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ItemPhenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder(Elsevier, 15-02-20) Rucker, James J H; Tansey, Katherine E; Rivera, Margarita; Pinto, Dalila; Cohen-Woods, Sarah; Uher, Rudolf; Aitchison, Katherine J; Craddock, Nick; Owen, Michael J; Jones, Lisa; Jones, Ian; Korszun, Ania; Barnes, Michael R; Preisig, Martin; Mors, Ole; Maier, Wolfgang; Rice, John P; Rietschel, Marcella; Holsboer, Florian; Farmer, Anne E; Craig, Ian W; Scherer, Stephen W; Scherer, Peter; Breen, GeromeBackground Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. Methods In this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. Results We found an enrichment of Turner’s syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). Conclusions After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders. ItemSecreted human Ro52 autoantibody proteomes express a restricted set of public clonotypes(Elsevier, Dec-12) Arentz, Georgia; Thurgood, Lauren Alexandra; Lindop, Rhianna; Chataway, Timothy Kennion; Gordon, Thomas PaulLong-lived secreted autoantibody responses in systemic autoimmunity are generally regarded to be polyclonal and to express a diverse B-cell repertoire. Here, we have used a proteomic approach based on de novo sequencing to determine the clonality and V region structures of human autoantibodies directed against a prototypic systemic autoantigen, Ro52 (TRIM21). Remarkably, anti-Ro52 autoantibodies from patients with primary Sjögren’s syndrome, systemic lupus erythematosus, systemic sclerosis or polymyositis were restricted to two IgG1 kappa clonotypes that migrated as a single species on isoelectric focusing; shared a common light chain paired with one of two closely-related heavy chains; and were public in unrelated patients. Targeted mass spectrometry using these uniquely mutated V region peptides as surrogates detected anti-Ro52 autoantibodies in human sera with high sensitivity and specificity compared with traditional ELISA. Mass spectrometry-based detection of specific autoantibody motifs provides a powerful new tool for analysis of humoral autoimmunity. ItemEffects of amino acid substitutions at positions 33 and 37 on UDP-glucuronosyltransferase 1A9 (UGT1A9) activity and substrate selectivity(Elsevier, Dec-12) Korprasertthaworn, Porntipa; Rowland, Andrew; Lewis, Benjamin Cavell; Mackenzie, Peter Ian; Yoovathaworn, Krontong; Miners, John OliverUGT1A9 contributes to the glucuronidation of numerous drugs and xenobiotics. There is evidence to suggest that the Met33Thr substitution, as occurs in the polymorphic variant UGT1A9*3, variably affects xenobiotic glucuronidation. The equivalent position in UGT1A4 is also known to influence enzyme activity, whilst an N-terminal domain histidine (His37 in UGT1A9) is believed to function as the catalytic base in most UGT enzymes. To elucidate the roles of key amino acids and characterise structure–function relationships, we determined the effects of amino acid substitutions at positions 33 and 37 of UGT1A9 on the kinetics of 4-methylumbelliferone (4-MU), mycophenolic acid (MPA), propofol (PRO), sulfinpyrazone (SFZ), frusemide (FSM), (S)-naproxen (NAP) and retigabine (RTB) glucuronidation, compounds that undergo glucuronidation at either a phenolic (4-MU, MPA, PRO), carboxylate (FSM, NAP), acidic carbon (SFZ) or amine (RTB) function. Substitution of Met33 with Val, Ile, Thr, and Gln, as occur in UGT1A1, UGT1A3, UGT1A4 and UGT1A6 respectively, variably affected kinetics and catalytic efficiency. Whilst Km values were generally higher and Vmax and CLint values were generally lower than for wild-type UGT1A9 with most substrate-mutant pairs, the pattern and the magnitude of the changes in each parameter differed substantially. Moreover, exceptions occurred; CLint values for MPA and FSM glucuronidation by the position-33 mutants were the same as or higher than that of UGT1A9. Mutation of His37 abolished activity towards all substrates, except RTB N-glucuronidation. The data confirm the importance of single amino acids for UGT enzyme activity and