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  • 1
    Publication Date: 2015-02-14
    Description: Although it is generally accepted that cellular differentiation requires changes to transcriptional networks, dynamic regulation of promoters and enhancers at specific sets of genes has not been previously studied en masse. Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Enhancer RNAs, then messenger RNAs encoding transcription factors, dominated the earliest responses. Binding sites for key lineage transcription factors were simultaneously overrepresented in enhancers and promoters active in each cellular system. Our data support a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681433/" 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/PMC4681433/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arner, Erik -- Daub, Carsten O -- Vitting-Seerup, Kristoffer -- Andersson, Robin -- Lilje, Berit -- Drablos, Finn -- Lennartsson, Andreas -- Ronnerblad, Michelle -- Hrydziuszko, Olga -- Vitezic, Morana -- Freeman, Tom C -- Alhendi, Ahmad M N -- Arner, Peter -- Axton, Richard -- Baillie, J Kenneth -- Beckhouse, Anthony -- Bodega, Beatrice -- Briggs, James -- Brombacher, Frank -- Davis, Margaret -- Detmar, Michael -- Ehrlund, Anna -- Endoh, Mitsuhiro -- Eslami, Afsaneh -- Fagiolini, Michela -- Fairbairn, Lynsey -- Faulkner, Geoffrey J -- Ferrai, Carmelo -- Fisher, Malcolm E -- Forrester, Lesley -- Goldowitz, Daniel -- Guler, Reto -- Ha, Thomas -- Hara, Mitsuko -- Herlyn, Meenhard -- Ikawa, Tomokatsu -- Kai, Chieko -- Kawamoto, Hiroshi -- Khachigian, Levon M -- Klinken, S Peter -- Kojima, Soichi -- Koseki, Haruhiko -- Klein, Sarah -- Mejhert, Niklas -- Miyaguchi, Ken -- Mizuno, Yosuke -- Morimoto, Mitsuru -- Morris, Kelly J -- Mummery, Christine -- Nakachi, Yutaka -- Ogishima, Soichi -- Okada-Hatakeyama, Mariko -- Okazaki, Yasushi -- Orlando, Valerio -- Ovchinnikov, Dmitry -- Passier, Robert -- Patrikakis, Margaret -- Pombo, Ana -- Qin, Xian-Yang -- Roy, Sugata -- Sato, Hiroki -- Savvi, Suzana -- Saxena, Alka -- Schwegmann, Anita -- Sugiyama, Daisuke -- Swoboda, Rolf -- Tanaka, Hiroshi -- Tomoiu, Andru -- Winteringham, Louise N -- Wolvetang, Ernst -- Yanagi-Mizuochi, Chiyo -- Yoneda, Misako -- Zabierowski, Susan -- Zhang, Peter -- Abugessaisa, Imad -- Bertin, Nicolas -- Diehl, Alexander D -- Fukuda, Shiro -- Furuno, Masaaki -- Harshbarger, Jayson -- Hasegawa, Akira -- Hori, Fumi -- Ishikawa-Kato, Sachi -- Ishizu, Yuri -- Itoh, Masayoshi -- Kawashima, Tsugumi -- Kojima, Miki -- Kondo, Naoto -- Lizio, Marina -- Meehan, Terrence F -- Mungall, Christopher J -- Murata, Mitsuyoshi -- Nishiyori-Sueki, Hiromi -- Sahin, Serkan -- Nagao-Sato, Sayaka -- Severin, Jessica -- de Hoon, Michiel J L -- Kawai, Jun -- Kasukawa, Takeya -- Lassmann, Timo -- Suzuki, Harukazu -- Kawaji, Hideya -- Summers, Kim M -- Wells, Christine -- FANTOM Consortium -- Hume, David A -- Forrest, Alistair R R -- Sandelin, Albin -- Carninci, Piero -- Hayashizaki, Yoshihide -- P30 CA010815/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 27;347(6225):1010-4. doi: 10.1126/science.1259418. Epub 2015 Feb 12.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25678556" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cattle ; Cell Differentiation/*genetics ; Dogs ; *Enhancer Elements, Genetic ; *Gene Expression Regulation, Developmental ; Mice ; RNA, Messenger/genetics/metabolism ; Rats ; Stem Cells/*cytology/metabolism ; Transcription Factors/*metabolism ; *Transcription, Genetic
    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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  • 2
    Publication Date: 2016-03-24
    Description: Developmental disabilities, including attention-deficit hyperactivity disorder (ADHD), intellectual disability (ID), and autism spectrum disorders (ASD), affect one in six children in the USA. Recently, gene mutations in patched domain containing 1 (PTCHD1) have been found in ~1% of patients with ID and ASD. Individuals with PTCHD1 deletion show symptoms of ADHD, sleep disruption, hypotonia, aggression, ASD, and ID. Although PTCHD1 is probably critical for normal development, the connection between its deletion and the ensuing behavioural defects is poorly understood. Here we report that during early post-natal development, mouse Ptchd1 is selectively expressed in the thalamic reticular nucleus (TRN), a group of GABAergic neurons that regulate thalamocortical transmission, sleep rhythms, and attention. Ptchd1 deletion attenuates TRN activity