Microarray Gene Expression Profiling in Meningiomas: Differential Expression According to Grade Or Histopathological Subtype
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1 the Genetic Architecture of the Human Cerebral Cortex. Katrina L. Grasby1*, Neda Jahanshad2*, Jodie N. Painter1, Lucía Colodr
bioRxiv preprint doi: https://doi.org/10.1101/399402; this version posted September 9, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The genetic architecture of the human cerebral cortex. Katrina L. Grasby1*, Neda Jahanshad2*, Jodie N. Painter1, Lucía Colodro-Conde1, Janita Bralten3,4, Derrek P. Hibar2,5, Penelope A. Lind1, Fabrizio Pizzagalli2, Christopher R.K. Ching2,6, Mary Agnes B. McMahon2, Natalia Shatokhina2, Leo C.P. Zsembik7, Ingrid Agartz8,9,10,11, Saud Alhusaini12,13, Marcio A.A. Almeida14, Dag Alnæs8,9, Inge K. Amlien15, Micael Andersson16,17, Tyler Ard18, Nicola J. Armstrong19, Allison Ashley-Koch20, Manon Bernard21, Rachel M. Brouwer22, Elizabeth E.L. Buimer22, Robin Bülow23, Christian Bürger24, Dara M. Cannon25, Mallar Chakravarty26,27, Qiang Chen28, Joshua W. Cheung2, Baptiste Couvy-Duchesne29,30,31, Anders M. Dale32,33, Shareefa Dalvie34, Tânia K. de Araujo35, Greig I. de Zubicaray36, Sonja M.C. de Zwarte22, Anouk den Braber37,38, Nhat Trung Doan8,9, Katharina Dohm24, Stefan Ehrlich39, Hannah-Ruth Engelbrecht40, Susanne Erk41, Chun Chieh Fan42, Iryna O. Fedko37, Sonya F. Foley43, Judith M. Ford44, Masaki Fukunaga45, Melanie E. Garrett20, Tian Ge46,47, Sudheer Giddaluru48, Aaron L. Goldman28, Nynke A. Groenewold34, Dominik Grotegerd24, Tiril P. Gurholt8,9,10, Boris A. Gutman2,49, Narelle K. Hansell31, Mathew A. Harris50,51, Marc B. Harrison2, Courtney C. Haswell52,53, Michael Hauser20, Stefan Herms54,55,56, Dirk J. Heslenfeld57, New Fei Ho58, David Hoehn59, Per Hoffmann54,55,60, Laurena Holleran25, Martine Hoogman3,4, Jouke-Jan Hottenga37, Masashi Ikeda61, Deborah Janowitz62, Iris E. -
Analysis of Trans Esnps Infers Regulatory Network Architecture
Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Anat Kreimer All rights reserved ABSTRACT Analysis of trans eSNPs infers regulatory network architecture Anat Kreimer eSNPs are genetic variants associated with transcript expression levels. The characteristics of such variants highlight their importance and present a unique opportunity for studying gene regulation. eSNPs affect most genes and their cell type specificity can shed light on different processes that are activated in each cell. They can identify functional variants by connecting SNPs that are implicated in disease to a molecular mechanism. Examining eSNPs that are associated with distal genes can provide insights regarding the inference of regulatory networks but also presents challenges due to the high statistical burden of multiple testing. Such association studies allow: simultaneous investigation of many gene expression phenotypes without assuming any prior knowledge and identification of unknown regulators of gene expression while uncovering directionality. This thesis will focus on such distal eSNPs to map regulatory interactions between different loci and expose the architecture of the regulatory network defined by such interactions. We develop novel computational approaches and apply them to genetics-genomics data in human. We go beyond pairwise interactions to define network motifs, including regulatory modules and bi-fan structures, showing them to be prevalent in real data and exposing distinct attributes of such arrangements. We project eSNP associations onto a protein-protein interaction network to expose topological properties of eSNPs and their targets and highlight different modes of distal regulation. -
Differential Gene Expression Profile in Endometrioid And
