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  • 1
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    The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-03-17
    Description: The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1beta production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1beta resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854628/" 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/PMC4854628/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ravindran, Rajesh -- Loebbermann, Jens -- Nakaya, Helder I -- Khan, Nooruddin -- Ma, Hualing -- Gama, Leonardo -- Machiah, Deepa K -- Lawson, Benton -- Hakimpour, Paul -- Wang, Yi-chong -- Li, Shuzhao -- Sharma, Prachi -- Kaufman, Randal J -- Martinez, Jennifer -- Pulendran, Bali -- R01 DK088227/DK/NIDDK NIH HHS/ -- R01 DK103185/DK/NIDDK NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 DK042394/DK/NIDDK NIH HHS/ -- R37 DK057665/DK/NIDDK NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19 AI090023/AI/NIAID NIH HHS/ -- ZIA ES103286-01/Intramural NIH HHS/ -- England -- Nature. 2016 Mar 24;531(7595):523-7. doi: 10.1038/nature17186. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508, Brazil. ; Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India. ; Division of Pathology, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Virology Core, Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Degenerative Disease Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037 USA. ; National Institute of Environmental Health Sciences, Mail Drop D2-01 Research Triangle Park, North Carolina 27709, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982722" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/administration & dosage/deficiency/*metabolism/pharmacology ; Animals ; Antigen-Presenting Cells/immunology/metabolism ; Autophagy ; Colitis/etiology/*metabolism/pathology/prevention & control ; Disease Models, Animal ; Epithelial Cells/metabolism ; Female ; Humans ; Inflammasomes/*antagonists & inhibitors/metabolism ; Inflammation/etiology/*metabolism/pathology/prevention & control ; Interleukin-1beta/immunology ; Intestines/*metabolism/*pathology ; Male ; Mice ; Microtubule-Associated Proteins/deficiency/metabolism ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Stress, Physiological ; Th17 Cells/immunology ; Ubiquitin-Activating Enzymes/deficiency/metabolism
    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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    PAPER CURRENT
  • 2
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    NASA's Plans for Developing Life Support and Environmental Monitoring and Control Systems (2006)
    In:  Other Sources
    Details
    Publication Date: 2019-07-19
    Description: Life Support and Monitoring have recently been reworked in response to the Vision for Space Exploration. The Exploration Life Support (ELS) Project has replaced the former Advanced Life Support Element of the Human Systems Research and Technology Office. Major differences between the two efforts include: the separation of thermal systems into a new stand alone thermal project, deferral of all work in the plant biological systems, relocation of food systems to another organization, an addition of a new project called habitation systems, and overall reduction in the number of technology options due to lower funding. The Advanced Environmental Monitoring and Control (AEMC) Element is retaining its name but changing its focus. The work planned in the ELS and AEMC projects is organized around the three major phases of the Exploration Program. The first phase is the Crew Exploration Vehicle (CEV). The ELS and AEMC projects will develop hardware for this short duration orbital and trans-lunar vehicle. The second phase is sortie landings on the moon. Life support hardware for lunar surface access vehicles including upgrades of the CEV equipment and technologies which could not be pursued in the first phase due to limited time and budget will be developed. Monitoring needs will address lunar dust issues, not applicable to orbital needs. The ELS and AEMC equipment is of short duration, but has different environmental considerations. The third phase will be a longer duration lunar outpost. This will consist of a new set of hardware developments better suited for long duration life support and associated monitoring needs on the lunar surface. The presentation will show the planned activities and technologies that are expected to be developed by the ELS and AEMC projects for these program phases.
    Keywords: Man/System Technology and Life Support
    Type: Space Technology and Applications International Conference; Feb 12, 2006 - Feb 16, 2006; Albuquerque, NM; United States
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    NASA TECHNICAL REPORTS
  • 3
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    Exploration Life Support Directions (2006)
    In:  Other Sources
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    Publication Date: 2019-07-19
    Description: The Exploration Life Support (ELS) Project is now developing new technologies for the Vision for Space Exploration announced in 2004. ELS project development work is organized around the three major vehicles of the Exploration Program. The first vehicle is the Orion Crew Exploration Vehicle (CEV). The ELS project will develop prototype hardware for this short duration orbital and trans-lunar vehicle s mission. The second vehicle is for sortie landings on the moon. Life support technology hardware for lunar surface access vehicles will include upgrades of existing CEV equipment and technologies to maximize commonality between the two vehicles as well as new technologies needed for the harsher thermal environments of the moon and the new element of dust. The third vehicle will be a longer duration lunar outpost. Crew stays of 180 days are planned for the lunar outpost. To minimize the need for consumables needed for resupply, a new set of hardware developments and processes better suited for long duration life support will be used. The water loop will be almost completely closed. The air revitalization will be partially closed. The outpost mission will have the continuous environment of 1/6th gravity making the separations of fluids and gases easier than the zero gravity for the CEV and orbital phases of lunar lander vehicles. This presentation will describe the planned technologies that are expected to be developed and considerations for how those technologies will be developed and demonstrated by the ELS project for these major program vehicles.
    Keywords: Man/System Technology and Life Support
    Type: Space Technoogy and Applications International; 12-15 Feb. 207; Albuquerque, NM; United States
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    NASA TECHNICAL REPORTS
  • 4
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    New Direction of NASA Exploration Life Support (2006)
    In:  Other Sources
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    Publication Date: 2019-07-13
    Description: NASA's activities in life support Research and Technology Development (R&TD) have changed in both focus and scope following implementation of recommendations from the Exploration System Architecture Study (ESAS). The limited resources available and the compressed schedule to conduct life support R&TD have required that future efforts address the needs of the Crew Exploration Vehicle (CEV), the Lunar Surface Access Module (LSAM) and Lunar Outpost (LO). Advanced Life Support (ALS) efforts related to long duration planetary bases have been deferred or canceled. This paper describes the scope of the new Exploration Life Support (ELS) project; how it differs from ALS, and how it supports critical needs for the CEV, LSAM and LO. In addition, this paper provides rationale for changes in the scope and focus of technical content within ongoing life support R&TD activities.
    Keywords: Man/System Technology and Life Support
    Type: SAE-2006-01-2241 , International Conference on Environmental Systems; Jul 17, 2006 - Jul 20, 2006; Norfolk, VA; United States
    Format: text
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    NASA TECHNICAL REPORTS
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