Social and Behavioral Sciences Commons^™

Rapid Cascade Synthesis Of Poly-Heterocyclic Architectures From Indigo, Alireza Shakoori Ghasabi, John Bremner, Anthony C. Willis, Rachada Haritakun, Paul A. Keller

Faculty of Science, Medicine and Health - Papers: part A

The base-induced propargylation of the dye indigo results in the rapid and unprecedented one-pot synthesis of highly functionalized representatives of the pyrazino[1,2-a:4,3-a′]diindole, pyrido[1,2-a:3,4-b′]diindole and benzo[b]indolo[1,2-h]naphthyridine heterocyclic systems, with the last two reflecting the core skeleton of the anticancer/antiplasmodial marine natural products fascaplysin and homofascaplysins and a ring B-homologue, respectively. The polycyclic compounds 6–8, whose structures were confirmed through single-crystal X-ray crystallographic analysis, arise from sequential inter/intramolecular substitution–addition reactions, and in some cases, ring rearrangement reactions. Preliminary studies on controlling the reaction path selectivity, and the potential reaction mechanisms, are also described. Initial biological activity studies with these new heterocyclic derivatives …

Concise Synthesis Of (-)-Steviamine And Analogues And Their Glycosidase Inhibitory Activities, Nadechanok Jiangseubchatveera, Marc E. Bouillon, Boonsom Liawruangrath, Saisunee Liawruangrath, Robert J. Nash, Stephen G. Pyne

Faculty of Science, Medicine and Health - Papers: part A

A concise synthesis of (−)-steviamine is reported along with the synthesis of its analogues 10-nor-steviamine, 10-nor-ent-steviamine and 5-epi-ent-steviamine. These compounds were tested against twelve glycosidases (at 143 μg mL−1 concentrations) and were found to have in general poor inhibitory activity against most enzymes. The 10-nor analogues however, showed 50–54% inhibition of α-L-rhamnosidase from Penicillium decumbens while one of these, 10-nor-steviamine, showed 51% inhibition of N-acetyl-β-D-glucosaminidase (from Jack bean) at the same concentration (760 μM).

Single Molecule Characterization Of The Interactions Between Amyloid-Β Peptides And The Membranes Of Hippocampal Cells, Priyanka Narayan, Kristina A. Ganzinger, James Mccoll, Laura Weimann, Sarah Meehan, Seema Qamar, John A. Carver, Mark R. Wilson, Peter St George-Hyslop, Christopher M. Dobson, David Klenerman

Faculty of Science, Medicine and Health - Papers: part A

Oligomers of the 40 and 42 residue amyloid-β peptides (Aβ40 and Aβ42) have been implicated in the neuronal damage and impaired cognitive function associated with Alzheimer’s disease. However, little is known about the specific mechanisms by which these misfolded species induce such detrimental effects on cells. In this work, we use single-molecule imaging techniques to examine the initial interactions between Aβ monomers and oligomers and the membranes of live cells. This highly sensitive method enables the visualization of individual Aβ species on the cell surface and characterization of their oligomerization state, all at biologically relevant, nanomolar concentrations. The results indicate …

Concise Synthesis Of Α-Substituted 2-Benzofuranmethamines And Other 2-Subsituted Benzofurans Via Α-Substituted 2-Benzofuranmethyl Carbocation Intermediates, Nikhom Wongsa, Ubonta Sommart, Thunwadee Ritthiwigrom, Arife Yazici, Somdej Kanokmedhakul, Kwanjai Kanokmedhakul, Anthony C. Willis, Stephen G. Pyne

