Anatomy and Neuroscience - Research Publications

Permanent URI for this collection

Search Results

Now showing 1 - 10 of 47
  • Item
    Thumbnail Image
    Diacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model
    Soon, CPW ; Donnelly, PS ; Turner, BJ ; Hung, LW ; Crouch, PJ ; Sherratt, NA ; Tan, J-L ; Lim, NK-H ; Lam, L ; Bica, L ; Lim, S ; Hickey, JL ; Morizzi, J ; Powell, A ; Finkelstein, DI ; Culvenor, JG ; Masters, CL ; Duce, J ; White, AR ; Barnham, KJ ; Li, Q-X (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-12-23)
    Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
  • Item
    Thumbnail Image
    Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes
    Schieber, C ; Howitt, J ; Putz, U ; White, JM ; Parish, CL ; Donnelly, PS ; Tan, S-S (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-03-11)
    The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.
  • Item
    Thumbnail Image
    Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study
    Fox, ER ; Young, JH ; Li, Y ; Dreisbach, AW ; Keating, BJ ; Musani, SK ; Liu, K ; Morrison, AC ; Ganesh, S ; Kutlar, A ; Ramachandran, VS ; Polak, JF ; Fabsitz, RR ; Dries, DL ; Farlow, DN ; Redline, S ; Adeyemo, A ; Hirschorn, JN ; Sun, YV ; Wyatt, SB ; Penman, AD ; Palmas, W ; Rotter, JI ; Townsend, RR ; Doumatey, AP ; Tayo, BO ; Mosley, TH ; Lyon, HN ; Kang, SJ ; Rotimi, CN ; Cooper, RS ; Franceschini, N ; Curb, JD ; Martin, LW ; Eaton, CB ; Kardia, SLR ; Taylor, HA ; Caulfield, MJ ; Ehret, GB ; Johnson, T ; Chakravarti, A ; Zhu, X ; Levy, D (OXFORD UNIV PRESS, 2011-06-01)
    The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
  • Item
    Thumbnail Image
    Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus
    Drew, BG ; Carey, AL ; Natoli, AK ; Formosa, MF ; Vizi, D ; Reddy-Luthmoodoo, M ; Weir, JM ; Barlow, CK ; van Hall, G ; Meikle, PJ ; Duffy, SJ ; Kingwell, BA (ELSEVIER, 2011-03)
    We recently demonstrated that reconstituted high-density lipoprotein (rHDL) modulates glucose metabolism in humans via both AMP-activated protein kinase (AMPK) in muscle and by increasing plasma insulin. Given the key roles of both AMPK and insulin in fatty acid metabolism, the current study investigated the effect of rHDL infusion on fatty acid oxidation and lipolysis. Thirteen patients with type 2 diabetes received separate infusions of rHDL and placebo in a randomized, cross-over study. Fatty acid metabolism was assessed using steady-state tracer methodology, and plasma lipids were measured by mass spectrometry (lipidomics). In vitro studies were undertaken in 3T3-L1 adipocytes. rHDL infusion inhibited fasting-induced lipolysis (P = 0.03), fatty acid oxidation (P < 0.01), and circulating glycerol (P = 0.04). In vitro, HDL inhibited adipocyte lipolysis in part via activation of AMPK, providing a possible mechanistic link for the apparent reductions in lipolysis observed in vivo. In contrast, circulating NEFA increased after rHDL infusion (P < 0.01). Lipidomic analyses implicated phospholipase hydrolysis of rHDL-associated phosphatidylcholine as the cause, rather than lipolysis of endogenous fat stores. rHDL infusion inhibits fasting-induced lipolysis and oxidation in patients with type 2 diabetes, potentially through both AMPK activation in adipose tissue and elevation of plasma insulin. The phospholipid component of rHDL also has the potentially undesirable effect of increasing circulating NEFA.
