UCL University College London Eprints
UCL Eprints collects the work of UCL researchers and makes it freely available over the web, helping the worldwide scholarly community to discover UCL research. Institutional repositories like UCL Eprints complement the traditional academic publishing and scholarly communications processes. They raise the visibility of research and help to maximise its impact. UCL researchers are encouraged to deposit a copy of each journal article, conference paper, working paper, and any other research output, in the UCL Eprints at the earliest opportunity, ensuring that their research reaches as wide an audience as possible.
Is the inflammasome a potential therapeutic target in renal disease? - Turner, CM; Arulkumaran, N; Singer, M; Unwin, RJ; Tam, FW
The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response to infection and tissue injury. Pattern recognition receptors that are either membrane bound or cytoplasmic trigger inflammasome assembly. These receptors sense danger signals including damage-associated molecular patterns and pathogen-associated molecular patterns (DAMPS and PAMPS respectively). The best-characterized inflammasome is the NLRP3 inflammasome. On assembly of the NLRP3 inflammasome, post-translational processing and secretion of pro-inflammatory cytokines IL-1beta and IL-18 occurs; in addition, cell death may be mediated via caspase-1. Intrinsic renal cells express components of the inflammasome pathway. This is most prominent in tubular epithelial cells and,...
Cardiac complications associated with goal-directed therapy in high-risk surgical patients: a meta-analysis. - Arulkumaran, N; Corredor, C; Hamilton, MA; Ball, J; Grounds, RM; Rhodes, A; Cecconi, M
Patients with limited cardiopulmonary reserve are at risk of mortality and morbidity after major surgery. Augmentation of oxygen delivery index (DO2I) with i.v. fluids and inotropes (goal-directed therapy, GDT) has been shown to reduce postoperative mortality and morbidity in high-risk patients. Concerns regarding cardiac complications associated with fluid challenges and inotropes may prevent clinicians from performing GDT in patients who need it most. We hypothesized that GDT is not associated with an increased risk of cardiac complications in high-risk, non-cardiac surgical patients. We performed a systematic search of Medline, Embase, and CENTRAL databases for randomized controlled trials (RCTs) of GDT...
Update on haemodynamic monitoring and management in septic patients. - Cecconi, M; Arulkumaran, N; Kilic, J; Ebm, C; Rhodes, A
Severe sepsis and septic shock are associated with significant mortality. Effective management of this clinical syndrome includes early resuscitation with fluids and vasoactive drugs to maintain vital organ perfusion and oxygen delivery. Understanding the different approach to the management of sepsis during the resuscitation and on-going management phases is essential to initiate context- and timespecific interventions. Manipulation of haemodynamic variables to achieve a balance between oxygen delivery and consumption forms the cornerstone of hemodynamic optimisation. Minimally invasive and completely non-invasive cardiac output monitors have been developed, but require validation in this specific cohort of patients. The trend in haemodynamic parameters...
A poly-γ-D-glutamic acid depolymerase that degrades the protective capsule of Bacillus anthracis. - Negus, D; Taylor, PW
A mixed culture of Pseudomonas fluorescens and Pusillimonas noertemanii, obtained by soil enrichment, elaborated an enzyme (EnvD) which rapidly hydrolyzed poly-γ-D-glutamic acid (PDGA), the constituent of the anti-phagocytic capsule conferring virulence on Bacillus anthracis. The EnvD gene is carried on the P. noertemanii genome but co-culture is required for the elaboration of PDGA depolymerase activity. EnvD showed strong sequence homology to dienelactone hydrolases from other Gram-negative bacteria, possessed no general protease activity but cleaved γ-links in both D- and L-glutamic acid-containing polymers. The stability at 37(o) C was markedly superior to that of CapD, a γ-glutamyltranspeptidase with PDGA depolymerase activity....
Combined jurisdiction for development appeals in the States and territories - Trenorden, CL; Hayes QC, BRM
The report followed a study in which the authors investigated the potential and implications for improving the efficiency of the development approval systems through the introduction of a combined jurisdiction for land and building development appeals and associated enforcement procedures in each of the States and Territories of Australia.
Environment - Risk Sharing - Trenorden, CL
The risks of parties to commercial transactions, from statutory liability under environmental legislation in Australia, are considered as are the impacts on lenders of the global trend for legislation to place occupiers at risk of liability for environmental damage. Legal tools for a precautionary approach and one which ensures the risk for liability for environmental damage is shared, and their likely reception in the community and interpretation by the courts in the case of actual environmental harm, are canvassed.
Strengthening South Australian communities in a changing world: 'The Council of the future' - Crafter AO, G; Trenorden, CL; Sansom, G
The Report followed a study into the present role and performance of local government in South Australia. Public comments were received following the publication of an issues paper and a discussion paper generated by the Panel of Experts (The Hon Greg Crafter AO, former judge Christine Trenorden and Prof Graham Sansom). The needs of local/community governance in the context of legislation, the relationships (including financial) with state and federal governments, an ageing demographic and community and other government expectations were considered. New models for community governance and community representation on councils were canvassed. The report makes recommendations for future local...
