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  • Humans  (53)
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  • 11
    Publication Date: 2009-04-03
    Description: CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 A structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined alpha-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437623/" 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/PMC3437623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Xiuhua -- Biswas, Anindita -- Suel, Katherine E -- Jackson, Laurie K -- Martinez, Rita -- Gu, Hongmei -- Chook, Yuh Min -- 5-T32-GM008297/GM/NIGMS NIH HHS/ -- R01 GM069909/GM/NIGMS NIH HHS/ -- R01GM069909/GM/NIGMS NIH HHS/ -- R01GM069909-03S1/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 30;458(7242):1136-41. doi: 10.1038/nature07975. Epub 2009 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, Texas 75390-9041, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19339969" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Crystallography, X-Ray ; Epitopes ; Fatty Acids, Unsaturated/pharmacology ; Humans ; Hydrophobic and Hydrophilic Interactions ; Karyopherins/*chemistry/*metabolism ; Leucine/*metabolism ; Models, Molecular ; Nuclear Export Signals/*physiology ; Protein Binding/drug effects ; Protein Conformation ; Receptors, Cytoplasmic and Nuclear/*chemistry/*metabolism ; Structure-Activity Relationship ; Substrate Specificity ; snRNP Core Proteins/chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 12
    Publication Date: 2009-02-17
    Description: Injury or impaired clearance of apoptotic cells leads to the pathological accumulation of necrotic corpses, which induce an inflammatory response that initiates tissue repair. In addition, antigens present in necrotic cells can sometimes provoke a specific immune response and it has been argued that necrosis could explain adaptive immunity in seemingly infection-free situations, such as after allograft transplantation or in spontaneous and therapy-induced tumour rejection. In the mouse, the CD8alpha+ subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8+ T cells against cell-associated antigens. Here we show that CD8alpha+ dendritic cells use CLEC9A (also known as DNGR-1), a recently-characterized C-type lectin, to recognize a preformed signal that is exposed on necrotic cells. Loss or blockade of CLEC9A does not impair the uptake of necrotic cell material by CD8+ dendritic cells, but specifically reduces cross-presentation of dead-cell-associated antigens in vitro and decreases the immunogenicity of necrotic cells in vivo. The function of CLEC9A requires a key tyrosine residue in its intracellular tail that allows the recruitment and activation of the tyrosine kinase SYK, which is also essential for cross-presentation of dead-cell-associated antigens. Thus, CLEC9A functions as a SYK-coupled C-type lectin receptor to mediate sensing of necrosis by the principal dendritic-cell subset involved in regulating cross-priming to cell-associated antigens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671489/" 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/PMC2671489/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sancho, David -- Joffre, Olivier P -- Keller, Anna M -- Rogers, Neil C -- Martinez, Dolores -- Hernanz-Falcon, Patricia -- Rosewell, Ian -- Reis e Sousa, Caetano -- A3598/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):899-903. doi: 10.1038/nature07750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunobiology Laboratory, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19219027" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD8/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Cross-Priming/immunology ; Dendritic Cells/*immunology/*metabolism ; Humans ; Lectins, C-Type/deficiency/genetics/*metabolism ; Ligands ; Mice ; Necrosis/*immunology/*metabolism ; Phagocytosis ; Receptors, Immunologic/deficiency/genetics/*metabolism ; Receptors, Mitogen/genetics/*metabolism ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 13
    Publication Date: 2010-05-21
