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  • 1
    Publication Date: 2011-09-03
    Description: The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Breitbach, Caroline J -- Burke, James -- Jonker, Derek -- Stephenson, Joe -- Haas, Andrew R -- Chow, Laura Q M -- Nieva, Jorge -- Hwang, Tae-Ho -- Moon, Anne -- Patt, Richard -- Pelusio, Adina -- Le Boeuf, Fabrice -- Burns, Joe -- Evgin, Laura -- De Silva, Naomi -- Cvancic, Sara -- Robertson, Terri -- Je, Ji-Eun -- Lee, Yeon-Sook -- Parato, Kelley -- Diallo, Jean-Simon -- Fenster, Aaron -- Daneshmand, Manijeh -- Bell, John C -- Kirn, David H -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Aug 31;477(7362):99-102. doi: 10.1038/nature10358.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jennerex Inc., 450 Sansome Street, 16th floor, San Francisco, California 94111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21886163" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; DNA, Viral/blood ; Female ; Gene Expression Regulation, Enzymologic ; Humans ; Infusions, Intravenous ; Male ; Middle Aged ; Neoplasms/pathology/surgery/*therapy/virology ; *Oncolytic Virotherapy ; Oncolytic Viruses/*physiology ; Organisms, Genetically Modified/physiology ; Poxviridae/*physiology ; Transgenes/genetics ; beta-Galactosidase/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-06-16
    Description: Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Won, Hyejung -- Lee, Hye-Ryeon -- Gee, Heon Yung -- Mah, Won -- Kim, Jae-Ick -- Lee, Jiseok -- Ha, Seungmin -- Chung, Changuk -- Jung, Eun Suk -- Cho, Yi Sul -- Park, Sae-Geun -- Lee, Jung-Soo -- Lee, Kyungmin -- Kim, Daesoo -- Bae, Yong Chul -- Kaang, Bong-Kiun -- Lee, Min Goo -- Kim, Eunjoon -- England -- Nature. 2012 Jun 13;486(7402):261-5. doi: 10.1038/nature11208.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, KAIST, Daejeon 305-701, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699620" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*genetics ; Animals ; Antimetabolites/pharmacology ; *Autistic Disorder/genetics/metabolism ; Behavior, Animal/*drug effects/physiology ; Benzamides/*pharmacology ; Cycloserine/*pharmacology ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/*genetics ; Pyrazoles/*pharmacology ; Receptors, N-Methyl-D-Aspartate/*agonists/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-01-07
    Description: A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA). Here we performed a genome-wide association study meta-analysis in a total of 〉100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating approximately 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2 - 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation, cis-acting expression quantitative trait loci and pathway analyses--as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes--to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944098/" 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/PMC3944098/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada, Yukinori -- Wu, Di -- Trynka, Gosia -- Raj, Towfique -- Terao, Chikashi -- Ikari, Katsunori -- Kochi, Yuta -- Ohmura, Koichiro -- Suzuki, Akari -- Yoshida, Shinji -- Graham, Robert R -- Manoharan, Arun -- Ortmann, Ward -- Bhangale, Tushar -- Denny, Joshua C -- Carroll, Robert J -- Eyler, Anne E -- Greenberg, Jeffrey D -- Kremer, Joel M -- Pappas, Dimitrios A -- Jiang, Lei -- Yin, Jian -- Ye, Lingying -- Su, Ding-Feng -- Yang, Jian -- Xie, Gang -- Keystone, Ed -- Westra, Harm-Jan -- Esko, Tonu -- Metspalu, Andres -- Zhou, Xuezhong -- Gupta, Namrata -- Mirel, Daniel -- Stahl, Eli A -- Diogo, Dorothee -- Cui, Jing -- Liao, Katherine -- Guo, Michael H -- Myouzen, Keiko -- Kawaguchi, Takahisa -- Coenen, Marieke J H -- van Riel, Piet L C M -- van de Laar, Mart A F J -- Guchelaar, Henk-Jan -- Huizinga, Tom W J -- Dieude, Philippe -- Mariette, Xavier -- Bridges, S Louis Jr -- Zhernakova, Alexandra -- Toes, Rene E M -- Tak, Paul P -- Miceli-Richard, Corinne -- Bang, So-Young -- Lee, Hye-Soon -- Martin, Javier -- Gonzalez-Gay, Miguel A -- Rodriguez-Rodriguez, Luis -- Rantapaa-Dahlqvist, Solbritt -- Arlestig, Lisbeth -- Choi, Hyon K -- Kamatani, Yoichiro -- Galan, Pilar -- Lathrop, Mark -- RACI consortium -- GARNET consortium -- Eyre, Steve -- Bowes, John -- Barton, Anne -- de Vries, Niek -- Moreland, Larry W -- Criswell, Lindsey A -- Karlson, Elizabeth W -- Taniguchi, Atsuo -- Yamada, Ryo -- Kubo, Michiaki -- Liu, Jun S -- Bae, Sang-Cheol -- Worthington, Jane -- Padyukov, Leonid -- Klareskog, Lars -- Gregersen, Peter K -- Raychaudhuri, Soumya -- Stranger, Barbara E -- De Jager, Philip L -- Franke, Lude -- Visscher, Peter M -- Brown, Matthew A -- Yamanaka, Hisashi -- Mimori, Tsuneyo -- Takahashi, Atsushi -- Xu, Huji -- Behrens, Timothy W -- Siminovitch, Katherine A -- Momohara, Shigeki -- Matsuda, Fumihiko -- Yamamoto, Kazuhiko -- Plenge, Robert M -- 20385/Arthritis Research UK/United Kingdom -- 79321/Canadian Institutes of Health Research/Canada -- K08-KAR055688A/PHS HHS/ -- K24 AR052403/AR/NIAMS NIH HHS/ -- P60 AR047785/AR/NIAMS NIH HHS/ -- R01 AR056768/AR/NIAMS NIH HHS/ -- R01 AR057108/AR/NIAMS NIH HHS/ -- R01 AR059648/AR/NIAMS NIH HHS/ -- R01 AR063759/AR/NIAMS NIH HHS/ -- R01-AR056291/AR/NIAMS NIH HHS/ -- R01-AR056768/AR/NIAMS NIH HHS/ -- R01-AR057108/AR/NIAMS NIH HHS/ -- R01-AR059648/AR/NIAMS NIH HHS/ -- R01-AR065944/AR/NIAMS NIH HHS/ -- R01AR063759-01A1/AR/NIAMS NIH HHS/ -- R21 AR056042/AR/NIAMS NIH HHS/ -- T15 LM007450/LM/NLM NIH HHS/ -- U01 GM092691/GM/NIGMS NIH HHS/ -- U01-GM092691/GM/NIGMS NIH HHS/ -- U19 HL065962/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Feb 20;506(7488):376-81. doi: 10.1038/nature12873. Epub 2013 Dec 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. [5] Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Victoria 3800, Australia. ; 1] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. ; Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan. ; Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; Department of Rheumatology and Clinical immunology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan. ; Immunology Biomarkers Group, Genentech, South San Francisco, California 94080, USA. ; 1] Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. [2] Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA. ; New York University Hospital for Joint Diseases, New York, New York 10003, USA. ; Department of Medicine, Albany Medical Center and The Center for Rheumatology, Albany, New York 12206, USA. ; Division of Rheumatology, Department of Medicine, New York, Presbyterian Hospital, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, China. ; Department of Pharmacology, Second Military Medical University, Shanghai 200433, China. ; 1] University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. [2] Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. [2] Toronto General Research Institute, Toronto, Ontario M5G 2M9, Canada. [3] Department of Medicine, University of Toronto, Toronto, Ontario M5S 2J7, Canada. ; Department of Medicine, Mount Sinai Hospital and University of Toronto, Toronto M5S 2J7, Canada. ; Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. ; 1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [2] Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. ; Estonian Genome Center, University of Tartu, Riia 23b, Tartu 51010, Estonia. ; School of Computer and Information Technology, Beijing Jiaotong University, Beijing 100044, China. ; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. ; The Department of Psychiatry at Mount Sinai School of Medicine, New York, New York 10029, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [3] Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA. ; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ; Department of Human Genetics, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. ; Department of Rheumatology, Radboud University Medical Centre, Nijmegen 6500 HB, the Netherlands. ; Department of Rheumatology and Clinical Immunology, Arthritis Center Twente, University Twente & Medisch Spectrum Twente, Enschede 7500 AE, the Netherlands. ; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; 1] Service de Rhumatologie et INSERM U699 Hopital Bichat Claude Bernard, Assistance Publique des Hopitaux de Paris, Paris 75018, France. [2] Universite Paris 7-Diderot, Paris 75013, France. ; Institut National de la Sante et de la Recherche Medicale (INSERM) U1012, Universite Paris-Sud, Rhumatologie, Hopitaux Universitaires Paris-Sud, Assistance Publique-Hopitaux de Paris (AP-HP), Le Kremlin Bicetre 94275, France. ; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. ; 1] Department of Genetics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Groningen 9700 RB, the Netherlands. [2] Department of Rheumatology, Leiden