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  • 1
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    N-myristoyltransferase inhibitors as new leads to treat sleeping sickness (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-04-03
    Description: African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma brucei spp., is responsible for approximately 30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target-T. brucei N-myristoyltransferase-leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917743/" 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/PMC2917743/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Frearson, Julie A -- Brand, Stephen -- McElroy, Stuart P -- Cleghorn, Laura A T -- Smid, Ondrej -- Stojanovski, Laste -- Price, Helen P -- Guther, M Lucia S -- Torrie, Leah S -- Robinson, David A -- Hallyburton, Irene -- Mpamhanga, Chidochangu P -- Brannigan, James A -- Wilkinson, Anthony J -- Hodgkinson, Michael -- Hui, Raymond -- Qiu, Wei -- Raimi, Olawale G -- van Aalten, Daan M F -- Brenk, Ruth -- Gilbert, Ian H -- Read, Kevin D -- Fairlamb, Alan H -- Ferguson, Michael A J -- Smith, Deborah F -- Wyatt, Paul G -- 077503/Wellcome Trust/United Kingdom -- 077705/Wellcome Trust/United Kingdom -- 085622/Wellcome Trust/United Kingdom -- 087590/Wellcome Trust/United Kingdom -- 1097737/Canadian Institutes of Health Research/Canada -- G0900138/Medical Research Council/United Kingdom -- G0900138(90614)/Medical Research Council/United Kingdom -- WT077503/Wellcome Trust/United Kingdom -- WT077705/Wellcome Trust/United Kingdom -- WT083481,/Wellcome Trust/United Kingdom -- WT085622/Wellcome Trust/United Kingdom -- England -- Nature. 2010 Apr 1;464(7289):728-32. doi: 10.1038/nature08893.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360736" target="_blank"〉PubMed〈/a〉
    Keywords: Acyltransferases/*antagonists & inhibitors/metabolism ; Aminopyridines/chemistry/metabolism/pharmacology/therapeutic use ; Animals ; Antiparasitic Agents/chemistry/metabolism/*pharmacology/*therapeutic use ; Enzyme Assays ; Enzyme Inhibitors/chemistry/metabolism/pharmacology/therapeutic use ; Female ; Humans ; Mice ; Molecular Structure ; Pyrazoles/chemistry/metabolism/pharmacology/therapeutic use ; Rats ; Sulfonamides/chemistry/metabolism/pharmacology/therapeutic use ; Time Factors ; Trypanosoma brucei brucei/*drug effects/*enzymology/growth & development ; Trypanosomiasis, African/*drug therapy/*parasitology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Partitioning regulatory mechanisms of within-host malaria dynamics using the effective propagation number (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-08-20
    Description: Immune clearance and resource limitation (via red blood cell depletion) shape the peaks and troughs of malaria parasitemia, which in turn affect disease severity and transmission. Quantitatively partitioning the relative roles of these effects through time is challenging. Using data from rodent malaria, we estimated the effective propagation number, which reflects the relative importance of contrasting within-host control mechanisms through time and is sensitive to the inoculating parasite dose. Our analysis showed that the capacity of innate responses to restrict initial parasite growth saturates with parasite dose and that experimentally enhanced innate immunity can affect parasite density indirectly via resource depletion. Such a statistical approach offers a tool to improve targeting of drugs or vaccines for human therapy by revealing the dynamics and interactions of within-host regulatory mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3891600/" 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/PMC3891600/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metcalf, C J E -- Graham, A L -- Huijben, S -- Barclay, V C -- Long, G H -- Grenfell, B T -- Read, A F -- Bjornstad, O N -- R01 GM089932/GM/NIGMS NIH HHS/ -- R01GM089932/GM/NIGMS NIH HHS/ -- R24 HD047879/HD/NICHD NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2011 Aug 19;333(6045):984-8. doi: 10.1126/science.1204588.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Zoology, Oxford University, Oxford OX1 3PS, UK. charlotte.metcalf@zoo.ox.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21852493" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptive Immunity ; Animals ; Antibodies/immunology ; CD4-Positive T-Lymphocytes/immunology ; Erythrocyte Aging ; Erythrocyte Count ; Erythrocytes/*parasitology/physiology ; Host-Parasite Interactions ; Humans ; Immunity, Innate ; Interleukin-10/immunology/metabolism ; Malaria/blood/*immunology/*parasitology ; Mice ; Models, Biological ; Models, Statistical ; *Parasitemia/blood/immunology/parasitology ; Plasmodium chabaudi/immunology/*physiology ; Receptors, Interleukin-10/immunology ; Regression Analysis
    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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  • 3
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    Fungal pathogen reduces potential for malaria transmission (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-06-11