substrate selectivity, and support a pivotal role for residue-33 in facilitating substrate binding to UGT1A9. ItemPreproglucagon neurons innervate neurochemically identified autonomic neurons in the mouse brainstem(Elsevier, Jan-13) Llewellyn-Smith, Ida Jonassen; Gnanamanickam, Greta J E; Reimann, Frank; Gribble, Fiona M; Trapp, StefanPreproglucagon (PPG) neurons produce glucagon-like peptide-1 (GLP-1) and occur primarily in the nucleus tractus solitarius (NTS). GLP-1 affects a variety of central autonomic circuits, including those controlling the cardiovascular system, thermogenesis, and most notably energy balance. Our immunohistochemical studies in transgenic mice expressing YFP under the control of the PPG promoter showed that PPG neurons project widely to central autonomic regions, including brainstem nuclei. Functional studies have highlighted the importance of hindbrain receptors for the anorexic effects of GLP-1. ItemLong-term Ro60 humoral autoimmunity in primary Sjogren's syndrome is maintained by rapid clonal turnover(Elsevier, Jul-13) Lindop, Rhianna; Arentz, Georgia; Bastian, Isabell; Whyte, Andrew F; Thurgood, Lauren Alexandra; Chataway, Timothy Kennion; Jackson, Michael W; Gordon, Thomas PaulLong-term humoral autoimmunity to RNA–protein autoantigens is considered a hallmark of systemic autoimmune diseases. We use high resolution Orbitrap mass spectrometric autoantibody sequencing to track the evolution of a Ro60-specific public clonotypic autoantibody in 4 patients with primary Sjögren's syndrome. This clonotype is specified by a VH3–23/VK3–20 heavy and light chain pairing. Despite apparent stability by conventional immunoassay, analysis of V-region molecular signatures of clonotypes purified from serum samples collected retrospectively over 7 years revealed sequential clonal replacement. Prospective longitudinal studies confirmed clonotype loss and replacement at approximately three-monthly intervals. Levels of secreted anti-Ro60 clonotypes fluctuated markedly over time, despite minimal changes in clonal affinity. Our novel findings indicate a relentless turnover of short-lived clonotypic variants, masquerading as long-lived Ro60 humoral autoimmunity. ItemHealth librarians and Grey Literature: what do we need to know?(1/10/2014) Tyndall, Jessica ItemWhose values in health? An empirical comparison of the application of adolescent and adult values for the CHU9D and AQOL-6D in the Australian adolescent general population(Elsevier, 11/06/2012) Ratcliffe, Julie; Stevens, Katherine; Flynn, Terry; Brazier, John; Sawyer, Michael GThe Child Health Utility-9D (CHU-9D) and the Assessment of Quality of Life-6D (AQOL-6D) presently represent the only two generic preference-based instruments developed for application with young people with both adult- and adolescent-specific scoring algorithms. The main objective of this study was to compare and contrast the application of adult and adolescent scoring algorithms for the CHU-9D and AQOL-6D in valuing the health of a community-based sample of adolescents. ItemWork organisation, job insecurity and occupational health disparities(Wiley-Blackwell, 16/10/2012) Landsbergis, PA; Grzywacz, JG; LaMontagne, Anthony DChanges in employment conditions in the global economy over the past 30 years have led to increased job insecurity and other work organization hazards. These hazards may play a role in creating and sustaining occupational health disparities by socioeconomic position, gender, race, ethnicity, and immigration status. ItemSelective expression of α-synuclein-immunoreactivity in vesicular acetylcholine transporter-immunoreactive axons in the guinea-pig rectum and human colon(Wiley-Blackwell, 17/12/2012) Sharrad, DF; de Vries, E; Brookes, Simon JonathanParkinson's disease is a neurodegenerative disorder characterized by motor and nonmotor impairments, including constipation. The hallmark pathological features of Parkinson's disease are Lewy bodies and neurites, of which aggregated α-synuclein is a major constituent. Frequently, Lewy pathology is identified in the distal gut of constipated