through mechanisms involving small conductance calcium-dependent potassium currents (SK). TRN-restricted deletion of Ptchd1 leads to attention deficits and hyperactivity, both of which are rescued by pharmacological augmentation of SK channel activity. Global Ptchd1 deletion recapitulates learning impairment, hyper-aggression, and motor defects, all of which are insensitive to SK pharmacological targeting and not found in the TRN-restricted deletion mouse. This study maps clinically relevant behavioural phenotypes onto TRN dysfunction in a human disease model, while also identifying molecular and circuit targets for intervention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4875756/" 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/PMC4875756/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wells, Michael F -- Wimmer, Ralf D -- Schmitt, L Ian -- Feng, Guoping -- Halassa, Michael M -- F31 MH098641/MH/NIMH NIH HHS/ -- R00 NS078115/NS/NINDS NIH HHS/ -- R01 MH097104/MH/NIMH NIH HHS/ -- R01 MH107680/MH/NIMH NIH HHS/ -- R01MH097104/MH/NIMH NIH HHS/ -- R01MH10768/MH/NIMH NIH HHS/ -- England -- Nature. 2016 Apr 7;532(7597):58-63. doi: 10.1038/nature17427. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Neuroscience Institute, New York University Langone Medical Center, New York, New York 10016, USA. ; Department of Neuroscience and Physiology, New York University Langone Medical Center, New York, New York 10016, USA. ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; Department of Psychiatry, New York University Langone Medical Center, New York, New York 10016, USA. ; Center for Neural Science, New York University, New York, New York 1003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007844" target="_blank"〉PubMed〈/a〉
    Keywords: Aggression ; Animals ; Animals, Newborn ; Attention ; Attention Deficit Disorder with ; Hyperactivity/genetics/*physiopathology/*psychology ; Behavior, Animal ; Disease Models, Animal ; Electric Conductivity ; Female ; GABAergic Neurons/metabolism/pathology ; *Gene Deletion ; Humans ; Learning Disorders/genetics/physiopathology ; Male ; Membrane Proteins/*deficiency/*genetics/metabolism ; Mice ; Mice, Knockout ; Motor Disorders/genetics/physiopathology ; Neural Inhibition ; Potassium Channels, Calcium-Activated/metabolism ; Sleep ; Sleep Deprivation/genetics/physiopathology ; Thalamic Nuclei/pathology/*physiopathology
    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: 2016-03-05
    Description: The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Travis K -- Jordan, Robert -- Lo, Michael K -- Ray, Adrian S -- Mackman, Richard L -- Soloveva, Veronica -- Siegel, Dustin -- Perron, Michel -- Bannister, Roy -- Hui, Hon C -- Larson, Nate -- Strickley, Robert -- Wells, Jay -- Stuthman, Kelly S -- Van Tongeren, Sean A -- Garza, Nicole L -- Donnelly, Ginger -- Shurtleff, Amy C -- Retterer, Cary J -- Gharaibeh, Dima -- Zamani, Rouzbeh -- Kenny, Tara -- Eaton, Brett P -- Grimes, Elizabeth -- Welch, Lisa S -- Gomba, Laura -- Wilhelmsen, Catherine L -- Nichols, Donald K -- Nuss, Jonathan E -- Nagle, Elyse R -- Kugelman, Jeffrey R -- Palacios, Gustavo -- Doerffler, Edward -- Neville, Sean -- Carra, Ernest -- Clarke, Michael O -- Zhang, Lijun -- Lew, Willard -- Ross, Bruce -- Wang, Queenie -- Chun, Kwon -- Wolfe, Lydia -- Babusis, Darius -- Park, Yeojin -- Stray, Kirsten M -- Trancheva, Iva -- Feng, Joy Y -- Barauskas, Ona -- Xu, Yili -- Wong, Pamela -- Braun, Molly R -- Flint, Mike -- McMullan, Laura K -- Chen, Shan-Shan -- Fearns, Rachel -- Swaminathan, Swami -- Mayers, Douglas L -- Spiropoulou, Christina F -- Lee, William A -- Nichol, Stuart T -- Cihlar, Tomas -- Bavari, Sina -- R01 AI113321/AI/NIAID NIH HHS/ -- R01AI113321/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA. ; United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. ; Boston University School of Medicine, Boston, Massachusetts 02118, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934220" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine/*analogs & derivatives/pharmacokinetics/pharmacology/therapeutic use ; Amino Acid Sequence ; Animals ; Antiviral Agents/pharmacokinetics/pharmacology/*therapeutic use ; Cell Line, Tumor ; Ebolavirus/drug effects ; Female ; HeLa Cells ; Hemorrhagic Fever, Ebola/*drug therapy/prevention & control ; Humans ; Macaca mulatta/*virology ; Male ; Molecular Sequence Data ; Organ Specificity ; Prodrugs/pharmacokinetics/pharmacology/therapeutic use ; Ribonucleotides/pharmacokinetics/pharmacology/*therapeutic use
