Ck1δ Over-Expressing Mice Display ADHD-Like Behaviors, Frontostriatal Neuronal Abnormalities and Altered Expressions of ADHD-Candidate Genes
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A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
CD19 As a Membrane-Anchored Adaptor Protein of B Lymphocytes: Costimulation of Lipid and Protein Kinases by Recruitment of Vav
Immunity, Vol. 8, 635±645, May, 1998, Copyright 1998 by Cell Press CD19 as a Membrane-Anchored Adaptor Protein of B Lymphocytes: Costimulation of Lipid and Protein Kinases by Recruitment of Vav Lorraine M. O'Rourke,* Reuben Tooze,* CD21 (Dempsey et al., 1996). CD19 also promotes the Martin Turner,³§ David M. Sandoval,² Robert H. Carter,² development and maintenance of the B-1 subset of B ³ Victor L. J. Tybulewicz, and Douglas T. Fearon*k lymphocytes (Engel et al., 1995; Rickert et al., 1995; *Wellcome Trust Immunology Unit Krop et al., 1996), which expresses a distinct V gene Department of Medicine repertoire, and it may regulate the expression of the University of Cambridge School of Clinical Medicine Rag-1 and Rag-2 genes during B lymphocyte develop- Cambridge CB2 2SP ment (Billips et al., 1995). United Kingdom The CD19±CD21 complex achieves these biological ² Departments of Medicine and Microbiology responses by synergistically enhancing signaling through University of Alabama, Birmingham mIg. Coligating CD19 or CD21 to mIg lowers the number Birmingham Veterans Affairs Medical Center of mIg required for inducing increases in intracellular 21 21 Birmingham, Alabama 35294 Ca concentration ([Ca ]i) (Carter et al.,1991; Dempsey ³ National Institute for Medical Research et al., 1996) and the proliferation of B lymphocytes (Car- The Ridgeway ter and Fearon, 1992). The costimulatory effect of CD19 21 London NW7 1AA on [Ca ]i is associated with the enhanced generation United Kingdom of inositol 1,4,5-trisphosphate [I(1,4,5)P3]; ligating CD19 alone also generates I(1,4,5)P3, although the amounts are less. -
VAV2 Is Required for DNA Repair and Implicated in Cancer Radiotherapy Resistance
Signal Transduction and Targeted Therapy www.nature.com/sigtrans ARTICLE OPEN VAV2 is required for DNA repair and implicated in cancer radiotherapy resistance Weiling Liu1, Chuanwang Miao1, Shaosen Zhang1, Yachen Liu1, Xiangjie Niu1, Yiyi Xi1, Wenjia Guo2,3, Jiahui Chu4, Ai Lin1, Hongjin Liu1, ✉ Xinyu Yang1, Xinjie Chen1, Ce Zhong1, Yuling Ma1, Yuqian Wang1, Shihao Zhu1, Shuning Liu1, Wen Tan1, Dongxin Lin 1,5,6,7 and ✉ Chen Wu1,6,7 Radiotherapy remains the mainstay for treatment of various types of human cancer; however, the clinical efficacy is often limited by radioresistance, in which the underlying mechanism is largely unknown. Here, using esophageal squamous cell carcinoma (ESCC) as a model, we demonstrate that guanine nucleotide exchange factor 2 (VAV2), which is overexpressed in most human cancers, plays an important role in primary and secondary radioresistance. We have discovered for the first time that VAV2 is required for the Ku70/Ku80 complex formation and participates in non-homologous end joining repair of DNA damages caused by ionizing radiation. We show that VAV2 overexpression substantially upregulates signal transducer and activator of transcription 1 (STAT1) and the STAT1 inhibitor Fludarabine can significantly promote the sensitivity of radioresistant patient-derived ESCC xenografts in vivo in mice to radiotherapy. These results shed new light on the mechanism of cancer radioresistance, which may be important for improving clinical radiotherapy. Signal Transduction and Targeted Therapy (2021) 6:322; https://doi.org/10.1038/s41392-021-00735-9 1234567890();,: INTRODUCTION and manageable.12,13 Unfortunately, the efficacy of radiotherapy for Resistance to radiotherapy is one of the well-known hallmarks of ESCC is modest and disparate in patients due to the radioresistance cancer. -
Reference Gene Validation Via RT–Qpcr for Human Ipsc-Derived Neural Stem Cells and Neural Progenitors
