Social and Behavioral Sciences Commons^™

Induced Pluripotent Stem Cells As Tools For Disease Modelling And Drug Discovery In Alzheimer's Disease, Lezanne Ooi, Kuldip Sidhu, Anne Poljak, Greg Sutherland, Michael D. O'Connor, Perminder Sachdev, Gerald Munch

Faculty of Science - Papers (Archive)

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder that leads to a progressive decline in a person’s memory and ability to communicate and carry out daily activities. The brain pathology in AD is characterized by extensive neuronal loss, particularly of cholinergic neurons, intracellular neurofibrillary tangles composed of the tau protein (NFTs) and extracellular deposition of plaques composed of β-amyloid (Aβ), a cleavage product of the amyloid precursor protein (APP). These two insoluble protein aggregates are accompanied by a chronic inflammatory response and extensive oxidative damage. Whereas dys-regulation of APP expression or processing appears to be important for the familial, …

The Role Of Streptokinase As A Virulence Determinant Of Streptococcus Pyogenes - Potential For Therapeutic Targeting, Jason D. Mcarthur, Simon M. Cook, Carola Venturini, Mark J. Walker

Faculty of Science - Papers (Archive)

Streptococcus pyogenes is a major human pathogen responsible for numerous diseases ranging from uncomplicated skin and throat infections to severe, life threatening invasive disease such as necrotising fasciitis and streptococcal toxic shock syndrome. These severe invasive infections progress rapidly and produce high rates of morbidity and mortality despite the implementation of aggressive treatment plans. The activation of plasminogen and the acquisition of plasmin activity at the bacterial cell surface is critical for the invasive pathogenesis of this organism. To facilitate this process, S. pyogenes secrete streptokinase, a potent plasminogen activating protein. Here, we describe the role of streptokinase in invasive …

Optimization Of Colorimetric Det Technique For The In Situ, Two-Dimensional Measurement Of Iron(Ii) Distributions In Sediment Porewaters, William W. Bennett, Peter R. Teasdale, David T. Welsh, Jarad G. Panther, Dianne F. Jolley

Faculty of Science - Papers (Archive)

No abstract provided.

Inorganic Arsenic And Iron(Ii) Distributions In Sediment Porewaters Investigated By A Combined Dgt - Colourimetric Det Technique, William Bennett, Peter R. Teasdale, David T. Welsh, Jarad Panther, Ryan R. Stewart, Helen L. Price, Dianne F. Jolley

Faculty of Science - Papers (Archive)

No abstract provided.

Different Radiolabelling Methods Alter The Pharmacokinetic And Biodistribution Properties Of Plasminogen Activator Inhibitor Type 2 (Pai-2) Forms, Marie Ranson, Paula Berghofer, Kara L. Vine, Ivan Greguric, Rachael Shepherd, Andrew Katsifis

Faculty of Science - Papers (Archive)

Introduction: Tumour-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, and it is recognised as having strong prognostic relevance as well as being a therapeutic target. The specific uPA inhibitor plasminogen activator inhibitor type-2 (PAI-2, SerpinB2) specifically targets cell bound uPA and is internalised. Furthermore, preclinical studies have established the “proof-of-principle” of uPA-targeting by PAI-2-cytotoxin conjugates in human carcinoma models. However, these studies also suggest that PAI-2 is rapidly cleared via the renal system with low total dose reaching the tumour. In this study, a comparative single photon emission computed tomography (SPECT) and biodistribution (BD) analysis …

Does Cytotoxicity Of Metallointercalators Correlate With Cellular Uptake Or Dna Affinity?, Kimberley J. Davis, Judith A. Carrall, Barry Lai, Janice R. Aldrich-Wright, Stephen F. Ralph, Carolyn T. Dillon

Faculty of Science - Papers (Archive)

