School of Chemistry - Research Publications
Now showing items 1-12 of 926
Zn-II(atsm) is protective in amyotrophic lateral sclerosis model mice via a copper delivery mechanism
(ACADEMIC PRESS INC ELSEVIER SCIENCE, 2015-09-01)
Mutations in the metalloprotein Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease for which effective therapeutics do not yet exist. Transgenic rodent models based on over-expression of mutant SOD1 have been developed and these have provided opportunity to test new therapeutic strategies and to study the mechanisms of mutant SOD1 toxicity. Although the mechanisms of mutant SOD1 toxicity are yet to be fully elucidated, incorrect or incomplete metallation of SOD1 confers abnormal folding, aggregation and biochemical properties, and improving the metallation state of SOD1 provides a viable therapeutic option. The therapeutic effects of delivering copper (Cu) to mutant SOD1 have been demonstrated recently. The aim of the current study was to determine if delivery of zinc (Zn) to SOD1 was also therapeutic. To investigate this, SOD1G37R mice were treated with the metal complex diacetyl-bis(4-methylthiosemicarbazonato)zinc(II) [Zn(II)(atsm)]. Treatment resulted in an improvement in locomotor function and survival of the mice. However, biochemical analysis of spinal cord tissue collected from the mice revealed that the treatment did not increase overall Zn levels in the spinal cord nor the Zn content of SOD1. In contrast, overall levels of Cu in the spinal cord were elevated in the Zn(II)(atsm)-treated SOD1G37R mice and the Cu content of SOD1 was also elevated. Further experiments demonstrated transmetallation of Zn(II)(atsm) in the presence of Cu to form the Cu-analogue Cu(II)(atsm), indicating that the observed therapeutic effects for Zn(II)(atsm) in SOD1G37R mice may in fact be due to in vivo transmetallation and subsequent delivery of Cu.
X-Ray Spectroscopy and Structure Elucidation of Reactive Electrogenerated Tri-iron Carbonyl Sulfide Clusters
(CSIRO PUBLISHING, 2012-01-01)
The design and operation of electrosynthesis cells for generation of samples for X-ray absorption spectroscopy are described. Optimization of continuous-flow methods allows the generation of highly reducing species, which may be combined with spectroscopic validation of the composition of the electrogenerated solution. It is shown that the large sample volume (10 mL) of the 1–10 mM (in the absorbing element) solution required for such experiments can be reduced to ~100 μL using a strategy in which the in situ electrosynthesis cell is amenable to freeze-quenching and transfer to a beamline cryostat. The working electrode in this case doubles as the X-ray absorption spectroscopy sample cell. The application of these techniques is illustrated by the reduction chemistry of Fe3S2(CO)9, 3Fe2S. Spectra recorded in the near-edge region confirm that quantitative preparation of samples of 3Fe2S, 3Fe2S1– and 3Fe2S2– can be prepared by either approach, but samples of a more reduced form, identified as [Fe3S(CO)9]2–, could only be generated using continuous-flow electrosynthesis techniques. Differences in the structural chemistry of the 3Fe2S0/1–/2– redox series were examined from the perspective of their near-edge spectra and the structures of 3Fe2S1– and 3Fe2S2– forms were deduced by a combination of computational (density functional theory), spectroscopic and X-ray absorption fine-structure analyses. These show that addition of the first electron is predominantly localized in one of the Fe–Fe bonds; cleavage of the Fe–Fe bond by addition of a second electron to the Fe–Fe antibonding orbital is associated with a more substantial rearrangement of the molecule. The reduced compounds have structural similarities to the reduced dithiolate-bridged di-iron hexacarbonyl compounds and this is related to the weak electrocatalytic proton reduction exhibited by Fe3S2(CO)9. The methods described provide a strategy for the collection and analysis of experimental data directed towards structure elucidation of redox-activated solution-state complexes.
