ALBERT

Description: Protease nexin-II (PN-II) [amyloid beta-protein precursor (APP)] and the amyloid beta-protein are major constituents of neuritic plaques and cerebrovascular deposits in individuals with Alzheimer's disease and Down syndrome. Both the brain and the circulation have been implicated as sources of these molecules, although they have not been detected in blood. Human platelets have now been found to contain relatively large amounts of PN-II/APP. Platelet PN-II/APP was localized in platelet alpha-granules and was secreted upon platelet activation. Because PN-II/APP is a potent protease inhibitor and possesses growth factor activity, these results implicate PN-II/APP in wound repair. In certain disease states, alterations in platelet release and processing and clearance of PN-II/APP and its derived fragments could lead to pathological accumulation of these proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Nostrand, W E -- Schmaier, A H -- Farrow, J S -- Cunningham, D D -- GM-31609/GM/NIGMS NIH HHS/ -- HL01615/HL/NHLBI NIH HHS/ -- HL35553/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 1990 May 11;248(4956):745-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Molecular Genetics, University of California, Irvine 92717.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2110384" target="_blank"〉PubMed〈/a〉

Description: Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254742/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254742/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lu -- Kostadima, Myrto -- Martens, Joost H A -- Canu, Giovanni -- Garcia, Sara P -- Turro, Ernest -- Downes, Kate -- Macaulay, Iain C -- Bielczyk-Maczynska, Ewa -- Coe, Sophia -- Farrow, Samantha -- Poudel, Pawan -- Burden, Frances -- Jansen, Sjoert B G -- Astle, William J -- Attwood, Antony -- Bariana, Tadbir -- de Bono, Bernard -- Breschi, Alessandra -- Chambers, John C -- BRIDGE Consortium -- Choudry, Fizzah A -- Clarke, Laura -- Coupland, Paul -- van der Ent, Martijn -- Erber, Wendy N -- Jansen, Joop H -- Favier, Remi -- Fenech, Matthew E -- Foad, Nicola -- Freson, Kathleen -- van Geet, Chris -- Gomez, Keith -- Guigo, Roderic -- Hampshire, Daniel -- Kelly, Anne M -- Kerstens, Hindrik H D -- Kooner, Jaspal S -- Laffan, Michael -- Lentaigne, Claire -- Labalette, Charlotte -- Martin, Tiphaine -- Meacham, Stuart -- Mumford, Andrew -- Nurnberg, Sylvia -- Palumbo, Emilio -- van der Reijden, Bert A -- Richardson, David -- Sammut, Stephen J -- Slodkowicz, Greg -- Tamuri, Asif U -- Vasquez, Louella -- Voss, Katrin -- Watt, Stephen -- Westbury, Sarah -- Flicek, Paul -- Loos, Remco -- Goldman, Nick -- Bertone, Paul -- Read, Randy J -- Richardson, Sylvia -- Cvejic, Ana -- Soranzo, Nicole -- Ouwehand, Willem H -- Stunnenberg, Hendrik G -- Frontini, Mattia -- Rendon, Augusto -- 082961/Wellcome Trust/United Kingdom -- 082961/Z/07/Z/Wellcome Trust/United Kingdom -- 084183/Z/07/Z/Wellcome Trust/United Kingdom -- 095908/Wellcome Trust/United Kingdom -- 100140/Wellcome Trust/United Kingdom -- C45041/A14953/Cancer Research UK/United Kingdom -- FS/12/27/29405/British Heart Foundation/United Kingdom -- MC_UP_0801/1/Medical Research Council/United Kingdom -- MR/J011711/1/Medical Research Council/United Kingdom -- MR/K006584/1/Medical Research Council/United Kingdom -- MR/K023489/1/Medical Research Council/United Kingdom -- RG/09/012/28096/British Heart Foundation/United Kingdom -- RG/09/12/28096/British Heart Foundation/United Kingdom -- RP-PG-0310-1002/British Heart Foundation/United Kingdom -- RP-PG-0310-1002/Department of Health/United Kingdom -- WT091310/Wellcome Trust/United Kingdom -- WT098051/Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 26;345(6204):1251033. doi: 10.1126/science.1251033.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Molecular Biology, Radboud University, 6525 GA Nijmegen, Netherlands. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Sanger Institute-EBI Single-Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ; Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK. The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London NW3 2QG, UK. ; CHIME Institute, University College London, Archway Campus, London NW1 2DA, UK. Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand. ; Centre for Genomic Regulation and University Pompeu Fabra, 08002 Barcelona, Spain. ; Imperial College Healthcare NHS Trust, DuCane Road, London W12 0HS, UK. Ealing Hospital NHS Trust, Southall, Middlesex UB1 3HW, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia 6009, Australia. ; Department of Laboratory Medicine, Laboratory of Hematology, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands. ; Assistance Publique-Hopitaux de Paris, INSERM U1009, 94805 Villejuif, France. ; Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, UK. ; Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium. ; The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free NHS Trust, London NW3 2QG, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge B2 0QQ, UK. ; Department of Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London W12 0HS, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Department of Twin Research & Genetic Epidemiology, Genetics and Molecular Medicine Division, St Thomas' Hospital, King's College, London SE1 7EH, UK. ; School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK. ; Department of Oncology, Addenbrooke's Cambridge University Hospital NHS Trust, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK. Cancer Research UK, Cambridge Institute, Cambridge Biomedical Campus, Cambridge CB2 0RE, UK. ; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; School of Clinical Sciences, University of Bristol, Bristol BS2 8DZ, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK. Genome Biology and Developmental Biology Units, European Molecular Biology Laboratory, 69117 Heidelberg, Germany. Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK. ; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0XY, UK. ; Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. ar506@cam.ac.uk mf471@cam.ac.uk. ; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Cambridge CB2 0PT, UK. Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge CB2 0SR, UK. ar506@cam.ac.uk mf471@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25258084" target="_blank"〉PubMed〈/a〉

Description: Vinblastine, a potent anticancer drug, is produced by Catharanthus roseus (Madagascar periwinkle) in small quantities, and heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. However, the chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing enzymes necessary for vinblastine biosynthesis in this plant: an oxidase and a reductase that isomerize stemmadenine acetate into dihydroprecondylocarpine acetate, which is then deacetoxylated and cyclized to either catharanthine or tabersonine via two hydrolases characterized herein. The pathways show how plants create chemical diversity and also enable development of heterologous platforms for generation of stemmadenine-derived bioactive compounds.