The cytotoxicity of the metallointercalators, [Pt(5,6-dimethyl-1,10-phenanthroline)(trans-1R,2Rdiaminocyclohexane)] 2+ ([56MERR]) and [Pt(5,6-dimethyl-1,10-phenanthroline)(trans-1S,2Sdiaminocyclohexane)] 2+ ([56MESS]), towards A549 human lung cancer cells was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The IC50 value obtained following exposure of A549 cells to [56MESS] for 4 h was approximately three times smaller than that obtained when [56MERR] was administered under the same conditions, indicating that the former complex displayed greater cytotoxicity. Both IC50 values were greater than that obtained after exposure of A549 cells to cisplatin, demonstrating that the latter compound was the most cytotoxic of the three examined. Microprobe synchrotron radiation X-ray fluorescence (SR-XRF) analyses of …

Antimalarial Alkaloids From A Bhutanese Traditional Medicinal Plant Corydalis Dubia, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Anthony C. Willis, Sumalee Kamchonwongpaisan

Faculty of Science - Papers (Archive)

Ethnopharmacological relevance: Corydalis dubia is used in Bhutanese traditional medicine as a febrifuge and for treating infections in the blood, liver and bile which correlate to the signs and symptoms of malarial and microbial infections.

Aim of the study: To validate the ethnopharmacological uses of the plant and to discover potential new therapeutic drug leads. Materials and methods C. dubia was collected from Bhutan and the alkaloids were obtained using acid–base fractionation and separation by repeated column and preparative plate chromatography. The alkaloids were identified from analysis of their physiochemical and spectroscopic data and were tested for antiplasmodial, antimicrobial and …

Binaphthyl-Anchored Antibacterial Tripeptide Derivatives With Hydrophobic C-Terminal Amino Acid Variations, John Bremner, Paul A. Keller, Stephen Pyne, Mark Robertson, Kandasamy Sakthivel, Kittiya Somphol, Dean Baylis, Jonathon A Coates, John Deadman, Dharshini Jeevarajah, David I. Rhodes

Faculty of Science - Papers (Archive)

The facile synthesis of seven new dicationic tripeptide benzyl ester derivatives, with hydrophobic group variations in the C-terminal amino acid component, is described. Moderate to good activity was seen against Gram-positive bacteria in vitro. One cyclohexyl-substituted compound 2c was tested more widely and showed good potency (MIC values ranging from 2–4 μg/mL) against antibiotic-resistant strains of Staphylococcus aureus and Enterococci (VRE, VSE), and against Staphylococcus epidermidis.

High-Yield Cell-Free Protein Synthesis For Site-Specific Incorporation Of Unnatural Amino Acids At Two Sites, Kiyoshi Ozawa, Karin V. Loscha, Kekini V. Kuppan, Choy Theng Loh, Nicholas E. Dixon, Gottfried Otting

Faculty of Science - Papers (Archive)

Using aminoacyl-tRNA synthetase/suppressor tRNA pairs derived from Methanocaldococcus jannaschii, an Escherichia coli cell-free protein production system affords proteins with site-specifically incorporated unnatural amino acids (UAAs) in high yields through the use of optimized amber suppressor tRNA_CUA opt and optimization of reagent concentrations. The efficiency of the cell-free system allows the incorporation of trifluoromethyl-phenylalanine using a polyspecific synthetase evolved previously for p-cyanophenylalanine, and the incorporation of UAAs at two different sites of the same protein without any re-engineering of the E. coli cells used to make the cell-free extract.

Dgt-Induced Copper Flux Predicts Bioaccumulation And Toxicity To Bivalves In Sediments With Varying Properties, Stuart L. Simpson, Heloise Yverneau, Anne Cremazy, Chad V. Jarolimek, Helen Price, Dianne F. Jolley

Faculty of Science - Papers (Archive)

Many regulatory frameworks for sediment quality assessment include consideration of contaminant bioavailability. However, the “snap-shots” of metal bioavailability provided by analyses of porewaters or acid-volatile sulfidesimultaneously extractable metal (AVS-SEM) relationships do not always contribute sufficient information. The use of inappropriate or inadequate information for assessing metal bioavailability in sediments may result in incorrect assessment decisions. The technique of diffusive gradients in thin films (DGT) enables the in situ measurement of metal concentrations in waters and fluxes from sediment porewaters. We utilized the DGT technique to interpret the bioavailability of copper to the benthic bivalve Tellina deltoidalis in sediments of varying …

