Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques
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FK506-Binding Protein 12.6/1B, a Negative Regulator of [Ca2+], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats
This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. A link to any extended data will be provided when the final version is posted online. Research Articles: Neurobiology of Disease FK506-Binding Protein 12.6/1b, a negative regulator of [Ca2+], rescues memory and restores genomic regulation in the hippocampus of aging rats John C. Gant1, Eric M. Blalock1, Kuey-Chu Chen1, Inga Kadish2, Olivier Thibault1, Nada M. Porter1 and Philip W. Landfield1 1Department of Pharmacology & Nutritional Sciences, University of Kentucky, Lexington, KY 40536 2Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294 DOI: 10.1523/JNEUROSCI.2234-17.2017 Received: 7 August 2017 Revised: 10 October 2017 Accepted: 24 November 2017 Published: 18 December 2017 Author contributions: J.C.G. and P.W.L. designed research; J.C.G., E.M.B., K.-c.C., and I.K. performed research; J.C.G., E.M.B., K.-c.C., I.K., and P.W.L. analyzed data; J.C.G., E.M.B., O.T., N.M.P., and P.W.L. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. NIH grants AG004542, AG033649, AG052050, AG037868 and McAlpine Foundation for Neuroscience Research Corresponding author: Philip W. Landfield, [email protected], Department of Pharmacology & Nutritional Sciences, University of Kentucky, 800 Rose Street, UKMC MS 307, Lexington, KY 40536 Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2234-17.2017 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. -
Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells
Leukemia (2010) 24, 756–764 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells A Pellagatti1, M Cazzola2, A Giagounidis3, J Perry1, L Malcovati2, MG Della Porta2,MJa¨dersten4, S Killick5, A Verma6, CJ Norbury7, E Hellstro¨m-Lindberg4, JS Wainscoat1 and J Boultwood1 1LRF Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, Oxford, UK; 2Department of Hematology Oncology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3Medizinische Klinik II, St Johannes Hospital, Duisburg, Germany; 4Division of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK; 6Albert Einstein College of Medicine, Bronx, NY, USA and 7Sir William Dunn School of Pathology, University of Oxford, Oxford, UK To gain insight into the molecular pathogenesis of the the World Health Organization.6,7 Patients with refractory myelodysplastic syndromes (MDS), we performed global gene anemia (RA) with or without ringed sideroblasts, according to expression profiling and pathway analysis on the hemato- poietic stem cells (HSC) of 183 MDS patients as compared with the the French–American–British classification, were subdivided HSC of 17 healthy controls. The most significantly deregulated based on the presence or absence of multilineage dysplasia. In pathways in MDS include interferon signaling, thrombopoietin addition, patients with RA with excess blasts (RAEB) were signaling and the Wnt pathways. Among the most signifi- subdivided into two categories, RAEB1 and RAEB2, based on the cantly deregulated gene pathways in early MDS are immuno- percentage of bone marrow blasts. -
University of California, San Diego
UNIVERSITY OF CALIFORNIA, SAN DIEGO The post-terminal differentiation fate of RNAs revealed by next-generation sequencing A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Biomedical Sciences by Gloria Kuo Lefkowitz Committee in Charge: Professor Benjamin D. Yu, Chair Professor Richard Gallo Professor Bruce A. Hamilton Professor Miles F. Wilkinson Professor Eugene Yeo 2012 Copyright Gloria Kuo Lefkowitz, 2012 All rights reserved. The Dissertation of Gloria Kuo Lefkowitz is approved, and it is acceptable in quality and form for publication on microfilm and electronically: __________________________________________________________________ __________________________________________________________________ __________________________________________________________________ __________________________________________________________________ __________________________________________________________________ Chair University of California, San Diego 2012 iii DEDICATION Ma and Ba, for your early indulgence and support. Matt and James, for choosing more practical callings. Roy, my love, for patiently sharing the ups and downs of this journey. iv EPIGRAPH It is foolish to tear one's hair in grief, as though sorrow would be made less by baldness. ~Cicero v TABLE OF CONTENTS Signature Page .............................................................................................................. iii Dedication .................................................................................................................... -