University Medical Center, Leiden 2300 RC, the Netherlands. ; 1] AMC/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. [2] GlaxoSmithKline, Stevenage SG1 2NY, UK. [3] University of Cambridge, Cambridge CB2 1TN, UK. ; Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, South Korea. ; Instituto de Parasitologia y Biomedicina Lopez-Neyra, CSIC, Granada 18100, Spain. ; Department of Rheumatology, Hospital Marques de Valdecilla, IFIMAV, Santander 39008, Spain. ; Hospital Clinico San Carlos, Madrid 28040, Spain. ; 1] Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. [2] Department of Rheumatology, Umea University, Umea SE-901 87, Sweden. ; 1] Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston 02115, Massachusetts, USA. [2] Section of Rheumatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. [3] Clinical Epidemiology Research and Training Unit, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Centre d'Etude du Polymorphisme Humain (CEPH), Paris 75010, France. ; Universite Paris 13 Sorbonne Paris Cite, UREN (Nutritional Epidemiology Research Unit), Inserm (U557), Inra (U1125), Cnam, Bobigny 93017, France. ; McGill University and Genome Quebec Innovation Centre, Montreal, Quebec H3A 0G1 Canada. ; 1] Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. [2] National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. ; Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK. ; Department of Clinical Immunology and Rheumatology & Department of Genome Analysis, Academic Medical Center/University of Amsterdam, Amsterdam 1105 AZ, the Netherlands. ; Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. ; Rosalind Russell Medical Research Center for Arthritis, Division of Rheumatology, Department of Medicine, University of California San Francisco, San Francisco, California 94117, USA. ; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Unit of Statistical Genetics, Center for Genomic Medicine Graduate School of Medicine Kyoto University, Kyoto 606-8507, Japan. ; Laboratory for Genotyping Development, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; Department of Statistics, Harvard University, Cambridge, Massachusetts 02138, USA. ; Rheumatology Unit, Department of Medicine (Solna), Karolinska Institutet, Stockholm SE-171 76, Sweden. ; The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA. ; 1] Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [2] Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA. [4] NIHR Manchester Musculoskeletal Biomedical, Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9NT, UK. ; 1] Section of Genetic Medicine, University of Chicago, Chicago, Illinois 60637, USA. [2] Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA. ; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4072, Australia. ; Laboratory for Statistical Analysis, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. ; 1] Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. [2] Core Research for Evolutional Science and Technology (CREST) program, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan. [3] Institut National de la Sante et de la Recherche Medicale (INSERM) Unite U852, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan. ; 1] Laboratory for Autoimmune Diseases, Center for Integrative Medical Sciences, RIKEN, Yokohama 230-0045, Japan. [2] Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24390342" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Arthritis, Rheumatoid/*drug therapy/*genetics/metabolism/pathology ; Asian Continental Ancestry Group/genetics ; Case-Control Studies ; Computational Biology ; *Drug Discovery ; Drug Repositioning ; European Continental Ancestry Group/genetics ; Female ; Genetic Predisposition to Disease/*genetics ; Genome-Wide Association Study ; Hematologic Neoplasms/genetics/metabolism ; Humans ; Male ; Mice ; Mice, Knockout ; *Molecular Targeted Therapy ; Polymorphism, Single Nucleotide/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2014-10-21
