Assessing Functional Impacts of Human Coding Variants
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Phenotypic and Molecular Genetic Analysis of Pyruvate Kinase Deficiency in a Tunisian Family
The Egyptian Journal of Medical Human Genetics (2016) 17, 265–270 HOSTED BY Ain Shams University The Egyptian Journal of Medical Human Genetics www.ejmhg.eg.net www.sciencedirect.com ORIGINAL ARTICLE Phenotypic and molecular genetic analysis of Pyruvate Kinase deficiency in a Tunisian family Jaouani Mouna a,1,*, Hamdi Nadia a,1, Chaouch Leila a, Kalai Miniar a, Mellouli Fethi b, Darragi Imen a, Boudriga Imen a, Chaouachi Dorra a, Bejaoui Mohamed b, Abbes Salem a a Laboratory of Molecular and Cellular Hematology, Pasteur Institute, Tunis, Tunisia b Service d’Immuno-He´matologie Pe´diatrique, Centre National de Greffe de Moelle Osseuse, Tunis, Tunisia Received 9 July 2015; accepted 6 September 2015 Available online 26 September 2015 KEYWORDS Abstract Pyruvate Kinase (PK) deficiency is the most frequent red cell enzymatic defect responsi- Pyruvate Kinase deficiency; ble for hereditary non-spherocytic hemolytic anemia. The disease has been studied in several ethnic Phenotypic and molecular groups. However, it is yet an unknown pathology in Tunisia. We report here, the phenotypic and investigation; molecular investigation of PK deficiency in a Tunisian family. Hemolytic anemia; This study was carried out on two Tunisian brothers and members of their family. Hematolog- Hydrops fetalis; ical, biochemical analysis and erythrocyte PK activity were performed. The molecular characteriza- PKLR mutation tion was carried out by gene sequencing technique. The first patient died few hours after birth by hydrops fetalis, the second one presented with neonatal jaundice and severe anemia necessitating urgent blood transfusion. This severe clinical pic- ture is the result of a homozygous mutation of PKLR gene at exon 8 (c.1079G>A; p.Cys360Tyr). -
A DNA Database in the NHS: Your Freedom up for Sale?
A DNA database in the NHS: Your freedom up for sale? May 2013 In April 2013, the Caldicott Committee, including Government Chief Scientist Sir Mark Walport, proposed new rules for data-sharing which would allow the Government to build a DNA database of the whole population of England in the NHS by stealth.1 The plan is to make NHS medical records and people’s genetic information available to commercial companies and to use public-private partnerships to build a system where all private information about every citizen is also accessible to the police, social workers, security services and Government. The Wellcome Trust, which was involved in the Human Genome Project and was led by Walport for ten years, has produced a plan which involves including a variant file, containing the whole genome of every person minus the reference genome, as an attachment to every medical record in the NHS in England.2 This data would be made available to ‘researchers’ (including commercial companies) for data-mining in the cloud and personalised risk assessments would be returned to individuals. The aim is to transform the NHS in line with proposals developed more than a decade ago by former GlaxoSmithKline Chairman Sir Richard Sykes. This is expected to massively expand the market for medicines, medical tests and other products, such as supplements and cholesterol-lowering margarines, by allowing products to be marketed to individuals based on personal risk assessments, created using statistical analysis of genetic data, medical records and other health information. The proposal to build a DNA database in the NHS was endorsed by the Human Genomics Strategy Group in 20123,4 and the Government (led by Prime Minister David Cameron) has quietly adopted this recommendation without telling members of the public. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
Protein Domain-Level Landscape of Cancer-Type-Specific Somatic We Explored the Protein Domain-Level Landscape of Cancer-Type-Specific Somatic Mutations