X-ray fluorescence imaging reveals subcellular biometal disturbances in a childhood neurodegenerative disorder
(ROYAL SOC CHEMISTRY, 2014-01-01)
Biometals such as zinc, iron, copper and calcium play key roles in diverse physiological processes in the brain, but can be toxic in excess. A hallmark of neurodegeneration is a failure of homeostatic mechanisms controlling the concentration and distribution of these elements, resulting in overload, deficiency or mislocalization. A major roadblock to understanding the impact of altered biometal homeostasis in neurodegenerative disease is the lack of rapid, specific and sensitive techniques capable of providing quantitative subcellular information on biometal homeostasis in situ. Recent advances in X-ray fluorescence detectors have provided an opportunity to rapidly measure biometal content at subcellular resolution in cell populations using X-ray Fluorescence Microscopy (XFM). We applied this approach to investigate subcellular biometal homeostasis in a cerebellar cell line isolated from a natural mouse model of a childhood neurodegenerative disorder, the CLN6 form of neuronal ceroid lipofuscinosis, commonly known as Batten disease. Despite no global changes to whole cell concentrations of zinc or calcium, XFM revealed significant subcellular mislocalization of these important biological second messengers in cerebellar Cln6nclf (CbCln6nclf ) cells. XFM revealed that nuclear-to-cytoplasmic trafficking of zinc was severely perturbed in diseased cells and the subcellular distribution of calcium was drastically altered in CbCln6nclf cells. Subtle differences in the zinc K-edge X-ray Absorption Near Edge Structure (XANES) spectra of control and CbCln6nclf cells suggested that impaired zinc homeostasis may be associated with an altered ligand set in CbCln6nclf cells. Importantly, a zinc-complex, ZnII(atsm), restored the nuclear-to-cytoplasmic zinc ratios in CbCln6nclf cells via nuclear zinc delivery, and restored the relationship between subcellular zinc and calcium levels to that observed in healthy control cells. ZnII(atsm) treatment also resulted in a reduction in the number of calcium-rich puncta observed in CbCln6nclf cells. This study highlights the complementarities of bulk and single cell analysis of metal content for understanding disease states. We demonstrate the utility and broad applicability of XFM for subcellular analysis of perturbed biometal metabolism and mechanism of action studies for novel therapeutics to target neurodegeneration.
What Role Does COA6 Play in Cytochrome C Oxidase Biogenesis: A Metallochaperone or Thiol Oxidoreductase, or Both?
(MDPI AG, 2020-10-01)
Complex IV (cytochrome c oxidase; COX) is the terminal complex of the mitochondrial electron transport chain. Copper is essential for COX assembly, activity, and stability, and is incorporated into the dinuclear CuA and mononuclear CuB sites. Multiple assembly factors play roles in the biogenesis of these sites within COX and the failure of this intricate process, such as through mutations to these factors, disrupts COX assembly and activity. Various studies over the last ten years have revealed that the assembly factor COA6, a small intermembrane space-located protein with a twin CX9C motif, plays a role in the biogenesis of the CuA site. However, how COA6 and its copper binding properties contribute to the assembly of this site has been a controversial area of research. In this review, we summarize our current understanding of the molecular mechanisms by which COA6 participates in COX biogenesis.
What Are the Potential Sites of Protein Arylation by N-Acetyl-p-benzoquinone Imine (NAPQI)?
(AMER CHEMICAL SOC, 2015-11-01)
Acetaminophen (paracetamol, APAP) is a safe and widely used analgesic medication when taken at therapeutic doses. However, APAP can cause potentially fatal hepatotoxicity when taken in overdose or in patients with metabolic irregularities. The production of the electrophilic and putatively toxic compound N-acetyl-p-benzoquinone imine (NAPQI), which cannot be efficiently detoxicated at high doses, is implicated in APAP toxicity. Numerous studies have identified that excess NAPQI can form covalent linkages to the thiol side chains of cysteine residues in proteins; however, the reactivity of NAPQI toward other amino acid side chains is largely unexplored. Here, we report a survey of the reactivity of NAPQI toward 11 N-acetyl amino acid methyl esters and four peptides. (1)H NMR analysis reveals that NAPQI forms covalent bonds to the side-chain functional groups of cysteine, methionine, tyrosine, and tryptophan residues. Analogous reaction products were observed when NAPQI was reacted with synthetic model peptides GAIL-X-GAILR for X = Cys, Met, Tyr, and Trp. Tandem mass spectrometry peptide sequencing showed that the NAPQI modification sites are located on the "X" residue in each case. However, when APAP and the GAIL-X-GAILR peptide were incubated with rat liver microsomes that contain many metabolic enzymes, NAPQI formed by oxidative metabolism reacted with GAIL-C-GAILR exclusively. For the peptides where X = Met, Tyr, and Trp, competing reactions between NAPQI and alternative nucleophiles precluded arylation of the target peptide by NAPQI. Although Cys residues are favorably targeted under these conditions, these data suggest that NAPQI can, in principle, also damage proteins at Met, Tyr, and Trp residues.
Wetting enhancement coating on intermediate transfer member (itm) for aqueous inkjet intermediate transfer architecture
Described herein is a method and apparatus for ink jet printing. The method includes providing a wetting enhancement coating on a transfer member. The wetting enhancement coating includes water; binders selected from the group consisting of acrylic polymers, styrene acrylic polymers, vinyl-acrylic polymers, vinyl acetate ethylene; and a surfactant. The wetting enhancement coating is dried to form a film having a surface energy greater than 25 mJ/m2. Ink droplets are ejected onto the film to form an ink image on the film. The ink image is dried and the ink image and film are transferred to a recording medium.
