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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. -
Genome-Wide Rnai Screens Identify Genes Required for Ricin and PE Intoxications
Developmental Cell Article Genome-Wide RNAi Screens Identify Genes Required for Ricin and PE Intoxications Dimitri Moreau,1 Pankaj Kumar,1 Shyi Chyi Wang,1 Alexandre Chaumet,1 Shin Yi Chew,1 He´ le` ne Chevalley,1 and Fre´ de´ ric Bard1,* 1Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Singapore *Correspondence: [email protected] DOI 10.1016/j.devcel.2011.06.014 SUMMARY In the lumen of the ER, these toxins are thought to interact with elements of the ER-associated degradation (ERAD) pathway, Protein toxins such as Ricin and Pseudomonas which targets misfolded proteins in the ER for degradation. exotoxin (PE) pose major public health challenges. This interaction is proposed to allow translocation to the cytosol Both toxins depend on host cell machinery for inter- without resulting in toxin degradation (Johannes and Ro¨ mer, nalization, retrograde trafficking from endosomes 2010). to the ER, and translocation to cytosol. Although Obviously, this complex set of membrane-trafficking and both toxins follow a similar intracellular route, it is membrane-translocation events involves many host proteins, some of which have already been described (Johannes and unknown how much they rely on the same genes. Ro¨ mer, 2010; Sandvig et al., 2010). Altering the function of these Here we conducted two genome-wide RNAi screens host proteins could in theory provide a toxin antidote. identifying genes required for intoxication and Consistently, inhibition of retrograde traffic by drugs such as demonstrating that requirements are strikingly Brefeldin A (Sandvig et al., 1991)(Yoshida et al., 1991) or Golgi- different between PE and Ricin, with only 13% over- cide A (Sa´ enz et al., 2009) and Retro-1 and 2 (Stechmann et al., lap. -
Structural and Functional Characterization of the NHR1 Domain of the Drosophila Neuralized E3 Ligase in the Notch Signaling Pathway
doi:10.1016/j.jmb.2009.08.020 J. Mol. Biol. (2009) 393, 478–495 Available online at www.sciencedirect.com Structural and Functional Characterization of the NHR1 Domain of the Drosophila Neuralized E3 Ligase in the Notch Signaling Pathway Fahu He1, Kohei Saito1, Naohiro Kobayashi1, Takushi Harada1, Satoru Watanabe1, Takanori Kigawa1,2, Peter Güntert1,3,4, Osamu Ohara5,6, Akiko Tanaka1, Satoru Unzai7, Yutaka Muto1⁎ and Shigeyuki Yokoyama1,8⁎ 1RIKEN Systems and The Notch signaling pathway is critical for many developmental processes Structural Biology Center, and requires complex trafficking of both Notch receptor and its ligands, 1-7-22 Suehiro-cho, Tsurumi-ku, Delta and Serrate. In Drosophila melanogaster, the endocytosis of Delta in the Yokohama 230-0045, Japan signal-sending cell is essential for Notch receptor activation. The Neuralized protein from D. melanogaster (Neur) is a ubiquitin E3 ligase, which binds to 2Department of Computational Delta through its first neuralized homology repeat 1 (NHR1) domain and Intelligence and Systems mediates the ubiquitination of Delta for endocytosis. Tom, a Bearded Science, Interdisciplinary protein family member, inhibits the Neur-mediated endocytosis through Graduate School of Science interactions with the NHR1 domain. We have identified the domain and Engineering, Tokyo boundaries of the novel NHR1 domain, using a screening system based on Institute of Technology, our cell-free protein synthesis method, and demonstrated that the identified 4259 Nagatsuta-cho, Neur NHR1 domain had binding activity to the 20-residue peptide Midori-ku, Yokohama 226-8502, corresponding to motif 2 of Tom by isothermal titration calorimetry Japan experiments. We also determined the solution structure of the Neur NHR1 3Tatsuo Miyazawa Memorial domain by heteronuclear NMR methods, using a 15N/13C-labeled sample. -
EGFR Confers Exquisite Specificity of Wnt9a-Fzd9b Signaling in Hematopoietic Stem Cell Development
