Computational Studies of Liver Receptor Homolog 1 in the Presence of Small Molecule Agonists: Allosteric Communication and Virtual Screening for New Potential Drug Candidates

Liver Receptor Homolog 1 (LRH-1) is a nuclear receptor whose dysfunction is affiliated with diseases such as diabetes and cancer. Recent investigations demonstrate that higher levels of activation and modulation of its activity can be achieved through its interaction with phospholipids (PLs) and synthetic small molecules. We employed molecular dynamics (MD) simulations to understand more about the structural basis of LRH-1’s activity when bound to small molecule agonist RJW100 as well as the RJW100 derivative 65endo. We find that RJW100 and derivative 65endo can trigger allosteric communication in LRH-1 despite the RJW100 scaffold inducing motions that differ from those induced by PLs. We also provide supporting evidence that a key threonine residue and a water network may be important in RJW100’s ability to activate LRH-1. Finally, in a campaign to identify new LRH-1 lead compounds, virtual screening was performed against RJW100, 65endo, and a second RJW100 derivative, 8AC

Workshop on Exercise Prescription for Long-Duration Space Flight

The National Aeronautics and Space Administration has a dedicated history of ensuring human safety and productivity in flight. Working and living in space long term represents the challenge of the future. Our concern is in determining the effects on the human body of living in space. Space flight provides a powerful stimulus for adaptation, such as cardiovascular and musculoskeletal deconditioning. Extended-duration space flight will influence a great many systems in the human body. We must understand the process by which this adaptation occurs. The NASA is agressively involved in developing programs which will act as a foundation for this new field of space medicine. The hallmark of these programs deals with prevention of deconditioning, currently referred to as countermeasures to zero g. Exercise appears to be most effective in preventing the cardiovascular and musculoskeletal degradation of microgravity

Summary and recommendations for initial exercise prescription

The recommendations summarized herein constitute a basis on which an initial exercise prescription can be formulated. It is noteworthy that any exercise program designed currently would be an approximation. Examination of the existing space-flight data reveals a scarcity of in-flight data on which to rigorously design an exercise program. The relevant experience within the U.S. space program (with regard to long-duration space flight) is limited to the Skylab Program. Lessons learned from Skylab are relevant to the design of a Space Station exercise program, especially with regard to the total length of exercise time required, cardiovascular (CV) deconditioning/reconditioning, and bone loss. Certain observations of the U.S.S.R. exercise activities can also contribute to the formulation of an exercise prescription of Space Station. Reportedly, the U.S.S.R. uses both a bicycle ergometer and a treadmill device on long-duration missions with some degree of success. Using the third crew of Salyut 6, which was a 175-day stay, as a representative mission, the typical time dedicated to exercise varies from 2 to 3 hours per day. In addition, the cosmonauts wear an elasticized suit, called a penquin suit, for time periods ranging from 12 to 16 hours per day. This device provides a load across the axial skeleton against which the wearer must exert himself. Despite these extensive countermeasures, the effects of adaptation are not totally prevented

Effects of Canard Planform and Wing-Leading-Edge Modification on Low-Speed Longitudinal Aerodynamic Characteristics of a Canard Airplane Configuration

An investigation has been conducted at low subsonic speeds to study the effects of canard planform and wing-leading-edge modification on the longitudinal aerodynamic characteristics of a general research canard airplane configuration. The basic wing of the model had a trapezoidal planform, an aspect ratio of 3.0, a taper ratio of 0.143, and an unswept 80-percent-chord line. Modifications to the wing included addition of full-span and partial-span leading-edge chord-extensions. Two canard planforms were employed in the study; one was a 60 deg sweptback delta planform and the other was a trapezoidal planform similar to that of the basic wing. Modifications to these canards included addition of a full-span leading-edge chord-extension to the trapezoidal planform and a fence to the delta planform. For the basic-wing-trapezoidal-canard configuration, rather abrupt increases in stability occurred at about 12 deg angle of attack. A slight pitch-up tendency occurred for the delta-canard configuration at approximately 8 deg angle of attack. A comparison of the longitudinal control effectiveness for the basic-wing-trapezoidal-canard combination and for the basic-wing-delta-canard combination indicates higher values of control effectiveness at law angles of attack for the trapezoidal canard. The control effectiveness for the delta-canard configuration, however, is seen to hold up for higher canard deflections and to higher angles of attack. Use of a full-span chord-extension deflected approximately 30 deg on the trapezoidal canard greatly improved the control characteristics of this configuration and enabled a sizeable increase in trim lift to be realized