Faculty of Science, Medicine and Health - Papers: part A

Propargyl amines 4, where R3 is aryl, undergo 5-exo-dig cyclization reactions under relatively mild conditions (AgNO3, DMF, 60 °C, 1 h) to give 3-amino-2,3-dihydro-2-arylmethylidenebenzofurans 5 (R3 = aryl). In contrast, substrates where R3 is alkyl undergo competing 6-endo-dig and 5-exo-dig cyclization processes. The hydroxymethyl substrate 4 (R3 = CH2OH), however, was smoothly converted to its corresponding 5-exo-dig cyclization product 5, likely due to the assistance of the primary hydroxyl group in the 5-exo-dig cyclization process by silver cation coordination. Under more enforcing conditions (AgNO3, DMF, 100 °C, 18 h), the initially formed products 5 undergo a 1,3-allylic rearrangement to their …

Daedalic Dna Vaccination Against Self Antigens As A Treatment For Chronic Kidney Disease, Yuan Min Wang, Jimmy Jianheng Zhou, Ya Wang, Debbie Watson, Geoff Yu Zhang, Min Hu, Huiling Wu, Guoping Zheng, Yiping Wang, Anne M. Durkan, David Ch Harris, Stephen I. Alexander

Faculty of Science, Medicine and Health - Papers: part A

Chronic kidney disease (CKD) is a major cause of death and morbidity in Australia and worldwide. DNA vaccination has been used for targeting foreign antigens to induce immune responses and prevent autoimmune disease, viral infection and cancer. However, the use of DNA vaccination has been restricted by a limited ability to induce strong immune responses, especially against self-antigens which are limited by mechanisms of self-tolerance. Furthermore, there have been few studies on the potential of DNA vaccination in chronic inflammatory diseases, including CKD. We have established strategies of DNA vaccination targeting specific self-antigens in the immune system including co-stimulatory pathways, …

Slow Avoidance Response To Contaminated Sediments Elicits Sublethal Toxicity To Benthic Invertebrates, Daniel J. Ward, Stuart L. Simpson, Dianne F. Jolley

Faculty of Science, Medicine and Health - Papers: part A

Advanced analytical techniques have identified the heterogeneity of sediments in aquatic environments which may impact the exposure of benthic organisms to contaminants. Acute and chronic toxicity associated with short, intermittent exposure to four field-collected contaminated sediments were assessed for the epi-benthic amphipod Melita plumulosa and the harpacticoid copepod Nitocra spinipes. Increasing the duration of exposure caused a decrease in survival of M. plumulosa and N. spinipes during 10-d bioassays. Increasing the frequency of exposure to a total exposure time >96-h resulted in a significant toxicity to M. plumulosa. Reproduction decreased for both species from exposure to contaminated sediment. For M. …

An Assessment Of The Bhutanese Traditional Medicine For Its Ethnopharmacology, Ethnobotany And Ethnoquality: Textual Understanding And The Current Practices, Phurpa Wangchuk, Stephen G. Pyne, Paul A. Keller

Faculty of Science, Medicine and Health - Papers: part A

Ethnopharmacological relevance : This study involves the assessment of the Bhutanese traditional medicine (BTM) which was integrated with the mainstream biomedicine in 1967 to provide primary health care services in the country. It caters to 20-30% of the daily out-patients within 49 traditional medicine units attached to 20 district modern hospitals and 29 Basic Health Units in the country. Aim of the study : This study presents the ethnopharmacological, ethnobotanical and the ethnoquality concepts in relation to mainstream Tibetan medicine and describes the current practices of BTM. Materials and methods : Experienced BTM practitioners (Drung-tshos and Smen-pas) were selected using …

The Role Of Hypothalamic H1 Receptor Antagonism In Antipsychotic-Induced Weight Gain, Meng He, Chao Deng, Xu-Feng Huang

Faculty of Science, Medicine and Health - Papers: part A

Treatment with second generation antipsychotics (SGAs), notably olanzapine and clozapine, causes severe obesity side effects. Antagonism of histamine H1 receptors has been identified as a main cause of SGA-induced obesity, but the molecular mechanisms associated with this antagonism in different stages of SGA-induced weight gain remain unclear. This review aims to explore the potential role of hypothalamic histamine H1 receptors in different stages of SGA-induced weight gain/obesity and the molecular pathways related to SGA-induced antagonism of these receptors. Initial data have demonstrated the importance of hypothalamic H1 receptors in both short- and long-term SGA-induced obesity. Blocking hypothalamic H1 receptors by …