bioRxiv preprint doi: https://doi.org/10.1101/387043; this version posted August 7, 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. Grainger, et al, 2018 EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development Stephanie Grainger1, Nicole Nguyen1, Jenna Richter1,2, Jordan Setayesh1, Brianna Lonquich1, Chet Huan Oon1, Jacob M. Wozniak2,3,4, Rocio Barahona1, Caramai N. Kamei5, Jack Houston1,2, Marvic Carrillo-Terrazas3,4, Iain A. Drummond5,6, David Gonzalez3.4, Karl Willert#,¥,1, and David Traver¥,1,7. ¥co-corresponding authors: [email protected]; [email protected] #Lead contact 1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, 92037, USA. 2Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California, 92037, USA. 3Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, La Jolla, California, 92093, USA. 4Department of Pharmacology, University of California, San Diego, La Jolla, California, 92092 5Massachusetts General Hospital Nephrology Division, Charlestown, Massachusetts, 02129, USA. 6Harvard Medical School, Department of Genetics, Boston MA 02115 7Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, 92037, USA. Running title: A mechanism for Wnt-Fzd specificity in hematopoietic stem cells Keywords: hematopoietic stem cell (HSC), Wnt, Wnt9a, human, zebrafish, Fzd, Fzd9b, FZD9, EGFR, APEX2 1 bioRxiv preprint doi: https://doi.org/10.1101/387043; this version posted August 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Conserved and Novel Properties of Clathrin-Mediated Endocytosis in Dictyostelium Discoideum" (2012)
Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2012 Conserved and Novel Properties of Clathrin- Mediated Endocytosis in Dictyostelium Discoideum Laura Macro Follow this and additional works at: http://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons Recommended Citation Macro, Laura, "Conserved and Novel Properties of Clathrin-Mediated Endocytosis in Dictyostelium Discoideum" (2012). Student Theses and Dissertations. Paper 163. This Thesis is brought to you for free and open access by Digital Commons @ RU. It has been accepted for inclusion in Student Theses and Dissertations by an authorized administrator of Digital Commons @ RU. For more information, please contact [email protected]. CONSERVED AND NOVEL PROPERTIES OF CLATHRIN- MEDIATED ENDOCYTOSIS IN DICTYOSTELIUM DISCOIDEUM A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Laura Macro June 2012 © Copyright by Laura Macro 2012 CONSERVED AND NOVEL PROPERTIES OF CLATHRIN- MEDIATED ENDOCYTOSIS IN DICTYOSTELIUM DISCOIDEUM Laura Macro, Ph.D. The Rockefeller University 2012 The protein clathrin mediates one of the major pathways of endocytosis from the extracellular milieu and plasma membrane. Clathrin functions with a network of interacting accessory proteins, one of which is the adaptor complex AP-2, to co-ordinate vesicle formation. Disruption of genes involved in clathrin-mediated endocytosis causes embryonic lethality in multicellular animals suggesting that clathrin-mediated endocytosis is a fundamental cellular process. However, loss of clathrin-mediated endocytosis genes in single cell eukaryotes, such as S.cerevisiae (yeast), does not cause lethality, suggesting that clathrin may convey specific advantages for multicellularity. -
Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer Stephen Shang1, Jiekun Yang1, Amir A
Published OnlineFirst July 29, 2019; DOI: 10.1158/0008-5472.CAN-19-0215 Cancer Genome and Epigenome Research Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer Stephen Shang1, Jiekun Yang1, Amir A. Jazaeri2, Alexander James Duval1, Turan Tufan1, Natasha Lopes Fischer1, Mouadh Benamar1,3, Fadila Guessous3, Inyoung Lee1, Robert M. Campbell4, Philip J. Ebert4, Tarek Abbas1,3, Charles N. Landen5, Analisa Difeo6, Peter C. Scacheri6, and Mazhar Adli1 Abstract Chemoresistance is driven by unique regulatory net- tance, our findings identified SOX9 as a critical SE-regulated works in the genome that are distinct from those necessary transcription factor that plays a critical role in acquiring for cancer development. Here, we investigate the contri- and maintaining the chemoresistant state in ovarian cancer. bution of enhancer elements to cisplatin resistance in The