Medicine and Health Sciences Commons^™

Exchange Between Escherichia Coli Polymerases Ii And Iii On A Processivity Clamp, James E. Kath, Seungwoo Chang, Michelle K. Scotland, Johannes H. Wilbertz, Slobodan Jergic, Nicholas E. Dixon, Mark D. Sutton, Joseph J. Loparo

Illawarra Health and Medical Research Institute

Escherichia coli has three DNA polymerases implicated in the bypass of DNA damage, a process called translesion synthesis (TLS) that alleviates replication stalling. Although these polymerases are specialized for different DNA lesions, it is unclear if they interact differently with the replication machinery. Of the three, DNA polymerase (Pol) II remains the most enigmatic. Here we report a stable ternary complex of Pol II, the replicative polymerase Pol III core complex and the dimeric processivity clamp, β. Single-molecule experiments reveal that the interactions of Pol II and Pol III with β allow for rapid exchange during DNA synthesis. As with …

Spontaneous Cleavage Of Proteins At Serine And Threonine Is Facilitated By Zinc, Brian Lyons, Ann H. Kwan, Roger J. W Truscott

Illawarra Health and Medical Research Institute

Old proteins are widely distributed in the body. Over time, they deteriorate and many spontaneous reactions, for example isomerisation of Asp and Asn, can be replicated by incubation of peptides under physiological conditions. One of the signatures of long-lived proteins that has proven to be difficult to replicate in vitro is cleavage on the N-terminal side of Ser residues, and this is important since cleavage at Ser, and also Thr, has been observed in a number of human proteins. In this study, the autolysis of Ser- and Thr-containing peptides was investigated with particular reference to discovering factors that promote cleavage …

Abca7 Deletion Does Not Affect Adult Neurogenesis In The Mouse, Hongyun Li, Tim Karl, Brett Garner

Illawarra Health and Medical Research Institute

ATP-binding cassette transporter A7 (ABCA7) is highly expressed in the brain. Recent genome-wide association studies (GWAS) have identified ABCA7 single nucleotide polymorphisms (SNPs) that increase Alzheimer's disease (AD) risk, however, the mechanisms by which ABCA7 may control AD risk remain to be fully elucidated. Based on previous research suggesting that certain ABC transporters may play a role in the regulation of neurogenesis, we conducted a study of cell proliferation and neurogenic potential using cellular bromodeoxyuridine (BrdU) incorporation and doublecortin (DCX) immunostaining in adult Abca7 deficient mice and wild-type-like (WT) littermates. In the present study counting of BrdU-positive and DCX-positive cells …

Ccnf Mutations In Amyotrophic Lateral Sclerosis And Frontotemporal Dementia, Kelly L. Williams, Simom Topp, Shu Yang, Bradley Smith, Jennifer A. Fifita, Sadaf T. Warraich, Katharine Y. Zhang, Natalie E. Farrawell, Caroline Vance, Xun Hu, Justin J. Yerbury

Illawarra Health and Medical Research Institute

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a …

Chlorogenic Acid Protects D-Galactose-Induced Liver And Kidney Injury Via Antioxidation And Anti-Inflammation Effects In Mice, Yan Feng, Yinghua Yu, Shu-Ting Wang, Jing Ren, Danielle Camer, Yu-Zhou Hua, Qian Zhang, Jie Huang, Dan-Lu Xue, Xiaofei Zhang, Xu-Feng Huang, Yi Liu

Illawarra Health and Medical Research Institute

Context Oxidative stress and inflammation are implicated in the aging process and its related hepatic and renal function decline. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in the human diet. Recently, CGA has shown in vivo and in vitro antioxidant properties. Objective The current study investigates the effects of protective effects of chlorogenic acid (CGA) on d-galactose-induced liver and kidney injury. Materials and methods Hepatic and renal injuries were induced in a mouse model by subcutaneously injection of d-galactose (d-gal; 100 mg/kg) once a day for 8 consecutive weeks and orally administered simultaneously with CGA included …