Extracellular Chaperones And Proteostasis, Amy R. Wyatt, Justin J. Yerbury, Heath Ecroyd, Mark R. Wilson

Faculty of Science, Medicine and Health - Papers: part A

There is a family of currently untreatable serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited but has significantly advanced with the discovery of a small but growing family of constitutively secreted extracellular chaperones (ECs). The available evidence strongly suggests that these chaperones act as both sensors and disposal-mediators of misfolded proteins in extracellular fluids, thereby normally protecting us from disease pathologies. It is critically important to further increase our understanding of the mechanisms that operate to effect …

Generation Of Hydrogen Peroxide-Resistant Murine Neuroblastoma Cells: A Target Discovery Platform For Novel Neuroprotective Genes, Annette E. Maczurek, Rebekka Wild, Daunia Laurenti, Megan L. Steele, Lezanne Ooi, Gerald Munch

Faculty of Science, Medicine and Health - Papers: part A

Oxidative stress has been suggested to play an important role in the pathogenesis of various neurodegenerative diseases including Alzheimer’s disease (AD). Hydrogen peroxide (H2O2), one of the main reactive oxygen species, is converted into the highly toxic ·OH radical in the presence of redox-active transition metals, which then oxidises nucleic acids, lipids and proteins, leading to neurodegeneration and cell death. There is an urgent need to gain more knowledge about relevant therapeutic targets to combat oxidative stress and it neurotoxic effects, and how this knowledge can be utilized to develop novel neuroprotective therapies for AD. One way to identify new …

Mechanism For The Synergistic Effect Of Rapamycin And Resveratrol On Hyperinsulinemia May Involve The Activation Of Protein Kinase B, J Chen, Xu-Feng Huang

Faculty of Science, Medicine and Health - Papers: part A

Dear Editor, We read with great interest Leontiev et al.'s paper entitled 'Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high-fat diet' recently published in Cell Death & Disease.1 Their finding that rapamycin and resveratrol have a synergistic effect is important for treating insulin resistance. They showed that rapamycin inhibited mammalian target of rapamycin (mTOR) activity, while resveratrol inhibited S6 kinase (S6K). We think that these compounds may exert their effects through activating protein kinase B (Akt), a key regulator of insulin sensitivity. Both the inhibition of mTOR by rapamycin and of S6K by resveratrol could …

Allosteric Activation Transitions In Enzymes And Biomolecular Motors: Insights From Atomistic And Coarse-Grained Simulations, Michael D. Daily, Haibo Yu, George N. Phillips, Qiang Cui

Faculty of Science, Medicine and Health - Papers: part A

The chemical step in enzymes is usually preceded by a kinetically distinct activation step that involves large-scale conformational transitions. In "simple" enzymes this step corresponds to the closure of the active site; in more complex enzymes, such as biomolecular motors, the activation step is more complex and may involve interactions with other biomolecules. These activation transitions are essential to the function of enzymes and perturbations in the scale and/or rate of these transitions are implicated in various serious human diseases; incorporating key flexibilities into engineered enzymes is also considered a major remaining challenge in rational enzyme design. Therefore it is …

Sequential 1,4- And 1,2-Addition Reactions To Α,Β-Unsaturated N-Acyliminium Ions: A New Strategy For The Synthesis Of Spiro And Bridged Heterocycles, Arife Yazici, Stephen G. Pyne

Faculty of Science, Medicine and Health - Papers: part A

Novel bicyclic and tetracyclic spirocycles and tricyclic bridged heterocyclic systems can be readily prepared from sequential 1,4- and 1,2-addition reactions of latent bis-nucleophiles to α,β-unsaturated N-acyliminium ions.

