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  • 1
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    Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions (2017)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2017-06-16
    Description: Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.
    Keywords: Chemistry, Engineering
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Magnetic Field and Plasma Observations at Mars: Initial Results of the Mars Global Surveyor Mission (1998)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1998-03-13
    Description: The magnetometer and electron reflectometer investigation (MAG/ER) on the Mars Global Surveyor spacecraft has obtained magnetic field and plasma observations throughout the near-Mars environment, from beyond the influence of Mars to just above the surface (at an altitude of approximately 100 kilometers). The solar wind interaction with Mars is in many ways similar to that at Venus and at an active comet, that is, primarily an ionospheric-atmospheric interaction. No significant planetary magnetic field of global scale has been detected to date (〈2 x 10(21) Gauss-cubic centimeter), but here the discovery of multiple magnetic anomalies of small spatial scale in the crust of Mars is reported.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Acuna -- Connerney -- Wasilewski -- Lin -- Anderson -- Carlson -- McFadden -- Curtis -- Mitchell -- Reme -- Mazelle -- Sauvaud -- d'Uston -- Cros -- Medale -- Bauer -- Cloutier -- Mayhew -- Winterhalter -- Ness -- New York, N.Y. -- Science. 1998 Mar 13;279(5357):1676-80.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉M. H. Acuna, J. E. P. Connerney, P. Wasilewski, NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA. R. P. Lin, Space Sciences Laboratory and Department of Physics, University of California, Berkeley, CA 94720, USA. K. A. Anderson, C. W. Carlson, J. McFadden, D. W. Curtis, D. Mitchell, Space Sciences Laboratory, University of California, Berkeley, CA 94720, USA. H. Reme, C. Mazelle, J. A. Sauvaud, C. d'Uston, A. Cros, J. L. Medale, Centre d'Etude Spatiale des Rayonnements, 31209 Toulouse Cedex, France. S. J. Bauer, University of Graz and Space Research Institute, A-8010 Graz, Austria. P. Cloutier, Department of Space Physics and Astronomy, Rice University, Houston, TX 77005, USA. M. Mayhew, National Science Foundation, Arlington, VA 22230, USA. D. Winterhalter, Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109, USA. N. F. Ness, Bartol Research Institute, University of Delaware, Newark, DE 19716, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9497279" target="_blank"〉PubMed〈/a〉
    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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  • 3
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    The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease (2001)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2001-11-27
    Description: Multiple sclerosis is a demyelinating disease, characterized by inflammation in the brain and spinal cord, possibly due to autoimmunity. Large-scale sequencing of cDNA libraries, derived from plaques dissected from brains of patients with multiple sclerosis (MS), indicated an abundance of transcripts for osteopontin (OPN). Microarray analysis of spinal cords from rats paralyzed by experimental autoimmune encephalomyelitis (EAE), a model of MS, also revealed increased OPN transcripts. Osteopontin-deficient mice were resistant to progressive EAE and had frequent remissions, and myelin-reactive T cells in OPN-/- mice produced more interleukin 10 and less interferon-gamma than in OPN+/+ mice. Osteopontin thus appears to regulate T helper cell-1 (TH1)-mediated demyelinating disease, and it may offer a potential target in blocking development of progressive MS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chabas, D -- Baranzini, S E -- Mitchell, D -- Bernard, C C -- Rittling, S R -- Denhardt, D T -- Sobel, R A -- Lock, C -- Karpuj, M -- Pedotti, R -- Heller, R -- Oksenberg, J R -- Steinman, L -- New York, N.Y. -- Science. 2001 Nov 23;294(5547):1731-5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, B002, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11721059" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Encephalomyelitis, Autoimmune, ; Experimental/genetics/immunology/metabolism/pathology ; Expressed Sequence Tags ; Gene Deletion ; *Gene Expression Profiling ; Gene Library ; Humans ; Inflammation/genetics/immunology/metabolism/pathology ; Interferon-gamma/genetics/metabolism ; Interleukin-10/genetics/metabolism ; Lymphocyte Activation ; Mice ; Mice, Knockout ; Multiple Sclerosis/*genetics/immunology/*metabolism/pathology ; Oligonucleotide Array Sequence Analysis ; Osteopontin ; RNA, Messenger/genetics/metabolism ; Rats ; Sialoglycoproteins/deficiency/genetics/*metabolism ; Spinal Cord/metabolism ; Th1 Cells/immunology
    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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  • 4
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    Global distribution of crustal magnetization discovered by the mars global surveyor MAG/ER experiment (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-04-30
    Description: Vector magnetic field observations of the martian crust were acquired by the Mars Global Surveyor (MGS) magnetic field experiment/electron reflectometer (MAG/ER) during the aerobraking and science phasing orbits, at altitudes between approximately 100 and 200 kilometers. Magnetic field sources of multiple scales, strength, and geometry were observed. There is a correlation between the location of the sources and the ancient cratered terrain of the martian highlands. The absence of crustal magnetism near large impact basins such as Hellas and Argyre implies cessation of internal dynamo action during the early Naochian epoch ( approximately 4 billion years ago). Sources with equivalent magnetic moments as large as 1.3 x 10(17) ampere-meter2 in the Terra Sirenum region contribute to the development of an asymmetrical, time-variable obstacle to solar wind flow around Mars.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Acuna -- Connerney -- Ness -- Lin -- Mitchell -- Carlson -- McFadden -- Anderson -- Reme -- Mazelle -- Vignes -- Wasilewski -- Cloutier -- New York, N.Y. -- Science. 1999 Apr 30;284(5415):790-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉NASA Goddard Space Flight Center, Greenbelt, MD 20771, USA. Bartol Research Institute, University of Delaware, Newark, DE 19716, USA. Space Sciences Laboratory, University of California, Berkeley, CA 94720, USA. Centre d'Etude Spatiale des Rayonn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10221908" target="_blank"〉PubMed〈/a〉
    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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  • 5
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    Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-08-10
    Description: Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.