Molecular Characterization Of A 21.4 Kilobase Antibiotic Resistance Plasmid From An Hemolytic Escherichia Coli O108:H-Human Clinical Isolate, Fay E. Dawes, Dieter M. Bulach, Alexander Kuzevski, Karl A. Bettelheim, Carola Venturini, Steven P. Djordjevic, Mark J. Walker

Faculty of Science - Papers (Archive)

This study characterizes the 21.4 kilobase plasmid pECTm80 isolated from Escherichia coli strain 80, an α hemolytic human clinical diarrhoeal isolate (serotype O108:H-). DNA sequence analysis of pECTm80 revealed it belonged to incompatibility group X1, and contained plasmid partition and toxin-antitoxin systems, an R6K-like triple origin (ori) replication system, genes required for replication regulation, insertion sequences IS1R, ISEc37 and a truncated transposase gene (Tn3-like ΔtnpA) of the Tn3 family, and carried a class 2 integron. The class 2 integron of pECTm80 contains an intact cassette array dfrA1-sat2, encoding resistance to trimethoprim and streptothricin, …

Isolation Of Tuberospironine A, A Novel Croomine Derivative From Stemona Tuberosa Lour., Pratiwi Pudjiastuti, Stephen G. Pyne, S Sugiyanto, Wilford Lie

Faculty of Science - Papers (Archive)

A novel croomine derivative, tuberospironine A (3-epi-tuberospironine) was isolated from the root extracts of Stemona tuberosa Lour. found growing on Seram Island, Moluccas Province, Indonesia. The structure of this novel alkaloid, with unprecedented configuration at C-3 for a croomine derivative, was determined from interpretation of its NMR spectroscopic data.

Activation Of The Damage-Associated Molecular Pattern Receptor P2x7 Induces Interleukin-1b Release From Canine Monocytes, Iman Jalilian, Michelle Peranec, Belinda L. Curtis, Aine Seavers, Mari Spildrejorde, Vanessa Sluyter, Ronald Sluyter

Faculty of Science - Papers (Archive)

P2X7, a damage-associated molecular pattern receptor and adenosine 5'-triphosphate (ATP)-gated cation channel, plays an important role in the activation of the NALP3 inflammasome and subsequent release of interleukin (IL)-1β from human monocytes; however its role in monocytes from other species including the dog remains poorly defined. This study investigated the role of P2X7 in canine monocytes, including its role in IL-1β release. A fixed-time flow cytometric assay demonstrated that activation of P2X7 by extracellular ATP induces the uptake of the organic cation, YO-PRO-1²⁺, into peripheral blood monocytes from various dog breeds, a process impaired by the specific P2X7 …

Molecular Dynamics Analysis Of Apolipoprotein-D - Lipid Hydroperoxide Interactions: Mechanism For Selective Oxidation Of Met-93, Aaron J. Oakley, Surabhi Bhatia, Heath Ecroyd, Brett Garner

Faculty of Science - Papers (Archive)

Background: Recent studies suggest reduction of radical-propagating fatty acid hydroperoxides to inert hydroxides by interaction with apolipoprotein-D (apoD) Met93 may represent an antioxidant function for apoD. The nature and structural consequences of this selective interaction are unknown.