Parkinson's disease patients. The neurons that innervate the distal gut that express α-synuclein have not been identified. We used multiple-labeling immunohistochemistry and anterograde tracing to quantify which neurons projecting to the guinea pig rectum and human colon expressed α-synuclein in their axons. α-Synuclein-immunoreactivity was present in 24 ± 0.7% of somatostatin (SOM)-immunoreactive (IR) varicosities; 20 ± 4.3% of substance P (SP)-IR varicosities and 9 ± 1.3% vasoactive intestinal polypeptide (VIP)-IR varicosities in guinea pig rectal myenteric ganglia. However, α-synuclein-immunoreactivity was localized in significantly more vesicular acetylcholine transporter (VAChT)-IR varicosities (88 ± 3%, P < 0.001). Of SOM-IR, SP-IR, and VIP-IR varicosities that lacked VAChT-immunoreactivity, only 1 ± 0.3%, 0 ± 0.3%, and 0% contained α-synuclein-immunoreactivity, respectively. 71 ± 0.8% of VAChT-IR varicosities in myenteric ganglia of human colon were α-synuclein-IR. In guinea pig rectal myenteric ganglia, α-synuclein- and VAChT-immunoreactivity coexisted in 15 ± 1.4% of biotinamide-labeled extrinsic varicosities; only 1 ± 0.3% of biotinamide-labeled extrinsic varicosities contained α-synuclein-immunoreactivity without VAChT-immunoreactivity. α-Synuclein expression in axons to the distal gut correlates closely with expression of the cholinergic marker, VAChT. This is the first report of cell-selective α-synuclein expression in the nervous system. Our results suggest cholinergic neurons in the gut may be vulnerable in Parkinson's disease. ItemViscerofugal neurons recorded from guinea-pig colonic nerves after organ culture(Wiley-Blackwell, 19/07/2012) Hibberd, TJ; Zagorodnyuk, Vladimir Petrovich; Spencer, Nicholas John; Brookes, Simon JonathanBackground Enteric viscerofugal neurons provide cholinergic synaptic inputs to prevertebral sympathetic neurons, forming reflex circuits that control motility and secretion. Extracellular recordings of identified viscerofugal neurons have not been reported. Methods Preparations of guinea pig distal colon were maintained in organotypic culture for 4-6 days (n = 12), before biotinamide tracing, immunohistochemistry, or extracellular electrophysiological recordings from colonic nerves. Key Results After 4-6 days in organ culture, calcitonin gene-related peptide and tyrosine hydroxylase immunoreactivity in enteric ganglia was depleted, and capsaicin-induced firing (0.4 micromol L-1) was not detected, indicating that extrinsic sympathetic and sensory axons degenerate in organ culture. Neuroanatomical tracing of colonic nerves revealed that viscerofugal neurons persist and increase as a proportion of surviving axons. Extracellular recordings of colonic nerves revealed ongoing action potentials. Interestingly, synchronous bursts of action potentials were seen in 10 of 12 preparations; bursts were abolished by hexamethonium, which also reduced firing rate (400 micromol L-1, P < 0.01, n = 7). DMPP (1,1-dimethyl-4-phenylpiperazinium; 10-4 mol L-1) evoked prolonged action potential discharge. Increased firing preceded both spontaneous and stretch-evoked contractions (X2 = 11.8, df = 1, P < 0.001). Firing was also modestly increased during distensions that did not evoke reflex contractions. All single units (11/11) responded to von Frey hairs (100-300 mg) in hexamethonium or Ca2+-free solution. Conclusions & Inferences Action potentials recorded from colonic nerves in organ cultured preparations originated from viscerofugal neurons. They receive nicotinic input, which coordinates ongoing burst firing. Large bursts preceded spontaneous and reflex-evoked contractions, suggesting their synaptic inputs may arise from enteric circuitry that also drives motility. Viscerofugal neurons were directly mechanosensitive to focal compression by von Frey hairs. ItemFindIt@Flinders: user experiences of the Primo discovery search solution(Australian Library and Information Association, 1905-07-04) Jarrett, Kylie AnneIn September 2011, Flinders University Library launched FindIt@Flinders, the Primo discovery layer search