free Zn ions, both of which may contribute to the pathogenesis of TBI. To further characterise the metal dyshomeostasis that occurs following brain trauma, we performed a quantitative time-course survey of spatial Fe, Cu and Zn distribution in mice receiving a controlled cortical impact TBI. Images of brain metal levels produced using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) in the upper quadrant of the ipsilateral hemisphere were compared to the corresponding contralateral hemisphere, together with regional areas radiating toward the center of the brain from the site of lesion. Significant regional and time point specific elevations in Fe, Zn and Cu were detected immediately and up to 28 days after TBI. The magnitude and timeframe of many of these changes suggest that TBI results in a pronounced and sustained alteration in normal metal levels within the brain. Such alterations are likely to play a role in both the short- and long-term consequences of head trauma and suggest that pharmacological modulation to normalize these metal levels may be efficacious in improving functional outcome

Computational Studies of Actinide Complexes with Expanded Porphyrins

Covalency in complexes of the actinides has been identified as the potential driving force behind selective behaviour exhibited by separation ligands of use to the nuclear industry. In this thesis, complexes of actinyls with hexadentate macrocyclic expanded porphyrin ligands are investigated at the density functional level of theory and their electron densities analysed in detail. Initially, strong correlations are established between the vibrational frequencies of the distinctive uranyl stretching modes and covalency in the equatorial bonds of several simple uranyl complexes with monodentate first row ligands, with redshift of the uranyl stretching modes indicating a weakening of the U-Oyl interaction as a result of competing interactions in the equatorial plane. Subsequently, strong similarities are established in the U-N and U-Oyl bonding character of two multidentate uranyl complexes: UO2-isoamethyrin(1.0.1.0.0.0) and [UO2(bis-triazinyl-pyridine)2]2+, where isoamethyrin(1.0.1.0.0.0) is a hexadentate macrocyclic expanded porphyrin ligand and bis-trizinyl-pyridine (BTP) is a tridentate ligand which has shown selectivity for An(III) over Ln(III). A series of uranyl hexaphyrin complexes is then investigated, finding moderate correlations between stability, equatorial covalency and the frequencies of the uranyl stretching modes, which crucially only hold when there is a degree of relative planarity in the ligand. It is found that smaller ligands have greater stability and equatorial covalency. Broadening the study to include neptunyl and plutonyl complexes finds that the isoamethyrin complex shows some evidence for selectivity for uranyl over later actinides in the same oxidation state, but significant spin contamination throws the appropriateness of these methodologies for dealing with open-shell actinide systems into question. Preliminary calculations performed using spin constrained DFT were found to be helpful here, but a full geometry reoptimisation will ultimately be necessary to fully appreciate the effects of spin contamination on the geometry and electronic structure of the neptunyl and plutonyl complexes

Metal chaperones prevent zinc-mediated cognitive decline

© 2014 Elsevier Inc. 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 6 weeks) 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 hippocampus. While we demonstrated a small regional increase in hippocampal 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 hippocampal 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

Gold and iodine diffusion in large area perovskite solar cells under illumination.

Operational stability is the main issue hindering the commercialisation of perovskite solar cells. Here, a long term light soaking test was performed on large area hybrid halide perovskite solar cells to investigate the morphological and chemical changes associated with the degradation of photovoltaic performance occurring within the devices. Using Scanning Transmission Electron Microscopy (STEM) in conjunction with EDX analysis on device cross sections, we observe the formation of gold clusters in the perovskite active layer as well as in the TiO2 mesoporous layer, and a severe degradation of the perovskite due to iodine migration into the hole transporter. All these phenomena are associated with a drastic drop of all the photovoltaic parameters. The use of advanced electron microscopy techniques and data processing provides new insights on the degradation pathways, directly correlating the nanoscale structure and chemistry to the macroscopic properties of hybrid perovskite devices.European Research Council (291522), European Research Council (259619

The non-compact elliptic genus: mock or modular

We analyze various perspectives on the elliptic genus of non-compact supersymmetric coset conformal field theories with central charge larger than three. We calculate the holomorphic part of the elliptic genus via a free field description of the model, and show that it agrees with algebraic expectations. The holomorphic part of the elliptic genus is directly related to an Appell-Lerch sum and behaves anomalously under modular transformation properties. We analyze the origin of the anomaly by calculating the elliptic genus through a path integral in a coset conformal field theory. The path integral codes both the holomorphic part of the elliptic genus, and a non-holomorphic remainder that finds its origin in the continuous spectrum of the non-compact model. The remainder term can be shown to agree with a function that mathematicians introduced to parameterize the difference between mock theta functions and Jacobi forms. The holomorphic part of the elliptic genus thus has a path integral completion which renders it non-holomorphic and modular.Comment: 13 page

Genetic and biochemical analyses of chromosome and plasmid gene homologues encoding ICL and ArCP domains in Vibrioanguillarum strain 775

Anguibactin, the siderophore produced by Vibrio anguillarum 775 is synthesized from 2,3-dihydroxybenzoic acid (DHBA), cysteine and hydroxyhistamine via a nonribosomal peptide synthetase (NRPS) mechanism. Most of the genes encoding anguibactin biosynthetic proteins are harbored by the pJM1 plasmid. In this work we report the identification of a homologue of the plasmid-encoded angB on the chromosome of strain 775. The product of both genes harbor an isochorismate lyase (ICL) domain that converts isochorismic acid to 2,3-dihydro-2,3-dihydroxybenzoic acid, one of the steps of DHBA synthesis. We show in this work that both ICL domains are functional in the production of DHBA in V. anguillarum as well as in E. coli. Substitution by alanine of the aspartic acid residue in the active site of both ICL domains completely abolishes their isochorismate lyase activity in vivo. The two proteins also carry an aryl carrier protein (ArCP) domain. In contrast with the ICL domains only the plasmid encoded ArCP can participate in anguibactin production as determined by complementation analyses and site-directed mutagenesis in the active site of the plasmid encoded protein, S248A. The site-directed mutants, D37A in the ICL domain and S248A in the ArCP domain of the plasmid encoded AngB were also tested in vitro and clearly show the importance of each residue for the domain function and that each domain operates independently.