Methodology/Principal Findings: Herein we used molecular dynamics (MD) analysis to address these issues. Longtimescale simulations of apoD suggest lipid molecules are bound flexibly, with the molecules free to explore multiple conformations in a binding site at the entrance to the classical lipocalin ligand-binding pocket. Models of 5s- 12s- and 15s hydroperoxyeicosatetraenoic acids were created and the lipids found to wrap around Met93 thus …

Molecular Mechanisms Of K+ Selectivity In Na/K Pump, Haibo Yu, Ian Ratheal, Pablo Artigas, Benoit Roux

Faculty of Science - Papers (Archive)

The sodium–potassium (Na/K) pump plays an essential role in maintaining cell volume and secondary active transport of other solutes by establishing the Na⁺ and K⁺ concentration gradients across the plasma membrane of animal cells. The recently determined crystal structures of the Na/K pump to atomic resolution provide a new impetus to investigate molecular determinants governing the binding of Na⁺ and K⁺ ions and conformational transitions during the functional cycle. The pump cycle is generally described by the alternating access mechanism, in which the pump toggles between different conformational states, where ions can bind from either the …

Fragment-Based Screening By Protein Crystallography: Successes And Pitfalls, Zorik Chilingaryan, Zhou Yin, Aaron J. Oakley

Faculty of Science - Papers (Archive)

Fragment-based drug discovery (FBDD) concerns the screening of low-molecular weight compounds against macromolecular targets of clinical relevance. These compounds act as starting points for the development of drugs. FBDD has evolved and grown in popularity over the past 15 years. In this paper, the rationale and technology behind the use of X-ray crystallography in fragment based screening (FBS) will be described, including fragment library design and use of synchrotron radiation and robotics for high-throughput X-ray data collection. Some recent uses of crystallography in FBS will be described in detail, including interrogation of the drug targets β-secretase, phenylethanolamine N-methyltransferase, phosphodiesterase …

Gelapin, A Degradable Genipin Cross-Linked Gelatin Hydrogel, Damian Kirchmajer, C Watson, Marie Ranson, Marc In Het Panhuis

Faculty of Science - Papers (Archive)

The synthesis of genipin cross-linked gelatin (Gelapin) hydrogel materials is presented. Gelapin hydrogels were comprehensively characterised through chemical, mechanical and physical analysis techniques. It was found that the hydrogels could be cross-linked to up to 90% using a genipin concentration of 24.4% (w/ w). The hydrogels reach a stable swollen state and cease leaching of residual starting materials after 72 h in phosphate buffered saline solution at 37 uC. The proteolytic degradation of Gelapin by collagenase is tuneable through manipulation of the material composition with the rate of degradation ranging from 60 mg per day up to 500 mg per …

Beyond Barcoding: A Mitochondrial Genomics Approach To Molecular Phylogenetics And Diagnostics Of Blowflies (Diptera: Calliphoridae), Leigh Nelson, Christine L. Lambkin, Philip Batterham, James F. Wallman, Mark P. Dowton, Michael F. Whiting, David K. Yeates, Stephen L. Cameron

Faculty of Science - Papers (Archive)

Members of the Calliphoridae (blowflies) are significant for medical and veterinary management, due to the ability of some species to consume living flesh as larvae, and for forensic investigations due to the ability of others to develop in corpses. Due to the difficulty of accurately identifying larval blowflies to species there is a need for DNA-based diagnostics for this family, however the widely used DNA-barcoding marker, cox1, has been shown to fail for several groups within this family. Additionally, many phylogenetic relationships within the Calliphoridae are still unresolved, particularly deeper level relationships. Sequencing whole mt genomes has been demonstrated both …

Selective Reduction Of Hydroperoxyeicosatetraenoic Acids To Their Hydroxy Derivatives By Apolipoprotein D: Implications For Lipid Antioxidant Activity And Alzheimer's Disease, Surabhi Bhatia, Bianca Knoch, Jenny Wong, Woojin Scott Kim, Paul Else, Aaron J. Oakley, Brett Garner

Faculty of Science - Papers (Archive)

