4,221 research outputs found
A Peptide Core Motif for Binding to Heterotrimeric G Protein α Subunits
Recently, in vitro selection using mRNA display was used to identify a novel peptide sequence that binds with high affinity to G{alpha}i1. The peptide was minimized to a 9-residue sequence (R6A-1) that retains high affinity and specificity for the GDP-bound state of G{alpha}i1 and acts as a guanine nucleotide dissociation inhibitor (GDI). Here we demonstrate that the R6A-1 peptide interacts with G{alpha} subunits representing all four G protein classes, acting as a core motif for G{alpha} interaction. This contrasts with the consensus G protein regulatory(GPR) sequence, a 28-mer peptide GDI derived from the GoLoco (G{alpha}i/0-Loco interaction)/GPR motif that shares no homology with R6A-1 and binds only to G{alpha}i1-3 in this assay. Binding of R6A-1 is generally specific to the GDP-bound state of the G{alpha} subunits and excludes association with G{beta}{gamma}. R6A-G{alpha}i1 complexes are resistant to trypsin digestion and exhibit distinct stability in the presence of Mg2+, suggesting that the R6A and GPR peptides exert their activities using different mechanisms. Studies using G{alpha}i1/G{alpha}s chimeras identify two regions of G{alpha}i1 (residues 1–35 and 57–88) as determinants for strong R6A-Gi{alpha}1 interaction. Residues flanking the R6A-1 peptide confer unique binding properties, indicating that the core motif could be used as a starting point for the development of peptides exhibiting novel activities and/or specificity for particular G protein subclasses or nucleotide-bound states
Commercialization and Human Settlement of the Moon and Cislunar Space A Look Ahead at the Possibilities over the Next 50 Years
Over 50 years have passed since the movie 2001: A Space Odyssey debuted in April 1968. In the film, Dr. Heywood Floyd flies to a large artificial gravity space station orbiting Earth aboard a commercial space plane. He then embarks on a commuter flight to the Moon arriving there 25hours later. Today, on the 50th anniversary of the Apollo 11 lunar landing, the images portrayed in 2001 still remain well beyond our capabilities. This paper examines key technologies and systems (in-situ resource utilization, fission power, advanced chemical and nuclear propulsion),and orbiting infrastructure elements (providing a propellant depot and cargo transfer function),that could be developed by NASA and the private sector in future decades allowing the operational capabilities presented in 2001 to be achieved, albeit on a more spartan scale. Lunar derived propellants (LDPs) will be essential to reducing the launch mass requirements from Earth and developing a reusable lunar transportation system (LTS) that can allow initial outposts to evolve into settlements supporting a variety of commercial activities like in-situ propellant production. Deposits of icy regolith found within permanently shadowed craters at the lunar pole scan supply the feedstock material to produce liquid oxygen (LO2) and hydrogen (LH2) propellan tneeded by surface-based lunar landing vehicles (LLVs) using chemical rocket engines. Along the Moon's nearside equatorial corridor, iron oxide-rich volcanic glass beads from vast pyroclasticdeposits, together with mare regolith, can provide the materials to produce lunar-derived LO2plus other important solar wind implanted (SWI) volatiles, including H2 and helium-3. Mega watt classfission power systems will be essential for providing continuous "24/7" power to LLVs will provide cargo and passenger "orbit-to-surface" access and willalso be used to transport LDP to Space Transportation Nodes (STNs) located in lunar polar(LPO) and equatorial orbits (LLO). Spaced-based, reusable lunar transfer vehicles (LTVs),operating between STNs in low Earth orbit (LEO), LLO, and LPO, and able to refuel with LDPs,can offer unique mission capabilities including short transit time crewed cargo transports. Even acommuter shuttle service similar to that portrayed in 2001 appears possible, allowing 1-way trip times to and from the Moon as short as 24 hours. The performance of LTVs using both RL10B-2chemical rockets, and a variant of the nuclear thermal rocket (NTR), the LO2-Augmented NTR(LANTR), are examined and compared. The bipropellant LANTR engine utilizes its divergent nozzle section as an afterburner into which oxygen is injected and supersonically combusted with reactor-heated hydrogen emerging from the engine's sonic throat. If only 1% of the LDP obtained from icy regolith, volcanic glass, and SWI volatile deposits were available for use in lunar orbit,such a supply could support routine commuter flights to the Moon for many thousands of years!This paper provides a look ahead at what might be possible in the not too distant future,quantifies the operational characteristics of key in-space and surface technologies and systems,and provides conceptual designs for the various architectural elements discussed
Key Technologies, Systems, and Infrastructure Enabling the Commercialization and Human Settlement of the Moon and Cislunar Space