    Description: Using a rodent malaria model, we found that exposure to surfaces treated with fungal entomopathogens following an infectious blood meal reduced the number of mosquitoes able to transmit malaria by a factor of about 80. Fungal infection, achieved through contact with both solid surfaces and netting for durations well within the typical post-feed resting periods, was sufficient to cause 〉90% mortality. Daily mortality rates escalated dramatically around the time of sporozoite maturation, and infected mosquitoes showed reduced propensity to blood feed. Residual sprays of fungal biopesticides might replace or supplement chemical insecticides for malaria control, particularly in areas of high insecticide resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blanford, Simon -- Chan, Brian H K -- Jenkins, Nina -- Sim, Derek -- Turner, Ruth J -- Read, Andrew F -- Thomas, Matt B -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2005 Jun 10;308(5728):1638-41.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institutes of Evolution, Immunology, and Infection Research, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, Edinburgh EH9 3JT Scotland, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15947189" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles/*microbiology/*parasitology/physiology ; Blood ; Feeding Behavior ; *Hypocreales/pathogenicity/physiology ; Insect Vectors/microbiology/parasitology/physiology ; Malaria/parasitology/prevention & control/*transmission ; Mice ; *Mitosporic Fungi/pathogenicity/physiology ; *Pest Control, Biological ; Plasmodium chabaudi/*growth & development/physiology ; Spores, Fungal ; Virulence
    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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    GTF2IRD1 in craniofacial development of humans and mice (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-11-19
    Description: Craniofacial abnormalities account for about one-third of all human congenital defects, but our understanding of the genetic mechanisms governing craniofacial development is incomplete. We show that GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development, and we implicate another member of the TFII-I transcription factor family, GTF2I, in both aspects. Gtf2ird1-null mice exhibit phenotypic abnormalities reminiscent of the human microdeletion disorder Williams-Beuren syndrome (WBS); craniofacial imaging reveals abnormalities in both skull and jaws that may arise through misregulation of goosecoid, a downstream target of Gtf2ird1. In humans, a rare WBS individual with an atypical deletion, including GTF2IRD1, shows facial dysmorphism and cognitive deficits that differ from those of classic WBS cases. We propose a mechanism of cumulative dosage effects of duplicated and diverged genes applicable to other human chromosomal disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tassabehji, May -- Hammond, Peter -- Karmiloff-Smith, Annette -- Thompson, Pamela -- Thorgeirsson, Snorri S -- Durkin, Marian E -- Popescu, Nicholas C -- Hutton, Timothy -- Metcalfe, Kay -- Rucka, Agnes -- Stewart, Helen -- Read, Andrew P -- Maconochie, Mark -- Donnai, Dian -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2005 Nov 18;310(5751):1184-7. Epub 2005 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Academic Unit of Medical Genetics, University of Manchester, St. Mary's Hospital, Manchester M13 9PL, UK. m.tassabehji@manchester.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16293761" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Animals ; Cell Line ; Child ; Child, Preschool ; Chromosomes, Human, Pair 7 ; Craniofacial Abnormalities/*genetics ; Face/*embryology ; Female ; Gene Deletion ; Goosecoid Protein/genetics/physiology ; Homozygote ; Humans ; Infant ; Infant, Newborn ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Mice, Transgenic ; Muscle Proteins/*physiology ; Nuclear Proteins/*physiology ; Skull/*embryology ; Trans-Activators/*physiology ; Transcription Factors, TFII/physiology ; Williams Syndrome/*genetics
    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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    Automated design of ligands to polypharmacological profiles (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-12-14
    Description: The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653568/" 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/PMC3653568/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Besnard, Jeremy -- Ruda, Gian Filippo -- Setola, Vincent -- Abecassis, Keren -- Rodriguiz, Ramona M -- Huang, Xi-Ping -- Norval, Suzanne -- Sassano, Maria F -- Shin, Antony I -- Webster, Lauren A -- Simeons, Frederick R C -- Stojanovski, Laste -- Prat, Annik -- Seidah, Nabil G -- Constam, Daniel B -- Bickerton, G Richard -- Read, Kevin D -- Wetsel, William C -- Gilbert, Ian H -- Roth, Bryan L -- Hopkins, Andrew L -- 083481/Wellcome Trust/United Kingdom -- BB/FOF/PF/15/09/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J010510/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MH082441/MH/NIMH NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- WT 083481/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):215-20. doi: 10.1038/nature11691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Automation ; Drug Delivery Systems ; *Drug Design ; Female ; *Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Models, Theoretical ; Pharmacological Phenomena ; Reproducibility of Results
