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 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

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

Confronting predictions of the galaxy stellar mass function with observations at high redshift

We investigate the evolution of the galaxy stellar mass function at high redshift (z ≥ 5) using a pair of large cosmological hydrodynamical simulations: MassiveBlack and MassiveBlack-II. By combining these simulations, we can study the properties of galaxies with stellar masses greater than 108 M⊙ h−1 and (comoving) number densities of log10(ϕ [Mpc−3 dex−1 h3]) > −8. Observational determinations of the galaxy stellar mass function at very high redshift typically assume a relation between the observed ultraviolet (UV) luminosity and stellar mass-to-light ratio which is applied to high-redshift samples in order to estimate stellar masses. This relation can also be measured from the simulations. We do this, finding two significant differences with the usual observational assumption: it evolves strongly with redshift and has a different shape. Using this relation to make a consistent comparison between galaxy stellar mass functions, we find that at z = 6 and above the simulation predictions are in good agreement with observed data over the whole mass range. Without using the correct UV luminosity and stellar mass-to-light ratio, the discrepancy would be up to two orders of magnitude for large galaxies (>1010 M⊙ h−1). At z = 5, however, the stellar mass function for low-mass galaxies (<109 M⊙ h−1) is overpredicted by factors of a few, consistent with the behaviour of the UV luminosity function, and perhaps a sign that feedback in the simulation is not efficient enough for these galaxies

Three-dimensional elemental bio-imaging of Fe, Zn, Cu, Mn and P in a 6-hydroxydopamine lesioned mouse brain

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 samples. © 2010 The Royal Society of Chemistry

Characterization of T Lymphocytes in Chronic Obstructive Pulmonary Disease

A new study adds to the mounting evidence implicating T cells as an important component of the inflammation in chronic obstructive pulmonary diseas

Quantitative elemental bio-imaging of Mn, Fe, Cu and Zn in 6-hydroxydopamine induced Parkinsonism mouse models

This study demonstrates the application of quantitative elemental bio-imaging for the determination of the distribution Cu, Mn, Fe and Zn in Parkinsonism mouse model brains. Elevated concentrations of these metals within the substantia nigra (SN) are suspected to play a role on the development of Parkinson's disease. Elemental bio-imaging employs laser ablation inductively coupled mass spectrometry (LA-ICP-MS) to construct images of trace element distribution. Quantitative data was produced by ablating the standard tissue sections and recording the mean signal intensity calibrated against multi level matrix matched tissue standards. The concentrations of Fe within the substantia nigra of the lesioned animals increased significantly when compared against control animals. Furthermore, the data was compared against solution nebulisation ICP-MS in which the whole substantia nigra was excised. The trends were the same for both methods; however the elemental bio-imaging method returned significantly higher concentrations. This was caused by dilution from inclusion of surrounding tissue of the SN during the excision procedure. © The Royal Society of Chemistry 2009

Enhancement of nonclassical properties of two qubits via deformed operators

We explore the dynamics of two atoms interacting with a cavity field via deformed operators. Properties of the asymptotic regularization of entanglement measures proving, for example, purity cost, regularized fidelity and accuracy of information transfer are analyzed. We show that the robustness of a bipartite system having a finite number of quantum states vanishes at finite photon numbers, for arbitrary interactions between its constituents and with cavity field. Finally it is shown that the stability of the purity and the fidelity is improved in the absence of the deformation parameters

On the warp drive space-time

In this paper the problem of the quantum stability of the two-dimensional warp drive spacetime moving with an apparent faster than light velocity is considered. We regard as a maximum extension beyond the event horizon of that spacetime its embedding in a three-dimensional Minkowskian space with the topology of the corresponding Misner space. It is obtained that the interior of the spaceship bubble becomes then a multiply connected nonchronal region with closed timelike curves and that the most natural vacuum allows quantum fluctuations which do not induce any divergent behaviour of the re-normalized stress-energy tensor, even on the event (Cauchy) chronology horizon. In such a case, the horizon encloses closed timelike curves only at scales close to the Planck length, so that the warp drive satisfies the Ford's negative energy-time inequality. Also found is a connection between the superluminal two-dimensional warp drive space and two-dimensional gravitational kinks. This connection allows us to generalize the considered Alcubierre metric to a standard, nonstatic metric which is only describable on two different coordinate patchesComment: 7 pages, minor comment on chronology protection added, RevTex, to appear in Phys. Rev.