[CANCER RESEARCH 63, 5697–5702, September 15, 2003] Advances in Brief Differential Gene Expression Profile in Endometrioid and Nonendometrioid Endometrial Carcinoma: STK15 Is Frequently Overexpressed and Amplified in Nonendometrioid Carcinomas1 Gema Moreno-Bueno, Carolina Sa´nchez-Este´vez, Rau´l Cassia, Sandra Rodrı´guez-Perales, Ramo´n Dı´az-Uriarte, Orlando Domı´nguez, David Hardisson, Miguel Andujar, Jaime Prat, Xavier Matias-Guiu, Juan C. Cigudosa, and Jose´Palacios2 Laboratory of Breast and Gynaecological Cancer, Molecular Pathology Programme [G. M-B., C. S-E., R. C., J. Pa.] and Biotechnology Programme [S. R-P., R. D-U., O. D., J. C. C.], Centro Nacional de Investigaciones Oncologicas, Madrid; Department of Pathology, Hospital Universitario La Paz, Madrid [D. H.]; Department of Pathology, Hospital Materno Infantil, Las Palmas [M. A.]; Department of Pathology, Hospital Sant Pau y Sant Creu, Barcelona [J. Pr.]; and Department of Pathology, Hospital Arnau de Villanova, Lleida [X. M-G.], Spain Abstract tiated endometrioid carcinomas that usually develop in pre- and perimenopausal women. They are associated with estrogen stimula- Endometrial carcinoma (EC) comprises at least two types of cancer: tion, coexist with, or are preceded by atypical endometrial hyperplasia endometrioid carcinomas (EECs) are estrogen-related tumors, which are and are associated with ER positivity and with K-RAS, PTEN, and frequently euploid and have a good prognosis. Nonendometrioid carcino-  mas (NEECs; serous and clear cell forms) are not estrogen related, are -catenin mutations, and microsatellite instability. Conversely, type II frequently aneuploid, and are clinically aggressive. We used cDNA mi- tumors are NEECs (papillary serous and clear cell carcinomas) that croarrays containing 6386 different genes to analyze gene expression occur in older women. -
Mechanical Forces Induce an Asthma Gene Signature in Healthy Airway Epithelial Cells Ayşe Kılıç1,10, Asher Ameli1,2,10, Jin-Ah Park3,10, Alvin T
www.nature.com/scientificreports OPEN Mechanical forces induce an asthma gene signature in healthy airway epithelial cells Ayşe Kılıç1,10, Asher Ameli1,2,10, Jin-Ah Park3,10, Alvin T. Kho4, Kelan Tantisira1, Marc Santolini 1,5, Feixiong Cheng6,7,8, Jennifer A. Mitchel3, Maureen McGill3, Michael J. O’Sullivan3, Margherita De Marzio1,3, Amitabh Sharma1, Scott H. Randell9, Jefrey M. Drazen3, Jefrey J. Fredberg3 & Scott T. Weiss1,3* Bronchospasm compresses the bronchial epithelium, and this compressive stress has been implicated in asthma pathogenesis. However, the molecular mechanisms by which this compressive stress alters pathways relevant to disease are not well understood. Using air-liquid interface cultures of primary human bronchial epithelial cells derived from non-asthmatic donors and asthmatic donors, we applied a compressive stress and then used a network approach to map resulting changes in the molecular interactome. In cells from non-asthmatic donors, compression by itself was sufcient to induce infammatory, late repair, and fbrotic pathways. Remarkably, this molecular profle of non-asthmatic cells after compression recapitulated the profle of asthmatic cells before compression. Together, these results show that even in the absence of any infammatory stimulus, mechanical compression alone is sufcient to induce an asthma-like molecular signature. Bronchial epithelial cells (BECs) form a physical barrier that protects pulmonary airways from inhaled irritants and invading pathogens1,2. Moreover, environmental stimuli such as allergens, pollutants and viruses can induce constriction of the airways3 and thereby expose the bronchial epithelium to compressive mechanical stress. In BECs, this compressive stress induces structural, biophysical, as well as molecular changes4,5, that interact with nearby mesenchyme6 to cause epithelial layer unjamming1, shedding of soluble factors, production of matrix proteins, and activation matrix modifying enzymes, which then act to coordinate infammatory and remodeling processes4,7–10. -
Differential Expression of Two Neuronal Intermediate-Filament Proteins, Peripherin and the Low-Molecular-Mass Neurofilament Prot