Mouse Rras2 Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Rras2 Knockout Project (CRISPR/Cas9) Objective: To create a Rras2 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Rras2 gene (NCBI Reference Sequence: NM_025846 ; Ensembl: ENSMUSG00000055723 ) is located on Mouse chromosome 7. 6 exons are identified, with the ATG start codon in exon 1 and the TAA stop codon in exon 6 (Transcript: ENSMUST00000069449). Exon 3~5 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Homozygote and heterozygote null mice are lymphopenic, resulting from diminished homeostatic proliferation and impaired T cell and B cell survival. Mice homozygous for a gene trap insertion exhibit retinal degeneration, and increased total body mass and total body fat. Exon 3 starts from about 32.19% of the coding region. Exon 3~5 covers 54.08% of the coding region. The size of effective KO region: ~8729 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 3 4 5 6 Legends Exon of mouse Rras2 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 1302 bp section upstream of Exon 3 is aligned with itself to determine if there are tandem repeats. Tandem repeats are found in the dot plot matrix. -
Seq2pathway Vignette
seq2pathway Vignette Bin Wang, Xinan Holly Yang, Arjun Kinstlick May 19, 2021 Contents 1 Abstract 1 2 Package Installation 2 3 runseq2pathway 2 4 Two main functions 3 4.1 seq2gene . .3 4.1.1 seq2gene flowchart . .3 4.1.2 runseq2gene inputs/parameters . .5 4.1.3 runseq2gene outputs . .8 4.2 gene2pathway . 10 4.2.1 gene2pathway flowchart . 11 4.2.2 gene2pathway test inputs/parameters . 11 4.2.3 gene2pathway test outputs . 12 5 Examples 13 5.1 ChIP-seq data analysis . 13 5.1.1 Map ChIP-seq enriched peaks to genes using runseq2gene .................... 13 5.1.2 Discover enriched GO terms using gene2pathway_test with gene scores . 15 5.1.3 Discover enriched GO terms using Fisher's Exact test without gene scores . 17 5.1.4 Add description for genes . 20 5.2 RNA-seq data analysis . 20 6 R environment session 23 1 Abstract Seq2pathway is a novel computational tool to analyze functional gene-sets (including signaling pathways) using variable next-generation sequencing data[1]. Integral to this tool are the \seq2gene" and \gene2pathway" components in series that infer a quantitative pathway-level profile for each sample. The seq2gene function assigns phenotype-associated significance of genomic regions to gene-level scores, where the significance could be p-values of SNPs or point mutations, protein-binding affinity, or transcriptional expression level. The seq2gene function has the feasibility to assign non-exon regions to a range of neighboring genes besides the nearest one, thus facilitating the study of functional non-coding elements[2]. Then the gene2pathway summarizes gene-level measurements to pathway-level scores, comparing the quantity of significance for gene members within a pathway with those outside a pathway. -
The Novel Membrane-Bound Proteins MFSD1 and MFSD3 Are Putative SLC Transporters Affected by Altered Nutrient Intake
J Mol Neurosci DOI 10.1007/s12031-016-0867-8 The Novel Membrane-Bound Proteins MFSD1 and MFSD3 are Putative SLC Transporters Affected by Altered Nutrient Intake Emelie Perland1,2 & Sofie V. Hellsten2 & Emilia Lekholm2 & Mikaela M. Eriksson2 & Vasiliki Arapi2 & Robert Fredriksson2 Received: 29 August 2016 /Accepted: 21 November 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Membrane-bound solute carriers (SLCs) are essen- Introduction tial as they maintain several physiological functions, such as nutrient uptake, ion transport and waste removal. The SLC Membrane-bound transporters are physiologically important family comprise about 400 transporters, and we have identi- as they keep the homeostasis of soluble molecules within cel- fied two new putative family members, major facilitator su- lular compartments, and it is crucial to study their basic his- perfamily domain containing 1 (MFSD1) and 3 (MFSD3). tology and function to understand the human body. The solute They cluster phylogenetically with SLCs of MFS type, and carrier (SLC) superfamily is the largest group of membrane- both proteins are conserved in chordates, while MFSD1 is also bound transporters in human and it includes 395 members, found in fruit fly. Based on homology modelling, we predict divided in 52 families (Hediger et al. 2004). SLCs utilize 12 transmembrane regions, a common feature for MFS trans- ATP-independent mechanisms to move nutrients, ions, drugs porters. The genes are expressed in abundance in mice, with and waste over lipid membranes, and SLC deficiencies are specific protein staining along the plasma membrane in neu- associated with several human diseases (Hediger et al. -
DNA Methylation Changes in Down Syndrome Derived Neural Ipscs Uncover Co-Dysregulation of ZNF and HOX3 Families of Transcription
