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Diagnosing Platelet Secretion Disorders: Examples Cases
Diagnosing platelet secretion disorders: examples cases Martina Daly Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Disclosures for Martina Daly In compliance with COI policy, ISTH requires the following disclosures to the session audience: Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Consultant No relevant conflicts of interest to declare Major Stockholder No relevant conflicts of interest to declare Speakers Bureau No relevant conflicts of interest to declare Honoraria No relevant conflicts of interest to declare Scientific Advisory No relevant conflicts of interest to declare Board Platelet granule release Agonists (FIIa, Collagen, ADP) Signals Activation Shape change Membrane fusion Release of granule contents Platelet storage organelles lysosomes a granules Enzymes including cathepsins Adhesive proteins acid hydrolases Clotting factors and their inhibitors Fibrinolytic factors and their inhibitors Proteases and antiproteases Growth and mitogenic factors Chemokines, cytokines Anti-microbial proteins Membrane glycoproteins dense (d) granules ADP/ATP Serotonin histamine inorganic polyphosphate Platelet a-granule contents Type Prominent components Membrane glycoproteins GPIb, aIIbb3, GPVI Clotting factors VWF, FV, FXI, FII, Fibrinogen, HMWK, FXIII? Clotting inhibitors TFPI, protein S, protease nexin-2 Fibrinolysis components PAI-1, TAFI, a2-antiplasmin, plasminogen, uPA Other protease inhibitors a1-antitrypsin, a2-macroglobulin -
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. -
Location Analysis of Estrogen Receptor Target Promoters Reveals That
Location analysis of estrogen receptor ␣ target promoters reveals that FOXA1 defines a domain of the estrogen response Jose´ e Laganie` re*†, Genevie` ve Deblois*, Ce´ line Lefebvre*, Alain R. Bataille‡, Franc¸ois Robert‡, and Vincent Gigue` re*†§ *Molecular Oncology Group, Departments of Medicine and Oncology, McGill University Health Centre, Montreal, QC, Canada H3A 1A1; †Department of Biochemistry, McGill University, Montreal, QC, Canada H3G 1Y6; and ‡Laboratory of Chromatin and Genomic Expression, Institut de Recherches Cliniques de Montre´al, Montreal, QC, Canada H2W 1R7 Communicated by Ronald M. Evans, The Salk Institute for Biological Studies, La Jolla, CA, July 1, 2005 (received for review June 3, 2005) Nuclear receptors can activate diverse biological pathways within general absence of large scale functional data linking these putative a target cell in response to their cognate ligands, but how this binding sites with gene expression in specific cell types. compartmentalization is achieved at the level of gene regulation is Recently, chromatin immunoprecipitation (ChIP) has been used poorly understood. We used a genome-wide analysis of promoter in combination with promoter or genomic DNA microarrays to occupancy by the estrogen receptor ␣ (ER␣) in MCF-7 cells to identify loci recognized by transcription factors in a genome-wide investigate the molecular mechanisms underlying the action of manner in mammalian cells (20–24). This technology, termed 17-estradiol (E2) in controlling the growth of breast cancer cells. ChIP-on-chip or location analysis, can therefore be used to deter- We identified 153 promoters bound by ER␣ in the presence of E2. mine the global gene expression program that characterize the Motif-finding algorithms demonstrated that the estrogen re- action of a nuclear receptor in response to its natural ligand. -