The Journal of Neuroscience, March 1990, fO(3): 764-764 Differential Expression of Two Neuronal Intermediate-Filament Proteins, Peripherin and the Low-Molecular-Mass Neurofilament Protein (NF-L), During the Development of the Rat Michel Escurat,’ Karima Djabali,’ Madeleine Gumpel,2 Franqois Gras,’ and Marie-Madeleine Portier’ lCollBne de France, Biochimie Cellulaire, 75231 Paris Cedex 05, France, *HBpital de la Salpktricke, Unite INSERM 134, 75651Paris Cedex 13, France The expression of peripherin, an intermediate filament pro- and Freeman, 1978), now more generally referred to respectively tein, had been shown by biochemical methods to be local- as high-, middle-, and low-molecular-mass NFP (NF-H, NF-M, ized in the neurons of the PNS. Using immunohistochemical and NF-L). These proteins are expressed in most mature neu- methods, we analyzed this expression more extensively dur- ronal populations belonging either to the CNS or to the PNS; ing the development of the rat and compared it with that of developing neurons generally do not express any of them until the low-molecular-mass neurofilament protein (NF-L), which they become postmitotic (Tapscott et al., 198 la). is expressed in every neuron of the CNS and PNS. We, however, described another IFP with a molecular weight The immunoreactivity of NF-L is first apparent at the 25 of about 57 kDa, which we had first observed in mouse neu- somite stage (about 11 d) in the ventral horn of the spinal roblastoma cell lines and which was also expressed in rat pheo- medulla and in the posterior part of the rhombencephalon. chromocytoma PC1 2 cell line. -
CD157 and CD200 at the Crossroads of Endothelial Remodeling and Immune Regulation
Editorial Commentary Page 1 of 7 CD157 and CD200 at the crossroads of endothelial remodeling and immune regulation Masuko Katoh1, Masaru Katoh2 1M & M PrecMed, Tokyo, Japan; 2Department of Omics Network, National Cancer Center, Tokyo, Japan Correspondence to: Masaru Katoh. Department of Omics Network, National Cancer Center, 5-1-1 Tsukiji, Chuo-ward, Tokyo 104-0045, Japan. Email: [email protected]. Comment on: Wakabayashi T, Naito H, Suehiro JI, et al. CD157 Marks Tissue-Resident Endothelial Stem Cells with Homeostatic and Regenerative Properties. Cell Stem Cell 2018;22:384-97.e6. Received: 11 March 2019; Accepted: 08 April 2019; Published: 19 April 2019. doi: 10.21037/sci.2019.04.01 View this article at: http://dx.doi.org/10.21037/sci.2019.04.01 The endothelial cells that coat the inner wall of blood cells formed more CD31 (PECAM1)-positive colonies than vessels are essential for the maintenance of the vascular CD200 single-positive or CD157/CD200 double-negative network, metabolic homeostasis and stem cell populations liver endothelial cells in vitro. The expression levels of Atf3, in tissue or tumor microenvironments (1-3). Angiogenesis Fosl2, Myc and Sox7 were significantly upregulated in the is defined as neovascular formation through the sprouting CD157/CD200 double-positive cells compared with the and proliferation of endothelial cells from preexisting CD200 single-positive or CD157/CD200 double-negative blood vessels. VEGF (VEGFA) and FGFs that transduce cells; however, the functions of these transcription factors signals through VEGFR2 and FGFRs, respectively, are in CD157/CD200 double-positive endothelial cells remain representative proangiogenic factors (4,5). -
Decorin As a Multivalent Therapeutic Agent Against Cancer
Thomas Jefferson University Jefferson Digital Commons Department of Pathology, Anatomy, and Cell Department of Pathology, Anatomy, and Cell Biology Faculty Papers Biology 2-1-2016 Decorin as a multivalent therapeutic agent against cancer. Thomas Neill Thomas Jefferson University Liliana Schaefer Goethe University Renato V. Iozzo Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/pacbfp Part of the Biochemistry Commons, Cancer Biology Commons, Cell Biology Commons, and the Molecular Biology Commons Let us know how access to this document benefits ouy Recommended Citation Neill, Thomas; Schaefer, Liliana; and Iozzo, Renato V., "Decorin as a multivalent therapeutic agent against cancer." (2016). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 199. https://jdc.jefferson.edu/pacbfp/199 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Department of Pathology, Anatomy, and Cell Biology Faculty Papers by an authorized administrator of the Jefferson -