RESEARCH ARTICLE Protein Domain-Level Landscape of Cancer- Type-Specific Somatic Mutations Fan Yang1,2,3, Evangelia Petsalaki2,3, Thomas Rolland4,5, David E. Hill4, Marc Vidal4, Frederick P. Roth1,2,3,4,6,7* 1 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada, 2 Donnelly Centre, University of Toronto, Toronto, Ontario, Canada, 3 Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada, 4 Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America, 5 Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America, 6 Canadian Institute for Advanced Research, Toronto, Ontario, Canada, 7 Department of Computer Science, University of Toronto, Toronto, Ontario, Canada * [email protected] Abstract OPEN ACCESS Identifying driver mutations and their functional consequences is critical to our understand- Citation: Yang F, Petsalaki E, Rolland T, Hill DE, ing of cancer. Towards this goal, and because domains are the functional units of a protein, Vidal M, Roth FP (2015) Protein Domain-Level Landscape of Cancer-Type-Specific Somatic we explored the protein domain-level landscape of cancer-type-specific somatic mutations. Mutations. PLoS Comput Biol 11(3): e1004147. Specifically, we systematically examined tumor genomes from 21 cancer types to identify doi:10.1371/journal.pcbi.1004147 domains with high mutational density in specific tissues, the positions of mutational hotspots Editor: Mona Singh, Princeton University, United within these domains, and the functional and structural context where possible. While hot- States of America spots corresponding to specific gain-of-function mutations are expected for oncoproteins, Received: August 22, 2014 we found that tumor suppressor proteins also exhibit strong biases toward being mutated in Accepted: January 22, 2015 particular domains. -
Reduced Expression of Pyruvate Kinase in Kidney Proximal Tubule
www.nature.com/scientificreports OPEN Reduced expression of pyruvate kinase in kidney proximal tubule cells is a potential mechanism Received: 29 March 2018 Accepted: 22 January 2019 of pravastatin altered glucose Published: xx xx xxxx metabolism Yong Pyo Lee1, Yuri Cho2, Eun Jee Kim2,3, Hyojung Lee2, Hoon Young Choi4, Hye Jin Wang5, Eun Seok Kang 5, Yu Seun Kim2,6, Myoung Soo Kim1,2,6 & Beom Seok Kim2,3,7 Recent studies have reported that statins are associated with increased incidence of diabetes. Although several mechanisms have been proposed, the role of the kidney’s glucose metabolism upon statin treatment is still unclear. Thus, we investigated the role of pravastatin in gluconeogenesis and glycolysis. HK-2 and HepG2 cells were treated with pravastatin and cultured under either high- or normal-cholesterol conditions. In HK-2 cells treated with pravastatin under both high- and normal- cholesterol conditions, the protein expression of only pyruvate kinase isozymes L/R (PKLR) decreased in a dose-dependent manner, while the protein expression of other glucose metabolism related enzymes remained unchanged. Within the in vivo experiment, male C57BL/6 mice were fed either pravastatin-treated normal-fat diets for 2 or 4 weeks or pravastatin-treated high-fat diets for 16 weeks. Protein expression of PKLR in the kidneys from mice that consumed pravastatin-treated high-fat diets decreased signifcantly compared to the controls. Upon the treatments of pravastatin, only the PKLR expression decreased in lean mice. Furthermore, PKLR activity decreased signifcantly in the kidney after pravastatin treatments. However, there was no change in enzyme activity in the liver, suggesting that pravastatin decreased PKLR activity only in the kidney. -
Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations
Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations Ays¸e Demirkan1., Cornelia M. van Duijn1,2,3., Peter Ugocsai4., Aaron Isaacs1,2.*, Peter P. Pramstaller5,6,7., Gerhard Liebisch4., James F. Wilson8.,A˚ sa Johansson9., Igor Rudan8,10,11., Yurii S. Aulchenko1, Anatoly V. Kirichenko12, A. Cecile J. W. Janssens13, Ritsert C. Jansen14, Carsten Gnewuch4, Francisco S. Domingues5, Cristian Pattaro5, Sarah H. Wild8, Inger Jonasson9,11, Ozren Polasek11, Irina V. Zorkoltseva12, Albert Hofman3,13, Lennart C. Karssen1, Maksim Struchalin1, James Floyd15, Wilmar Igl9, Zrinka Biloglav16, Linda Broer1, Arne Pfeufer5, Irene Pichler5, Susan Campbell8, Ghazal Zaboli9, Ivana Kolcic11, Fernando Rivadeneira3,13,17, Jennifer Huffman18, Nicholas D. Hastie18, Andre Uitterlinden3,13,17, Lude Franke19, Christopher S. Franklin15, Veronique Vitart8,18, DIAGRAM Consortium{, Christopher P. Nelson20, Michael Preuss21, CARDIoGRAM Consortium{, Joshua C. Bis22, Christopher J. O’Donnell23,24, Nora Franceschini25, CHARGE Consortium, Jacqueline C. M. Witteman3,13, Tatiana Axenovich12, Ben A. Oostra2,13,26", Thomas Meitinger27,28,29", Andrew A. Hicks5", Caroline Hayward18", Alan F. Wright18", Ulf Gyllensten9", Harry Campbell8", Gerd Schmitz4", on behalf of the EUROSPAN consortium 1 Genetic Epidemiology Unit, Departments of Epidemiology and Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands, 2 Centre for Medical Sytems Biology, Leiden, The Netherlands, 3 Netherlands Consortium -
Supporting Information
Supporting Information Wakabayashi et al. 10.1073/pnas.1521754113 SI Materials and Methods DNA Transfection and Puromycin Selection. K562 cells were cotrans- Plasmid Preparation. Short guide RNA (sgRNA) sequences (Table fected with 1 μg total of Cas9 nuclease and sgRNA plasmids using S1) were cloned into the pSg1 vector (Addgene) and the XPR5 Lipofectamine LTX Plus Reagent (Thermo Fisher Scientific) at a lentiviral vector (Broad Institute), respectively. [The XPR5 1:2 ratio of Cas9 to sgRNA. For a control, K562 cells were co- vector contains the Cas9 nuclease and a red fluorescent protein transfectedwith1μg total of Cas9 nuclease and pLKO.1-GFP (RFP) cassette.] The Cas9 nuclease expression vector used was plasmid at a 1:2 ratio of Cas9 to pLKO.1-GFP. At 24 h after co- μ pxPR_BRD001, which contains a puromycin resistance cassette transfection, puromycin was added at a concentration of 2 g/mL, μ as a selection marker. Off-target scores for each guide were followed 24 h later by a reduction to 1 g/mL for an additional 24 h. calculated using the CRISPR design tool (CRISPR Design; Selection efficiency was assessed by flow cytometry with propidium crispr.mit.edu); only guides with a score >50 (except for a score iodide staining (to assess viability) on a FACSCanto II flow cy- of 49 in one case) were used. tometer (BD Biosciences). Limiting dilutions were performed to obtain single cell-derived clonal populations for both cells targeted Cell Culture and Lentivirus Production. The K562 cells (American with sgRNAs as well as for GFP controls. Unless specified other- Type Culture Collection) were maintained in RPMI medium 1640 wise, three matching clonal GFP controls were analyzed for each plus L-glutamine (Life Technologies) supplemented with 10% experiment. -
Protein Interactions in the Cancer Proteome† Cite This: Mol
Molecular BioSystems View Article Online PAPER View Journal | View Issue Small-molecule binding sites to explore protein– protein interactions in the cancer proteome† Cite this: Mol. BioSyst., 2016, 12,3067 David Xu,ab Shadia I. Jalal,c George W. Sledge Jr.d and Samy O. Meroueh*aef The Cancer Genome Atlas (TCGA) offers an unprecedented opportunity to identify small-molecule binding sites on proteins with overexpressed mRNA levels that correlate with poor survival. Here, we analyze RNA-seq and clinical data for 10 tumor types to identify genes that are both overexpressed and correlate with patient survival. Protein products of these genes were scanned for binding sites that possess shape and physicochemical properties that can accommodate small-molecule probes or therapeutic agents (druggable). These binding sites were classified as enzyme active sites (ENZ), protein–protein interaction sites (PPI), or other sites whose function is unknown (OTH). Interestingly, the overwhelming majority of binding sites were classified as OTH. We find that ENZ, PPI, and OTH binding sites often occurred on the same structure suggesting that many of these OTH cavities can be used for allosteric modulation of Creative Commons Attribution 3.0 Unported Licence. enzyme activity or protein–protein interactions with small molecules. We discovered several ENZ (PYCR1, QPRT,andHSPA6)andPPI(CASC5, ZBTB32,andCSAD) binding sites on proteins that have been seldom explored in cancer. We also found proteins that have been extensively studied in cancer that have not been previously explored with small molecules that harbor ENZ (PKMYT1, STEAP3,andNNMT) and PPI (HNF4A, MEF2B,andCBX2) binding sites. All binding sites were classified by the signaling pathways to Received 29th March 2016, which the protein that harbors them belongs using KEGG. -
2019-2020 PO No
HOLY CROSS COLLEGE (AUTONOMOUS) Affiliated to Bharathidasan University Nationally Accredited (3rd Cycle) with 'A' Grade by NAAC College with Potential for Excellence. Tiruchirappalli - 620002. PG DEPARTMENT OF BIOCHEMISTRY Programme: M.Sc. BIOCHEMISTRY 2019-2020 PO No. Programme Outcomes Upon completion of the B.Sc. Degree Programme, the graduate will be able to PO-1 To enable to get quality education in the areas of Biochemistry PO-2 Acquire practical skills to gather information, assess, create and execute new ideas to develop entrepreneurial skills. PO-3 Gain Proficiency in basic laboratory techniques and able to apply the scientific method on lab to land PO-4 Inculcate a domestic and international perspective and be competent enough in the area of life sciences. PO-5 Learn to recognize potential laboratory safety and conserve nature and the environment. PSO No. Programme Specific Outcomes Upon completion of these courses the student would PSO-1 Will use current biochemical and molecular techniques and carry out experiments PSO-2 Monitoring the changes in modern life styles leads to modern diseases PSO-3 Develop skills in cultivation of plants. PSO-4 Prepare them to do higher studies in other biological fields like Genetic, Entomology, Biological Oceanography etc PSO-5 Developed critical thinking skills/laboratory techniques to be capable of designing, carrying out ,interpreting scientific experiments 1 HOLY CROSS COLLEGE (AUTONOMOUS) PG DEPARTMENT OF BIOCHEMISTRY (Students admitted from the year 2018 onwards) M.Sc. Biochemistry-Course -
Chrebp Regulates Fructose-Induced Glucose Production Independently of Insulin Signaling
ChREBP regulates fructose-induced glucose production independently of insulin signaling Mi-Sung Kim, … , Michelle Lai, Mark A. Herman J Clin Invest. 2016;126(11):4372-4386. https://doi.org/10.1172/JCI81993. Research Article Endocrinology Metabolism Obese, insulin-resistant states are characterized by a paradoxical pathogenic condition in which the liver appears to be selectively insulin resistant. Specifically, insulin fails to suppress glucose production, yet successfully stimulates de novo lipogenesis. The mechanisms underlying this dysregulation remain controversial. Here, we hypothesized that carbohydrate-responsive element-binding protein (ChREBP), a transcriptional activator of glycolytic and lipogenic genes, plays a central role in this paradox. Administration of fructose increased hepatic hexose-phosphate levels, activated ChREBP, and caused glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis in mice. Activation of ChREBP was required for the increased expression of glycolytic and lipogenic genes as well as glucose-6- phosphatase (G6pc) that was associated with the effects of fructose administration. We found that fructose-induced G6PC activity is a major determinant of hepatic glucose production and reduces hepatic glucose-6-phosphate levels to complete a homeostatic loop. Moreover, fructose activated ChREBP and induced G6pc in the absence of Foxo1a, indicating that carbohydrate-induced activation of ChREBP and G6PC dominates over the suppressive effects of insulin to enhance glucose production. This ChREBP/G6PC signaling axis is conserved in humans. Together, these findings support a carbohydrate-mediated, ChREBP-driven mechanism that contributes to hepatic insulin resistance. Find the latest version: https://jci.me/81993/pdf RESEARCH ARTICLE The Journal of Clinical Investigation ChREBP regulates fructose-induced glucose production independently of insulin signaling Mi-Sung Kim,1 Sarah A. -