Beneficial Effects Of Increased Lysozyme Levels In Alzheimer's Disease Modelled In Drosophila Melanogaster, Linnea Sandin, Liza Bergkvist, Sangeeta Nath, Claudia Kielkopf, Camilla Janefjord, Linda Helmfors, Henrik Zetterberg, Kaj Blennow, Hongyun Li, Camilla Nilsberth, Brett Garner, Ann-Christin Brorsson, Katarina Kagedal

Illawarra Health and Medical Research Institute

Genetic polymorphisms of immune genes that associate with higher risk to develop Alzheimer's disease (AD) have led to an increased research interest on the involvement of the immune system in AD pathogenesis. A link between amyloid pathology and immune gene expression was suggested in a genome-wide gene expression study of transgenic amyloid mouse models. In this study, the gene expression of lysozyme, a major player in the innate immune system, was found to be increased in a comparable pattern as the amyloid pathology developed in transgenic mouse models of AD. A similar pattern was seen at protein levels of lysozyme …

Videomicroscopy As A Tool For Investigation Of The Microcirculation In The Newborn, Ian M. R Wright, Joanna L. Latter, Rebecca M. Dyson, Christopher (Chris) Levi, Vicki L. Clifton

Illawarra Health and Medical Research Institute

The perinatal period remains a time of significant risk of death or disability. Increasing evidence suggests that this depends on microcirculatory behavior. Sidestream dark-field orthogonal polarized light videomicroscopy (OPS) has emerged as a useful assessment of adult microcirculation but the values derived are not delineated for the newborn. We aimed to define these parameters in well term newborn infants. Demographic details were collected prospectively on 42 healthy term neonates (n = 20 females, n = 22 males). OPS videomicroscopy (Microscan) was used to view ear conch skin microcirculation at 6, 24, and 72 h of age. Stored video was analyzed …

Intake Of 7,8-Dihydroxyflavone During Juvenile And Adolescent Stages Prevents Onset Of Psychosis In Adult Offspring After Maternal Immune Activation, Mei Han, Ji-Chun Zhang, Wei Yao, Chun Yang, Tamaki Ishima, Qian Ren, Min Ma, Chao Dong, Xu-Feng Huang, Kenji Hashimoto

Illawarra Health and Medical Research Institute

Prenatal infection and subsequent abnormal neurodevelopment of offspring is involved in the etiology of schizophrenia. Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB) signaling plays a key role in the neurodevelopment. Pregnant mice exposed to polyriboinosinic-polyribocytidylic acid [poly(I:C)] causes schizophrenia-like behavioral abnormalities in their offspring at adulthood. Here we found that the juvenile offspring of poly(I:C)-treated mice showed cognitive deficits, as well as reduced BDNF-TrkB signaling in the prefrontal cortex (PFC). Furthermore, the adult offspring of poly(I:C)-treated mice showed cognitive deficits, prepulse inhibition (PPI) deficits, reduced BDNF-TrkB signaling, immunoreactivity of parvalbumin (PV) and peroxisome …

Neurodevelopmental Expression Profile Of Dimeric And Monomeric Group 1 Mglurs: Relevance To Schizophrenia Pathogenesis And Treatment, Jeremy Lum, Francesca Fernandez-Enright, Natalie Matosin, Jessica L. Andrews, Xu-Feng Huang, Lezanne Ooi, Kelly A. Newell

Illawarra Health and Medical Research Institute

Group 1 metabotropic glutamate receptors (mGluR1/mGluR5) play an integral role in neurodevelopment and are implicated in psychiatric disorders, such as schizophrenia. mGluR1 and mGluR5 are expressed as homodimers, which is important for their functionality and pharmacology. We examined the protein expression of dimeric and monomeric mGluR1α and mGluR5 in the prefrontal cortex (PFC) and hippocampus throughout development (juvenile/adolescence/adulthood) and in the perinatal phencyclidine (PCP) model of schizophrenia. Under control conditions, mGluR1α dimer expression increased between juvenile and adolescence (209-328%), while monomeric levels remained consistent. Dimeric mGluR5 was steadily expressed across all time points; monomeric mGluR5 was present in juveniles, dramatically …

Scorpine-Like Peptides, Karen S. Luna Ramirez, Juana María Jimenez-Vargas, Lourival D. Possani

Illawarra Health and Medical Research Institute

Scorpine-like peptides are intriguing and unique compounds of scorpion venom. They possess two well-defined regions that confers them bi-functionality. The N-terminal region is similar to scorpion antimicrobial peptides lacking disulfide bridges, whereas the C-terminal region contains six cysteines forming three disulfide bridges that tightly bind the peptide. Scorpine-like peptides have shown activity against bacteria (i.e. B. subtilis, K. pneumoniae, P. aeruginosa), fungi and also as potassium channel blockers. Additionally, they have been successful in controlling malaria and some types of viruses.

