An Organelle-Specific Protein Landscape Identifies
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I HIGH MASS ACCURACY COUPLED to SPATIALLY-DIRECTED
HIGH MASS ACCURACY COUPLED TO SPATIALLY-DIRECTED PROTEOMICS FOR IMPROVED PROTEIN IDENTIFICATIONS IN IMAGING MASS SPECTROMETRY EXPERIMENTS By David Geoffrey Rizzo Dissertation Submitted to the Faculty of the Graduate School of Vanderbilt University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry August, 2016 Nashville, Tennessee Approved: Richard M. Caprioli, Ph.D. Kevin L. Schey, Ph.D. John A. McLean, Ph.D. Michael P. Stone, Ph.D. i Copyright © 2016 by David Geoffrey Rizzo All Rights Reserved ii This work is dedicated to my family and friends, who have shown nothing but support for me in all of life’s endeavors. iii ACKNOWLEDGEMENTS “As we express our gratitude, we must never forget that the highest appreciation is not to utter words, but to live by them.” - John F. Kennedy – There are many people I must thank for showing kindness, encouragement, and support for me during my tenure as a graduate student. First and foremost, I would like to thank my research advisor, Richard Caprioli, for providing both ample resources and guidance that allowed me to grow as a scientist. Our discussions about my research and science in general have helped me become a much more focused and discerning analytical chemist. I must also thank my Ph.D. committee members, Drs. Kevin Schey, John McLean, and Michael Stone, who have brought valuable insight into my research and provided direction along the way. My undergraduate advisor, Dr. Facundo Fernández, encouraged me to begin research in his lab and introduced me to the world of mass spectrometry. -
Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants. -
1 Metabolic Dysfunction Is Restricted to the Sciatic Nerve in Experimental
Page 1 of 255 Diabetes Metabolic dysfunction is restricted to the sciatic nerve in experimental diabetic neuropathy Oliver J. Freeman1,2, Richard D. Unwin2,3, Andrew W. Dowsey2,3, Paul Begley2,3, Sumia Ali1, Katherine A. Hollywood2,3, Nitin Rustogi2,3, Rasmus S. Petersen1, Warwick B. Dunn2,3†, Garth J.S. Cooper2,3,4,5* & Natalie J. Gardiner1* 1 Faculty of Life Sciences, University of Manchester, UK 2 Centre for Advanced Discovery and Experimental Therapeutics (CADET), Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK 3 Centre for Endocrinology and Diabetes, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, UK 4 School of Biological Sciences, University of Auckland, New Zealand 5 Department of Pharmacology, Medical Sciences Division, University of Oxford, UK † Present address: School of Biosciences, University of Birmingham, UK *Joint corresponding authors: Natalie J. Gardiner and Garth J.S. Cooper Email: [email protected]; [email protected] Address: University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, United Kingdom Telephone: +44 161 275 5768; +44 161 701 0240 Word count: 4,490 Number of tables: 1, Number of figures: 6 Running title: Metabolic dysfunction in diabetic neuropathy 1 Diabetes Publish Ahead of Print, published online October 15, 2015 Diabetes Page 2 of 255 Abstract High glucose levels in the peripheral nervous system (PNS) have been implicated in the pathogenesis of diabetic neuropathy (DN). However our understanding of the molecular mechanisms which cause the marked distal pathology is incomplete. Here we performed a comprehensive, system-wide analysis of the PNS of a rodent model of DN. -
European School of Genetic Medicine Eye Genetics
European School of Genetic Medicine th 4 Course in Eye Genetics Bertinoro, Italy, September 27-29, 2015 Bertinoro University Residential Centre Via Frangipane, 6 – Bertinoro www.ceub.it Course Directors: R. Allikmets (Columbia University, New York) A. Ciardella (U.O. Oftalmologia, Policlinico Sant’ Orsola, Bologna) B. P. Leroy (Ghent University, Ghent) M. Seri (U.O Genetica Medica, Bologna). th 4 Course in Eye Genetics Bertinoro, Italy, September 27-29, 2015 CONTENTS PROGRAMME 3 ABSTRACTS OF LECTURES 6 ABSTRACTS OF STUDENTS POSTERS 26 STUDENTS WHO IS WHO 39 FACULTY WHO IS WHO 41 2 4TH COURSE IN EYE GENETICS Bertinoro University Residential Centre Bertinoro, Italy, September 27-29, 2015 Arrival day: Saturday, September 26th September 27 