ApoD (apolipoprotein D) is up-regulated in AD (Alzheimer's disease) and upon oxidative stress. ApoD inhibits brain lipid peroxidation in vivo, but the mechanism is unknown. Specific methionine residues may inhibit lipid peroxidation by reducing radical-propagating L-OOHs (lipid hydroperoxides) to non-reactive hydroxides via a reaction that generates MetSO (methionine sulfoxide). Since apoD has three conserved methionine residues (Met49, Met93 and Met157), we generated recombinant proteins with either one or all methionine residues replaced by alanine and assessed their capacity to reduce HpETEs (hydroperoxyeicosatetraenoic acids) to their HETE (hydroxyeicosatetraenoic acid) derivatives. ApoD, apoDM49-A and apoDM157-A all catalysed the reduction of HpETEs to …

Dissociation Of Erk Signalling Inhibition From The Anti-Amyloidogenic Action Of Synthetic Ceramide Analogues, Hongyun Li, Genevieve Evin, Andrew F. Hill, Ya Hui Hung, Ashley I. Bush, Brett Garner

Faculty of Science - Papers (Archive)

Inhibition of GSL (glycosphingolipid) synthesis reduces Aβ (amyloid β-peptide) production in vitro. Previous studies indicate that GCS (glucosylceramide synthase) inhibitors modulate phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) and that the ERK pathway may regulate some aspects of Aβ production. It is not clear whether there is a causative relationship linking GSL synthesis inhibition, ERK phosphorylation and Aβ production. In the present study, we treated CHO cells (Chinese-hamster ovary cells) and SH-SY5Y neuroblastoma cells, that both constitutively express human wild-type APP (amyloid precursor protein) and process this to produce Aβ, with GSL-modulating agents to explore this relationship. We found that three …

Synthesis And Anti-Leukaemic Activity Of Pyrrolo[3,2,1-Hi]Indole-1,2- Diones, Pyrrolo[3,2,1-Ij]Quinoline-1,2-Diones And Other Polycyclic Isatin Derivatives, Lidia Matesic, Julie M. Locke, Kara Vine, Marie Ranson, John B. Bremner, Danielle Skropeta

Faculty of Science - Papers (Archive)

To further expand the structure–cytotoxic activity relationships of isatin derivatives and to reduce flexibility in substituent groups at nitrogen, 20 analogues incorporating a ring system between the N1 and C7 atoms of isatin were prepared using a variety of synthetic strategies. This yielded pyrroloindole-, pyrroloquinoline-, pyrroloacridine-, pyrrolophenanthridine- and benzopyrrolophenanthridine-based systems with embedded isatin moieties, the latter possessing a novel carbon skeleton. These compounds were subsequently assessed for their in vitro cytotoxicity against human U937 lymphoma cells, with the brominated pyrroloacridine dione 27 showing the most promising activity (IC50 3.01 μM) after 24 h.

Bacterial Plasminogen Receptors: Mediators Of A Multifaceted Relationship, Martina L. Sanderson-Smith, David M. P De Oliveira, Marie Ranson, Jason D. Mcarthur

Faculty of Science - Papers (Archive)

Multiple species of bacteria are able to sequester the host zymogen plasminogen to the cell surface. Once localised to the bacterial surface, plasminogen can act as a cofactor in adhesion, or, following activation to plasmin, provide a source of potent proteolytic activity. Numerous bacterial plasminogen receptors have been identified, and the mechanisms by which they interact with plasminogen are diverse. Here we provide an overview of bacterial plasminogen receptors and discuss the diverse role bacterial plasminogen acquisition plays in the relationship between bacteria and the host.

Phytochemical And Biological Activity Studies Of The Bhutanese Medicinal Plant Corydalis Crispa, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Thanapat Sastraruji, Malai Taweechotipatr, Roonglawan Rattanajak, Aunchalee Tonsomboon, Sumalee Kamchonwongpaisan

Faculty of Science - Papers (Archive)