Mouse Vipas39 Conditional Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Vipas39 Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Vipas39 conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Vipas39 gene (NCBI Reference Sequence: NM_001142580 ; Ensembl: ENSMUSG00000021038 ) is located on Mouse chromosome 12. 20 exons are identified, with the ATG start codon in exon 2 and the TAA stop codon in exon 20 (Transcript: ENSMUST00000072744). Exon 3 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Vipas39 gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-213E8 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a conditional allele activated by an inducible cre exhibit dry and scaly skin, hair loss, and defects in tail tendon collagen I structure. Exon 3 starts from about 6.38% of the coding region. The knockout of Exon 3 will result in frameshift of the gene. The size of intron 2 for 5'-loxP site insertion: 3170 bp, and the size of intron 3 for 3'-loxP site insertion: 1410 bp. The size of effective cKO region: ~603 bp. The cKO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele gRNA region 5' gRNA region 3' 1 3 4 20 Targeting vector Targeted allele Constitutive KO allele (After Cre recombination) Legends Exon of mouse Vipas39 Homology arm cKO region loxP site Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot Window size: 10 bp Forward Reverse Complement Sequence 12 Note: The sequence of homologous arms and cKO region is aligned with itself to determine if there are tandem repeats. -
1 Supporting Information for a Microrna Network Regulates
Supporting Information for A microRNA Network Regulates Expression and Biosynthesis of CFTR and CFTR-ΔF508 Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fishere, Shaf Keshavjeeh, Kim A. Lennoxi, Ashley M. Jacobii, Scott D. Rosei, Mark A. Behlkei, Michael J. Welshb,c,d,g, Yi Xingb,c,f, Paul B. McCray Jr.a,b,c Author Affiliations: Department of Pediatricsa, Interdisciplinary Program in Geneticsb, Departments of Internal Medicinec, Molecular Physiology and Biophysicsd, Anatomy and Cell Biologye, Biomedical Engineeringf, Howard Hughes Medical Instituteg, Carver College of Medicine, University of Iowa, Iowa City, IA-52242 Division of Thoracic Surgeryh, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada-M5G 2C4 Integrated DNA Technologiesi, Coralville, IA-52241 To whom correspondence should be addressed: Email: [email protected] (M.J.W.); yi- [email protected] (Y.X.); Email: [email protected] (P.B.M.) This PDF file includes: Materials and Methods References Fig. S1. miR-138 regulates SIN3A in a dose-dependent and site-specific manner. Fig. S2. miR-138 regulates endogenous SIN3A protein expression. Fig. S3. miR-138 regulates endogenous CFTR protein expression in Calu-3 cells. Fig. S4. miR-138 regulates endogenous CFTR protein expression in primary human airway epithelia. Fig. S5. miR-138 regulates CFTR expression in HeLa cells. Fig. S6. miR-138 regulates CFTR expression in HEK293T cells. Fig. S7. HeLa cells exhibit CFTR channel activity. Fig. S8. miR-138 improves CFTR processing. Fig. S9. miR-138 improves CFTR-ΔF508 processing. Fig. S10. SIN3A inhibition yields partial rescue of Cl- transport in CF epithelia. -
SPTLC2 Polyclonal Antibody
SPTLC2 polyclonal antibody It catalyzes the pyridoxal-5-prime-phosphate-dependent condensation of L-serine and palmitoyl-CoA to Catalog Number: PAB4377 3-oxosphinganine. Mutations in this gene were identified in patients with hereditary sensory neuropathy type I. Regulatory Status: For research use only (RUO) Alternatively spliced variants encoding different isoforms have been identified. [provided by RefSeq] Product Description: Rabbit polyclonal antibody raised against synthetic peptide of SPTLC2. References: 1. Permeability barrier disruption increases the level of Immunogen: A synthetic peptide (conjugated with KLH) serine palmitoyltransferase in human epidermis. corresponding to amino acids 532-562 of human Stachowitz S, Alessandrini F, Abeck D, Ring J, Behrendt SPTLC2. H. J Invest Dermatol. 2002 Nov;119(5):1048-52. 2. Shotgun sequencing of the human transcriptome with Host: Rabbit ORF expressed sequence tags. Dias Neto E, Correa RG, Verjovski-Almeida S, Briones MR, Nagai MA, da Reactivity: Human,Mouse Silva W Jr, Zago MA, Bordin S, Costa FF, Goldman GH, Applications: ELISA, WB-Ti Carvalho AF, Matsukuma A, Baia GS, Simpson DH, (See our web site product page for detailed applications Brunstein A, de Oliveira PS, Bucher P, Jongeneel CV, information) O'Hare MJ, Soares F, Brentani RR, Reis LF, de Souza SJ, Simpson AJ. Proc Natl Acad Sci U S A. 2000 Mar Protocols: See our web site at 28;97(7):3491-6. http://www.abnova.com/support/protocols.asp or product 3. Human and murine serine-palmitoyl-CoA page for detailed protocols transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis. Weiss B, Form: Liquid Stoffel W. -
WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US). -
IL-17 Induces an Expanded Range of Downstream Genes in Reconstituted Human Epidermis Model
IL-17 Induces an Expanded Range of Downstream Genes in Reconstituted Human Epidermis Model Andrea Chiricozzi1,2,3*, Kristine E. Nograles1,2, Leanne M. Johnson-Huang1, Judilyn Fuentes-Duculan1, Irma Cardinale1, Kathleen M. Bonifacio1, Nicholas Gulati1, Hiroshi Mitsui1, Emma Guttman-Yassky1,2,4, Mayte Sua´rez-Farin˜ as1,2", James G. Krueger1,2" 1 Laboratory for Investigative Dermatology, The Rockefeller University, New York City, New York, United States of America, 2 Center for Clinical and Translational Science, The Rockefeller University, New York City, New York, United States of America, 3 Department of Dermatology, University of Rome ‘‘Tor Vergata’’, Rome, Italy, 4 Department of Dermatology, Mount Sinai School of Medicine, New York City, New York, United States of America Abstract Background: IL-17 is the defining cytokine of the Th17, Tc17, and cd T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-c, TNF-a, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. -
Lipid Related Genes Altered in NASH Connect Inflammation in Liver Pathogenesis Progression to HCC: a Canonical Pathway
Lipid related genes altered in NASH connect inflammation in liver pathogenesis progression to HCC: a canonical pathway Christophe Desterke1, Franck Chiappini2* 1 Inserm, U935, Villejuif, F-94800, France 2 Cell Growth and Tissue Repair (CRRET) Laboratory, Université Paris-Est Créteil (UPEC), EA 4397 / ERL CNRS 9215, F-94010, Créteil, France. Corresponding author: *Franck Chiappini. Laboratoire du CRRET (Croissance, Réparation et Régénération Tissulaires), Université Paris-Est Créteil, 61 avenue du Général de Gaulle F- 94010, Créteil Cedex, Val de Marne, France. Email address: [email protected]; Tel: +33(0)145177080; Fax: +33(0)145171816 Supplementary Information Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Supplementary Datasets Table S2: Expression fold change of lipid related genes found differentially expressed between NASH and healthy obese liver samples. Supplementary Datasets Table S3: Liver as principal filter for prioritization of lipid related genes found differentially expressed in NASH. Supplementary Datasets Table S4: Gene prioritization secondary filters (immunological, inflammation, liver pathogenesis progression) table found with lipid related genes differentially expressed in NASH. Supplementary Datasets Table S5: Identification of protein partners of YWHAZ gene using InnateDB database. Supplementary Datasets Table S1: Text-mining list of genes associated in PubMed literature with lipid related keywords. Ranking of "lipidic" textmining Gene symbol -
Supplemental Table 1. List of Candidate Gene Filters Used in the Analysis of Exome Sequencing. MYOPATHY NEUROPATHY MND ABHD5
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Neurol Neurosurg Psychiatry Supplemental table 1. List of candidate gene filters used in the analysis of exome sequencing. MYOPATHY NEUROPATHY MND ABHD5 AAAS AAAS ACADL AARS1 AARS1 ACADM ABCA1 AGT ACADS ABCD1 ALAD ACADVL ABHD12 ALS2 ACTA1 ADCY6 ANG ADSSL1 AFG3L2 APEX1 AGL AIFM1 APOE AGPAT2 AMACR AR AGRN ANG ASAH1 AIRE AP1S1 ATM ALDOA APOA1 ATP7A ALG14 APTX ATXN2 ALG2 ARHGEF10 ATXN3 ALG3 ARL6IP1 B4GALT6 ANKRD2 ARSA BCL11B ANO5 ASAH1 BCL6 ASCC1 ATL1 BICD2 ATGL ATL3 BSCL2 ATP2A1 ATM C19orf12 ATRN ATXN1 C9orf72 B3GALNT2 ATXN10 CCS B3GNT2 ATXN2 CDH13 BAG3 ATXN3 CDH22 BIN1 ATXN7 CHCHD10 BSCL2 B2M CHMP2B BVES B4GALNT1 CNTF CACNA1S BAG3 CNTN4 CAPN3 BCKDHB CNTN6 CASQ1 BSCL2 CRIM1 CAV1 C12orf65 CRYM CAV3 C9orf72 CSNK1G3 CAVIN1 CLP1 CST3 CCDC78 CNTNAP1 CUL4B CDKN1C COX10 CYP2D6 CFL2 COX6A1 DAO Grunseich C, et al. J Neurol Neurosurg Psychiatry 2021;0:1–11. doi: 10.1136/jnnp-2020-325437 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Neurol Neurosurg Psychiatry CHAT CPOX DCAF15 CHCHD10 CRYAB DCTN1 CHD7 CTDP1 DIAPH3 CHKB CTSA DISC1 CHN1 CYP27A1 DNAJB2 CHRM3 DARS2 DOC2B CHRNA1 DDHD1 DPP6 CHRNB1 DGUOK DYNC1H1 CHRND DHH EFEMP1 CHRNE DHTKD1 ELP3 CIDEC DMD EPHA4 CLCN1 DNAJB2 EWSR1 CLN3 DNAJC3 EXOSC3 CNBP DNM2 FBLN5 CNTN1 DYNC1H1 FBXO38 COA3 EGR2 FEZF2 COL12A1 EMD FGGY COL13A1 ERCC6 FIG4 COL6A ERCC8 FUS COL6A1 FAH GARS1 COL6A2 FAM126A GBE1 COL6A3 FBLN5 GMPPA COL9A3 FGD4 GRB14 COLQ FGF14 GRN COX10 FIG4 HEXA COX15 FLNC HFE CPT2 FLRT1 HINT1 CRAT FLVCR1 HSPB1 CRPPA FMR1 HSPB3 CRYAB FUS HSPB8 CTNS FXN IGHMBP2 DAG1 GALC ITPR2 DECR1 GAN KDR DES GARS1 KIFAP3 DGUOK GBA2 KLHL9 DIH1 GBE1 LAMA2 DMD GDAP1 LAS1L DMPK GJB1 LIF DNAJB6 GJB3 LIPC DNAJC19 GLA LOX Grunseich C, et al. -