Alkaloids From The Roots And Leaves Of Stichoneuron Halabalensis And Their Acetylcholinesterase Inhibitory Activities, Rosdayati Alino Ramli, Wilford Lie, Stephen G. Pyne

Faculty of Science, Medicine and Health - Papers: part A

A study of the hitherto unreported Stichoneuron halabalensis Inthachub led to the characterization of the known compounds (+)-α-tocopherol and (R)-(+)- goniothalamin; four known Stemona alkaloids, bisdehydoxystemoninine A (1), stemoninine (2), sessilistemonamine C (3) and sessilistemonamine A (4); and three new alkaloids, stichoneurine C (5), D (6) and E (7). The structures of these compounds were determined on the basis of their spectroscopic data. Alkaloid 7 showed significant inhibitory activity against electric eel acetylcholinesterase (AChE) (IC50 5.90+0.084 μM), while goniothalamin and compounds 1 and 2 showed significant inhibitory activities against human AChE (IC50 7.24+0.52, 5.52+0.13 and 3.74+0.09 μM, respectively).

The Small Heat Shock Proteins Αb-Crystallin And Hsp27 Suppress Sod1 Aggregation In Vitro, Justin J. Yerbury, Dane Gower, Laura Vanags, Kate Roberts, Jodi A. Lee, Heath Ecroyd

Faculty of Science, Medicine and Health - Papers: part A

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease. The mechanism that underlies amyotrophic lateral sclerosis (ALS) pathology remains unclear, but protein inclusions are associated with all forms of the disease. Apart from pathogenic proteins, such as TDP-43 and SOD1, other proteins are associated with ALS inclusions including small heat shock proteins. However, whether small heat shock proteins have a direct effect on SOD1 aggregation remains unknown. In this study, we have examined the ability of small heat shock proteins αB-crystallin and Hsp27 to inhibit the aggregation of SOD1 in vitro. We show that these chaperone proteins suppress the increase in …

Extracellular Chaperones, Rebecca A. Dabbs, Amy R. Wyatt, Justin J. Yerbury, Heath Ecroyd, Mark R. Wilson

Faculty of Science, Medicine and Health - Papers: part A

The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundamental prerequisite for life. Life has evolved complex mechanisms to maintain proteostasis and many of these that operate inside cells are now well understood. The same cannot yet be said of corresponding processes in extracellular fluids of the human body, where inappropriate protein aggregation is known to underpin many serious diseases such as Alzheimer's disease, type II diabetes and prion diseases. Recent research has uncovered a growing family of abundant extracellular chaperones in body fluids which appear to selectively bind to exposed regions of hydrophobicity on …

Deletion Of Abca7 Increases Cerebral Amyloid-Β Accumulation In The J20 Mouse Model Of Alzheimer's Disease, Woojin S. Kim, Hongyun Li, Kalani Ruberu, Sharon Chan, David A. Elliott, Jac Kee Low, David Cheng, Tim Karl, Brett Garner

Faculty of Science, Medicine and Health - Papers: part A

ATP-binding cassette transporter A7 (ABCA7) is expressed in the brain and has been detected in macrophages, microglia, and neurons. ABCA7 promotes efflux of lipids from cells to apolipoproteins and can also regulate phagocytosis and modulate processing of amyloid precursor protein (APP) to generate the Alzheimer's disease (AD) amyloid-β (Aβ) peptide. Genome-wide association studies have indicated that ABCA7 single nucleotide polymorphisms confer increased risk for late-onset AD; however, the role that ABCA7 plays in the brain in the AD context is unknown. In the present study, we crossed ABCA7-deficient (A7-/-) mice with J20 amyloidogenic mice to address this issue. We show …

Cytoprotective Properties Of Traditional Chinese Medicinal Herbal Extracts In Hydrogen Peroxide Challenged Human U373 Astroglia Cells, Megan L. Steele, John Truong, Suresh Govindaraghavan, Lezanne Ooi, Nikolaus J. Sucher, Gerald Munch