The chemical constituents and biological activities of Corydalis crispa (Fumariaceae) were investigated for the first time. The phytochemical study resulted in the isolation of nine known isoquinoline alkaloids: protopine (1), 13-oxoprotopine (2), 13-oxocryptopine (3), stylopine (4), coreximine (5), rheagenine (6), ochrobirine (7), sibiricine (8) and bicuculline (9), with complete NMR data for 2 and 3 provided here for the first time. Crude extracts exhibitedsignificant anti-inflammatory (p < 0.01) activity against TNF-alpha production in LPS activated THP-1 cells. The acetylcholinesterase inhibitory activity of compounds 2, 4 and 7 and the antiplasmodial activity of compound 5 against P. falciparum strains TM4/8.2 and K1CB1 (multidrug resistant strain) are reported here for the first time. Stylopine (4) did not show antimalarial activity against the K1CB1 strain in contrast to a previous report. This study generated a scientific basis for the use of this plant in Bhutanese traditional medicine, either individually or in combination with other medicinal ingredients to treat a broad range of disorders. This study also identified compound 5 as potential new antimalarial lead compound.

Structural Insights Into The Dehydroascorbate Reductase Activity Of Human Omega-Class Glutathione Transferases, Huina Zhou, Joseph Brock, Dan Liu, Philip G. Board, Aaron J. Oakley

Faculty of Science - Papers (Archive)

The reduction of dehydroascorbate (DHA) to ascorbic acid (AA) is a vital cellular function. The omega-class glutathione transferases (GSTs) catalyze several reductive reactions in cellular biochemistry, including DHA reduction. In humans, two isozymes (GSTO1-1 and GSTO2-2) with significant DHA reductase (DHAR) activity are found, sharing 64% sequence identity. While the activity of GSTO2-2 is higher, it is significantly more unstable in vitro. We report the first crystal structures of human GSTO2-2, stabilized through site-directed mutagenesis and determined at 1.9Å resolution in the presence and absence of glutathione (GSH). The structure of a human GSTO1-1 has been determined at 1.7Å resolution …

Investigating Arsenic Speciation And Mobilization In Sediments With Dgt And Det: A Mesocosm Evaluation Of Oxic-Anoxic Transitions, William W. Bennett, Peter R. Teasdale, Jarad G. Panther, David T. Welsh, Huijun Zhao, Dianne F. Jolley

Faculty of Science - Papers (Archive)

Mobilization of arsenic from freshwater and estuarine sediments during the transition from oxic to anoxic conditions was investigated using recently developed diffusive sampling techniques. Arsenic speciation and Fe(II) concentrations were measured at high resolution (1−3 mm) with in situ diffusive gradients in thin films (DGT) and diffusive equilibration in thin films (DET) techniques. Water column anoxia induced Fe(II) and As(III) fluxes from the sediment. A correlation between water column Fe(II) and As(III) concentrations was observed in both freshwater (r_s = 0.896, p < 0.001) and estuarine (r_s = 0.557, p < 0.001) mesocosms. Porewater sampling by DGT and DET techniques confirmed that arsenic mobilization was associated with the reductive dissolution of Fe(III) (hydr)oxides in the suboxic zone of the sediment; a relationship that was visible because of the ability to measure the coincident profiles of these species using combined DGT and DET samplers. The selective measurement of As(III) and total inorganic arsenic by separate DGT samplers indicated that As(III) was the primary species mobilized from the solid phase to the porewater. This measurement approach effectively ruled out substantial As(V) mobilization from the freshwater and estuarine sediments in this experiment. This study demonstrates the capabilities of the DGT and DET techniques for investigating arsenic speciation and mobilization over a range of sediment conditions.

The Extracellular Chaperone Clusterin Sequesters Oligomeric Forms Of The Amyloid-Beta 1-40 Peptide, Priyanka Narayan, Angel Orte, Richard W. Clarke, Benedetta Bolognesi, Sharon Hook, Kristina A. Ganzinger, Sarah Meehan, Mark R. Wilson, Christopher M. Dobson, David Klenerman

Faculty of Science - Papers (Archive)