Molecular Neurobiology https://doi.org/10.1007/s12035-019-1538-x Reference Gene Validation via RT–qPCR for Human iPSC-Derived Neural Stem Cells and Neural Progenitors Justyna Augustyniak1 & Jacek Lenart2 & Gabriela Lipka1 & Piotr P. Stepien3 & Leonora Buzanska1 Received: 26 November 2018 /Accepted: 22 February 2019 # The Author(s) 2019 Abstract Correct selection of the reference gene(s) is the most important step in gene expression analysis. The aims of this study were to identify and evaluate the panel of possible reference genes in neural stem cells (NSC), early neural progenitors (eNP) and neural progenitors (NP) obtained from human-induced pluripotent stem cells (hiPSC). The stability of expression of genes commonly used as the reference in cells during neural differentiation is variable and does not meet the criteria for reference genes. In the present work, we evaluated the stability of expression of 16 candidate reference genes using the four most popular algorithms: the ΔCt method, BestKeeper, geNorm and NormFinder. All data were analysed using the online tool RefFinder to obtain a comprehensive ranking. Our results indicate that NormFinder is the best tool for reference gene selection in early stages of hiPSC neural differentiation. None of the 16 tested genes is suitable as reference gene for all three stages of development. We recommend using different genes (panel of genes) to normalise RT–qPCR data for each of the neural differentiation stages. Keywords human induced Pluripotent Stem Cell (hiPSC) . Neural Stem Cells . Neural -
CNV Analysis in 169 Patients with Bladder Exstrophy-Epispadias
von Lowtzow et al. BMC Medical Genetics (2016) 17:35 DOI 10.1186/s12881-016-0299-x RESEARCH ARTICLE Open Access CNV analysis in 169 patients with bladder exstrophy-epispadias complex Catharina von Lowtzow1, Andrea Hofmann1,2, Rong Zhang1,2, Florian Marsch1, Anne-Karoline Ebert3, Wolfgang Rösch4, Raimund Stein5, Thomas M. Boemers6, Karin Hirsch7, Carlo Marcelis8, Wouter F. J. Feitz9, Alfredo Brusco10, Nicola Migone10, Massimo Di Grazia11, Susanne Moebus12, Markus M. Nöthen1,2, Heiko Reutter1,13, Michael Ludwig14*† and Markus Draaken1,2† Abstract Background: The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the congenital uro-rectal malformation spectrum. Initial studies have implicated rare copy number variations (CNVs), including recurrent duplications of chromosomal region 22q11.21, in BEEC etiology. Methods: To detect further CNVs, array analysis was performed in 169 BEEC patients. Prior to inclusion, 22q11.21 duplications were excluded using multiplex ligation-dependent probe amplification. Results: Following the application of stringent filter criteria, seven rare CNVs were identified: n = 4, not present in 1307 in-house controls; n = 3, frequency of <0.002 in controls. These CNVs ranged from 1 to 6.08 Mb in size. To identify smaller CNVs, relaxed filter criteria used in the detection of previously reported BEEC associated chromosomal regions were applied. This resulted in the identification of six additional rare CNVs: n = 4, not present in 1307 in-house controls; n = 2, frequency <0.0008 in controls. These CNVs ranged from 0.03–0.08 Mb in size. For 10 of these 13 CNVs, confirmation and segregation analyses were performed (5 of maternal origin; 5 of paternal origin). -
Role of the Oncogene Vav2 in Lung Tumorigenesis