Over 50 years have passed since 2001: A Space Odyssey debuted in April 1968. In the film, Dr. Heywood Floydflies to a large artificial gravity space station orbiting Earth aboard a commercial space plane. He then embarks on acommuter flight to the Moon arriving there 25 hours later. Today, in this the 50th anniversary year of the Apollo 11lunar landing, the images portrayed in 2001 still remain well beyond our capabilities. This paper examines keytechnologies and systems (e.g., in-situ resource utilization, fission power, advanced chemical and nuclearpropulsion), and supporting orbital infrastructure (providing a propellant and cargo transfer function), that could bedeveloped by NASA and industry over the next 30 years allowing the operational capabilities presented in 2001 to beachieved, albeit on a more spartan scale. Lunar-derived propellants (LDPs) will be essential to developing a reusablelunar transportation system that can allow initial outposts to evolve into settlements supporting a variety ofcommercial activities. Deposits of icy regolith discovered at the lunar poles can supply the feedstock material neededto produce liquid oxygen (LO2) and hydrogen (LH2) propellants. On the lunar nearside, near the equator, iron oxiderichvolcanic glass beads from vast pyroclastic deposits, together with mare regolith, can provide the feedstockmaterials to produce lunar-derived LO2 plus other important solar wind implanted (SWI) volatiles, including H2and helium-3. Megawatt-class fission power systems will be essential for providing continuous "24/7" power toprocessing plants, human settlements and commercial enterprises that develop on the Moon and in orbit. Reusablelunar landing vehicles will provide cargo and passenger "orbit-to-surface" access and will also transport LDP to Space Transportation Nodes (STNs) located in lunar polar (LPO) and equatorial orbits (LLO). Reusable space-based,lunar transfer vehicles (LTVs), operating between STNs in low Earth orbit, LLO, and LPO, and able to refuel with LDPs, offer unique mission capabilities including short transit time crewed cargo transports. Even commuter flights similar to that portrayed in 2001 appear possible, allowing 1-way trip times to and from the Moon as short as 24hours. The performance of LTVs using both RL10B-2 chemical rockets, and a variant of the nuclear thermal rocket(NTR), the LO2-Augmented NTR (LANTR), are examined and compared. If only 1% of the LDP obtained from icyregolith, volcanic glass, and SWI volatile deposits were available for use in lunar orbit, such a supply could support routine commuter flights to the Moon for many thousands of years. This paper provides a look ahead at what might be possible in the not too distant future, quantifies the operational characteristics of key in-space and surface technologies and systems, and provides conceptual designs for the various architectural elements discussed
Key Technologies, Systems, and Infrastructure Enabling the Commercialization and Human Settlement of the Moon and Cislunar Space
Over 50 years have passed since 2001: A Space Odyssey debuted in April 1968. In the film, Dr. Heywood Floydflies to a large artificial gravity space station orbiting Earth aboard a commercial space plane. He then embarks on acommuter flight to the Moon arriving there 25 hours later. Today, in this the 50th anniversary year of the Apollo 11lunar landing, the images portrayed in 2001 still remain well beyond our capabilities. This paper examines keytechnologies and systems (e.g., in-situ resource utilization, fission power, advanced chemical and nuclearpropulsion), and supporting orbital infrastructure (providing a propellant and cargo transfer function), that could bedeveloped by NASA and industry over the next 30 years allowing the operational capabilities presented in 2001 to beachieved, albeit on a more spartan scale. Lunar-derived propellants (LDPs) will be essential to developing a reusablelunar transportation system that can allow initial outposts to evolve into settlements supporting a variety ofcommercial activities. Deposits of icy regolith discovered at the lunar poles can supply the feedstock material neededto produce liquid oxygen (LO2) and hydrogen (LH2) propellants. On the lunar nearside, near the equator, iron oxiderichvolcanic glass beads from vast pyroclastic deposits, together with mare regolith, can provide the feedstockmaterials to produce lunar-derived LO2 plus other important solar wind implanted (SWI) volatiles, including H2and helium-3. Megawatt-class fission power systems will be essential for providing continuous "24/7" power toprocessing plants, human settlements and commercial enterprises that develop on the Moon and in orbit. Reusablelunar landing vehicles will provide cargo and passenger "orbit-to-surface" access and will also transport LDP toSpace Transportation Nodes (STNs) located in lunar polar (LPO) and equatorial orbits (LLO). Reusable space-based,lunar transfer vehicles (LTVs), operating between STNs in low Earth orbit, LLO, and LPO, and able to refuel withLDPs, offer unique mission capabilities including short transit time crewed cargo transports. Even commuter flightssimilar to that portrayed in 2001 appear possible, allowing 1-way trip times to and from the Moon as short as 24hours. The performance of LTVs using both RL10B-2 chemical rockets, and a variant of the nuclear thermal rocket(NTR), the LO2-Augmented NTR (LANTR), are examined and compared. If only 1% of the LDP obtained from icyregolith, volcanic glass, and SWI volatile deposits were available for use in lunar orbit, such a supply could supportroutine commuter flights to the Moon for many thousands of years. This paper provides a look ahead at what mightbe possible in the not too distant future, quantifies the operational characteristics of key in-space and surfacetechnologies and systems, and provides conceptual designs for the various architectural elements discussed