    Description: Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874979/" 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/PMC2874979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guiguemde, W Armand -- Shelat, Anang A -- Bouck, David -- Duffy, Sandra -- Crowther, Gregory J -- Davis, Paul H -- Smithson, David C -- Connelly, Michele -- Clark, Julie -- Zhu, Fangyi -- Jimenez-Diaz, Maria B -- Martinez, Maria S -- Wilson, Emily B -- Tripathi, Abhai K -- Gut, Jiri -- Sharlow, Elizabeth R -- Bathurst, Ian -- El Mazouni, Farah -- Fowble, Joseph W -- Forquer, Isaac -- McGinley, Paula L -- Castro, Steve -- Angulo-Barturen, Inigo -- Ferrer, Santiago -- Rosenthal, Philip J -- Derisi, Joseph L -- Sullivan, David J -- Lazo, John S -- Roos, David S -- Riscoe, Michael K -- Phillips, Margaret A -- Rathod, Pradipsinh K -- Van Voorhis, Wesley C -- Avery, Vicky M -- Guy, R Kiplin -- AI045774/AI/NIAID NIH HHS/ -- AI053680/AI/NIAID NIH HHS/ -- AI067921/AI/NIAID NIH HHS/ -- AI075517/AI/NIAID NIH HHS/ -- AI075594/AI/NIAID NIH HHS/ -- AI080625/AI/NIAID NIH HHS/ -- AI082617/AI/NIAID NIH HHS/ -- AI28724/AI/NIAID NIH HHS/ -- AI35707/AI/NIAID NIH HHS/ -- AI53862/AI/NIAID NIH HHS/ -- AI772682/AI/NIAID NIH HHS/ -- CA78039/CA/NCI NIH HHS/ -- F32 AI077268/AI/NIAID NIH HHS/ -- F32 AI077268-03/AI/NIAID NIH HHS/ -- P01 AI035707/AI/NIAID NIH HHS/ -- P01 AI035707-140007/AI/NIAID NIH HHS/ -- P01 CA078039-10/CA/NCI NIH HHS/ -- P41 RR001614/RR/NCRR NIH HHS/ -- P41 RR001614-246970/RR/NCRR NIH HHS/ -- R01 AI045774/AI/NIAID NIH HHS/ -- R01 AI045774-09/AI/NIAID NIH HHS/ -- R37 AI028724/AI/NIAID NIH HHS/ -- R37 AI028724-17/AI/NIAID NIH HHS/ -- R56 AI082617/AI/NIAID NIH HHS/ -- R56 AI082617-01/AI/NIAID NIH HHS/ -- U01 AI053862/AI/NIAID NIH HHS/ -- U01 AI053862-05/AI/NIAID NIH HHS/ -- U01 AI075594-03/AI/NIAID NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 May 20;465(7296):311-5. doi: 10.1038/nature09099.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20485428" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antimalarials/*analysis/isolation & purification/*pharmacology ; Cell Line ; *Drug Discovery ; Drug Evaluation, Preclinical ; Drug Resistance/drug effects ; Drug Therapy, Combination ; Erythrocytes/drug effects/parasitology ; Humans ; Malaria, Falciparum/drug therapy/parasitology ; Mice ; Phenotype ; Phylogeny ; Plasmodium falciparum/*drug effects/*genetics/metabolism ; Reproducibility of Results ; Small Molecule Libraries/chemistry/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 14
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1990-11-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martinez, F -- Poet, T S -- Watson, R R -- New York, N.Y. -- Science. 1990 Nov 23;250(4984):1070.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2251495" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cocaine/metabolism/pharmacokinetics ; Hair/*chemistry/metabolism ; Humans ; Male ; Mice ; Morphine/metabolism/pharmacokinetics ; *Substance Abuse Detection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 15
    Publication Date: 1992-03-13
    Description: Oncostatin M, a cytokine produced by activated lymphoid cells, regulates the growth and differentiation of a number of tumor and normal cells. In contrast to its effects on normal endothelial and aortic smooth muscle cell cultures, Oncostatin M was a potent mitogen for cells derived from acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS). After exposure to Oncostatin M, AIDS-KS cells assumed a spindle morphology, had an increased ability to proliferate in soft agar, and secreted increased amounts of interleukin-6. Oncostatin M RNA and immunoreactive Oncostatin M protein were found in AIDS-KS-derived cell isolates. These results suggest that Oncostatin M may play a role in the pathogenesis of AIDS-KS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miles, S A -- Martinez-Maza, O -- Rezai, A -- Magpantay, L -- Kishimoto, T -- Nakamura, S -- Radka, S F -- Linsley, P S -- AI27660/AI/NIAID NIH HHS/ -- CA 01588/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1992 Mar 13;255(5050):1432-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UCLA AIDS Center 90024.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/1542793" target="_blank"〉PubMed〈/a〉