    Keywords: Development, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis (2008)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2008-03-01
    Description: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder characterized pathologically by ubiquitinated TAR DNA binding protein (TDP-43) inclusions. The function of TDP-43 in the nervous system is uncertain, and a mechanistic role in neurodegeneration remains speculative. We identified neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases. TARDBPM337V segregated with disease within one kindred and a genome-wide scan confirmed that linkage was restricted to chromosome 1p36, which contains the TARDBP locus. Mutant forms of TDP-43 fragmented in vitro more readily than wild type and, in vivo, caused neural apoptosis and developmental delay in the chick embryo. Our evidence suggests a pathophysiological link between TDP-43 and ALS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sreedharan, Jemeen -- Blair, Ian P -- Tripathi, Vineeta B -- Hu, Xun -- Vance, Caroline -- Rogelj, Boris -- Ackerley, Steven -- Durnall, Jennifer C -- Williams, Kelly L -- Buratti, Emanuele -- Baralle, Francisco -- de Belleroche, Jacqueline -- Mitchell, J Douglas -- Leigh, P Nigel -- Al-Chalabi, Ammar -- Miller, Christopher C -- Nicholson, Garth -- Shaw, Christopher E -- G0500289/Medical Research Council/United Kingdom -- G0501573/Medical Research Council/United Kingdom -- G0600974/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2008 Mar 21;319(5870):1668-72. doi: 10.1126/science.1154584. Epub 2008 Feb 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, and Institute of Psychiatry, London, SE5 8AF, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18309045" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Amino Acid Sequence ; Amino Acid Substitution ; Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Apoptosis ; CHO Cells ; Chick Embryo ; Chromosomes, Human, Pair 1/genetics ; Cricetinae ; Cricetulus ; DNA-Binding Proteins/chemistry/*genetics/physiology ; Embryonic Development ; Female ; Humans ; Male ; Microsatellite Repeats ; Middle Aged ; Molecular Sequence Data ; Mutant Proteins/chemistry/physiology ; *Mutation, Missense ; Neurons/cytology/physiology
    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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  • 7
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    Global observations of the interstellar interaction from the Interstellar Boundary Explorer (IBEX) (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-10-17
    Description: The Sun moves through the local interstellar medium, continuously emitting ionized, supersonic solar wind plasma and carving out a cavity in interstellar space called the heliosphere. The recently launched Interstellar Boundary Explorer (IBEX) spacecraft has completed its first all-sky maps of the interstellar interaction at the edge of the heliosphere by imaging energetic neutral atoms (ENAs) emanating from this region. We found a bright ribbon of ENA emission, unpredicted by prior models or theories, that may be ordered by the local interstellar magnetic field interacting with the heliosphere. This ribbon is superposed on globally distributed flux variations ordered by both the solar wind structure and the direction of motion through the interstellar medium. Our results indicate that the external galactic environment strongly imprints the heliosphere.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McComas, D J -- Allegrini, F -- Bochsler, P -- Bzowski, M -- Christian, E R -- Crew, G B -- DeMajistre, R -- Fahr, H -- Fichtner, H -- Frisch, P C -- Funsten, H O -- Fuselier, S A -- Gloeckler, G -- Gruntman, M -- Heerikhuisen, J -- Izmodenov, V -- Janzen, P -- Knappenberger, P -- Krimigis, S -- Kucharek, H -- Lee, M -- Livadiotis, G -- Livi, S -- MacDowall, R J -- Mitchell, D -- Mobius, E -- Moore, T -- Pogorelov, N V -- Reisenfeld, D -- Roelof, E -- Saul, L -- Schwadron, N A -- Valek, P W -- Vanderspek, R -- Wurz, P -- Zank, G P -- New York, N.Y. -- Science. 2009 Nov 13;326(5955):959-62. doi: 10.1126/science.1180906. Epub 2009 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Southwest Research Institute, San Antonio, TX 78228, USA. dmccomas@swri.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19833923" target="_blank"〉PubMed〈/a〉
    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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  • 8
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    Areawide suppression of European corn borer with Bt maize reaps savings to non-Bt maize growers (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-10-12