Faculty of Science, Medicine and Health - Papers: part A

Age is the leading risk factor for many of the most prevalent and devastating diseases including neurodegenerative diseases. A number of herbal medicines have been used for centuries to ameliorate the deleterious effects of ageing-related diseases and increase longevity. Oxidative stress is believed to play a role in normal ageing as well as in neurodegenerative processes. Since many of the constituents of herbal extracts are known antioxidants, it is believed that restoring oxidative balance may be one of the underlying mechanisms by which medicinal herbs can protect against ageing and cognitive decline. Based on the premise that astrocytes are key …

Metabotropic Glutamate Receptor 5 Binding And Protein Expression In Schizophrenia And Following Antipsychotic Drug Treatment, Natalie Matosin, Elisabeth Frank, Chao Deng, Xu-Feng Huang, Kelly A. Newell

Faculty of Science, Medicine and Health - Papers: part A

Metabotropic glutamate receptor 5 (mGluR5) has been identified as a potential therapeutic target for schizophrenia, primarily due to its ability to indirectly modulate glutamatergic signalling through the NMDA receptor (NMDAR). Despite its potential, molecular studies characterising mGluR5 in schizophrenia are limited. We therefore aimed to determine if the mGluR5 binding site or protein levels were altered in schizophrenia or by current antipsychotics. Using in-situ radioligand binding and immunoblot, we measured [3H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC; BA46) of 37 schizophrenia and 37 matched control subjects. Subsequently, we measured [3H]MPEP binding in …

Synthesis Of Cephalosporin-3′-Diazeniumdiolates: Biofilm Dispersing No-Donor Prodrugs Activated By Β-Lactamase, Nageshwar Rao Yepuri, Nicolas Barraud, Nasim Shah Mohammadi, Bharat G. Kardak, Staffan Kjelleberg, Scott A. Rice, Michael J. Kelso

Faculty of Science, Medicine and Health - Papers: part A

Use of biofilm dispersing NO-donor compounds in combination with antibiotics has emerged as a promising new strategy for treating drug-resistant bacterial biofilm infections. This paper details the synthesis and preliminary evaluation of six cephalosporin-3′-diazeniumdiolates as biofilm-targeted NO-donor prodrugs. Each of the compounds is shown to selectively release NO following reaction with the bacteria-specific enzyme β-lactamase and to trigger dispersion of Pseudomonas aeruginosa biofilms in vitro.

Protease-Activated Alpha-2-Macroglobulin Can Inhibit Amyloid Formation Via Two Distinct Mechanisms, Amy R. Wyatt, Patrick Constantinescu, Heath Ecroyd, Christopher M. Dobson, Mark R. Wilson, Janet R. Kumita, Justin J. Yerbury

Faculty of Science, Medicine and Health - Papers: part A

α2-Macroglobulin (α2M) is an extracellular chaperone that inhibits amorphous and fibrillar protein aggregation. The reaction of α2M with proteases results in an ‘activated’ conformation, where the proteases become covalently-linked within the interior of a cage-like structure formed by α2M. This study investigates, the effect of activation on the ability of α2M to inhibit amyloid formation by Aβ1–42 and I59T human lysozyme and shows that protease-activated α2M can act via two distinct mechanisms: (i) by trapping proteases that remain able to degrade polypeptide chains and (ii) by a chaperone action that prevents misfolded clients from continuing along the amyloid forming pathway.

Escherichia Coli Single-Stranded Dna-Binding Protein: Nanoesi-Ms Studies Of Salt-Modulated Subunit Exchange And Dna Binding Transactions, Claire E. Mason, Slobodan Jergic, Allen Lo, Yao Wang, Nicholas E. Dixon, Jennifer L. Beck

Faculty of Science, Medicine and Health - Papers: part A

Single-stranded DNA-binding proteins (SSBs) are ubiquitous oligomeric proteins that bind with very high affinity to single-stranded DNA and have a variety of essential roles in DNA metabolism. Nanoelectrospray ionization mass spectrometry (nanoESI-MS) was used to monitor subunit exchange in full-length and truncated forms of the homotetrameric SSB from Escherichia coli. Subunit exchange in the native protein was found to occur slowly over a period of hours, but was significantly more rapid in a truncated variant of SSB from which the eight C-terminal residues were deleted. This effect is proposed to result from C-terminus mediated stabilization of the SSB tetramer, in …