approach and findings presented here suggest that ovarian cancers. Epigenome profiling of multiple cellular integrative analysis of epigenome and transcriptional pro- models of chemoresistance identified unique sets of distal grams could identify targetable key drivers of chemoresis- enhancers, super-enhancers (SE), and their gene targets tance in cancers. that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharma- Significance: Integrative genome-wide epigenomic and cologic inhibition of distal enhancers through small- transcriptomic analyses of platinum-sensitive and -resistant molecule epigenetic inhibitors suppressed the expression ovarian lines identify key distal regulatory regions and of their target genes and restored cisplatin sensitivity in vitro associated master regulator transcription factors that can be and in vivo. In addition to known drivers of chemoresis- targeted by small-molecule epigenetic inhibitors. -
Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia. -
Expression of the Tumor Necrosis Factor Receptor-Associated Factors
Expression of the Tumor Necrosis Factor Receptor- Associated Factors (TRAFs) 1 and 2 is a Characteristic Feature of Hodgkin and Reed-Sternberg Cells Keith F. Izban, M.D., Melek Ergin, M.D, Robert L. Martinez, B.A., HT(ASCP), Serhan Alkan, M.D. Department of Pathology, Loyola University Medical Center, Maywood, Illinois the HD cell lines. Although KMH2 showed weak Tumor necrosis factor receptor–associated factors expression, the remaining HD cell lines also lacked (TRAFs) are a recently established group of proteins TRAF5 protein. These data demonstrate that consti- involved in the intracellular signal transduction of tutive expression of TRAF1 and TRAF2 is a charac- several members of the tumor necrosis factor recep- teristic feature of HRS cells from both patient and tor (TNFR) superfamily. Recently, specific members cell line specimens. Furthermore, with the excep- of the TRAF family have been implicated in promot- tion of TRAF1 expression, HRS cells from the three ing cell survival as well as activation of the tran- HD cell lines showed similar TRAF protein expres- scription factor NF- B. We investigated the consti- sion patterns. Overall, these findings demonstrate tutive expression of TRAF1 and TRAF2 in Hodgkin the expression of several TRAF proteins in HD. Sig- and Reed–Sternberg (HRS) cells from archived nificantly, the altered regulation of selective TRAF paraffin-embedded tissues obtained from 21 pa- proteins may reflect HRS cell response to stimula- tients diagnosed with classical Hodgkin’s disease tion from the microenvironment and potentially (HD). In a selective portion of cases, examination of contribute both to apoptosis resistance and cell HRS cells for Epstein-Barr virus (EBV)–encoded maintenance of HRS cells. -
The Mir-199–Dynamin Regulatory Axis Controls Receptor-Mediated Endocytosis Juan F
© 2015. Published by The Company of Biologists Ltd | Journal of Cell Science (2015) 128, 3197-3209 doi:10.1242/jcs.165233 RESEARCH ARTICLE The miR-199–dynamin regulatory axis controls receptor-mediated endocytosis Juan F. Aranda1,2, Alberto Canfrán-Duque1,2, Leigh Goedeke1,2, Yajaira Suárez1,2 and Carlos Fernández-Hernando1,2,* ABSTRACT mechanism for the selective uptake of essential nutrients such as Small non-coding RNAs (microRNAs) are important regulators of low-density lipoprotein (LDL), through the LDL receptor (LDLR) gene expression that modulate many physiological processes; (Brown and Goldstein, 1986), or iron, through transferrin receptor however, their role in regulating intracellular transport remains (TfR) (Harding et al., 1983). Thus, factors that affect RME have a largely unknown. Intriguingly, we found that the dynamin (DNM) direct effect on these receptors, and, in the case of LDLR, to regulate genes, a GTPase family of proteins responsible for endocytosis in intracellular cholesterol levels. In both the LDLR and TfR eukaryotic cells, encode the conserved miR-199a and miR-199b internalization processes, clathrin plays a key role during the family of miRNAs within their intronic sequences. Here, we formation of coated vesicles (Moore et al., 1987). Once vesicles are demonstrate that miR-199a and miR-199b regulate endocytic internalized, their passage through a broad endosomal compartment transport by controlling the expression of important mediators of system is required; first they are rapidly transported into early endocytosis such as clathrin heavy chain (CLTC), Rab5A, low- endosomes, where Rab5A is a key regulator (Nielsen et al., 1999), density lipoprotein receptor (LDLR) and caveolin-1 (Cav-1). -