Water Diffusion in Complex Systems Measured by PGSE NMR Using Chemical Shift Selective Stimulated Echo: Elimination of Magnetization Exchange Effects
(AIP Publishing, 2021)
The interpretation of molecular translational diffusion as measured by pulsed gradient spin-echo NMR (PGSE NMR) can be complicated by the presence of chemical exchange and/or dipolar cross-relaxation (including relayed cross-relaxation via spin diffusion). The magnitude of influence depends on the kinetics of exchange and/or dipolar cross-relaxation present within the system as well as the PGSE NMR sequences chosen for the measurements. Firstly, we present an exchange induced zero-crossing phenomenon for signal attenuation of water in lipidic cubic phases (LCPs, formed by a mixture of monoolein and water) in the presence of pulsed gradients observed using a standard STimulated Echo (STE) sequence. This magnetization exchange induced zero-crossing phenomenon, a pseudo negative diffraction-like feature, resembles that reported previously for restricted diffusion when locally anisotropic pores are polydisperse or randomly oriented. We then demonstrate the elimination of these exchange and/or dipolar cross-relaxation induced effects with the use of a chemical shift selective STE (CHESS-STE) sequence, adapted from the previously reported band-selective short transient STE (BEST-STE) sequence, along with results obtained from the bipolar pulse pair STE (BPP-STE) sequence for comparison. The CHESS-STE sequence introduced here represents a generic form of PGSE NMR sequences for obtaining water diffusion coefficients free from influence of exchange and/or dipolar cross-relaxation in complex systems. It has potential applications in measuring translational diffusion of water in biopolymer mixtures as well as probing microscopic structure in materials via water restricted diffusion measured by PGSE NMR, particularly when the potential presence of exchange/cross-relaxation is of concern.
Voltage-Controlled Switching of Strong Light-Matter Interactions using Liquid Crystals
(WILEY-V C H VERLAG GMBH, 2017-12-22)
We experimentally demonstrate a fine control over the coupling strength of vibrational light-matter hybrid states by controlling the orientation of a nematic liquid crystal. Through an external voltage, the liquid crystal is seamlessly switched between two orthogonal directions. Using these features, for the first time, we demonstrate electrical switching and increased Rabi splitting through transition dipole moment alignment. The C-Nstr vibration on the liquid crystal molecule is coupled to a cavity mode, and FT-IR is used to probe the formed vibropolaritonic states. A switching ratio of the Rabi splitting of 1.78 is demonstrated between the parallel and the perpendicular orientation. Furthermore, the orientational order increases the Rabi splitting by 41 % as compared to an isotropic liquid. Finally, by examining the influence of molecular alignment on the Rabi splitting, the scalar product used in theoretical modeling between light and matter in the strong coupling regime is verified.
Volatile chemical emissions from fragranced baby products
(SPRINGER INTERNATIONAL PUBLISHING AG, 2018-08-01)
Fragranced consumer products have been associated with adverse effects on human health. Babies are exposed to a variety of fragranced consumer products, which can emit numerous volatile organic compounds (VOCs), some considered potentially hazardous. However, fragranced baby products are exempt from disclosure of all ingredients. Consequently, parents and the public have little information on product emissions. This study investigates VOCs emitted from a range of fragranced baby products, including baby hair shampoos, body washes, lotions, creams, ointments, oils, hair sprays, and fragrance. The products were analysed using gas chromatography/mass spectrometry (GC/MS) headspace analysis. Of the 42 baby products tested, 21 products made claims of green, organic, or all-natural. Results of the analysis found 684 VOCs emitted collectively from the 42 products, representing 228 different VOCs. Of these 684 VOCs, 207 are classified as potentially hazardous under federal regulations, representing 43 different VOCs. The most common VOCs emitted were limonene, acetaldehyde, ethanol, alpha-pinene, linalool, beta-myrcene, acetone, and beta-pinene. A comparison between ingredients emitted and ingredients listed reveals that only 5% of the 684 VOCs, including 12% of 207 potentially hazardous VOCs, were listed on the product label, safety data sheet, or website. More than 95% of both green and regular products emitted one or more potentially hazardous VOCs. Further, emissions of the most prevalent VOCs from green, organic, or all-natural products were not significantly different from regular products. Results from this study can help improve public awareness about emissions from baby products, with the aim to reduce pollutant exposure and potential adverse effects on babies.