Wellcome Trust Annual Report and Financial Statements 2019 Is © the Wellcome Trust and Is Licensed Under Creative Commons Attribution 2.0 UK
Annual Report and Financial Statements 2019 Table of contents Report from Chair 3 Report from Director 5 Trustee’s Report 7 What we do 8 Review of Charitable Activities 9 Review of Investment Activities 21 Financial Review 31 Structure and Governance 36 Social Responsibility 40 Risk Management 42 Remuneration Report 44 Remuneration Committee Report 46 Nomination Committee Report 47 Investment Committee Report 48 Audit and Risk Committee Report 49 Independent Auditor’s Report 52 Financial Statements 61 Consolidated Statement of Financial Activities 62 Consolidated Balance Sheet 63 Statement of Financial Activities of the Trust 64 Balance Sheet of the Trust 65 Consolidated Cash Flow Statement 66 Notes to the Financial Statements 67 Alternative Performance Measures and Key Performance Indicators 114 Glossary of Terms 115 Reference and Administrative Details 116 Table of Contents Wellcome Trust Annual Report 2019 | 2 Report from Chair During my tenure at Wellcome, which ends in The macro environment is increasingly challenging, 2020, I count myself lucky to have had the which has created volatility in financial markets. opportunity to meet inspiring people from a rich Q4 2018 was a very difficult quarter, but the diversity of sectors, backgrounds, specialisms resumption of interest rate cuts by the US Federal and scientific fields. Reserve underpinned another year of gains for our portfolio. We recognise that the cycle is extended, Wellcome’s achievements belong to the people and that the portfolio is likely to face more who work here and to the people we fund – it is challenging times ahead. a partnership that continues to grow stronger, more influential and more ambitious, spurred by The team is working hard to ensure that our independence. -
OVER £140 Prime Minister, the Rt Hon David Came
PRIME MINISTER QUARTERLY INFORMATION: 1 APRIL – 30 JUNE 2011 GIFTS (RECEIVED) OVER £140 Prime Minister, The Rt Hon David Cameron MP Date gift From Gift Value Outcome received April 2011 Prime Minister of Furniture Over Held by Department Pakistan limit April 2011 Prime Minister of Rug Over Held by BHC Pakistan limit Islamabad April 2011 Italian Aeronautica Leather jacket Over Held by Department Militare limit April 2011 Portmeirion Potteries China Over Held by Department Group limit May 2011 President Obama and Silver jewellery and Over Held by Department Mrs Obama First Edition Book limit May 2011 President of Russia Painting Over Held by Department limit May 2011 President of France Pen Set and Over Held by Department Glassware limit June 2011 Prime Minister of Picture Over Held by Department Malaysia limit GIFTS (GIVEN) OVER £140 Prime Minister, The Rt Hon David Cameron MP Date gift From Gift Value Outcome given Nil return HOSPITALITY1 Prime Minister, The Rt Hon David Cameron MP Date Name of Organisation Type of Hospitality Received NIL RETURN 1 Does not normally include attendance at functions hosted by HM Government; ‘diplomatic’ functions in the UK or abroad, hosted by overseas governments; minor refreshments at meetings, receptions, conferences, and seminars; and offers of hospitality which were declined. OVERSEAS TRAVEL Prime Minister Date(s) of trip Destination Purpose of ‘No 32 (The Number of Total cost trip Royal) officials including travel Squadron’ accompanying and or ‘other Minister, where accommodation of RAF’ or non-scheduled