to provide simultaneous results from the Library’s collections and subscription databases. This research project was an exploratory case study, which aimed to show whether students are finding relevant information for their course learning and research. The Library staff ran student usability sessions and an online survey for this search interface. These two methods uncovered data on what elements participants are finding useful or not useful, and what problems they are encountering. The results of this study showed a variety of feedback, which was mainly positive. This feedback has informed how the Library can modify Primo for a better user experience and incorporate beneficial approaches to FindIt@Flinders into its student training plan. ItemEstablishing a culture of research practice in an academic library: an Australian case study(Emerald, 1905-07-05) McBain, Ian; Culshaw, Helen; Walkley Hall, ElizabethThe purpose of this paper is to describe the establishment of a Research Working Group at Flinders University Library, a mid-sized teaching and research university located in South Australia. The group was founded to encourage staff to develop a more reflective, research-oriented and evidence-based professional practice initially for a three year term. This paper comes at about two years into the pilot and provides an interim report of the group’s experiences and achievements. ItemReview of 'Shakespeare's metrics' by Dorothy L. Sipe(Australasian Universities Language and Literature Association, 1970-11) Daalder, JoostMiss Sipe sets out to prove correct the debated assumption that Shakespeare "wrote carefully constructed iambic verse into which he introduced only those few minor variations considered permissible in his time". Her labour is extensive, her methodology questionable. ItemSome Problems of Punctuation and Syntax in Egerton MS 2711 of Wyatt's Verse(Oxford University Press, 1971) Daalder, JoostIn this brief article, Professor Daalder discusses a number of instances where the punctuation of Muir and Thomson's 'Collected Poems of Sir Thomas Wyatt', which the modern reader is meant to find comprehensible and helpful, does not seem to do justice to Wyatt's syntax. ItemReview of 'Collected poems of Sir Thomas Wyatt' edited by Muir and Thomson(Australasian Universities Language and Literature Association, 1971-05) Daalder, JoostDaalder reviews 'Collected poems of Sir Thomas Wyatt', edited by Kenneth Muir and Patricia Thomson (Liverpool University Press, 1969). ItemReview of 'A linguistic guide to English poetry' by Geoffrey N Leech(Australasian Universities Language and Literature Association, 1971-05) Daalder, JoostThe author reviews 'A linguistic guide to English poetry'. (London and Harrow: Longmans, English Language Series, 1969.) ItemReview of 'Triumphal forms: structural patterns in Elizabethan poetry' by Alastair Fowler(Australasian Universities Language and Literature Association, 1971-05) Daalder, JoostDaalder reviews "Triumphal forms: structural patterns in Elizabethan poetry' by Alastair Fowler (Cambridge University Press, 1970). ItemWyatt's 'There was never nothing more me payned': a reply to John Douglas Boyd(Oxford University Press, 1971-10) Daalder, JoostAs far as Wyatt's poem is concerned, I think Boyd's critical problems are largely of his own making. This does not necessarily invalidate his claim that a critic, in interpreting a literary work, may seize on one interpretation rather than another because of his own personal background. However, I would at all times argue that such a critic's interpretation is academically legitimate only if it is supported by textual evidence; secondly, that if the text supports another interpretation the first critic's view of it is only an incomplete truth; thirdly, that the literary critic can only appeal to the text and such 'objective' background (i.e. not the experience of a single reader) as may help to explain the text, and that the study of 'fundamental moral, psychological, even ontological judgments derived from our experience outside the poem' lies outside our province.