Defining Functional Interactions During Biogenesis of Epithelial Junctions
ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. -
Supporting Online Material
1 2 3 4 5 6 7 Supplementary Information for 8 9 Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic 10 retinopathy 11 12 *Samuel A. Mills, *Andrew I. Jobling, *Michael A. Dixon, Bang V. Bui, Kirstan A. Vessey, Joanna A. Phipps, 13 Ursula Greferath, Gene Venables, Vickie H.Y. Wong, Connie H.Y. Wong, Zheng He, Flora Hui, James C. 14 Young, Josh Tonc, Elena Ivanova, Botir T. Sagdullaev, Erica L. Fletcher 15 * Joint first authors 16 17 Corresponding author: 18 Prof. Erica L. Fletcher. Department of Anatomy & Neuroscience. The University of Melbourne, Grattan St, 19 Parkville 3010, Victoria, Australia. 20 Email: [email protected] ; Tel: +61-3-8344-3218; Fax: +61-3-9347-5219 21 22 This PDF file includes: 23 24 Supplementary text 25 Figures S1 to S10 26 Tables S1 to S7 27 Legends for Movies S1 to S2 28 SI References 29 30 Other supplementary materials for this manuscript include the following: 31 32 Movies S1 to S2 33 34 35 36 1 1 Supplementary Information Text 2 Materials and Methods 3 Microglial process movement on retinal vessels 4 Dark agouti rats were anaesthetized, injected intraperitoneally with rhodamine B (Sigma-Aldrich) to label blood 5 vessels and retinal explants established as described in the main text. Retinal microglia were labelled with Iba-1 6 and imaging performed on an inverted confocal microscope (Leica SP5). Baseline images were taken for 10 7 minutes, followed by the addition of PBS (10 minutes) and then either fractalkine or fractalkine + candesartan 8 (10 minutes) using concentrations outlined in the main text. -
Lgr5 Homologues Associate with Wnt Receptors and Mediate R-Spondin Signalling
ARTICLE doi:10.1038/nature10337 Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling Wim de Lau1*, Nick Barker1{*, Teck Y. Low2, Bon-Kyoung Koo1, Vivian S. W. Li1, Hans Teunissen1, Pekka Kujala3, Andrea Haegebarth1{, Peter J. Peters3, Marc van de Wetering1, Daniel E. Stange1, Johan E. van Es1, Daniele Guardavaccaro1, Richard B. M. Schasfoort4, Yasuaki Mohri5, Katsuhiko Nishimori5, Shabaz Mohammed2, Albert J. R. Heck2 & Hans Clevers1 The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of Lgr4/5 in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues. The genes Lgr4, Lgr5 and Lgr6 encode orphan 7-transmembrane 4–5 post-induction onwards. -
Absence of NEFL in Patient-Specific Neurons in Early-Onset Charcot-Marie-Tooth Neuropathy Markus T
ARTICLE OPEN ACCESS Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy Markus T. Sainio, MSc, Emil Ylikallio, MD, PhD, Laura M¨aenp¨a¨a, MSc, Jenni Lahtela, PhD, Pirkko Mattila, PhD, Correspondence Mari Auranen, MD, PhD, Johanna Palmio, MD, PhD, and Henna Tyynismaa, PhD Dr. Tyynismaa [email protected] Neurol Genet 2018;4:e244. doi:10.1212/NXG.0000000000000244 Abstract Objective We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (NEFL) underlying early-onset Charcot- Marie-Tooth (CMT) disease. Methods Motor neurons were differentiated from induced pluripotent stem cells of a patient with early- onset CMT carrying a novel homozygous nonsense mutation in NEFL. Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons. Results We show that the recessive nonsense mutation causes a nearly total loss of NEFL messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient’s cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neuro- filaments. Single-neuron gene expression fingerprinting pinpointed NEFL as the most down- regulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of NEFL mRNA. Conclusions The strict neuronal specificity of neurofilament has hindered the mechanistic studies of re- cessive NEFL nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism. -
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.