  • Item
    Thumbnail Image
    Homozygous staggerer (sg/sg) mice display improved insulin sensitivity and enhanced glucose uptake in skeletal muscle
    Lau, P ; Fitzsimmons, RL ; Pearen, MA ; Watt, MJ ; Muscat, GEO (SPRINGER, 2011-05)
    AIMS/HYPOTHESIS: Homozygous staggerer (sg/sg) mice, which have decreased and dysfunctional Rorα (also known as Rora) expression in all tissues, display a lean and dyslipidaemic phenotype. They are also resistant to (high fat) diet-induced obesity. We explored whether retinoic acid receptor-related orphan receptor (ROR) α action in skeletal muscle was involved in the regulation of glucose metabolism. METHODS: We used a three-armed genomic approach, including expression profiling, ingenuity analysis and quantitative PCR validation to identify the signalling pathway(s) in skeletal muscle that are perturbed in sg/sg mice. Moreover, western analysis, functional insulin and glucose tolerance tests, and ex vivo glucose uptake assays were used to phenotypically characterise the impact of aberrant v-AKT murine thymoma viral oncogene homologue (AKT) signalling. RESULTS: Homozygous and heterozygous (sg/sg and sg/+) animals exhibited decreased fasting blood glucose levels, mildly improved glucose tolerance and increased insulin sensitivity. Illumina expression profiling and bioinformatic analysis indicated the involvement of RORα in metabolic disease and phosphatidylinositol 3-kinase-AKT signalling. Quantitative PCR and western analysis validated increased AKT2 (mRNA and protein) and phosphorylation in sg/sg mice in the basal state. This was associated with increased expression of Tbc1d1 and Glut4 (also known as Slc2a4) mRNA and protein. Finally, in agreement with the phenotype, we observed increased (absolute) levels of AKT and phosphorylated AKT (in the basal and insulin stimulated states), and of (ex vivo) glucose uptake in skeletal muscle from sg/sg mice relative to wild-type littermates. CONCLUSIONS/INTERPRETATION: We propose that Rorα plays an important role in regulation of the AKT2 signalling cascade, which controls glucose uptake in skeletal muscle.
  • Item
    Thumbnail Image
    Differential gene expression in migratory streams of cortical interneurons.
    Antypa, M ; Faux, C ; Eichele, G ; Parnavelas, JG ; Andrews, WD (Wiley, 2011-11)
    Cortical interneurons originate in the ganglionic eminences of the subpallium and migrate into the cortex in well-defined tangential streams. At the start of corticogenesis, two streams of migrating neurons are evident: a superficial one at the level of the preplate (PPL), and a deeper one at the level of the intermediate zone (IZ). Currently, little is known about the signalling mechanisms that regulate interneuron migration, and almost nothing is known about the molecules that may be involved in their choice of migratory stream. Here, we performed a microarray analysis, comparing the changes in gene expression between cells migrating in the PPL and those migrating in the IZ at embryonic day 13.5. This analysis identified genes, many of them novel, that were upregulated in one of the two streams. Moreover, polymerase chain reaction, in situ hybridization experiments and immunohistochemistry showed the expression of these genes in interneurons migrating within the PPL or IZ, suggesting that they play a role in their migration and choice of stream.
  • Item
    No Preview Available
    attract: A Method for Identifying Core Pathways That Define Cellular Phenotypes
    Mar, JC ; Matigian, NA ; Quackenbush, J ; Wells, CA ; Csermely, P (PUBLIC LIBRARY SCIENCE, 2011-10-14)
    attract is a knowledge-driven analytical approach for identifying and annotating the gene-sets that best discriminate between cell phenotypes. attract finds distinguishing patterns within pathways, decomposes pathways into meta-genes representative of these patterns, and then generates synexpression groups of highly correlated genes from the entire transcriptome dataset. attract can be applied to a wide range of biological systems and is freely available as a Bioconductor package and has been incorporated into the MeV software system.