Key Structural Determinants In The Agonist Binding Loops Of Human Β2 And Β4 Nicotinic Acetylcholine Receptor Subunits Contribute To Α3Β4 Subtype Selectivity Of Α-Conotoxins, Hartmut Cuny, Shiva N. Kompella, Han Shen Tae, Rilei Yu, David J. Adams

Illawarra Health and Medical Research Institute

α-Conotoxins represent a large group of pharmacologically active peptides that antagonize nicotinic acetylcholine receptors (nAChRs). The α3β4 nAChR, a predominant subtype in the peripheral nervous system, has been implicated in various pathophysiological conditions. As many α-conotoxins have multiple pharmacological targets, compounds specifically targeting individual nAChR subtypes are needed. In this study, we performed mutational analyses to evaluate the key structural components of human β2 and β4 nAChR subunits that determine α-conotoxin selectivity for α3β4 nAChR. α-Conotoxin RegIIA was used to evaluate the impact of non-conserved human β2 and β4 residues on peptide affinity. Two mutations, α3β2[T59K] and α3β2[S113R], strongly enhanced …

Early Antipsychotic Treatment In Juvenile Rats Elicits Long-Term Alterations To The Dopamine Neurotransmitter System, Michael De Santis, Jiamei Lian, Xu-Feng Huang, Chao Deng

Illawarra Health and Medical Research Institute

Prescription of antipsychotic drugs (APDs) to children has substantially increased in recent years. Whilst current investigations into potential long-term effects have uncovered some alterations to adult behaviours, further investigations into potential changes to neurotransmitter systems are required. The current study investigated potential long-term changes to the adult dopamine (DA) system following aripiprazole, olanzapine and risperidone treatment in female and male juvenile rats. Levels of tyrosine hydroxylase (TH), phosphorylated-TH (p-TH), dopamine active transporter (DAT), and D₁ and D₂ receptors were measured via Western blot and/or receptor autoradiography. Aripiprazole decreased TH and D₁ receptor levels in the ventral tegmental …

Dietary Iodine Intake Of The Australian Population After Introduction Of A Mandatory Iodine Fortification Programme, Karen E. Charlton, Yasmine Probst, Gabriella Kiene

Illawarra Health and Medical Research Institute

To address mild iodine deficiency in Australia, a mandatory fortification program of iodised salt in bread was implemented in 2009. This study aimed to determine factors associated with achieving an adequate dietary iodine intake in the Australian population post-fortification, and to assess whether bread consumption patterns affect iodine intake in high-risk groups. Using nationally representative data of repeated 24-h dietary recalls from the 2011-2012 Australian National Nutrition and Physical Activity Survey, dietary iodine intakes and food group contributions were compared by age, socioeconomic status (SES), and geographical remoteness (N = 7735). The association between fortified bread intake and adequacy …

A Lipidomic Analysis Of Placenta In Preeclampsia: Evidence For Lipid Storage, Simon H. J Brown, Samuel Eather, Dilys J. Freeman, Barbara J. Meyer, Todd W. Mitchell

Illawarra Health and Medical Research Institute

In preeclampsia, maternal insulin resistance leads to defective expansion of adipocytes, enhanced adipocyte lipolysis, up-regulation of very low density lipoprotein synthesis, maternal hypertriglyceridaemia and the potential for ectopic fat storage. Our aim was to quantitate and compare the total amount and type of lipid in placenta from pregnancies complicated with preeclampsia and healthy pregnancies. Quantitative lipid analysis of lipid extracts from full thickness placental biopsies was carried out by shotgun lipidomics. Placental lipid profiles from pregnancies complicated by preeclampsia (n = 23) were compared to healthy pregnancies (n = 68), and placenta from intrauterine growth restriction pregnancies (n = 10) …