Proofreading Exonuclease On A Tether: The Complex Between The E. Coli Dna Polymerase Iii Subunits Α, Ε, Θ And Β Reveals A Highly Flexible Arrangement Of The Proofreading Domain, Kiyoshi Ozawa, Nicholas P. Horan, Andrew Robinson, Hiromasa Yagi, Flynn R. Hill, Slobodan Jergic, Zhi-Qiang Xu, Karin V. Loscha, Nan Li, Moeava Tehei, Aaron J. Oakley, Gottfried Otting, Thomas Huber, Nicholas E. Dixon

Faculty of Science, Medicine and Health - Papers: part A

A complex of the three (αεθ) core subunits and the β2 sliding clamp is responsible for DNA synthesis by Pol III, the Escherichia coli chromosomal DNA replicase. The 1.7 Å crystal structure of a complex between the PHP domain of α (polymerase) and the C-terminal segment of ε (proofreading exonuclease) subunits shows that ε is attached to α at a site far from the polymerase active site. Both α and ε contain clamp-binding motifs (CBMs) that interact simultaneously with β2 in the polymerization mode of DNA replication by Pol III. Strengthening of both CBMs enables isolation of stable αεθ:β2 complexes. …

Inhibition Of Tnf-Α Production In Lps-Activated Thp-1 Monocytic Cells By The Crude Extracts Of Seven Bhutanese Medicinal Plants, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Malai Taweechotipatr

Faculty of Science, Medicine and Health - Papers: part A

Ethnopharmacological relevance Seven studied medicinal plants; Aconitum laciniatum, Ajania nubigena, Codonopsis bhutanica, Corydalis crispa, Corydalis dubia, Meconopsis simplicifolia and Pleurospermum amabile, are currently used in the Bhutanese Traditional Medicine (BTM) for the management of different types of disorders including the diseases that bore relevance to various inflammatory conditions.

Aims of the study This study aimed to evaluate the inhibition of TNF-α production in LPS-activated THP-1 monocytic cells by the crude extracts of seven selected Bhutanese medicinal plants. It is expected to; (a) generate a scientific basis for their use in the BTM and (b) form a basis for prioritization of …

An Evaluation Of Ferrihydrite- And Metsorb™-Dgt Techniques For Measuring Oxyanion Species (As, Se, V, P): Effective Capacity, Competition And Diffusion Coefficients, Helen L. Price, Peter R. Teasdale, Dianne F. Jolley

Faculty of Science, Medicine and Health - Papers: part A

tThis study investigated several knowledge gaps with respect to the diffusive gradients in thin films(DGT) technique for measurement of oxyanions (As(III), As(V), Se(IV), Se(VI), PO43−, and V(V)) usingthe ferrihydrite and MetsorbTMbinding layers. Elution efficiencies for each binding layer were higherwith 1:20 dilutions, as analytical interferences for ICP-MS were minimised. Diffusion coefficients mea-sured by diffusion cell and by DGT time-series experiments were found to agree well and generallyagreed with previously reported values, although a range of diffusion coefficients have been reportedfor inorganic As and Se species. The relative binding affinity for both ferrihydrite and MetsorbTMwasPO43−≈ As(V) > V(V) ≈ As(III) > Se(IV) ≫ …

Gc/Gc-Ms Analysis, Isolation And Identification Of Bioactive Essential Oil Components From The Bhutanese Medicinal Plant, Pleurospermum Amabile, Phurpa Wangchuk, Paul A. Keller, Stephen G. Pyne, Malai Taweechotipatr, Sumalee Kamchonwongpaisan