  • Item
    No Preview Available
    Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
    Ehret, GB ; Munroe, PB ; Rice, KM ; Bochud, M ; Johnson, AD ; Chasman, DI ; Smith, AV ; Tobin, MD ; Verwoert, GC ; Hwang, S-J ; Pihur, V ; Vollenweider, P ; O'Reilly, PF ; Amin, N ; Bragg-Gresham, JL ; Teumer, A ; Glazer, NL ; Launer, L ; Zhao, JH ; Aulchenko, Y ; Heath, S ; Sober, S ; Parsa, A ; Luan, J ; Arora, P ; Dehghan, A ; Zhang, F ; Lucas, G ; Hicks, AA ; Jackson, AU ; Peden, JF ; Tanaka, T ; Wild, SH ; Rudan, I ; Igl, W ; Milaneschi, Y ; Parker, AN ; Fava, C ; Chambers, JC ; Fox, ER ; Kumari, M ; Go, MJ ; van der Harst, P ; Kao, WHL ; Sjogren, M ; Vinay, DG ; Alexander, M ; Tabara, Y ; Shaw-Hawkins, S ; Whincup, PH ; Liu, Y ; Shi, G ; Kuusisto, J ; Tayo, B ; Seielstad, M ; Sim, X ; Khanh-Dung, HN ; Lehtimaki, T ; Matullo, G ; Wu, Y ; Gaunt, TR ; Onland-Moret, NC ; Cooper, MN ; Platou, CGP ; Org, E ; Hardy, R ; Dahgam, S ; Palmen, J ; Vitart, V ; Braund, PS ; Kuznetsova, T ; Uiterwaal, CSPM ; Adeyemo, A ; Palmas, W ; Campbell, H ; Ludwig, B ; Tomaszewski, M ; Tzoulaki, I ; Palmer, ND ; Aspelund, T ; Garcia, M ; Chang, Y-PC ; O'Connell, JR ; Steinle, NI ; Grobbee, DE ; Arking, DE ; Kardia, SL ; Morrison, AC ; Hernandez, D ; Najjar, S ; McArdle, WL ; Hadley, D ; Brown, MJ ; Connell, JM ; Hingorani, AD ; Day, INM ; Lawlor, DA ; Beilby, JP ; Lawrence, RW ; Clarke, R ; Hopewell, JC ; Ongen, H ; Dreisbach, AW ; Li, Y ; Young, JH ; Bis, JC ; Kahonen, M ; Viikari, J ; Adair, LS ; Lee, NR ; Chen, M-H ; Olden, M ; Pattaro, C ; Bolton, JAH ; Koettgen, A ; Bergmann, S ; Mooser, V ; Chaturvedi, N ; Frayling, TM ; Islam, M ; Jafar, TH ; Erdmann, J ; Kulkarni, SR ; Bornstein, SR ; Graessler, J ; Groop, L ; Voight, BF ; Kettunen, J ; Howard, P ; Taylor, A ; Guarrera, S ; Ricceri, F ; Emilsson, V ; Plump, A ; Barroso, IS ; Khaw, K-T ; Weder, AB ; Hunt, SC ; Sun, YV ; Bergman, RN ; Collins, FS ; Bonnycastle, LL ; Scott, LJ ; Stringham, HM ; Peltonen, L ; Perola, M ; Vartiainen, E ; Brand, S-M ; Staessen, JA ; Wang, TJ ; Burton, PR ; Artigas, MS ; Dong, Y ; Snieder, H ; Wang, X ; Zhu, H ; Lohman, KK ; Rudock, ME ; Heckbert, SR ; Smith, NL ; Wiggins, KL ; Doumatey, A ; Shriner, D ; Veldre, G ; Viigimaa, M ; Kinra, S ; Prabhakaran, D ; Tripathy, V ; Langefeld, CD ; Rosengren, A ; Thelle, DS ; Corsi, AM ; Singleton, A ; Forrester, T ; Hilton, G ; McKenzie, CA ; Salako, T ; Iwai, N ; Kita, Y ; Ogihara, T ; Ohkubo, T ; Okamura, T ; Ueshima, H ; Umemura, S ; Eyheramendy, S ; Meitinger, T ; Wichmann, H-E ; Cho, YS ; Kim, H-L ; Lee, J-Y ; Scott, J ; Sehmi, JS ; Zhang, W ; Hedblad, B ; Nilsson, P ; Smith, GD ; Wong, A ; Narisu, N ; Stancakova, A ; Raffel, LJ ; Yao, J ; Kathiresan, S ; O'Donnell, CJ ; Schwartz, SM ; Ikram, MA ; Longstreth, WT ; Mosley, TH ; Seshadri, S ; Shrine, NRG ; Wain, LV ; Morken, MA ; Swift, AJ ; Laitinen, J ; Prokopenko, I ; Zitting, P ; Cooper, JA ; Humphries, SE ; Danesh, J ; Rasheed, A ; Goel, A ; Hamsten, A ; Watkins, H ; Bakker, SJL ; van Gilst, WH ; Janipalli, CS ; Mani, KR ; Yajnik, CS ; Hofman, A ; Mattace-Raso, FUS ; Oostra, BA ; Demirkan, A ; Isaacs, A ; Rivadeneira, F ; Lakatta, EG ; Orru, M ; Scuteri, A ; Ala-Korpela, M ; Kangas, AJ ; Lyytikainen, L-P ; Soininen, P ; Tukiainen, T ; Wurtz, P ; Ong, RT-H ; Doerr, M ; Kroemer, HK ; Voelker, U ; Voelzke, H ; Galan, P ; Hercberg, S ; Lathrop, M ; Zelenika, D ; Deloukas, P ; Mangino, M ; Spector, TD ; Zhai, G ; Meschia, JF ; Nalls, MA ; Sharma, P ; Terzic, J ; Kumar, MVK ; Denniff, M ; Zukowska-Szczechowska, E ; Wagenknecht, LE ; Fowkes, FGR ; Charchar, FJ ; Schwarz, PEH ; Hayward, C ; Guo, X ; Rotimi, C ; Bots, ML ; Brand, E ; Samani, NJ ; Polasek, O ; Talmud, PJ ; Nyberg, F ; Kuh, D ; Laan, M ; Hveem, K ; Palmer, LJ ; van der Schouw, YT ; Casas, JP ; Mohlke, KL ; Vineis, P ; Raitakari, O ; Ganesh, SK ; Wong, TY ; Tai, ES ; Cooper, RS ; Laakso, M ; Rao, DC ; Harris, TB ; Morris, RW ; Dominiczak, AF ; Kivimaki, M ; Marmot, MG ; Miki, T ; Saleheen, D ; Chandak, GR ; Coresh, J ; Navis, G ; Salomaa, V ; Han, B-G ; Zhu, X ; Kooner, JS ; Melander, O ; Ridker, PM ; Bandinelli, S ; Gyllensten, UB ; Wright, AF ; Wilson, JF ; Ferrucci, L ; Farrall, M ; Tuomilehto, J ; Pramstaller, PP ; Elosua, R ; Soranzo, N ; Sijbrands, EJG ; Altshuler, D ; Loos, RJF ; Shuldiner, AR ; Gieger, C ; Meneton, P ; Uitterlinden, AG ; Wareham, NJ ; Gudnason, V ; Rotter, JI ; Rettig, R ; Uda, M ; Strachan, DP ; Witteman, JCM ; Hartikainen, A-L ; Beckmann, JS ; Boerwinkle, E ; Vasan, RS ; Boehnke, M ; Larson, MG ; Jarvelin, M-R ; Psaty, BM ; Abecasis, GR ; Chakravarti, A ; Elliott, P ; van Duijn, CM ; Newton-Cheh, C ; Levy, D ; Caulfield, MJ ; Johnson, T (NATURE PUBLISHING GROUP, 2011-10-06)
    Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
  • Item
    No Preview Available
    Differential Roles of HOW in Male and Female Drosophila Germline Differentiation
    Monk, AC ; Siddall, NA ; Fraser, B ; McLaughlin, EA ; Hime, GR ; Dearden, PK (PUBLIC LIBRARY SCIENCE, 2011-12-06)
    The adult gonads in both male and female Drosophila melanogaster produce gametes that originate from a regenerative pool of germline stem cells (GSCs). The differentiation programme that produces gametes must be co-ordinated with GSC maintenance and proliferation in order to regulate tissue regeneration. The HOW RNA-binding protein has been shown to maintain mitotic progression of male GSCs and their daughters by maintenance of Cyclin B expression as well as suppressing accumulation of the differentiation factor Bam. Loss of HOW function in the male germline results in loss of GSCs due to a delay in G2 and subsequent apoptosis. Here we show that female how mutant GSCs do not have any cell cycle defects although HOW continues to bind bam mRNA and suppress Bam expression. The role of HOW in suppressing germ cell Bam expression appears to be conserved between sexes, leading to different cellular outcomes in how mutants due to the different functions of Bam. In addition the role in maintaining Cyclin B expression has not been conserved so female how GSCs differentiate rather than arrest.
  • Item
    Thumbnail Image
    Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model
    Broadhead, ML ; Dass, CR ; Choong, PFM (NATURE PUBLISHING GROUP, 2011-11-08)
    BACKGROUND: Pigment epithelium-derived factor (PEDF) is an endogenous glycoprotein with a potential role as a therapeutic for osteosarcoma. Animal studies have demonstrated the biological effects of PEDF on osteosarcoma; however, these results are difficult to extrapolate for human use due to the chosen study design and drug delivery methods. METHODS: In this study we have attempted to replicate the human presentation and treatment of osteosarcoma using a murine orthotopic model of osteosarcoma. The effects of PEDF on osteosarcoma cell lines were evaluated in vitro prior to animal experimentation. Orthotopic tumours were induced by intra-tibial injection of SaOS-2 osteosarcoma cells. Treatment with PEDF was delayed until after the macroscopic appearance of primary tumours. Pigment epithelium-derived factor was administered systemically via an implanted intraperitoneal micro-osmotic pump. RESULTS: In vitro, PEDF inhibited proliferation, induced apoptosis and inhibited cell cycling of osteosarcoma cells. Pigment epithelium-derived factor promoted adhesion to Collagen I and inhibited invasion through Collagen I. In vivo, treatment with PEDF caused a reduction in both primary tumour volume and burden of pulmonary metastases. Systemic administration of PEDF did not cause toxic effects on normal tissues. CONCLUSION: Systemically delivered PEDF is effective in suppressing the size of primary and secondary tumours in an orthotopic murine model of osteosarcoma.