Factors Influencing Deprescribing For Residents In Advanced Care Facilities: Insights From General Practitioners In Australia And Sweden, Beata Borgström Bolmsjö, Anna Palagyi, Lisa Keay, Jan M. Potter, Richard I. Lindley

Illawarra Health and Medical Research Institute

Background: General Practitioners (GPs) are responsible for primary prescribing decisions in most settings. Elderly patients living in Advanced Care Facilities (ACFs) often have significant co-morbidities to consider when selecting an appropriate drug therapy. Careful assessment is required when considering appropriate medication use in frail older patients as they have multiple diseases and thus multiple medication. Many physicians seem reluctant to discontinue other physicians' prescriptions, resulting in further polypharmacy. Therefore it is relevant to ascertain and synthesise the GP views from multiple settings to understand the processes that might promote appropriate deprescribing medications in the elderly. The aims of this …

Local Birthing Services For Rural Women: Adaptation Of A Rural New South Wales Maternity Service, Michelle Durst, Margaret I. Rolfe, Jo Longman, Sarah Robin, Beverley Dhnaram, Kathryn L. Mullany, Ian M. R Wright, Lesley M. Barclay

Illawarra Health and Medical Research Institute

Objective: To describe the outcomes of a public hospital maternity unit in rural New South Wales (NSW) following the adaptation of the service from an obstetrician and general practitioner-obstetrician (GPO)-led birthing service to a low-risk midwifery group practice (MGP) model of care with a planned caesarean section service (PCS).

Design: A retrospective descriptive study using quantitative methodology.

Setting: Maternity unit in a small public hospital in rural New South Wales, Australia.

Participants: Data were extracted from the wardbased birth register for 1172 births at the service between July 2007 and June 2012.

Main outcome measures: Birth …

Discontinuation Of Peri-Operative Gentamicin Use For Indwelling Urinary Catheter Manipulation In Orthopaedic Surgery, Stuart Bond, Craig S. Boutlis, Stuart G. Jansen, Spiros Miyakis

Illawarra Health and Medical Research Institute

Background Gentamicin has historically been used prior to insertion and removal of indwelling urinary catheters (IDCs) around elective joint replacement surgery to prevent infection; however, this indication is not recognized in the Australian Therapeutic Guidelines: Antibiotic and the paradigm for safe use of gentamicin has shifted.

Methods The antimicrobial stewardship team of a 500 bed tertiary regional hospital performed a retrospective clinical study of gentamicin IDC prophylaxis around total hip and knee arthroplasties. Results were presented to the orthopaedic surgeons. A literature review identified no guidelines to support gentamicin prophylaxis and only a very low risk of bacteraemia associated with …

Ar-12 Inhibits Multiple Chaperones Concomitant With Stimulating Autophagosome Formation Collectively Preventing Virus Replication, Laurence Booth, Jane L. Roberts, Heath Ecroyd, Sarah R. Tritsch, Sina Bavari, St. Patrick Reid, Stefan Proniuk, Alexander Zukiwski, Abraham Jacob, Claudia S. Sepulveda

Illawarra Health and Medical Research Institute

We have recently demonstrated that AR-12 (OSU-03012) reduces the function and ATPase activities of multiple HSP90 and HSP70 family chaperones. Combined knock down of chaperones or AR-12 treatment acted to reduce the expression of virus receptors and essential glucosidase proteins. Combined knock down of chaperones or AR-12 treatment inactivated mTOR and elevated ATG13 S318 phosphorylation concomitant with inducing an endoplasmic reticulum stress response that in an eIF2α-dependent fashion increased Beclin1 and LC3 expression and autophagosome formation. Over-expression of chaperones prevented the reduction in receptor/glucosidase expression, mTOR inactivation, the ER stress response, and autophagosome formation. AR-12 reduced the reproduction of viruses …

