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Author Shcheglovitov, A.; Shcheglovitova, O.; Yazawa, M.; Portmann, T.; Shu, R.; Sebastiano, V.; Krawisz, A.; Froehlich, W.; Bernstein, J.A.; Hallmayer, J.F.; Dolmetsch, R.E. url  doi
openurl 
  Title SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients Type Journal Article
  Year 2013 Publication Nature Abbreviated Journal Nature  
  Volume (down) 503 Issue 7475 Pages 267-271  
  Keywords Cell Line; Child; Chromosome Deletion; Chromosome Disorders/genetics/*physiopathology; Chromosomes, Human, Pair 22/genetics; Female; GABA Agents/pharmacology; Gene Expression Regulation/drug effects; Humans; Insulin-Like Growth Factor I/*pharmacology; Lentivirus/genetics; Male; Nerve Tissue Proteins/*genetics/*metabolism; Neurons/cytology/drug effects/*physiology; Pluripotent Stem Cells/cytology; Receptors, Glutamate/genetics; Sequence Deletion; Synapses/*drug effects/genetics/*physiology; Synaptic Transmission/drug effects/genetics  
  Abstract Phelan-McDermid syndrome (PMDS) is a complex neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and an increased risk of autism spectrum disorders (ASDs). PMDS is caused by heterozygous deletions of chromosome 22q13.3. Among the genes in the deleted region is SHANK3, which encodes a protein in the postsynaptic density (PSD). Rare mutations in SHANK3 have been associated with idiopathic ASDs, non-syndromic intellectual disability, and schizophrenia. Although SHANK3 is considered to be the most likely candidate gene for the neurological abnormalities in PMDS patients, the cellular and molecular phenotypes associated with this syndrome in human neurons are unknown. We generated induced pluripotent stem (iPS) cells from individuals with PMDS and autism and used them to produce functional neurons. We show that PMDS neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in PMDS neurons can be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor 1 (IGF1). IGF1 treatment promotes formation of mature excitatory synapses that lack SHANK3 but contain PSD95 and N-methyl-D-aspartate (NMDA) receptors with fast deactivation kinetics. Our findings provide direct evidence for a disruption in the ratio of cellular excitation and inhibition in PMDS neurons, and point to a molecular pathway that can be recruited to restore it.  
  Address Department of Neurobiology, Stanford University, Stanford, California 94305, USA  
  Corporate Author Thesis  
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  Language English Summary Language Original Title  
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  Series Volume Series Issue Edition  
  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:24132240 Approved no  
  Call Number refbase @ user @ Serial 16867  
Permanent link to this record
 

 
Author King, I.F.; Yandava, C.N.; Mabb, A.M.; Hsiao, J.S.; Huang, H.-S.; Pearson, B.L.; Calabrese, J.M.; Starmer, J.; Parker, J.S.; Magnuson, T.; Chamberlain, S.J.; Philpot, B.D.; Zylka, M.J. url  doi
openurl 
  Title Topoisomerases facilitate transcription of long genes linked to autism Type Journal Article
  Year 2013 Publication Nature Abbreviated Journal Nature  
  Volume (down) 501 Issue 7465 Pages 58-62  
  Keywords Animals; Autistic Disorder/*genetics; DNA Topoisomerases, Type I/deficiency/*metabolism; DNA Topoisomerases, Type II/deficiency/metabolism; DNA-Binding Proteins/antagonists & inhibitors/deficiency/metabolism; Gene Knockdown Techniques; Genomic Imprinting/genetics; Humans; Mice; Mutation/genetics; RNA Polymerase II/metabolism; Synapses/metabolism; Topoisomerase Inhibitors/pharmacology; Topotecan/pharmacology; *Transcription Elongation, Genetic/drug effects  
  Abstract Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders.  
  Address Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA  
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  Language English Summary Language Original Title  
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  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:23995680; PMCID:PMC3767287 Approved no  
  Call Number refbase @ user @ Serial 16875  
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Author Wu, Y.; Koschan, M.; Li, Q.; Greeley, I.; Melcher, C.L. openurl 
  Title Revealing the role of calcium codoping on optical and scintillation homogeneity in Lu2SiO5:Ce single crystals Type Journal Article
  Year 2018 Publication J. Cryst. Growth Abbreviated Journal  
  Volume (down) 498 Issue Pages 362  
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  Notes Approved no  
  Call Number refbase @ user @ Serial 17761  
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Author "Hooper, W.L. & W., Roy T." openurl 
  Title Electrical problems : for engineering students Type Book Whole
  Year 1902 Publication Abbreviated Journal  
  Volume (down) 000477 Issue Pages 170p  
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  Publisher "Ginn And Company, Boston" Place of Publication Editor  
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  Notes Approved no  
  Call Number refbase @ user @ 408 Serial 12803  
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Author Yazawa, M.; Hsueh, B.; Jia, X.; Pasca, A.M.; Bernstein, J.A.; Hallmayer, J.; Dolmetsch, R.E. url  doi
openurl 
  Title Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome Type Journal Article
  Year 2011 Publication Nature Abbreviated Journal Nature  
  Volume (down) 471 Issue 7337 Pages 230-234  
  Keywords Action Potentials/drug effects; Autistic Disorder; Calcium Channels, L-Type/genetics/metabolism; Calcium Signaling/drug effects; Cell Transdifferentiation; Cellular Reprogramming/genetics; Drug Evaluation, Preclinical/*methods; Fibroblasts/cytology; HEK293 Cells; Humans; Induced Pluripotent Stem Cells/*pathology; Long QT Syndrome/drug therapy/genetics/metabolism/pathology; Mutation, Missense/genetics; Myocytes, Cardiac/*drug effects/metabolism/*pathology; Patch-Clamp Techniques; Phenotype; Purines/pharmacology; Single-Cell Analysis; Syndactyly/drug therapy/genetics/metabolism/pathology  
  Abstract Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life-threatening ventricular arrhythmia. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors. A missense mutation in the L-type calcium channel Ca(V)1.2 leads to LQTS in patients with Timothy syndrome. To explore the effect of the Timothy syndrome mutation on the electrical activity and contraction of human cardiomyocytes, we reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated these cells into cardiomyocytes. Electrophysiological recording and calcium (Ca(2+)) imaging studies of these cells revealed irregular contraction, excess Ca(2+) influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine, a compound that increases the voltage-dependent inactivation of Ca(V)1.2 (refs 6-8), restored the electrical and Ca(2+) signalling properties of cardiomyocytes from Timothy syndrome patients. This study provides new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.  
  Address Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA  
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  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0028-0836 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:21307850; PMCID:PMC3077925 Approved no  
  Call Number refbase @ user @ Serial 16987  
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