School of Chemistry - Research Publications

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    Diacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model
    Soon, CPW ; Donnelly, PS ; Turner, BJ ; Hung, LW ; Crouch, PJ ; Sherratt, NA ; Tan, J-L ; Lim, NK-H ; Lam, L ; Bica, L ; Lim, S ; Hickey, JL ; Morizzi, J ; Powell, A ; Finkelstein, DI ; Culvenor, JG ; Masters, CL ; Duce, J ; White, AR ; Barnham, KJ ; Li, Q-X (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-12-23)
    Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
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    Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes
    Schieber, C ; Howitt, J ; Putz, U ; White, JM ; Parish, CL ; Donnelly, PS ; Tan, S-S (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-03-11)
    The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.
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    Anionic Phospholipid Interactions of the Prion Protein N Terminus Are Minimally Perturbing and Not Driven Solely by the Octapeptide Repeat Domain
    Boland, MP ; Hatty, CR ; Separovic, F ; Hill, AF ; Tew, DJ ; Barnham, KJ ; Haigh, CL ; James, M ; Masters, CL ; Collins, SJ (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-10-15)
    Although the N terminus of the prion protein (PrP(C)) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23-110) and N2 (23-89) fragments derived from constitutive processing of PrP(C) and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed.
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    Electronic Structure Engineering in ZnSe/CdS Type-II Nanoparticles by Interface Alloying
    Boldt, K ; Schwarz, KN ; Kirkwood, N ; Smith, TA ; Mulvaney, P (American Chemical Society, 2014-06-19)
    We report the synthesis and characterization of type-II ZnSe/CdS semiconductor nanocrystals that exhibit strong charge separation, high photoluminescence quantum yields, low optical gain thresholds, and alloyed core–shell interfaces. Shell growth rates and the degree of alloying both depend strongly on the shelling temperature. The core–shell NCs exhibit band edge PL with emission wavelengths spanning the blue to orange region of the electromagnetic spectrum (380–562 nm). Fluorescence quantum yields up to 75% can be obtained by deposition of an additional ZnS layer. Transient absorption spectroscopy reveals that the population of the first two exciton states (1Se–1Sh, 1Se–2Sh) in the type-II structures can be controlled by alloying. Increased alloying leads to a greater population of the 2S hole state exciton.
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    Nanoscale magnetometry through quantum control of nitrogen-vacancy centres in rotationally diffusing nanodiamonds
    MACLAURIN, D ; Hall, LT ; Martin, AM ; Hollenberg, LC (IOP Publishing, 2013)
    The confluence of quantum physics and biology is driving a new generation of quantum-based sensing and imaging technology capable of harnessing the power of quantum effects to provide tools to understand the fundamental processes of life. One of the most promising systems in this area is the nitrogen–vacancy centre in diamond—a natural spin qubit which remarkably has all the right attributes for nanoscale sensing in ambient biological conditions. Typically the nitrogen–vacancy qubits are fixed in tightly controlled/isolated experimental conditions. In this work quantum control principles of nitrogen–vacancy magnetometry are developed for a randomly diffusing diamond nanocrystal. We find that the accumulation of geometric phases, due to the rotation of the nanodiamond plays a crucial role in the application of a diffusing nanodiamond as a bio-label and magnetometer. Specifically, we show that a freely diffusing nanodiamond can offer real-time information about local magnetic fields and its own rotational behaviour, beyond continuous optically detected magnetic resonance monitoring, in parallel with operation as a fluorescent biomarker.
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    DFT Studies on the Stereoselectivity of α-Silyloxy Diazoalkane Cycloadditions.
    O'Connor, MJ ; Liu, H ; Lee, D ; Zhou, T ; Xia, Y (MDPI AG, 2015-12-02)
    The intramolecular [3+2] cycloaddition (32CA) of alkene-tethered α-silyloxydiazoalkanes provides variable stereoselectivity in generating bicyclic pyrazolines where the silyloxy group is either syn or anti to the newly formed pyrazoline ring. To elucidate the origin of the stereoselectivity, density functional theory (DFT) calculations were carried out for the energy of each transition state structure (TSs) and product. Steric effects were identified as the major determining factors in the diastereoselectivity of the 32CA reaction with regards to substrate structure (cyclic or acyclic α-silyloxydiazoalkanes).