8:30 - 8:40 Welcome 8:40 - 9:10 History of Medical Genetics Giovanni Romeo 9:15 - 10:00 2 parallel talks: (40 min + 5 min discussion) Garrison Room 1. Overview of clinical ophthalmology for basic scientists Antonio Ciardella Jacopo da Bertinoro Room 2. Overview of basic medical genetics for ophthalmologists Bart Leroy 10:05 - 11:35 2 talks (40 min + 5 min discussion) 3. Stargardt disease, the complex simple retinal disorder Rando Allikmets 4. Overview of inherited corneal disorders Graeme Black 11:35 - 12:00 Break 12:00 - 13:30 2 talks (40 min + 5 min discussion) 1. Molecular basis of non-syndromic and syndromic retinal and vitreoretinal diseases Wolfgang Berger 2. Introduction to next-generation sequencing for eye diseases Lonneke Haer-Wigman 13:30 - 14:30 Lunch 14:30 - 16:15 3 parallel workshops -
Cellular and Molecular Signatures in the Disease Tissue of Early
Cellular and Molecular Signatures in the Disease Tissue of Early Rheumatoid Arthritis Stratify Clinical Response to csDMARD-Therapy and Predict Radiographic Progression Frances Humby1,* Myles Lewis1,* Nandhini Ramamoorthi2, Jason Hackney3, Michael Barnes1, Michele Bombardieri1, Francesca Setiadi2, Stephen Kelly1, Fabiola Bene1, Maria di Cicco1, Sudeh Riahi1, Vidalba Rocher-Ros1, Nora Ng1, Ilias Lazorou1, Rebecca E. Hands1, Desiree van der Heijde4, Robert Landewé5, Annette van der Helm-van Mil4, Alberto Cauli6, Iain B. McInnes7, Christopher D. Buckley8, Ernest Choy9, Peter Taylor10, Michael J. Townsend2 & Costantino Pitzalis1 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Departments of 2Biomarker Discovery OMNI, 3Bioinformatics and Computational Biology, Genentech Research and Early Development, South San Francisco, California 94080 USA 4Department of Rheumatology, Leiden University Medical Center, The Netherlands 5Department of Clinical Immunology & Rheumatology, Amsterdam Rheumatology & Immunology Center, Amsterdam, The Netherlands 6Rheumatology Unit, Department of Medical Sciences, Policlinico of the University of Cagliari, Cagliari, Italy 7Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK 8Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham B15 2WB, UK 9Institute of -
Treatment Potential for LCA5-Associated Leber Congenital Amaurosis
Retina Treatment Potential for LCA5-Associated Leber Congenital Amaurosis Katherine E. Uyhazi,1,2 Puya Aravand,1 Brent A. Bell,1 Zhangyong Wei,1 Lanfranco Leo,1 Leona W. Serrano,2 Denise J. Pearson,1,2 Ivan Shpylchak,1 Jennifer Pham,1 Vidyullatha Vasireddy,1 Jean Bennett,1 and Tomas S. Aleman1,2 1Center for Advanced Retinal and Ocular Therapeutics (CAROT) and F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Philadelphia, PA, USA 2Scheie Eye Institute at The Perelman Center for Advanced Medicine, University of Pennsylvania, Philadelphia, PA, USA Correspondence: Tomas S. Aleman, PURPOSE. To determine the therapeutic window for gene augmentation for Leber congen- Perelman Center for Advanced ital amaurosis (LCA) associated with mutations in LCA5. Medicine, University of Pennsylvania, 3400 Civic Center METHODS. Five patients (ages 6–31) with LCA and biallelic LCA5 mutations underwent Blvd, Philadelphia, PA 19104, USA; an ophthalmic examination including optical coherence tomography (SD-OCT), full-field [email protected]. stimulus testing (FST), and pupillometry. The time course of photoreceptor degeneration in the Lca5gt/gt mouse model and the efficacy of subretinal gene augmentation therapy Received: November 19, 2019 with AAV8-hLCA5 delivered at postnatal day 5 (P5) (early, n = 11 eyes), P15 (mid, n = 14), Accepted: March 16, 2020 = Published: May 19, 2020 and P30 (late, n 13) were assessed using SD-OCT, histologic study, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease. Citation: Uyhazi KE, Aravand P, Bell BA, et al. Treatment potential for RESULTS. Patients with LCA5-LCA showed a maculopathy with detectable outer nuclear LCA5-associated Leber congenital layer (ONL) in the pericentral retina and at least 4 log units of dark-adapted sensitivity amaurosis. -
Genotype-Phenotype Correlation for Leber Congenital Amaurosis in Northern Pakistan