    Description: Reproduction in jawed vertebrates (gnathostomes) involves either external or internal fertilization. It is commonly argued that internal fertilization can evolve from external, but not the reverse. Male copulatory claspers are present in certain placoderms, fossil jawed vertebrates retrieved as a paraphyletic segment of the gnathostome stem group in recent studies. This suggests that internal fertilization could be primitive for gnathostomes, but such a conclusion depends on demonstrating that copulation was not just a specialized feature of certain placoderm subgroups. The reproductive biology of antiarchs, consistently identified as the least crownward placoderms and thus of great interest in this context, has until now remained unknown. Here we show that certain antiarchs possessed dermal claspers in the males, while females bore paired dermal plates inferred to have facilitated copulation. These structures are not associated with pelvic fins. The clasper morphology resembles that of ptyctodonts, a more crownward placoderm group, suggesting that all placoderm claspers are homologous and that internal fertilization characterized all placoderms. This implies that external fertilization and spawning, which characterize most extant aquatic gnathostomes, must be derived from internal fertilization, even though this transformation has been thought implausible. Alternatively, the substantial morphological evidence for placoderm paraphyly must be rejected.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Long, John A -- Mark-Kurik, Elga -- Johanson, Zerina -- Lee, Michael S Y -- Young, Gavin C -- Min, Zhu -- Ahlberg, Per E -- Newman, Michael -- Jones, Roger -- den Blaauwen, Jan -- Choo, Brian -- Trinajstic, Kate -- England -- Nature. 2015 Jan 8;517(7533):196-9. doi: 10.1038/nature13825. Epub 2014 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] School of Biological Sciences, Flinders University, 2100, Adelaide, South Australia 5001, Australia [2] Natural History Museum of Los Angeles County, 900 Exposition Boulevard, Los Angeles, California 9007, USA [3] Museum Victoria, PO Box 666, Melbourne, Victoria 3001, Australia. ; Institute of Geology at Tallinn University of Technology, Ehitajate tee 5, 19086 Tallinn, Estonia. ; Department of Earth Sciences, Natural History Museum, London SW7 5BD, UK. ; 1] South Australian Museum, North Terrace, Adelaide, South Australia 5000, Australia [2] School of Earth and Environmental Sciences, The University of Adelaide, South Australia 5005, Australia. ; Research School of Earth Sciences, The Australian National University, Canberra, Australian Capital Territory 0200, Australia. ; Key Laboratory of Evolutionary Systematics of Vertebrates, Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, PO Box 643, Beijing 100044, China. ; Department of Organismal Biology, Evolutionary Biology Centre, Uppsala University, Norbyvagen 18A, 752 36 Uppsala, Sweden. ; Vine Lodge, Vine Road, Johnston, Haverfordwest, Pembrokeshire SA62 3NZ, UK. ; 6 Burghley Road, Wimbledon, London SW19 5BH, UK. ; University of Amsterdam, Science Park 904, 1098XH, Amsterdam, The Netherlands. ; School of Biological Sciences, Flinders University, 2100, Adelaide, South Australia 5001, Australia. ; 1] Western Australian Organic and Isotope Geochemistry Centre, Department of Chemistry, Curtin University, Perth, Western Australia 6102, Australia [2] Earth and Planetary Sciences, Western Australian Museum, Perth, Western Australia 6000, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25327249" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Copulation/*physiology ; Female ; Fertilization/*physiology ; Fishes/*anatomy & histology/*physiology ; Fossils ; *Jaw ; Male ; Models, Biological ; Phylogeny ; Sex Characteristics ; Vertebrates/anatomy & histology/*physiology
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2014-12-17
    Description: Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC-derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tonge, Peter D -- Corso, Andrew J -- Monetti, Claudio -- Hussein, Samer M I -- Puri, Mira C -- Michael, Iacovos P -- Li, Mira -- Lee, Dong-Sung -- Mar, Jessica C -- Cloonan, Nicole -- Wood, David L -- Gauthier, Maely E -- Korn, Othmar -- Clancy, Jennifer L -- Preiss, Thomas -- Grimmond, Sean M -- Shin, Jong-Yeon -- Seo, Jeong-Sun -- Wells, Christine A -- Rogers, Ian M -- Nagy, Andras -- MOP102575/Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Dec 11;516(7530):192-7. doi: 10.1038/nature14047.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5T 3H7, Canada. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5T 3H7, Canada. ; 1] Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, South Korea. ; Department of Systems &Computational Biology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA. ; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia. ; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia. ; Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), Australian Capital Territory 2601, Australia. ; 1] Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), Australian Capital Territory 2601, Australia [2] Victor Chang Cardiac Research Institute, Darlinghurst (Sydney), New South Wales 2010, Australia. ; 1] Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea [2] Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea. ; 1] Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, South Korea [4] Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Department of Physiology, University of Toronto, Toronto, Ontario M5T 3H7, Canada [3] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5T 3H7, Canada. ; 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada [2] Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada [3] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario M5T 3H7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25503232" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cellular Reprogramming/*genetics/*physiology ; Embryonic Stem Cells/cytology/metabolism ; *Epigenesis, Genetic ; Female ; Fibroblasts/classification/cytology/metabolism ; Histone Deacetylases/metabolism ; Induced Pluripotent Stem Cells/classification/*cytology/*metabolism ; Mice ; Mice, Nude ; Transcription Factors/genetics/metabolism ; Transgenes/genetics
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  • 6
    Publication Date: 2013-08-16
    Description: Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Emicro-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but not TIS-incompetent Suv39h1(-) lymphomas show increased glucose utilization and much higher ATP production. We demonstrate that this is linked to massive proteotoxic stress, which is a consequence of the senescence-associated secretory phenotype (SASP) described previously. SASP-producing TIS cells exhibited endoplasmic reticulum stress, an unfolded protein response (UPR), and increased ubiquitination, thereby targeting toxic proteins for autophagy in an acutely energy-consuming fashion. Accordingly, TIS lymphomas, unlike senescence models that lack a strong SASP response, were more sensitive to blocking glucose utilization or autophagy, which led to their selective elimination through caspase-12- and caspase-3-mediated endoplasmic-reticulum-related apoptosis. Consequently, pharmacological targeting of these metabolic demands on TIS induction in vivo prompted tumour regression and improved treatment outcomes further. These findings unveil the hypercatabolic nature of TIS that is therapeutically exploitable by synthetic lethal metabolic targeting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dorr, Jan R -- Yu, Yong -- Milanovic, Maja -- Beuster, Gregor -- Zasada, Christin -- Dabritz, J Henry M -- Lisec, Jan -- Lenze, Dido -- Gerhardt, Anne -- Schleicher, Katharina -- Kratzat, Susanne -- Purfurst, Bettina -- Walenta, Stefan -- Mueller-Klieser, Wolfgang -- Graler, Markus -- Hummel, Michael -- Keller, Ulrich -- Buck, Andreas K -- Dorken, Bernd -- Willmitzer, Lothar -- Reimann, Maurice -- Kempa, Stefan -- Lee, Soyoung -- Schmitt, Clemens A -- England -- Nature. 2013 Sep 19;501(7467):421-5. doi: 10.1038/nature12437. Epub 2013 Aug 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Charite-Universitatsmedizin Berlin, Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23945590" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/drug effects ; *Autophagy/drug effects ; Caspase 12/metabolism ; Caspase 3/metabolism ; *Cell Aging/drug effects ; Disease Models, Animal ; Endoplasmic Reticulum Stress ; Female ; Glucose/*metabolism ; Lymphoma, B-Cell/*drug therapy/genetics/*metabolism/pathology ; Male ; Mice ; Mice, Transgenic ; Proteolysis ; Stress, Physiological ; Survival Rate
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2012-10-30