The Physical Activity 4 Everyone Cluster Randomized Trial: 2-Year Outcomes Of A School Physical Activity Intervention Among Adolescents, Rachel L. Sutherland, Elizabeth M. Campbell, David R. Lubans, Philip J. Morgan, Nicole K. Nathan, Luke Wolfenden, Anthony D. Okely, Karen E. Gillham, Jenna L. Hollis, Christopher J. Oldmeadow, Amanda J. Williams, Lynda J. Davies, Jarrod S. Wiese, Alessandra Bisquera, John H. Wiggers

Illawarra Health and Medical Research Institute

Introduction: Few interventions have been successful in reducing the physical activity decline typically observed among adolescents. The aim of this paper is to report the 24-month effectiveness of a multicomponent school-based intervention (Physical Activity 4 Everyone) in reducing the decline in moderate to vigorous physical activity (MVPA) among secondary school students in disadvantaged areas of New South Wales, Australia.

Study design: A cluster RCT was conducted in five intervention and five control schools with follow-up measures taken at 24 months post-randomization.

Setting/participants: The trial was undertaken within secondary schools located in disadvantaged communities in New South Wales, …

Recent Developments In Geant4, J Allison, K Amako, J Apostolakis, Pedro Arce, M Asai, T Aso, E Bagli, A Bagulya, S Banerjee, G Barrand, Susanna Guatelli

Illawarra Health and Medical Research Institute

GEANT4 is a software toolkit for the simulation of the passage of particles through matter. It is used by a large number of experiments and projects in a variety of application domains, including high energy physics, astrophysics and space science, medical physics and radiation protection. Over the past several years, major changes have been made to the toolkit in order to accommodate the needs of these user communities, and to efficiently exploit the growth of computing power made available by advances in technology. The adaptation of GEANT4 to multithreading, advances in physics, detector modeling and visualization, extensions to the toolkit, …

Dha Supplementation During Pregnancy Does Not Reduce Bmi Or Body Fat Mass In Children: Follow-Up Of The Dha To Optimize Mother Infant Outcome Randomized Controlled Trial, Beverly Muhlhausler, Lisa Yelland, Robyn Mcdermott, Linda C. Tapsell, Andrew J. Mcphee, Robert A. Gibson, Maria Makrides

Illawarra Health and Medical Research Institute

Background: The omega-3 (n-3) long-chain polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) has proven effective at reducing fat storage in animal studies. However, a systematic review of human trials showed a lack of quality data to support or refute this hypothesis. Objective: We sought to determine whether maternal DHA supplementation during the second half of pregnancy results in a lower body mass index (BMI) and percentage of body fat in children. Design: We conducted a follow-up at 3 and 5 y of age of children who were born to mothers enrolled in the DOMInO (DHA to Optimize Mother Infant Outcome) …

Chronic Rhein Treatment Improves Recognition Memory In High-Fat Diet-Induced Obese Male Mice, Sen Wang, Xu-Feng Huang, Peng Zhang, Hongqin Wang, Qingsheng Zhang, Shijia Yu, Yinghua Yu

Illawarra Health and Medical Research Institute

High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/day in HF …

Olanzapine Prevents The Pcp-Induced Reduction In The Neurite Outgrowth Of Prefrontal Cortical Neurons Via Nrg1, Qingsheng Zhang, Yinghua Yu, Xu-Feng Huang

Illawarra Health and Medical Research Institute

Accumulating evidence suggests that reducing neurite outgrowth and synaptic plasticity plays a critical role in the pathology of cognitive deficits in schizophrenia. The N-methyl-D-aspartate receptor antagonist phencyclidine (PCP) can induce symptoms of schizophrenia as well as reduce dendritic spine density and neurite growth. The antipsychotic drug olanzapine may improve these deficits. This study aimed to investigate: (1) if olanzapine prevents PCP-induced suppression of neurite outgrowth and synaptic protein expression; (2) if olanzapine affects the Akt-GSK3 signaling pathway; and (3) the role of neuregulin 1 (NRG1) in this process. Immunofluorescence revealed that PCP treatment for 24 hours reduces both neurite length …

Cerebral Apolipoprotein-D Is Hypoglycosylated Compared To Peripheral Tissues And Is Variably Expressed In Mouse And Human Brain Regions, Hongyun Li, Kalani R. Ruberu, Tim Karl, Brett Garner