    Keywords: Acquired Immunodeficiency Syndrome/*complications ; Base Sequence ; Cell Division/drug effects ; Growth Substances/biosynthesis/*physiology ; Humans ; Molecular Sequence Data ; Neoplasm Proteins/biosynthesis ; Oncostatin M ; Peptide Biosynthesis ; Peptides/*physiology ; Recombinant Proteins/pharmacology ; Sarcoma, Kaposi/etiology/metabolism/*pathology ; Tumor Cells, Cultured
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 16
    Publication Date: 2011-02-12
    Description: Splicing of mammalian precursor transfer RNA (tRNA) molecules involves two enzymatic steps. First, intron removal by the tRNA splicing endonuclease generates separate 5' and 3' exons. In animals, the second step predominantly entails direct exon ligation by an elusive RNA ligase. Using activity-guided purification of tRNA ligase from HeLa cell extracts, we identified HSPC117, a member of the UPF0027 (RtcB) family, as the essential subunit of a tRNA ligase complex. RNA interference-mediated depletion of HSPC117 inhibited maturation of intron-containing pre-tRNA both in vitro and in living cells. The high sequence conservation of HSPC117/RtcB proteins is suggestive of RNA ligase roles of this protein family in various organisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Popow, Johannes -- Englert, Markus -- Weitzer, Stefan -- Schleiffer, Alexander -- Mierzwa, Beata -- Mechtler, Karl -- Trowitzsch, Simon -- Will, Cindy L -- Luhrmann, Reinhard -- Soll, Dieter -- Martinez, Javier -- New York, N.Y. -- Science. 2011 Feb 11;331(6018):760-4. doi: 10.1126/science.1197847.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), A-1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21311021" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Exons ; HeLa Cells ; Humans ; Introns ; Molecular Sequence Data ; Proteins/*chemistry/isolation & purification/*metabolism ; RNA Interference ; RNA Ligase (ATP)/*chemistry/isolation & purification/*metabolism ; RNA Precursors/*metabolism ; *RNA Splicing ; RNA, Transfer/*metabolism ; Spliceosomes/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 17
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2012-11-20
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621126/" 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/PMC3621126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martinez, Gustavo J -- Rao, Anjana -- R01 CA042471/CA/NCI NIH HHS/ -- R01 CA42471/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2012 Nov 16;338(6109):891-2. doi: 10.1126/science.1231310.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23161983" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Humans ; Immunomodulation/*genetics ; Interferon Regulatory Factors/*metabolism ; *Regulatory Elements, Transcriptional ; Th17 Cells/*immunology ; Transcription Factor AP-1/*metabolism ; *Transcriptional Activation
    Print ISSN: 0036-8075
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  • 18
    Publication Date: 2013-07-06
    Description: The efficacy of therapeutics is dependent on a drug binding to its cognate target. Optimization of target engagement by drugs in cells is often challenging, because drug binding cannot be monitored inside cells. We have developed a method for evaluating drug binding to target proteins in cells and tissue samples. This cellular thermal shift assay (CETSA) is based on the biophysical principle of ligand-induced thermal stabilization of target proteins. Using this assay, we validated drug binding for a set of important clinical targets and monitored processes of drug transport and activation, off-target effects and drug resistance in cancer cell lines, as well as drug distribution in tissues. CETSA is likely to become a valuable tool for the validation and optimization of drug target engagement.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martinez Molina, Daniel -- Jafari, Rozbeh -- Ignatushchenko, Marina -- Seki, Takahiro -- Larsson, E Andreas -- Dan, Chen -- Sreekumar, Lekshmy -- Cao, Yihai -- Nordlund, Par -- New York, N.Y. -- Science. 2013 Jul 5;341(6141):84-7. doi: 10.1126/science.1233606.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23828940" target="_blank"〉PubMed〈/a〉