Faculty of Science, Medicine and Health - Papers: part A

We have hydrodistilled the essential oil (EO) from the aerial parts of the Bhutanese medicinal plant, Pleurospermum amabile using a Clevenger apparatus and evaluated this EO by GC/GC-MS and NMR analysis followed by testing for bioactivity. The GC-MS analysis identified 52 compounds with (E)-isomyristicin as a major component (32.2%). Repeated purification yielded four compounds; (E)-isomyristicin (1), (E)-isoapiol (2), methyl eugenol (3) and (E)-isoelemicin (4). Compound 2 and the mother EO showed the best antiplasmodial activity against the Plasmodium falciparum strains, TM4/8.2 (chloroquine and antifolate sensitive) and K1CB1 (multidrug resistant). They exhibited mild antibacterial activity against Bacillus subtilis. None of the …

Parviflorals A-F, Trinorcadalenes And Bis-Trinorcadalenes From The Roots Of Decaschistia Parviflora, Nikhom Wongsa, Somdej Kanokmedhakul, Kwanjai Kanokmedhakul, Palangpon Kongsaeree, Samran Prabpai, Stephen G. Pyne

Faculty of Science, Medicine and Health - Papers: part A

Trinorcadalenes, parviflorals A and B (1 and 2), and four bis-trinorcadalenes, parviflorals C–F (3–6), together with the known trinorcadalenes, syriacusins A (7) and C (8), scopoletin (9) and stigmasterol were isolated from roots of Decaschistia parviflora. Their structures were established by spectroscopic techniques. The CD spectra of the bis-trinorcadalenes (3–6) established their absolute configurations at the binaphthyl axis. Further, structure 6 was confirmed by a single-crystal X-ray crystallographic analysis. Compounds 2 and 6 showed antimalarial activity against Plasmodium falciparum with IC50 values of 11.45 and 6.85 μM, respectively. Compounds 1, 5, 7 and 8 also exhibited weak antifungal activity against …

Neuregulin-1 Signalling And Antipsychotic Treatment: Potential Therapeutic Targets In A Schizophrenia Candidate Signalling Pathway, Chao Deng, Bo Pan, Martin Engel, Xu-Feng Huang

Faculty of Science, Medicine and Health - Papers: part A

Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or …

Human P2x7 Receptor Activation Induces The Rapid Shedding Of Cxcl16, Aleta Pupovac, Christopher M. Foster, Ronald Sluyter

Faculty of Science, Medicine and Health - Papers: part A

Activation of the purinergic P2X7 receptor by extracellular ATP induces the shedding of cell-surface molecules including the low-affinity IgE receptor, CD23 from leukocytes. CD23 is a known substrate of a disintegrin and metalloprotease (ADAM)10. The aim of the current study was to determine if P2X7 activation induced the shedding of the chemokine CXCL16, an ADAM10 substrate. Using immunolabelling and flow cytometry we demonstrate that human RPMI 8226 multiple myeloma B cells, which have been previously shown to express P2X7, also express CXCL16. Flow cytometric and ELISA measurements of ATP-induced loss of cell-surface CXCL16 showed that ATP treatment of RPMI 8226 …

Ozone-Induced Dissociation Of Conjugated Lipids Reveals Significant Reaction Rate Enhancements And Characteristic Odd-Electron Product Ions, Huong T. Pham, Alan T. Maccarone, J Larry Campbell, Todd W. Mitchell, Stephen J. Blanksby

Faculty of Science, Medicine and Health - Papers: part A

Ozone-induced dissociation (OzID) is an alternative ion activation method that relies on the gas phase ion-molecule reaction between a mass-selected target ion and ozone in an ion trap mass spectrometer. Herein, we evaluated the performance of OzID for both the structural elucidation and selective detection of conjugated carbon-carbon double bond motifs within lipids. The relative reactivity trends for [M + X]+ ions (where X = Li, Na, K) formed via electrospray ionization (ESI) of conjugated versus nonconjugated fatty acid methyl esters (FAMEs) were examined using two different OzID-enabled linear ion-trap mass spectrometers. Compared with nonconjugated analogues, FAMEs derived from conjugated …