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 6
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    Disentangling genetic variation for resistance and tolerance to infectious diseases in animals (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-11-03
    Description: Hosts can in principle employ two different strategies to defend themselves against parasites: resistance and tolerance. Animals typically exhibit considerable genetic variation for resistance (the ability to limit parasite burden). However, little is known about whether animals can evolve tolerance (the ability to limit the damage caused by a given parasite burden). Using rodent malaria in laboratory mice as a model system and the statistical framework developed by plant-pathogen biologists, we demonstrated genetic variation for tolerance, as measured by the extent to which anemia and weight loss increased with increasing parasite burden. Moreover, resistance and tolerance were negatively genetically correlated. These results mean that animals, like plants, can evolve two conceptually different types of defense, a finding that has important implications for the understanding of the epidemiology and evolution of infectious diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raberg, Lars -- Sim, Derek -- Read, Andrew F -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2007 Nov 2;318(5851):812-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Evolutionary Biology and Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK. lars.raberg@zooekol.lu.se〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17975068" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia/genetics/physiopathology ; Animals ; Biological Evolution ; Disease Models, Animal ; Erythrocyte Count ; *Genetic Variation ; Host-Parasite Interactions ; Immunity, Innate/*genetics ; Malaria/*genetics/physiopathology ; Mice ; Mice, Inbred Strains ; *Plasmodium chabaudi ; Statistics as Topic
    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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    Variations in the Free Chlorine Content of the Stratosphere (1991-1997): Anthropogenic an Volcanic Influences (1999)
    In:  Other Sources
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    Publication Date: 2018-06-08
    Description: Remote sensing of chlorine monoxide (CIO) by the Microwave Limb Sounder (MLS) experiment aboard the Upper Atmosphere Research Satellite (UARS) has provided global measurements of variations in stratospheric free chlorine (for 1991 to 1997).
    Keywords: Geophysics
    Type: Journal of Geophysical Research
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  • 8
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    The Evolution of UARS MLS Ozone in Relation to the Northern Hemisphere Polar Vortex (1993)
    In:  Other Sources
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    Publication Date: 2018-06-08
    Description: The evolution of ozone observed by UARS MLS in the Northern Hemisphere polar vortex is shown as a function of time throughout the stratosphere, for the 1991-1992 and 1992-1993 winters.
    Keywords: Geophysics
    Type: American Geophysical Union; Baltimore, MD; United States
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  • 9
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    Mid-latitude Ozone and CIO Trends Based on Two Years of UARS MLS Data (1993)
    In:  Other Sources
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    Publication Date: 2018-06-08
    Description: Variations in ozone and chlorine monoxide observed by the Microwave Limb Sounder (MLS) abroad the Upper Atmosphere Research Satellite (UARS) during the first two years of operation are presented. We focus on mid-latitudes, where significant ozone decreases are observed in the lower stratosphere, and we offer some comparisons with other data sets. We will attempt to place the mid-latitude changes in context with changes observed at other latitudes. Possible correlations between the MLS ozone and CIO observations will be discussed.
    Keywords: Geophysics
    Type: American Geophysical Union: Geophysics; San Francisco, CA; United States
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  • 10
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    Enhancements in lower stratospheric CH3CN observed by the upper atmosphere research Sattellite Microwave Limb Sounder following boreal forest fires (2004)
    In:  Other Sources
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    Publication Date: 2018-06-08
    Description: On 25 August 1992, the Microwave Limb Sounder (MLS) on the Upper Atmosphere Research Satellite observed a significant enhancement in the abundance of lower stratospheric methyl cyanide (CH3CN) at 100??hPa (~16??km altitude) in a small region off the east coast of Florida.
    Keywords: Geophysics
    Type: Journal of Geophysical Research; Volume 109
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