Role of the oncogene Vav2 in lung tumorigenesis Regina Bou Puerto Dirigido por: Dr. Xosé R. Bustelo Codirigido por: Dra. Myriam Cuadrado TRABAJO DE FIN DE MÁSTER MÁSTER EN BIOLOGÍA Y CLÍNICA DEL CÁNCER SALAMANCA, 20 de junio 2016 INDEX ABSTRACT . - 1 - 1 | INTRODUCTION . - 2 - 1.1 Rho GTPases: function and regulation…………………………………….2 1.2 The Vav family of GEFs for Rho GTPases………………………………....2 1.3 Rho GTPases and Vav GEFs: implication in cancer……………………..3 1.4 Vav2 in lung tumorigenesis………………………………………………...4 1.4.1 Introduction to the model of study 1.4.2 Importance of Vav2 in the formation of lung tumors 2 | MATERIALS AND METHODS . - 6 - 3 | RESULTS AND DISCUSSION. - 9 - 3.1 Role of Vav2 in lung homeostasis………...............………..........................10 3.2 Generation of Vav2-KO cells using CRISPR-Cas9 technology………….11 3.3 Validation of Vav2 knockdown cell lines………………............................13 3.4 Vav2-deficient cells show a decrease in cell proliferation………………..14 3.5 Vav2-deficient cells show a decrease in cell survival………………..........15 3.6 Rescue of Vav2 knockdown cell lines………………..................................16 3.7 Overexpression of RhoA, Rac1 and Cdc42 in Vav2-deficient cells……...18 3.8 Overexpression of Vav3 in Vav2-deficient cells………………..................20 4 | CONCLUSIONS AND FUTURE WORK . - 21 - 5 | REFERENCES . - 21 - I ABSTRACT Vav proteins are a family of guanosine nucleotide exchange factors (GEFs) for the Rho family of GTPases. They regulate the exchange of GDP for GTP and the subsequent activation of Rho GTPases. These proteins control in turn a variety of cellular processes which include proliferation, migration or gene transcription, among others. -
Identification of Candidate Genes and Pathways Associated with Obesity
animals Article Identification of Candidate Genes and Pathways Associated with Obesity-Related Traits in Canines via Gene-Set Enrichment and Pathway-Based GWAS Analysis Sunirmal Sheet y, Srikanth Krishnamoorthy y , Jihye Cha, Soyoung Choi and Bong-Hwan Choi * Animal Genome & Bioinformatics, National Institute of Animal Science, RDA, Wanju 55365, Korea; [email protected] (S.S.); [email protected] (S.K.); [email protected] (J.C.); [email protected] (S.C.) * Correspondence: [email protected]; Tel.: +82-10-8143-5164 These authors contributed equally. y Received: 10 October 2020; Accepted: 6 November 2020; Published: 9 November 2020 Simple Summary: Obesity is a serious health issue and is increasing at an alarming rate in several dog breeds, but there is limited information on the genetic mechanism underlying it. Moreover, there have been very few reports on genetic markers associated with canine obesity. These studies were limited to the use of a single breed in the association study. In this study, we have performed a GWAS and supplemented it with gene-set enrichment and pathway-based analyses to identify causative loci and genes associated with canine obesity in 18 different dog breeds. From the GWAS, the significant markers associated with obesity-related traits including body weight (CACNA1B, C22orf39, U6, MYH14, PTPN2, SEH1L) and blood sugar (PRSS55, GRIK2), were identified. Furthermore, the gene-set enrichment and pathway-based analysis (GESA) highlighted five enriched pathways (Wnt signaling pathway, adherens junction, pathways in cancer, axon guidance, and insulin secretion) and seven GO terms (fat cell differentiation, calcium ion binding, cytoplasm, nucleus, phospholipid transport, central nervous system development, and cell surface) which were found to be shared among all the traits. -
Signal Transduction in L-DOPA-Induced Dyskinesia: from Receptor Sensitization to Abnormal… Et Al
Journal of Neural Transmission https://doi.org/10.1007/s00702-018-1847-7 NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE Signal transduction in L‑DOPA‑induced dyskinesia: from receptor sensitization to abnormal gene expression Giada Spigolon1 · Gilberto Fisone1 Received: 1 November 2017 / Accepted: 23 January 2018 © The Author(s) 2018. This article is an open access publication Abstract A large number of signaling abnormalities have been implicated in the emergence and expression of L-DOPA-induced dyskinesia (LID). The primary cause for many of these changes is the development of sensitization at dopamine receptors located on striatal projection neurons (SPN). This initial priming, which is particularly evident at the level of dopamine D1 receptors (D1R), can be viewed as a homeostatic response to dopamine depletion and is further exacerbated by chronic administration of