Laan et al. Clinical Epigenetics (2020) 12:9 https://doi.org/10.1186/s13148-019-0803-1 RESEARCH Open Access DNA methylation changes in Down syndrome derived neural iPSCs uncover co- dysregulation of ZNF and HOX3 families of transcription factors Loora Laan1†, Joakim Klar1†, Maria Sobol1, Jan Hoeber1, Mansoureh Shahsavani2, Malin Kele2, Ambrin Fatima1, Muhammad Zakaria1, Göran Annerén1, Anna Falk2, Jens Schuster1 and Niklas Dahl1* Abstract Background: Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages. Results: Using the Illumina Infinium 450K array, we assessed the DNA methylation pattern of known CpG regions and promoters across the genome in trisomic neural iPSC derivatives, and we identified a total of 500 stably and differentially methylated CpGs that were annotated to CpG islands of 151 genes. The genes were enriched within the DNA binding category, uncovering 37 factors of importance for transcriptional regulation and chromatin structure. In particular, we observed regional epigenetic changes of the transcription factor genes ZNF69, ZNF700 and ZNF763 as well as the HOXA3, HOXB3 and HOXD3 genes. A similar clustering of differential methylation was found in the CpG islands of the HIST1 genes suggesting effects on chromatin remodeling. Conclusions: The study shows that early established differential methylation in neural iPSC derivatives with T21 are associated with a set of genes relevant for DS brain development, providing a novel framework for further studies on epigenetic changes and transcriptional dysregulation during T21 neurogenesis. -
ADD1 Pt445) Antibody Catalogue No.:Abx326604
Datasheet Version: 1.0.0 Revision date: 02 Nov 2020 Alpha Adducin Phospho-Thr445 (ADD1 pT445) Antibody Catalogue No.:abx326604 Alpha Adducin (ADD1) (pT445) Antibody is a Rabbit Polyclonal against Alpha Adducin (ADD1) (pT445). Adducins are a family of cytoskeletal proteins encoded by three genes (alpha, beta, and gamma). Adducin acts as a heterodimer of the related alpha, beta, or gamma subunits. The protein encoded by this gene represents the alpha subunit. Alpha- and beta-adducin include a protease-resistant N-terminal region and a protease-sensitive, hydrophilic C-terminal region. Adducin binds with high affinity to Ca(2+)/calmodulin and is a substrate for protein kinases A and C. Target: Alpha Adducin Phospho-Thr445 (ADD1 pT445) Clonality: Polyclonal Target Modification: Thr445 Modification: Phosphorylation Reactivity: Human, Mouse, Rat Tested Applications: ELISA, IHC Host: Rabbit Recommended dilutions: IHC: 1/100 - 1/300, ELISA: 1/5000. Optimal dilutions/concentrations should be determined by the end user. Conjugation: Unconjugated Immunogen: Synthesized peptide derived from human Adducin α around the phosphorylation site of T445. Isotype: IgG Form: ForLiquid Reference Only Purification: Affinity Chromatography. Storage: Aliquot and store at -20°C. Avoid repeated freeze/thaw cycles. UniProt Primary AC: P35611 (UniProt, ExPASy) Q9QYC0 (UniProt, ExPASy) Gene Symbol: ADD1 GeneID: 118 v1.0.0 Abbexa Ltd, Cambridge, UK · Phone: +44 1223 755950 · Fax: +44 1223 755951 1 Abbexa LLC, Houston, TX, USA · Phone: +1 832 327 7413 www.abbexa.com · -
The Landscape of Genomic Imprinting Across Diverse Adult Human Tissues
Downloaded from genome.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Research The landscape of genomic imprinting across diverse adult human tissues Yael Baran,1 Meena Subramaniam,2 Anne Biton,2 Taru Tukiainen,3,4 Emily K. Tsang,5,6 Manuel A. Rivas,7 Matti Pirinen,8 Maria Gutierrez-Arcelus,9 Kevin S. Smith,5,10 Kim R. Kukurba,5,10 Rui Zhang,10 Celeste Eng,2 Dara G. Torgerson,2 Cydney Urbanek,11 the GTEx Consortium, Jin Billy Li,10 Jose R. Rodriguez-Santana,12 Esteban G. Burchard,2,13 Max A. Seibold,11,14,15 Daniel G. MacArthur,3,4,16 Stephen B. Montgomery,5,10 Noah A. Zaitlen,2,19 and Tuuli Lappalainen17,18,19 1The Blavatnik School of Computer Science, Tel-Aviv University, Tel Aviv 69978, Israel; 2Department of Medicine, University of California San Francisco, San Francisco, California 94158, USA; 3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA; 4Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA; 5Department of Pathology, Stanford University, Stanford, California 94305, USA; 6Biomedical Informatics Program, Stanford University, Stanford, California 94305, USA; 7Wellcome Trust Center for Human Genetics, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7BN, United Kingdom; 8Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; 9Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; -
Identification of Novel E2F1 Target Genes Regulated in Cell Cycle