In recent genome-wide association studies, the extracellular chaperone protein, clusterin, has been identified as a newly-discovered risk factor in Alzheimer's disease. We have examined the interactions between human clusterin and the Alzheimer's disease-associated amyloid-β _1-40 peptide (Aβ _1-40), which is prone to aggregate into an ensemble of oligomeric intermediates implicated in both the proliferation of amyloid fibrils and in neuronal toxicity. Using highly sensitive single-molecule fluorescence methods, we have found that Aβ _1-40 forms a heterogeneous distribution of small oligomers (from dimers to 50-mers), all of which interact with clusterin to form long-lived, stable complexes. Consequently, clusterin is able …

Roles Of Extracellular Chaperones In Amyloidosis, Amy R. Wyatt, Justin J. Yerbury, Rebecca A. Dabbs, Mark R. Wilson

Faculty of Science - Papers (Archive)

Extracellular protein misfolding and aggregation underlie many of the most serious amyloidoses including Alzheimer's disease, spongiform encephalopathies and type II diabetes. Despite this, protein homeostasis (proteostasis) research has largely focussed on characterising systems that function to monitor protein conformation and concentration within cells. We are now starting to identify elements of corresponding systems, including an expanding family of secreted chaperones, which exist in the extracellular space. Like their intracellular counterparts, extracellular chaperones are likely to play a central role in systems that maintain proteostasis; however, the precise details of how they participate are only just emerging. It is proposed that …

Synthesis Of Stemofoline Analogues As Acetylcholinesterase Inhibitors, Kwankamol Sastraruji, Thanapat Sastraruji, Alison T. Ung, Renate Griffith, Araya Jatisatienr, Stephen G. Pyne

Faculty of Science - Papers (Archive)

Thirty two new stemofoline analogues were prepared from didehydrostemofoline for studies as AChE inhibitors. C-3 side-chain modified amino, carbamate, triazole and oxazole stemofoline derivatives were prepared. In general the amine derivatives were found to be stronger inhibitors of AChE than their alcohol analogues that we previously reported. Compounds 5 and 26, with small C-3 side chain substituents, were two of the most active inhibitors. Preliminary molecular docking studies suggested that these compounds may inhibit AChE by binding horizontally along the passage of the active-site gorge and block access to acetylcholine.

P2x7 Receptor Activation Mediates Organic Cation Uptake Into Human Myeloid Leukaemic Kg-1 Cells, Safina Gadeock, Aleta Pupovac, Vanessa Sluyter, Mari Spildrejorde, Ronald Sluyter

Faculty of Science - Papers (Archive)

The P2X7 purinergic receptor is an ATP-gated cation channel with an emerging role in neoplasia. In this study we demonstrate that the human KG-1 cell line, a model of acute myelogenous leukaemia, expresses functional P2X7. RT-PCR and immunochemical techniques demonstrated the presence of P2X7 mRNA and protein respectively in KG-l cells, as well as in positive control multiple myeloma RPMI 8226 cells. Flow cytometric measurements demonstrated that ATP induced ethidium(+) uptake into KG-l cells suspended in sucrose medium (EC(50) of ∼3 μM), but not into cells in NaCl medium. In contrast, ATP induced ethidium(+) uptake into RPMI 8226 cells suspended …

The Synthesis, Structures And Reactions Of Zinc And Cobalt Metal-Organic Frameworks Incorporating An Alkyne-Based Dicarboxylate Linker, Andrew D. Burrows, L C. Fisher, David M. Hodgson, Mary F. Mahon, Naomi Cessford, Tina Duren, Christopher Richardson, S P. Rigby

Faculty of Science - Papers (Archive)

The reaction of zinc(II) nitrate and 4,4′-ethynylenedibenzoic acid (H₂edb) in DMF at 80 °C gave the metal–organic framework material [Zn₄O(edb)₃(H₂O)₂]·6DMF 1 in which edb ligands connect Zn₄O centres into a doubly-interpenetrated cubic network with a similar topology to observed with other linear dicarboxylates in the IRMOF series. Analysis of the nitrogen isotherm revealed the material to have a BET surface area of 1088 m² g⁻¹, which is approximately one-third of the value calculated from GCMC simulations, suggesting incomplete activation or pore blocking in the activated …