Illawarra Health and Medical Research Institute

Recent studies have shown that cerebral apoD levels increase with age and in Alzheimer's disease (AD). In addition, loss of cerebral apoD in the mouse increases sensitivity to lipid peroxidation and accelerates AD pathology. Very little data are available, however, regarding the expression of apoD protein levels in different brain regions. This is important as both brain lipid peroxidation and neurodegeneration occur in a region-specific manner. Here we addressed this using western blotting of seven different regions (olfactory bulb, hippocampus, frontal cortex, striatum, cerebellum, thalamus and brain stem) of the mouse brain. Our data indicate that compared to most brain …

Immunisation For Medical Researchers: An Ethical And Practical Imperative, Michelle L. Townsend, Brin F. S Grenyer, Wilfred W. Yeo, Ian M. R Wright

Illawarra Health and Medical Research Institute

we believe it is essential that all researchers who have direct contact with participants are fully immunised.

Synthesis And Preliminary Evaluation Of 5,7-Dimethyl-2-Aryl-3h-Pyrrolizin-3-Ones As Angiogenesis Inhibitors, Nicholas Kirk, Anna Bezos, Anthony C. Willis, Pichit Sudta, Sunit Suksamrarn, Christopher R. Parish, Marie Ranson, Michael J. Kelso

Illawarra Health and Medical Research Institute

Sunitinib (Sutent®) is a receptor tyrosine kinase (RTK) and angiogenesis inhibitor approved for the treatment of renal cell carcinomas, gastrointestinal stromal tumours and pancreatic neuroendocrine tumours. A key structural motif retained throughout medicinal chemistry efforts during sunitinib's development was the indoline-2-one group. In the search for new anti-angiogenic scaffolds, we previously reported that non-indoline-2-one-based derivatives of semaxanib (SU5416, a structurally simpler sunitinib predecessor that underwent Phase III trials) are active as angiogenesis inhibitors, indicating that the group is not essential for activity. This Letter describes the synthesis and structure-activity relationships of another class of non-indoline-2-one angiogenesis inhibitors related to sunitinib/semaxanib; …

Aripiprazole And Haloperidol Activate Gsk3Β-Dependent Signalling Pathway Differentially In Various Brain Regions Of Rats, Bo Pan, Xu-Feng Huang, Chao Deng

Illawarra Health and Medical Research Institute

Aripiprazole, a dopamine D2 receptor (D2R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D2R antagonist) and bifeprunox (a D2R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, …

Structure-Activity Studies Of Cysteine-Rich Α-Conotoxins That Inhibit High Voltage-Activated Calcium Channels Via GabaB Receptor Activation Reveal A Minimal Functional Motif, Bodil B. Carstens, Géza Berecki, James T. Daniel, Han Siean Lee, Kathryn A. V Jackson, Han Shen Tae, Mahsa Sadeghi, Joel Castro, Tracy O'Donnell, Annemie Deiteren, Stuart Brierley, David J. Craik, David J. Adams, Richard J. Clark

Illawarra Health and Medical Research Institute

α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABAB receptor (GABABR) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABABR activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR …

Aripiprazole Increases The Pka Signalling And Expression Of The GabaA Receptor And Creb1 In The Nucleus Accumbens Of Rats, Bo Pan, Jiamei Lian, Xu-Feng Huang, Chao Deng

Illawarra Health and Medical Research Institute

The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The cAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-Cα and p-PKA in the …

Validation Of An Automated Colony Counting System For Group A Streptococcus, H R. Frost, S K. Tsoi, C A. Baker, D Laho, Martina L. Sanderson-Smith, Andrew C. Steer, Pierre R. Smeesters

Illawarra Health and Medical Research Institute

Background The practice of counting bacterial colony forming units on agar plates has long been used as a method to estimate the concentration of live bacteria in culture. However, due to the laborious and potentially error prone nature of this measurement technique, an alternative method is desirable. Recent technologic advancements have facilitated the development of automated colony counting systems, which reduce errors introduced during the manual counting process and recording of information. An additional benefit is the significant reduction in time taken to analyse colony counting data. Whilst automated counting procedures have been validated for a number of microorganisms, the …