OPHTHALMIC MOLECULAR GENETICS Genotype-Phenotype Correlation for Leber Congenital Amaurosis in Northern Pakistan Martin McKibbin, FRCOphth; Manir Ali, PhD; Moin D. Mohamed, FRCS; Adam P. Booth, FRCOphth; Fiona Bishop, FRCOphth; Bishwanath Pal, FRCOphth; Kelly Springell, BSc; Yasmin Raashid, FRCOG; Hussain Jafri, MBA; Chris F. Inglehearn, PhD Objectives: To report the genetic basis of Leber con- in predicting the genotype. Many of the phenotypic vari- genital amaurosis (LCA) in northern Pakistan and to de- ables became more prevalent with increasing age. scribe the phenotype. Conclusions: Leber congenital amaurosis in northern Methods: DNA from 14 families was analyzed using single- Pakistan is genetically heterogeneous. Mutations in RP- nucleotide polymorphism and microsatellite genotyping GRIP1, AIPL1, and LCA5 accounted for disease in 10 of and direct sequencing to determine the genes and muta- the 14 families. This study illustrates the differences in tions involved. The history and examination findings from phenotype, for both the anterior and posterior seg- 64 affected individuals were analyzed to show genotype- ments, seen between patients with identical or different phenotype correlation and phenotypic progression. mutations in the LCA genes and also suggests that at least some of the phenotypic variation is age dependent. Results: Homozygous mutations were found in RPGRIP1 (4 families), AIPL1 and LCA5 (3 families each), and RPE65, Clinical Relevance: The LCA phenotype, especially one CRB1, and TULP1 (1 family each). Six of the mutations including different generations in the same family, may are novel. An additional family demonstrated linkage to be used to refine a molecular diagnostic strategy. the LCA9 locus. Visual acuity, severe keratoconus, cata- ract, and macular atrophy were the most helpful features Arch Ophthalmol. -
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Pediatrics Research International Journal Vol. 2015 (2015), Article ID 935983, 103 minipages. DOI:10.5171/2015.935983 www.ibimapublishing.com Copyright © 2015. Alba Faus-Pérez, Amparo Sanchis-Calvo and Pilar Codoñer-Franch. Distributed under Creative Commons CC-BY 4.0 Research Article Ciliopathies: an Update Authors Alba Faus-Pérez 1, Amparo Sanchis-Calvo 1,2 and Pilar Codoñer- Franch 1,3 1 Department of Pediatrics, Dr. Peset University Hospital, Valencia, 2 CIBER de Enfermedades raras, Madrid, Spain 3 Departments of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain Received date: 18 April 2014 Accepted date: 31 July 2014 Published date: 4 December 2015 Academic Editor: Michael David Shields Cite this Article as : Alba Faus-Pérez, Amparo Sanchis-Calvo and Pilar Codoñer-Franch (2015), " Ciliopathies: an Update", Pediatrics Research International Journal, Vol. 2015 (2015), Article ID 935983, DOI: 10.5171/2015.935983 Abstract Cilia are hair-like organelles that extend from the surface of almost all human cells. Nine doublet microtubule pairs make up the core of each cilium, known as the axoneme. Cilia are classified as motile or immotile; non motile or primary cilia are involved in sensing the extracellular environment. These organelles mediate perception of chemo-, mechano- and osmosensations that are then transmitted into the cell via signaling pathways. They also play a crucial role in cellular functions including planar cell polarity, cell division, proliferation and apoptosis. Because of cilia are located on almost all polarized human cell types, cilia-related disorders, can affect many organs and systems. The ciliopathies comprise a group of genetically heterogeneous clinical entities due to the molecular complexity of the ciliary axoneme. -
Perkinelmer Genomics to Request the Saliva Swab Collection Kit for Patients That Cannot Provide a Blood Sample As Whole Blood Is the Preferred Sample