Unconscious influences on decision making: A critical review. - Newell, BR; Shanks, DR
To what extent do we know our own minds when making decisions? Variants of this question have preoccupied researchers in a wide range of domains, from mainstream experimental psychology (cognition, perception, social behavior) to cognitive neuroscience and behavioral economics. A pervasive view places a heavy explanatory burden on an intelligent cognitive unconscious, with many theories assigning causally effective roles to unconscious influences. This article presents a novel framework for evaluating these claims and reviews evidence from three major bodies of research in which unconscious factors have been studied: multiple-cue judgment, deliberation without attention, and decisions under uncertainty. Studies of priming...
Xenopus laevis RIC-3 enhances the functional expression of the C. elegans homomeric nicotinic receptor, ACR-16, in Xenopus oocytes. - Bennett, HM; Lees, K; Harper, KM; Jones, AK; Sattelle, DB; Wonnacott, S; Wolstenholme, AJ
RIC-3 enhances the functional expression of certain nicotinic acetylcholine receptors (nAChRs) in vertebrates and invertebrates and increases the availability of functional receptors in cultured cells and Xenopus laevis oocytes. Maximal activity of RIC-3 may be cell-type dependent, so neither mammalian nor invertebrate proteins is optimal in amphibian oocytes. We cloned the X. laevis ric-3 cDNA and tested the frog protein in oocyte expression studies. X. laevis RIC-3 shares 52% amino acid identity with human RIC-3 and only 17% with that of Caenorhabditis elegans. We used the C. elegans nicotinic receptor, ACR-16, to compare the ability of RIC-3 from three species...
Invertebrate models of spinal muscular atrophy: insights into mechanisms and potential therapeutics. - Grice, SJ; Sleigh, JN; Liu, JL; Sattelle, DB
Invertebrate genetic models with their tractable neuromuscular systems are effective vehicles for the study of human nerve and muscle disorders. This is exemplified by insights made into spinal muscular atrophy (SMA) using the fruit fly Drosophila melanogaster and the nematode worm Caenorhabditis elegans. For speed and economy, these invertebrates offer convenient, whole-organism platforms for genetic screening as well as RNA interference (RNAi) and chemical library screens, permitting the rapid testing of hypotheses related to disease mechanisms and the exploration of new therapeutic routes and drug candidates. Here, we discuss recent developments encompassing synaptic physiology, RNA processing, and screening of compound...
Cotinine reduces amyloid-β aggregation and improves memory in Alzheimer's disease mice. - Echeverria, V; Zeitlin, R; Burgess, S; Patel, S; Barman, A; Thakur, G; Mamcarz, M; Wang, L; Sattelle, DB; Kirschner, DA; Mori, T; Leblanc, RM; Prabhakar, R; Arendash, GW
Alzheimer's disease (AD) affects millions of people world-wide and new effective and safe therapies are needed. Cotinine, the main metabolite of nicotine, has a long half-life and does not have cardiovascular or addictive side effects in humans. We studied the effect of cotinine on amyloid-β (Aβ) aggregation as well as addressed its impact on working and reference memories. Cotinine reduced Aβ deposition, improved working and reference memories, and inhibited Aβ oligomerization in the brains of transgenic (Tg) 6799 AD mice. In vitro studies confirmed the inhibitory effect of cotinine on Aβ1-42 aggregation. Cotinine stimulated Akt signaling, including the inhibition of...
Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans. - Glendinning, SK; Buckingham, SD; Sattelle, DB; Wonnacott, S; Wolstenholme, AJ
Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects...
Identification of ion channel genes in the Acyrthosiphon pisum genome. - Dale, RP; Jones, AK; Tamborindeguy, C; Davies, TG; Amey, JS; Williamson, S; Wolstenholme, A; Field, LM; Williamson, MS; Walsh, TK; Sattelle, DB
Aphids are major pests of crops, causing hundreds of millions of dollars worth of damage annually. Ion channel proteins are often the targets of modern insecticides and mutations in ion channel genes can lead to resistance to many leading classes of insecticides. The sequencing of the pea aphid, Acyrthosiphon pisum, genome has now allowed detailed in silico analysis of the aphid ion channels. The study has revealed significant differences in the composition of the ion channel families between the aphid and other insects. For example A. pisum does not appear to contain a homologue of the nACh receptor alpha 5...
The cys-loop ligand-gated ion channel gene superfamily of the parasitoid wasp, Nasonia vitripennis. - Jones, AK; Bera, AN; Lees, K; Sattelle, DB
Members of the cys-loop ligand-gated ion channel (cysLGIC) superfamily mediate chemical neurotransmission and are studied extensively as potential targets of drugs used to treat neurological disorders, such as Alzheimer's disease. Insect cys-loop LGICs also have central roles in the nervous system and are targets of highly successful insecticides. Here, we describe the cysLGIC superfamily of the parasitoid wasp, Nasonia vitripennis, which is emerging as a highly useful model organism and is deployed as a biological control of insect pests. The wasp superfamily consists of 26 genes, which is the largest insect cysLGIC superfamily characterized, whereas Drosophila melanogaster, Apis mellifera and...