The Role of Fatty Acids in Ceramide Pathways and Their Influence On
International Journal of Molecular Sciences Review The Role of Fatty Acids in Ceramide Pathways and Their Influence on Hypothalamic Regulation of Energy Balance: A Systematic Review Andressa Reginato 1,2,3,*, Alana Carolina Costa Veras 2,3, Mayara da Nóbrega Baqueiro 2,3, Carolina Panzarin 2,3, Beatriz Piatezzi Siqueira 2,3, Marciane Milanski 2,3 , Patrícia Cristina Lisboa 1 and Adriana Souza Torsoni 2,3,* 1 Biology Institute, State University of Rio de Janeiro, UERJ, Rio de Janeiro 20551-030, Brazil; [email protected] 2 Faculty of Applied Science, University of Campinas, UNICAMP, Campinas 13484-350, Brazil; [email protected] (A.C.C.V.); [email protected] (M.d.N.B.); [email protected] (C.P.); [email protected] (B.P.S.); [email protected] (M.M.) 3 Obesity and Comorbidities Research Center, University of Campinas, UNICAMP, Campinas 13083-864, Brazil * Correspondence: [email protected] (A.R.); [email protected] (A.S.T.) Abstract: Obesity is a global health issue for which no major effective treatments have been well established. High-fat diet consumption is closely related to the development of obesity because it negatively modulates the hypothalamic control of food intake due to metaflammation and lipotoxicity. The use of animal models, such as rodents, in conjunction with in vitro models of hypothalamic cells, can enhance the understanding of hypothalamic functions related to the control of energy Citation: Reginato, A.; Veras, A.C.C.; balance, thereby providing knowledge about the impact of diet on the hypothalamus, in addition Baqueiro, M.d.N.; Panzarin, C.; to targets for the development of new drugs that can be used in humans to decrease body weight. -
CORVET, CHEVI and HOPS – Multisubunit Tethers of the Endo
© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs189134. doi:10.1242/jcs.189134 REVIEW SUBJECT COLLECTION: CELL BIOLOGY AND DISEASE CORVET, CHEVI and HOPS – multisubunit tethers of the endo-lysosomal system in health and disease Jan van der Beek‡, Caspar Jonker*,‡, Reini van der Welle, Nalan Liv and Judith Klumperman§ ABSTRACT contact between two opposing membranes and pull them close Multisubunit tethering complexes (MTCs) are multitasking hubs that together to allow interactions between SNARE proteins (Murray form a link between membrane fusion, organelle motility and signaling. et al., 2016). SNARE assembly then provides additional fusion CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. specificity and drives the actual fusion process (Ohya et al., 2009; They regulate the major membrane flows required for endocytosis, Stroupe et al., 2009). In this Review, we focus on the role of tethering lysosome biogenesis, autophagy and phagocytosis. In addition, proteins in endo-lysosomal fusion events. individual subunits control complex-independent transport of specific Tethering proteins can be divided into two main groups: long cargoes and exert functions beyond tethering, such as attachment to coiled-coil proteins (Gillingham and Munro, 2003) and microtubules and SNARE activation. Mutations in CHEVI subunits multisubunit tethering complexes (MTCs). MTCs form a lead to arthrogryposis, renal dysfunction and cholestasis (ARC) heterogenic group of protein complexes that consist of up to ten ∼ syndrome, while defects in CORVET and, particularly, HOPS are subunits resulting in a general length of 50 nm (Brocker et al., associated with neurodegeneration, pigmentation disorders, liver 2012; Chou et al., 2016; Hsu et al., 1998; Lürick et al., 2018; Ren malfunction and various forms of cancer.