L-DOPA, through a variety of mechanisms afecting various components of the G-protein-coupled receptor machinery. Sensitization of dopamine receptors in combination with pulsatile administration of L-DOPA leads to intermit- tent and coordinated hyperactivation of signal transduction cascades, ultimately resulting in long-term modifcations of gene expression and protein synthesis. A detailed mapping of these pathological changes and of their involvement in LID has been produced during the last decade. According to this emerging picture, activation of sensitized D1R results in the stimulation of cAMP-dependent protein kinase and of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa. This, in turn, activates the extracellular signal-regulated kinases 1 and 2 (ERK), leading to chromatin remodeling and aberrant gene transcription. Dysregulated ERK results also in the stimulation of the mammalian target of rapamycin complex 1, which promotes protein synthesis. -
Supplemental Data Olig2-Regulated Lineage-Restricted Pathway Controls Replication Competence in Neural Stem Cells and Malignant
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Caltech Authors Neuron, Volume 53 Supplemental Data Olig2-Regulated Lineage-Restricted Pathway Controls Replication Competence in Neural Stem Cells and Malignant Glioma Keith L. Ligon, Emmanuelle Huillard, Shwetal Mehta, Santosh Kesari, Hongye Liu, John A. Alberta, Robert M. Bachoo, Michael Kane, David N. Louis, Ronald A. DePinho, David J. Anderson, Charles D. Stiles, and David H. Rowitch Figure S1. Olig1/2+/- Ink4a/Arf-/-EGFRvIII Gliomas Express Characteristic Morphologic and Immunophenotypic Features of Human Malignant Gliomas (A) Tumors exhibit dense cellularity and atypia. (B) Characteristic infiltration of host SVZ stem cell niche. (C) Although occasional tumors exhibited pseudopalisading necrosis (n, arrowhead) and hemorrhage (h, arrowhead) similar to human GBM (Astrocytoma WHO Grade IV), most tumors lacked these features. (D) IHC for hEGFR highlights hallmark feature of human gliomas, including perivascular (pv) and subpial (sp) accumulation of tumor cells, (E) striking white matter tropism of tumor cells in corpus callosum (cc), and (F) distant single cell infiltration of cerebellar white matter (wm, arrows). (G-J) Immunohistochemical markers characteristic of human tumors (Gfap, Olig2, Olig1, Nestin) are present. (K and L) Weak staining for the early neuronal marker TuJ1 and absence of the differentiated neuronal marker, NeuN similar to human glioma and consistent with heterogeneous lines of partial differentiation. Figure S2. Olig1/2+/- Ink4a/Arf-/-EGFRvIII Neurospheres Are Multipotent and Olig1/2-/- Ink4a/Arf-/-EGFRvIII Neurospheres Are Bipotent Olig1/2+/- or Olig1/2-/- Ink4a/Arf-/-EGFRvIII neurospheres were allowed to differentiate for 6 days in medium without EGF. -
Mai Muudatuntuu Ti on Man Mini
MAIMUUDATUNTUU US009809854B2 TI ON MAN MINI (12 ) United States Patent ( 10 ) Patent No. : US 9 ,809 ,854 B2 Crow et al. (45 ) Date of Patent : Nov . 7 , 2017 Whitehead et al. (2005 ) Variation in tissue - specific gene expression ( 54 ) BIOMARKERS FOR DISEASE ACTIVITY among natural populations. Genome Biology, 6 :R13 . * AND CLINICAL MANIFESTATIONS Villanueva et al. ( 2011 ) Netting Neutrophils Induce Endothelial SYSTEMIC LUPUS ERYTHEMATOSUS Damage , Infiltrate Tissues, and Expose Immunostimulatory Mol ecules in Systemic Lupus Erythematosus . The Journal of Immunol @(71 ) Applicant: NEW YORK SOCIETY FOR THE ogy , 187 : 538 - 552 . * RUPTURED AND CRIPPLED Bijl et al. (2001 ) Fas expression on peripheral blood lymphocytes in MAINTAINING THE HOSPITAL , systemic lupus erythematosus ( SLE ) : relation to lymphocyte acti vation and disease activity . Lupus, 10 :866 - 872 . * New York , NY (US ) Crow et al . (2003 ) Microarray analysis of gene expression in lupus. Arthritis Research and Therapy , 5 :279 - 287 . * @(72 ) Inventors : Mary K . Crow , New York , NY (US ) ; Baechler et al . ( 2003 ) Interferon - inducible gene expression signa Mikhail Olferiev , Mount Kisco , NY ture in peripheral blood cells of patients with severe lupus . PNAS , (US ) 100 ( 5 ) : 2610 - 2615. * GeneCards database entry for IFIT3 ( obtained from < http : / /www . ( 73 ) Assignee : NEW YORK SOCIETY FOR THE genecards. org /cgi - bin / carddisp .pl ? gene = IFIT3 > on May 26 , 2016 , RUPTURED AND CRIPPLED 15 pages ) . * Navarra et al. (2011 ) Efficacy and safety of belimumab in patients MAINTAINING THE HOSPITAL with active systemic lupus erythematosus : a randomised , placebo FOR SPECIAL SURGERY , New controlled , phase 3 trial . The Lancet , 377 :721 - 731. * York , NY (US ) Abramson et al . ( 1983 ) Arthritis Rheum . -
The Genetic Factors of Bilaterian Evolution Peter Heger1*, Wen Zheng1†, Anna Rottmann1, Kristen a Panfilio2,3, Thomas Wiehe1
RESEARCH ARTICLE The genetic factors of bilaterian evolution Peter Heger1*, Wen Zheng1†, Anna Rottmann1, Kristen A Panfilio2,3, Thomas Wiehe1 1Institute for Genetics, Cologne Biocenter, University of Cologne, Cologne, Germany; 2Institute for Zoology: Developmental Biology, Cologne Biocenter, University of Cologne, Cologne, Germany; 3School of Life Sciences, University of Warwick, Gibbet Hill Campus, Coventry, United Kingdom Abstract The Cambrian explosion was a unique animal radiation ~540 million years ago that produced the full range of body plans across bilaterians. The genetic mechanisms underlying these events are unknown, leaving a fundamental question in evolutionary biology unanswered. Using large-scale comparative genomics and advanced orthology evaluation techniques, we identified 157 bilaterian-specific genes. They include the entire Nodal pathway, a key regulator of mesoderm development and left-right axis specification; components for nervous system development, including a suite of G-protein-coupled receptors that control physiology and behaviour, the Robo- Slit midline repulsion system, and the neurotrophin signalling system; a high number of zinc finger transcription factors; and novel factors that previously escaped attention. Contradicting the current view, our study reveals that genes with bilaterian origin are robustly associated with key features in extant bilaterians, suggesting a causal relationship. *For correspondence: [email protected] Introduction The taxon Bilateria consists of multicellular animals -
Human Induced Pluripotent Stem Cell–Derived Podocytes Mature Into Vascularized Glomeruli Upon Experimental Transplantation
BASIC RESEARCH www.jasn.org Human Induced Pluripotent Stem Cell–Derived Podocytes Mature into Vascularized Glomeruli upon Experimental Transplantation † Sazia Sharmin,* Atsuhiro Taguchi,* Yusuke Kaku,* Yasuhiro Yoshimura,* Tomoko Ohmori,* ‡ † ‡ Tetsushi Sakuma, Masashi Mukoyama, Takashi Yamamoto, Hidetake Kurihara,§ and | Ryuichi Nishinakamura* *Department of Kidney Development, Institute of Molecular Embryology and Genetics, and †Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; ‡Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Hiroshima, Japan; §Division of Anatomy, Juntendo University School of Medicine, Tokyo, Japan; and |Japan Science and Technology Agency, CREST, Kumamoto, Japan ABSTRACT Glomerular podocytes express proteins, such as nephrin, that constitute the slit diaphragm, thereby contributing to the filtration process in the kidney. Glomerular development has been analyzed mainly in mice, whereas analysis of human kidney development has been minimal because of limited access to embryonic kidneys. We previously reported the induction of three-dimensional primordial glomeruli from human induced pluripotent stem (iPS) cells. Here, using transcription activator–like effector nuclease-mediated homologous recombination, we generated human iPS cell lines that express green fluorescent protein (GFP) in the NPHS1 locus, which encodes nephrin, and we show that GFP expression facilitated accurate visualization of nephrin-positive podocyte formation in