    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: 2019-07-12
    Description: FLOPS has been the primary aircraft synthesis software used by the Aeronautics Systems Analysis Branch at NASA Langley Research Center. It was created for rapid conceptual aircraft design and advanced technology impact assessments. FLOPS is a single computer program that includes weights estimation, aerodynamics estimation, engine cycle analysis, propulsion data scaling and interpolation, detailed mission performance analysis, takeoff and landing performance analysis, noise footprint estimation, and cost analysis. It is well known as a baseline and common denominator for aircraft design studies. FLOPS is capable of calibrating a model to known aircraft data, making it useful for new aircraft and modifications to existing aircraft. The weight estimation method in FLOPS is known to be of high fidelity for conventional tube with wing aircraft and a substantial amount of effort went into its development. This report serves as a comprehensive documentation of the FLOPS weight estimation method. The development process is presented with the weight estimation process.
    Keywords: Aircraft Design, Testing and Performance
    Type: NASA/TM-2017-219627/VOL1 , L-20820 , NF1676L-27097
    Format: application/pdf
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  • 5
    Publication Date: 2019-07-20
    Description: Weight estimation is critical in the aircraft conceptual design process. The Flight Optimization System (FLOPS) is an aircraft conceptual design tool that has been the primary aircraft synthesis software used by the Systems Analysis and Concepts Directorate at NASA Langley Research Center. FLOPS includes multiple modules that represent aircraft design disciplines. The FLOPS weight module includes estimation methods that are similar in nature to other regression based aircraft preliminary weight estimation methods, however the FLOPS methods were created to use a minimum number of input parameters to limit the effort required by the designer to apply it. As FLOPS has recently been made publically available, this work compares the FLOPS weight estimation methods with several similar methods with the goal of explaining the differences in FLOPS, providing conceptual designers with a brief introduction to the method before attempting to apply it, and providing a reference to inform the development of future weight estimating relationships. In this paper, the Boeing 737-200 is used as a test case to highlight to differences and similarities in the methods.
    Keywords: Aircraft Design, Testing and Performance
    Type: NF1676L-27388 , AIAA Science and Technology Forum and Exposition; Jan 08, 2018 - Jan 12, 2018; Kissimmee, FL; United States
    Format: application/pdf
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  • 6
    Publication Date: 2019-07-13
    Description: NASA's investment and research in aviation has led to new technologies and concepts that make aircraft more efficient and environmentally friendly. One aircraft design operational concept is the reduction of cruise speed to reduce fuel burned during a mission. Although this is not a new idea, it was used by all of the contractors involved in a 2008 NASA sponsored study that solicited concept and technology ideas to reduce environmental impacts for future subsonic passenger transports. NASA is currently improving and building new analysis capabilities to analyze advanced concepts. To test some of these new capabilities, a transonic truss braced wing configuration was used as a test case. This paper examines the effects due to changes in the design cruise speed and other tradeoffs in the design space. The analysis was baselined to the Boeing SUGAR High truss braced wing concept. An optimization was run at five different design cruise Mach numbers. These designs are compared to provide an initial assessment space and the parameters that should be considered when selecting a design cruise speed. A discussion of the design drivers is also included. The results show that the wing weight in the current analysis has more influence on the takeoff gross weight than expected. This effect caused lower than expected wing sweep angle values for higher cruise speed designs.
    Keywords: Aircraft Design, Testing and Performance
    Type: NF1676L-24665 , AIAA SciTech 2017; Jan 09, 2017 - Jan 13, 2017; Grapevine, TX; United States
    Format: application/pdf
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