    Keywords: Antimetabolites, Antineoplastic/metabolism ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Drug Monitoring/*methods ; Folic Acid Antagonists/metabolism ; *Hot Temperature ; Humans ; Kidney/metabolism ; Ligands ; Liver/metabolism ; *Molecular Targeted Therapy ; Pharmaceutical Preparations/*metabolism ; Protein Binding ; Protein Stability ; Proteins/*metabolism ; Quinazolines/metabolism ; Thiophenes/metabolism ; Tissue Distribution
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 19
    Publication Date: 2014-06-21
    Description: Seventeen Middle Pleistocene crania from the Sima de los Huesos site (Atapuerca, Spain) are analyzed, including seven new specimens. This sample makes it possible to thoroughly characterize a Middle Pleistocene hominin paleodeme and to address hypotheses about the origin and evolution of the Neandertals. Using a variety of techniques, the hominin-bearing layer could be reassigned to a period around 430,000 years ago. The sample shows a consistent morphological pattern with derived Neandertal features present in the face and anterior vault, many of which are related to the masticatory apparatus. This suggests that facial modification was the first step in the evolution of the Neandertal lineage, pointing to a mosaic pattern of evolution, with different anatomical and functional modules evolving at different rates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arsuaga, J L -- Martinez, I -- Arnold, L J -- Aranburu, A -- Gracia-Tellez, A -- Sharp, W D -- Quam, R M -- Falgueres, C -- Pantoja-Perez, A -- Bischoff, J -- Poza-Rey, E -- Pares, J M -- Carretero, J M -- Demuro, M -- Lorenzo, C -- Sala, N -- Martinon-Torres, M -- Garcia, N -- Alcazar de Velasco, A -- Cuenca-Bescos, G -- Gomez-Olivencia, A -- Moreno, D -- Pablos, A -- Shen, C-C -- Rodriguez, L -- Ortega, A I -- Garcia, R -- Bonmati, A -- Bermudez de Castro, J M -- Carbonell, E -- New York, N.Y. -- Science. 2014 Jun 20;344(6190):1358-63. doi: 10.1126/science.1253958.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. Departamento de Paleontologia, Facultad Ciencias Geologicas, Universidad Complutense de Madrid, Spain. jlarsuaga@isciii.es. ; Area de Paleontologia, Departamento de Geologia, Geografia y Medio Ambiente, Universidad de Alcala, Spain.Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. ; Centro Nacional de Investigacion sobre la Evolucion Humana Burgos, Spain. School of Earth and Environmental Sciences, the Environment Institute, and the Institute for Photonics and Advanced Sensing (IPAS), University of Adelaide, Australia. ; Departamento Mineralogia y Petrologia, Facultad de Ciencia y Tecnologia, Universidad del Pais Vasco, Spain. ; Berkeley Geochronology Center, Berkeley, CA, USA. ; Department of Anthropology, Binghamton University (State University of New York), Binghamton, NY, USA. Division of Anthropology, American Museum of Natural History, New York, NY, USA.Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. ; Departement de Prehistoire, Museum National d'Histoire Naturelle, Paris, France. ; Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. Departamento de Paleontologia, Facultad Ciencias Geologicas, Universidad Complutense de Madrid, Spain. ; U.S. Geological Survey, Menlo Park, CA,USA. ; Centro Nacional de Investigacion sobre la Evolucion Humana Burgos, Spain. ; Laboratorio de Evolucion Humana, Departamento de Ciencias Historicas y Geografia, Universidad de Burgos, Spain. ; Centro Nacional de Investigacion sobre la Evolucion Humana Burgos, Spain. Institute for Photonics and Advanced Sensing (IPAS), School of Chemistry and Physics, University of Adelaide, Australia. ; Area de Prehistoria, Departamento d'Historia i Historia de l'Art, Universitat Rovira i Virgili (URV), Tarragona, Spain. Institut Catala de Paleoecologia Humana i Evolucio Social, Tarragona, Spain.Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. ; Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. ; Paleontologia, Aragosaurus-IUCA and Facultad Ciencias, Universidad de Zaragoza, Spain. ; Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. Departement de Prehistoire, Museum National d'Histoire Naturelle, Paris, France. PAVE Research Group, Division of Biological Anthropology, Cambridge, UK. ; Departement de Prehistoire, Museum National d'Histoire Naturelle, Paris, France. Laboratorio de Evolucion Humana, Departamento de Ciencias Historicas y Geografia, Universidad de Burgos, Spain. ; Centro Mixto UCM-ISCIII de Evolucion y Comportamiento Humanos, Madrid, Spain. Centro Nacional de Investigacion sobre la Evolucion Humana Burgos, Spain. Laboratorio de Evolucion Humana, Departamento de Ciencias Historicas y Geografia, Universidad de Burgos, Spain. ; High-Precision Mass Spectrometry and Environment Change Laboratory (HISPEC), Department of Geosciences, National Taiwan University, Taiwan ROC. ; Institut Catala de Paleoecologia Humana i Evolucio Social, Tarragona, Spain. Area de Prehistoria, Departamento d'Historia i Historia de l'Art, Universitat Rovira i Virgili (URV), Tarragona, Spain. Institute of Vertebrate Paleontology and Paleoanthropology of Beijing (IVPP), China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24948730" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/anatomy & histology ; Extinction, Biological ; *Fossils ; Genetic Drift ; Humans ; Neanderthals/*anatomy & histology/*genetics ; Organ Size ; Reproductive Isolation ; Skull/*anatomy & histology ; Spain
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 20
    Publication Date: 2014-10-04
    Description: The thermal stability of proteins can be used to assess ligand binding in living cells. We have generalized this concept by determining the thermal profiles of more than 7000 proteins in human cells by means of mass spectrometry. Monitoring the effects of small-molecule ligands on the profiles delineated more than 50 targets for the kinase inhibitor staurosporine. We identified the heme biosynthesis enzyme ferrochelatase as a target of kinase inhibitors and suggest that its inhibition causes the phototoxicity observed with vemurafenib and alectinib. Thermal shifts were also observed for downstream effectors of drug treatment. In live cells, dasatinib induced shifts in BCR-ABL pathway proteins, including CRK/CRKL. Thermal proteome profiling provides an unbiased measure of drug-target engagement and facilitates identification of markers for drug efficacy and toxicity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Savitski, Mikhail M -- Reinhard, Friedrich B M -- Franken, Holger -- Werner, Thilo -- Savitski, Maria Falth -- Eberhard, Dirk -- Martinez Molina, Daniel -- Jafari, Rozbeh -- Dovega, Rebecca Bakszt -- Klaeger, Susan -- Kuster, Bernhard -- Nordlund, Par -- Bantscheff, Marcus -- Drewes, Gerard -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):1255784. doi: 10.1126/science.1255784. Epub 2014 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. mikhail.m.savitski@gsk.com marcus.x.bantscheff@gsk.com gerard.c.drewes@gsk.com. ; Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany. ; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. ; Department of Proteomics and Bioanalytics, Technische Universitat Munchen, Emil Erlenmeyer Forum 5, Freising, Germany. German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany. ; Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Centre for Biomedical Structural Biology, Nanyang Technological University, Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278616" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Antineoplastic Agents/*pharmacology ; Hot Temperature ; Humans ; K562 Cells ; Ligands ; Protein Binding ; Protein Denaturation ; Protein Stability ; Proteome/*drug effects ; Proteomics/*methods
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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