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    A monophasic extraction strategy for the simultaneous lipidome analysis of polar and nonpolar retina lipids
    Lydic, TA ; Busik, JV ; Reid, GE (ELSEVIER, 2014-08)
    Lipid extraction using a monophasic chloroform/methanol/water mixture, coupled with functional group selective derivatization and direct infusion nano-ESI-high-resolution/accurate MS, is shown to facilitate the simultaneous analysis of both highly polar and nonpolar lipids from a single retina lipid extract, including low abundance highly polar ganglioside lipids, nonpolar sphingolipids, and abundant glycerophospholipids. Quantitative comparison showed that the monophasic lipid extraction method yielded similar lipid distributions to those obtained from established "gold standard" biphasic lipid extraction methods known to enrich for either highly polar gangliosides or nonpolar lipids, respectively, with only modest relative ion suppression effects. This improved lipid extraction and analysis strategy therefore enables detailed lipidome analyses of lipid species across a broad range of polarities and abundances, from minimal amounts of biological samples and without need for multiple lipid class-specific extractions or chromatographic separation prior to analysis.
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    n-3 PUFAs enhance the frequency of murine B-cell subsets and restore the impairment of antibody production to a T-independent antigen in obesity
    Teague, H ; Fhaner, CJ ; Harris, M ; Duriancik, DM ; Reid, GE ; Shaikh, SR (ELSEVIER, 2013-11)
    The role of n-3 polyunsaturated fatty acids (PUFA) on in vivo B-cell immunity is unknown. We first investigated how n-3 PUFAs impacted in vivo B-cell phenotypes and antibody production in the absence and presence of antigen compared with a control diet. Lean mice consuming n-3 PUFAs for 4 weeks displayed increased percentage and frequency of splenic transitional 1 B cells. Upon stimulation with trinitrophenylated-lipopolysaccharide, n-3 PUFAs increased the number of splenic transitional 1/2, follicular, premarginal, and marginal zone B cells. n-3 PUFAs also increased surface, but not circulating, IgM. We next tested the effects of n-3 PUFAs in a model of obesity that is associated with suppressed humoral immunity. An obesogenic diet after ten weeks of feeding, relative to a lean control, had no effect on the frequency of B cells but lowered circulating IgM upon antigen stimulation. Administration of n-3 PUFAs to lean and obese mice increased the percentage and/or frequency of transitional 1 and marginal zone B cells. Furthermore, n-3 PUFAs in lean and obese mice increased circulating IgM relative to controls. Altogether, the data show n-3 PUFAs enhance B cell-mediated immunity in vivo, which has implications for immunocompromised populations, such as the obese.
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    A Comparison of the Effectiveness of Sonication, High Shear Mixing and Homogenisation on Improving the Heat Stability of Whey Protein Solutions
    Koh, LLA ; Chandrapala, J ; Zisu, B ; Martin, GJO ; Kentish, SE ; Ashokkumar, M (SPRINGER, 2014-02)
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    A novel low-cost detection method for screening of arsenic in groundwater
    Fontas, C ; Vera, R ; Batalla, A ; Kolev, SD ; Antico, E (SPRINGER HEIDELBERG, 2014-10-01)
    In the present work, a novel and simple detection system for As inorganic species contained in groundwater is presented. To reach the required detection limit, the proposed methodology is based on two steps: first is the transport and preconcentration of the inorganic arsenic species using a polymer inclusion membrane (PIM) system and second is the formation of a coloured complex, the absorbance of which is measured. Different parameters related to the membrane composition and the transport kinetics have been studied, and it was found that membranes made of polyvinyl chloride (PVC) as a polymer, and Aliquat 336 as a carrier, ensured efficient arsenic transport when the carrier content was at least 31 % (w/w). The implementation of the designed PIM in a special device that contained only 5 mL of the stripping solution (0.1 M NaCl) allowed As preconcentration from a 100-mL water sample, thus facilitating its detection with the colorimetric method. The new method developed here was validated, and its analytical figures of merit were determined, i.e. limit of detection of 4.5 μg L(-1) at 820 nm and a relative standard deviation within the range 8-10 %. Finally, the method was successfully applied to the analysis of different water samples from Catalonia region with naturally occurring As.