    Description: Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg's cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle-chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561483/" 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/PMC3561483/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tachibana, Masahito -- Amato, Paula -- Sparman, Michelle -- Woodward, Joy -- Sanchis, Dario Melguizo -- Ma, Hong -- Gutierrez, Nuria Marti -- Tippner-Hedges, Rebecca -- Kang, Eunju -- Lee, Hyo-Sang -- Ramsey, Cathy -- Masterson, Keith -- Battaglia, David -- Lee, David -- Wu, Diana -- Jensen, Jeffrey -- Patton, Phillip -- Gokhale, Sumita -- Stouffer, Richard -- Mitalipov, Shoukhrat -- 8P51OD011092/OD/NIH HHS/ -- EY021214/EY/NEI NIH HHS/ -- HD057121/HD/NICHD NIH HHS/ -- HD059946/HD/NICHD NIH HHS/ -- HD063276/HD/NICHD NIH HHS/ -- P51 OD011092/OD/NIH HHS/ -- P51 RR000163/RR/NCRR NIH HHS/ -- R01 EY021214/EY/NEI NIH HHS/ -- R01 HD057121/HD/NICHD NIH HHS/ -- R01 HD059946/HD/NICHD NIH HHS/ -- R01 HD063276/HD/NICHD NIH HHS/ -- England -- Nature. 2013 Jan 31;493(7434):627-31. doi: 10.1038/nature11647. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103867" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Cell Nucleus/genetics ; Cryopreservation ; Cytoplasm/genetics ; DNA, Mitochondrial/analysis/genetics ; Embryo, Mammalian/embryology ; Embryonic Stem Cells/cytology ; Female ; Fertilization ; *Genetic Therapy ; Humans ; Macaca mulatta/genetics/growth & development ; Microsatellite Repeats/genetics ; Mitochondrial Diseases/*genetics/*therapy ; Nuclear Transfer Techniques/*standards ; Oocytes/cytology ; Pregnancy ; Young Adult ; Zygote/cytology/pathology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
    Publication Date: 2014-06-06
    Description: The mir-34/449 family consists of six homologous miRNAs at three genomic loci. Redundancy of miR-34/449 miRNAs and their dominant expression in multiciliated epithelia suggest a functional significance in ciliogenesis. Here we report that mice deficient for all miR-34/449 miRNAs exhibited postnatal mortality, infertility and strong respiratory dysfunction caused by defective mucociliary clearance. In both mouse and Xenopus, miR-34/449-deficient multiciliated cells (MCCs) exhibited a significant decrease in cilia length and number, due to defective basal body maturation and apical docking. The effect of miR-34/449 on ciliogenesis was mediated, at least in part, by post-transcriptional repression of Cp110, a centriolar protein suppressing cilia assembly. Consistent with this, cp110 knockdown in miR-34/449-deficient MCCs restored ciliogenesis by rescuing basal body maturation and docking. Altogether, our findings elucidate conserved cellular and molecular mechanisms through which miR-34/449 regulate motile ciliogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119886/" 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/PMC4119886/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Song, Rui -- Walentek, Peter -- Sponer, Nicole -- Klimke, Alexander -- Lee, Joon Sub -- Dixon, Gary -- Harland, Richard -- Wan, Ying -- Lishko, Polina -- Lize, Muriel -- Kessel, Michael -- He, Lin -- 1R21CA175560-01/CA/NCI NIH HHS/ -- GM42341/GM/NIGMS NIH HHS/ -- R01 CA139067/CA/NCI NIH HHS/ -- R01 GM042341/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 5;510(7503):115-20. doi: 10.1038/nature13413.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Cellular and Developmental Biology, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA [2]. ; 1] Division of Genetics, Genomics and Development, Centre for Integrative Genomics, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA [2]. ; Department of Molecular Cell Biology, Max Planck Institute for Biophysical Chemistry, Goettingen 37077, Germany. ; Division of Cellular and Developmental Biology, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA. ; Division of Genetics, Genomics and Development, Centre for Integrative Genomics, MCB Department, University of California at Berkeley, Berkeley, California 94705, USA. ; The Third Military Medical University, Chongqing 400038, China. ; Department of Molecular Oncology, University of Goettingen, Goettingen 37073, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24899310" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Basal Bodies/metabolism/pathology/ultrastructure ; Base Sequence ; Calmodulin-Binding Proteins/*deficiency/*genetics/metabolism ; Centrioles/metabolism ; Cilia/*genetics/pathology/*physiology/ultrastructure ; Epidermis/embryology/pathology ; Female ; Infertility/genetics/physiopathology ; Kartagener Syndrome/genetics/pathology/physiopathology ; Male ; Mice ; Mice, Knockout ; MicroRNAs/*genetics/metabolism ; Morphogenesis/*genetics ; Phenotype ; Respiratory System/pathology/physiopathology ; Survival Analysis ; Xenopus laevis/embryology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
