116 research outputs found
Soil erosion by landing rockets Final report
Cratering effect of descending rocket exhaust expected from soft earth landin
Genetic Heterogeneity in a Cyclical Forest Pest, the Southern Pine Beetle, Dendroctonus frontalis, is Differentiated Into East and West Groups in the Southeastern United States
The southern pine beetle, Dendroctonus frontalis Zimmerman (Coleoptera: Curculionidae) is an economically important pest species throughout the southeastern United States, Arizona, Mexico, and Central America. Previous research identified population structure among widely distant locations, yet failed to detect population structure among national forests in the state of Mississippi. This study uses microsatellite variation throughout the southeastern United States to compare the southern pine beetle's pattern of population structure to phylogeographic patterns in the region, and to provide information about dispersal. Bayesian clustering identified east and west genetic groups spanning multiple states. The east group had lower heterozygosity, possibly indicating greater habitat fragmentation or a more recent colonization. Significant genetic differentiation (ΞST = 0.01, p < 0.0001) followed an isolation-by-distance pattern (r = 0.39, p < 0.001) among samples, and a hierarchical AMOVA indicated slightly more differentiation occurred between multi-state groups. The observed population structure matches a previously identified phylogeographic pattern, division of groups along the Appalachian Mountain/Apalachicola River axis. Our results indicate that the species likely occurs as a large, stable metapopulation with considerable gene flow among subpopulations. Also, the relatively low magnitude of genetic differentiation among samples suggests that southern pine beetles may respond similarly to management across their range
An Economic Explanation of the Early Bank of Amsterdam, Debasement, Bills of Exchange, and the Emergence of the First Central Bank
Unveiling a novel transient druggable pocket in BACE-1 through molecular simulations: conformational analysis and binding mode of multisite inhibitors
The critical role of BACE-1 in the formation of neurotoxic Ă-amyloid peptides in the brain makes it an attractive target for an efficacious treatment of Alzheimerâs disease. However, the development of clinically useful BACE-1 inhibitors has proven to be extremely challeng- ing. In this study we examine the binding mode of a novel potent inhibitor (compound 1, with IC50 80 nM) designed by synergistic combination of two fragmentsâhuprine and rheinâ that individually are endowed with very low activity against BACE-1. Examination of crystal structures reveals no appropriate binding site large enough to accommodate 1. Therefore we have examined the conformational flexibility of BACE-1 through extended molecular dynamics simulations, paying attention to the highly flexible region shaped by loops 8â14, 154â169 and 307â318. The analysis of the protein dynamics, together with studies of pocket druggability, has allowed us to detect the transient formation of a secondary binding site, which contains Arg307 as a key residue for the interaction with small molecules, at the edge of the catalytic cleft. The formation of this druggable âfloppyâ pocket would enable the bind- ing of multisite inhibitors targeting both catalytic and secondary sites. Molecular dynamics simulations of BACE-1 bound to huprine-rhein hybrid compounds support the feasibility of this hypothesis. The results provide a basis to explain the high inhibitory potency of the two enantiomeric forms of 1, together with the large dependence on the length of the oligo- methylenic linker. Furthermore, the multisite hypothesis has allowed us to rationalize the inhibitory potency of a series of tacrine-chromene hybrid compounds, specifically regarding the apparent lack of sensitivity of the inhibition constant to the chemical modifications intro- duced in the chromene unit. Overall, these findings pave the way for the exploration of novel functionalities in the design of optimized BACE-1 multisite inhibitors
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