Investigation of the Underlying Hub Genes and Molexular Pathogensis in Gastric Cancer by Integrated Bioinformatic Analyses
bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. 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. Investigation of the underlying hub genes and molexular pathogensis in gastric cancer by integrated bioinformatic analyses Basavaraj Vastrad1, Chanabasayya Vastrad*2 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.20.423656; this version posted December 22, 2020. 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. Abstract The high mortality rate of gastric cancer (GC) is in part due to the absence of initial disclosure of its biomarkers. The recognition of important genes associated in GC is therefore recommended to advance clinical prognosis, diagnosis and and treatment outcomes. The current investigation used the microarray dataset GSE113255 RNA seq data from the Gene Expression Omnibus database to diagnose differentially expressed genes (DEGs). Pathway and gene ontology enrichment analyses were performed, and a proteinprotein interaction network, modules, target genes - miRNA regulatory network and target genes - TF regulatory network were constructed and analyzed. Finally, validation of hub genes was performed. The 1008 DEGs identified consisted of 505 up regulated genes and 503 down regulated genes. -
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Molecular BioSystems Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/molecularbiosystems Page 1 of 29 Molecular BioSystems Mutated Genes and Driver Pathways Involved in Myelodysplastic Syndromes—A Transcriptome Sequencing Based Approach Liang Liu1*, Hongyan Wang1*, Jianguo Wen2*, Chih-En Tseng2,3*, Youli Zu2, Chung-che Chang4§, Xiaobo Zhou1§ 1 Center for Bioinformatics and Systems Biology, Division of Radiologic Sciences, Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157, USA. 2 Department of Pathology, the Methodist Hospital Research Institute, -
Integrative Genomics Discoveries and Development at the Center for Applied Genomics at CHOP
The Children’s Hospital of Philadelphia Integrative Genomics Discoveries and Development at The Center for Applied Genomics at CHOP Novel Genome-based Therapeutic Approaches Hakon Hakonarson, MD, PhD, Professor of Pediatrics CHOP’s Endowed Chair in Genetic Research Director, Center for Applied Genomics The Children’s Hospital of Philadelphia University of Pennsylvania, School of Medicine Duke Center for Applied Genomics and Precision Medicine 2019 Genomic and Precision Medicine Forum Nov 07, 2019 Genomics in the 21st Century Disclosures Dr. Hakonarson and CHOP own stock in Aevi Genomic Medicine Inc. developing anti-LIGHT therapy for IBD. Dr. Hakonarson is an inventor of technology involving therapeutic development of ADHD, GLA and HCCAA Novel Therapeutic Stem Cell/Gene Editing Approaches § iPS and stem cell therapy shows early promise § Gene therapy for LCA (RPE65) at CHOP via AAV § Targeted T cell therapy for cancer (UPENN/CHOP) § CRISPR-cas9 gene editing § Single cell sequencing The Center for Applied Genomics (CAG) at CHOP u Founded in June 2006 u Staff of 70 u Over 100 active disease projects with CHOP/Penn collaborators u TARGET: Genotype 100,000 children u ~450k GWAS samples >130k kids u IC - participation in future studies >85% u Database u Electronic Health Records u extensive information on each child u >1.2 million visits per year to Population Genomics Research CHOP Recruitment of CHOP/PENN HealthCare Network Patients u High-level of automation ADHD, Autism, Diabetes, IBD, Autoimmunity, Asthma/Atopy, Cancer, RDs - all high priority