Commercial and Human Settlement of the Moon and Cislunar Space A Look Ahead at the Possibilities over the Next 50 Years
Over 50 years have passed since the movie 2001: A Space Odyssey debuted in April 1968. In the film, Dr. Heywood Floyd flies to a large artificial gravity space station orbiting Earth aboard a commercial space plane. He then embarks on a commuter flight to the Moon arriving there 25 hours later. Today, on the 50th anniversary of the Apollo 11 lunar landing, the images portrayed in 2001 still remain well beyond our capabilities. This paper examines key technologies and systems (in-situ resource utilization, fission power, advanced chemical and nuclear propulsion), and orbiting infrastructure elements (providing a propellant depot and cargo transfer function), that could be developed by NASA and the private sector in future decades allowing the operational capabilities presented in 2001 to be achieved, albeit on a more spartan scale. Lunar-derived propellants (LDPs) will be essential to reducing the launch mass requirements from Earth and developing a reusable lunar transportation system (LTS) that can allow initial outposts to evolve into settlements supporting a variety of commercial activities like in-situ propellant production. Deposits of icy regolith found within permanently shadowed craters at the lunar poles can supply the feedstock material to produce liquid oxygen (LO2) and hydrogen (LH2) propellant needed by surface-based lunar landing vehicles (LLVs) using chemical rocket engines. Along the Moons nearside equatorial corridor, iron oxide-rich volcanic glass beads from vast pyroclastic deposits, together with mare regolith, can provide the materials to produce lunar-derived LO2 plus other important solar wind implanted (SWI) volatiles, including H2 and helium-3. Megawatt-class fission power systems will be essential for providing continuous 24/7 power to processing plants, evolving human settlements, and other commercial activities that develop on the Moon and in orbit. Reusable LLVs will provide cargo and passenger orbit-to-surface access and will also be used to transport LDP to Space Transportation Nodes (STNs) located in lunar polar (LPO) and equatorial orbits (LLO). Spaced-based, reusable lunar transfer vehicles (LTVs), operating between STNs in low Earth orbit (LEO), LLO, and LPO, and able to refuel with LDPs, can offer unique mission capabilities including short transit time crewed cargo transports. Even a commuter shuttle service similar to that portrayed in 2001 appears possible, allowing 1-way trip times to and from the Moon as short as 24 hours. The performance of LTVs using both RL10B-2 chemical rockets, and a variant of the nuclear thermal rocket (NTR), the LO2-Augmented NTR (LANTR), are examined and compared. The bipropellant LANTR engine utilizes its divergent nozzle section as an afterburner into which oxygen is injected and supersonically combusted with reactor-heated hydrogen emerging from the engines sonic throat. If only 1% of the LDP obtained from icy regolith, volcanic glass, and SWI volatile deposits were available for use in lunar orbit, such a supply could support routine commuter flights to the Moon for many thousands of years! This paper provides a look ahead at what might be possible in the not too distant future, quantifies the operational characteristics of key in-space and surface technologies and systems, and provides conceptual designs for the various architectural elements discussed
Ubiquitination and proteasomal degradation of ATG12 regulates its proapoptotic activity
During macroautophagy, conjugation of ATG12 to ATG5 is essential for LC3 lipidation and autophagosome formation. Additionally, ATG12 has ATG5-independent functions in diverse processes including mitochondrial fusion and mitochondrial-dependent apoptosis. In this study, we investigated the regulation of free ATG12. In stark contrast to the stable ATG12–ATG5 conjugate, we find that free ATG12 is highly unstable and rapidly degraded in a proteasome-dependent manner. Surprisingly, ATG12, itself a ubiquitin-like protein, is directly ubiquitinated and this promotes its proteasomal degradation. As a functional consequence of its turnover, accumulation of free ATG12 contributes to proteasome inhibitor-mediated apoptosis, a finding that may be clinically important given the use of proteasome inhibitors as anticancer agents. Collectively, our results reveal a novel interconnection between autophagy, proteasome activity, and cell death mediated by the ubiquitin-like properties of ATG12
Carbon monoxide poisoning: novel magnetic resonance imaging pattern in the acute setting
The presentation of carbon monoxide (CO) poisoning is non-specific and highly variable. The diagnosis is made when a compatible history and examination occur in a patient with elevated carboxyhaemoglobin levels. The severity of intoxication is difficult to assess accurately based on laboratory markers alone. Magnetic resonance imaging (MRI) has been shown to have superior sensitivity to computed tomography for the detection of abnormalities post CO poisoning. We report a novel imaging pattern on MRI undertaken in the acute setting in a patient with CO intoxication. We also discuss the management and follow up of patients with CO poisoning
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