    Description: Transgenic maize engineered to express insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) has become widely adopted in U.S. agriculture. In 2009, Bt maize was planted on more than 22.2 million hectares, constituting 63% of the U.S. crop. Using statistical analysis of per capita growth rate estimates, we found that areawide suppression of the primary pest Ostrinia nubilalis (European corn borer) is associated with Bt maize use. Cumulative benefits over 14 years are an estimated $3.2 billion for maize growers in Illinois, Minnesota, and Wisconsin, with more than $2.4 billion of this total accruing to non-Bt maize growers. Comparable estimates for Iowa and Nebraska are $3.6 billion in total, with $1.9 billion for non-Bt maize growers. These results affirm theoretical predictions of pest population suppression and highlight economic incentives for growers to maintain non-Bt maize refugia for sustainable insect resistance management.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hutchison, W D -- Burkness, E C -- Mitchell, P D -- Moon, R D -- Leslie, T W -- Fleischer, S J -- Abrahamson, M -- Hamilton, K L -- Steffey, K L -- Gray, M E -- Hellmich, R L -- Kaster, L V -- Hunt, T E -- Wright, R J -- Pecinovsky, K -- Rabaey, T L -- Flood, B R -- Raun, E S -- New York, N.Y. -- Science. 2010 Oct 8;330(6001):222-5. doi: 10.1126/science.1190242.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Entomology, University of Minnesota, St. Paul, MN 55108, USA. hutch002@umn.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20929774" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacillus thuringiensis/genetics ; Bacterial Proteins/*genetics ; Crops, Agricultural/*economics/growth & development ; Endotoxins/*genetics ; Hemolysin Proteins/*genetics ; Insecticide Resistance ; Midwestern United States ; *Moths/physiology ; *Pest Control, Biological/economics/methods ; Plants, Genetically Modified/growth & development ; Population Density ; Population Dynamics ; Zea mays/*genetics/growth & development
    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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  • 9
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    Ecosystem service supply and vulnerability to global change in Europe (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-10-29
    Description: Global change will alter the supply of ecosystem services that are vital for human well-being. To investigate ecosystem service supply during the 21st century, we used a range of ecosystem models and scenarios of climate and land-use change to conduct a Europe-wide assessment. Large changes in climate and land use typically resulted in large changes in ecosystem service supply. Some of these trends may be positive (for example, increases in forest area and productivity) or offer opportunities (for example, "surplus land" for agricultural extensification and bioenergy production). However, many changes increase vulnerability as a result of a decreasing supply of ecosystem services (for example, declining soil fertility, declining water availability, increasing risk of forest fires), especially in the Mediterranean and mountain regions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schroter, Dagmar -- Cramer, Wolfgang -- Leemans, Rik -- Prentice, I Colin -- Araujo, Miguel B -- Arnell, Nigel W -- Bondeau, Alberte -- Bugmann, Harald -- Carter, Timothy R -- Gracia, Carlos A -- de la Vega-Leinert, Anne C -- Erhard, Markus -- Ewert, Frank -- Glendining, Margaret -- House, Joanna I -- Kankaanpaa, Susanna -- Klein, Richard J T -- Lavorel, Sandra -- Lindner, Marcus -- Metzger, Marc J -- Meyer, Jeannette -- Mitchell, Timothy D -- Reginster, Isabelle -- Rounsevell, Mark -- Sabate, Santi -- Sitch, Stephen -- Smith, Ben -- Smith, Jo -- Smith, Pete -- Sykes, Martin T -- Thonicke, Kirsten -- Thuiller, Wilfried -- Tuck, Gill -- Zaehle, Sonke -- Zierl, Barbel -- New York, N.Y. -- Science. 2005 Nov 25;310(5752):1333-7. Epub 2005 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Potsdam Institute for Climate Impact Research, 14473 Potsdam, Germany. dagmar.schroeter@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16254151" target="_blank"〉PubMed〈/a〉
    Keywords: Agriculture ; Biodiversity ; Carbon ; Climate ; Conservation of Natural Resources ; Crops, Agricultural ; *Ecosystem ; Environment ; Europe ; Greenhouse Effect ; Humans ; Models, Statistical ; Models, Theoretical ; Socioeconomic Factors ; Trees/growth & development ; Urban Population ; Water Supply ; Wood
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 10
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    What causes lesions in sperm whale bones? (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-05-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mitchell, Edward D -- New York, N.Y. -- Science. 2005 Apr 29;308(5722):631-2; author reply 631-2.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15864831" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone and Bones/*pathology ; Diving ; Fossils ; Humans ; Whales/*anatomy & histology/physiology
    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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