Oncogene (2006) 25, 1786–1798 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE Identification of novel E2F1 target genes regulated in cell cycle-dependent and independent manners R Iwanaga1,3, H Komori1, S Ishida2, N Okamura3, K Nakayama4, KI Nakayama5 and K Ohtani1 1Human Gene Sciences Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan; 2Division of Pharmacology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan; 3Laboratory of Microbiology and Immunology, Graduate School of Health Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan; 4Department of Developmental Biology, Center for Translational and Advanced Animal Research on Human Disease, Graduate School of Medicine, Tohoku University, Aoba-ku, Sendai, Japan and 5Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan The transcription factor E2F mediates cell cycle-depen- cell cycle progression (Nevins et al., 1997; Dyson, 1998; dent expression of genes important for cell proliferation in Trimarchi and Lees, 2002). The transcriptional ability of response to growth stimulation. To further understand the E2F is cell cycle-regulated mainly through association role of E2F, we utilized a sensitive subtraction method to with the retinoblastoma tumor suppressor family of explore new E2F1 targets, which are expressed at low proteins pRb, p107 and p130. During the progression of levels and might have been unrecognized in previous cells from G1 to S phase, G1 cyclin-dependent kinases studies. We identified 33 new E2F1-inducible genes, (cdks)phosphorylate and dissociate the pRb family including checkpoint genes Claspin and Rad51ap1, and proteins from E2F, resulting in the activation of a group four genes with unknown function required for cell cycle of genes required for progression into the S phase. -
Mouse Wasf1 Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Wasf1 Knockout Project (CRISPR/Cas9) Objective: To create a Wasf1 knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Wasf1 gene (NCBI Reference Sequence: NM_031877 ; Ensembl: ENSMUSG00000019831 ) is located on Mouse chromosome 10. 9 exons are identified, with the ATG start codon in exon 2 and the TAA stop codon in exon 9 (Transcript: ENSMUST00000019975). Exon 3~7 will be selected as target site. Cas9 and gRNA will be co-injected into fertilized eggs for KO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mutation of this gene has been associated with both morphological and functional defects of the central nervous system. Targeted mutagenesis has resulted in mice that display sensorimotor and cognitive defects similar to those exhibited by patients with 3p-syndrome mental retardation. Exon 3 starts from about 7.99% of the coding region. Exon 3~7 covers 45.32% of the coding region. The size of effective KO region: ~8173 bp. The KO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele 5' gRNA region gRNA region 3' 1 3 4 5 6 7 9 Legends Exon of mouse Wasf1 Knockout region Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot (up) Window size: 15 bp Forward Reverse Complement Sequence 12 Note: The 2000 bp section upstream of Exon 3 is aligned with itself to determine if there are tandem repeats. No significant tandem repeat is found in the dot plot matrix. -
Phosphorylation of Synaptic Vesicle Protein 2A at Thr84 by Casein Kinase 1 Family Kinases Controls the Specific Retrieval of Synaptotagmin-1
2492 • The Journal of Neuroscience, February 11, 2015 • 35(6):2492–2507 Cellular/Molecular Phosphorylation of Synaptic Vesicle Protein 2A at Thr84 by Casein Kinase 1 Family Kinases Controls the Specific Retrieval of Synaptotagmin-1 Ning Zhang,1* X Sarah L. Gordon,2* XMaximilian J. Fritsch,1* Noor Esoof,1* XDavid G. Campbell,1 Robert Gourlay,1 Srikannathasan Velupillai,1 XThomas Macartney,1 XMark Peggie,1 Daan M.F. van Aalten,1 Michael A. Cousin,2* and Dario R. Alessi1* 1Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom, and 2Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, Scotland, United Kingdom Synapticvesicleprotein2A(SV2A)isaubiquitouscomponentofsynapticvesicles(SVs).IthasrolesinbothSVtraffickingandneurotransmitter release. We demonstrate that Casein kinase 1 family members, including isoforms of Tau–tubulin protein kinases (TTBK1 and TTBK2), phos- phorylate human SV2A at two constellations of residues, namely Cluster-1 (Ser42, Ser45, and Ser47) and Cluster-2 (Ser80, Ser81, and Thr84). These residues are also phosphorylated in vivo, and the phosphorylation of Thr84 within Cluster-2 is essential for triggering binding to the C2B domain of human synaptotagmin-1. We show by crystallographic and other analyses that the phosphorylated Thr84 residue binds to a pocket formed by three conserved Lys residues (Lys314, Lys326, and Lys328) on the surface of the synaptotagmin-1 C2B domain. Finally, we observed dysfunctionalsynaptotagmin-1retrievalduringSVendocytosisbyablatingitsphospho-dependentinteractionwithSV2A,knockdownofSV2A, or rescue with a phosphorylation-null Thr84 SV2A mutant in primary cultures of mouse neurons. This study reveals fundamental details of how phosphorylation of Thr84 on SV2A controls its interaction with synaptotagmin-1 and implicates SV2A as a phospho-dependent chaperone required for the specific retrieval of synaptotagmin-1 during SV endocytosis.