Eye Disorders Comprehensive Panel Test Code D4306 Test Summary This test analyzes 211 genes that have been associated with ocular disorders. Turn-Around-Time (TAT)* 3 - 5 weeks Acceptable Sample Types Whole Blood (EDTA) (Preferred sample type) DNA, Isolated Dried Blood Spots Saliva Acceptable Billing Types Self (patient) Payment Institutional Billing Commercial Insurance Indications for Testing Individuals with an eye disease suspected to be genetic in origin Individuals with a family history of eye disease Individuals suspected to have a syndrome associated with an eye disease Test Description This panel analyzes 211 genes that have been associated with ocular disorders. Both sequencing and deletion/duplication (CNV) analysis will be performed on the coding regions of all genes included (unless otherwise marked). All analysis is performed utilizing Next Generation Sequencing (NGS) technology. CNV analysis is designed to detect the majority of deletions and duplications of three exons or greater in size. Smaller CNV events may also be detected and reported, but additional follow-up testing is recommended if a smaller CNV is suspected. All variants are classified according to ACMG guidelines. Condition Description Diseases associated with this panel include microphtalmia, anophthalmia, coloboma, progressive external ophthalmoplegia, optic nerve atrophy, retinal dystrophies, retinitis pigementosa, macular degeneration, flecked-retinal disorders, Usher syndrome, albinsm, Aloprt syndrome, Bardet Biedl syndrome, pulmonary fibrosis, and Hermansky-Pudlak -
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 -
Discovery of a Molecular Glue That Enhances Uprmt to Restore
bioRxiv preprint doi: https://doi.org/10.1101/2021.02.17.431525; this version posted February 17, 2021. 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. Title: Discovery of a molecular glue that enhances UPRmt to restore proteostasis via TRKA-GRB2-EVI1-CRLS1 axis Authors: Li-Feng-Rong Qi1, 2 †, Cheng Qian1, †, Shuai Liu1, 2†, Chao Peng3, 4, Mu Zhang1, Peng Yang1, Ping Wu3, 4, Ping Li1 and Xiaojun Xu1, 2 * † These authors share joint first authorship Running title: Ginsenoside Rg3 reverses Parkinson’s disease model by enhancing mitochondrial UPR Affiliations: 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China. 2 Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China. 3. National Facility for Protein Science in Shanghai, Zhangjiang Lab, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai 201210, China 4. Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai, 201204, China. Corresponding author: Ping Li, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China. Email: [email protected], Xiaojun Xu, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, 210009, Nanjing, Jiangsu, China. Telephone number: +86-2583271203, E-mail: [email protected]. bioRxiv preprint doi: https://doi.org/10.1101/2021.02.17.431525; this version posted February 17, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
The Ciliopathy Gene Nphp-2 Functions in Multiple Gene Networks and Regulates
THE CILIOPATHY GENE NPHP-2 FUNCTIONS IN MULTIPLE GENE NETWORKS AND REGULATES CILIOGENESIS IN C. ELEGANS By SIMON ROBERT FREDERICK WARBURTON-PITT A dissertation submitted to the Graduate School – New Brunswick and The Graduate School of Biomedical Sciences Rutgers, The State University of New Jersey In partial fulfillment of the requirements For the degree of Doctor of Philosophy Graduate Program in Molecular Genetics and Microbiology Written under the direction of Maureen M. Barr, PhD And approved by New Brunswick, New Jersey January, 2015 © 2015 Simon Warburton-Pitt ALL RIGHTS RESERVED ABSTRACT OF THE DISSERTATION The ciliopathy gene nphp-2 functions in multiple gene networks and regulates ciliogenesis in C. elegans By SIMON ROBERT FREDERICK WARBURTON-PITT Dissertation Director: Maureen Barr Cilia are hair-like organelles that function as cellular antennae. Cilia are conserved across eukaryotes, and play a vital role in many biological processes including signal transduction, signal cascades, cell-cell signaling, cell orientation, cell-cell adhesion, motility, interorganismal communication, building extracellular matrix, and inducing fluid flow. In humans, cilia are present in a majority of tissue types, and cilia dysfunction can lead to a range of syndromic ciliopathies, including nephronopthisis (NPHP) and Meckel Syndrome (MKS). Cilia have a microtubule backbone, the axoneme, and are composed of multiple subcompartments, each with a specific function and composition: the transition zone (TZ) anchoring to the axoneme to the membrane, the doublet region extending from the TZ, and in some cilia types, the singlet region extending from the doublet region. The nematode C. elegans is a well-established model of cilia biology, and possesses cilia at the distal end of sensory dendrites.