    Publication Date: 2015-11-13
    Description: The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo. Here we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumour, a small proportion of tumour cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumour cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662610/" 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/PMC4662610/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fischer, Kari R -- Durrans, Anna -- Lee, Sharrell -- Sheng, Jianting -- Li, Fuhai -- Wong, Stephen T C -- Choi, Hyejin -- El Rayes, Tina -- Ryu, Seongho -- Troeger, Juliane -- Schwabe, Robert F -- Vahdat, Linda T -- Altorki, Nasser K -- Mittal, Vivek -- Gao, Dingcheng -- 1 F31 CA186510-01/CA/NCI NIH HHS/ -- F31 CA186510/CA/NCI NIH HHS/ -- R01 CA135417/CA/NCI NIH HHS/ -- U01 CA188388/CA/NCI NIH HHS/ -- U54 CA149196-05/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):472-6. doi: 10.1038/nature15748. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA. ; Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA. ; Neuberger Berman Lung Cancer Center, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA. ; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA. ; Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas 77030, USA. ; Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas, 77030 USA. ; Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, 25 Bongjeong-ro Cheonan-Si, Chungcheongnam-do 31151, South Korea. ; Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. ; Institute of Human Nutrition, Columbia University, New York, New York 10032, USA. ; Department of Medicine, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560033" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents, Alkylating/pharmacology/therapeutic use ; Apoptosis/drug effects ; Cell Lineage ; Cell Proliferation/drug effects ; Cell Tracking ; Cyclophosphamide/pharmacology/therapeutic use ; Disease Models, Animal ; Disease Progression ; *Drug Resistance, Neoplasm/drug effects/genetics ; *Epithelial-Mesenchymal Transition/drug effects/genetics ; Female ; Lung Neoplasms/drug therapy/genetics/*pathology/*secondary ; Male ; Mammary Neoplasms, Experimental/*drug therapy/genetics/*pathology ; Mice ; MicroRNAs/genetics ; Neoplasm Metastasis/drug therapy/genetics/*pathology ; Reproducibility of Results
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2014-04-25
    Description: The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139287/" 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/PMC4139287/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bellott, Daniel W -- Hughes, Jennifer F -- Skaletsky, Helen -- Brown, Laura G -- Pyntikova, Tatyana -- Cho, Ting-Jan -- Koutseva, Natalia -- Zaghlul, Sara -- Graves, Tina -- Rock, Susie -- Kremitzki, Colin -- Fulton, Robert S -- Dugan, Shannon -- Ding, Yan -- Morton, Donna -- Khan, Ziad -- Lewis, Lora -- Buhay, Christian -- Wang, Qiaoyan -- Watt, Jennifer -- Holder, Michael -- Lee, Sandy -- Nazareth, Lynne -- Alfoldi, Jessica -- Rozen, Steve -- Muzny, Donna M -- Warren, Wesley C -- Gibbs, Richard A -- Wilson, Richard K -- Page, David C -- P51 RR013986/RR/NCRR NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Apr 24;508(7497):494-9. doi: 10.1038/nature13206.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute, Howard Hughes Medical Institute, & Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; The Genome Institute, Washington University School of Medicine, St. Louis, Missouri 63108, USA. ; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759411" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromosomes, Human, X/genetics ; Chromosomes, Human, Y/genetics ; Disease ; *Evolution, Molecular ; Female ; Gene Dosage/*genetics ; Gene Expression Regulation ; Health ; Humans ; Male ; Mammals/*genetics ; Marsupialia/genetics ; Molecular Sequence Annotation ; Molecular Sequence Data ; Protein Biosynthesis/genetics ; Protein Stability ; Selection, Genetic/genetics ; Sequence Homology ; Sex Characteristics ; Spermatogenesis/genetics ; Testis/metabolism ; Transcription, Genetic/genetics ; Turner Syndrome/genetics ; X Chromosome/genetics ; Y Chromosome/*genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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