Proceedings of the National Academy of Sciences of the United States of America
-
Proc. Natl. Acad. Sci. U.S.A. · Mar 2008
Historical ArticleThe protracted Holocene extinction of California's flightless sea duck (Chendytes lawi) and its implications for the Pleistocene overkill hypothesis.
Bones of the flightless sea duck (Chendytes lawi) from 14 archaeological sites along the California coast indicate that humans hunted the species for at least 8,000 years before it was driven to extinction. Direct (14)C dates on Chendytes bones show that the duck was exploited on the southern California islands as early as approximately 11,150-10,280 calendar years B. P., and on the mainland by at least 8,500 calendar years B. ⋯ That the extermination of Chendytes was so protracted and archaeologically visible suggests that, if the terminal Pleistocene megafauna extinctions were primarily the result of human exploitation, there should also be a long and readily detectable archaeological record of their demise. The brief window now attributed to the Clovis culture ( approximately 13,300-12,900 B. P.) seems inconsistent with an overhunting event.
-
Proc. Natl. Acad. Sci. U.S.A. · Mar 2008
Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin.
The mechanism of action of the antiepileptic and antinociceptive drugs of the gabapentinoid family has remained poorly understood. Gabapentin (GBP) binds to an exofacial epitope of the alpha(2)delta-1 and alpha(2)delta-2 auxiliary subunits of voltage-gated calcium channels, but acute inhibition of calcium currents by GBP is either very minor or absent. We formulated the hypothesis that GBP impairs the ability of alpha(2)delta subunits to enhance voltage-gated Ca(2+)channel plasma membrane density by means of an effect on trafficking. ⋯ However, it is mediated by alpha(2)delta subunits, being prevented by mutations in either alpha(2)delta-1 or alpha(2)delta-2 that abolish GBP binding, and is not observed for alpha(2)delta-3, which does not bind GBP. Furthermore, the trafficking of alpha(2)delta-2 and Ca(V)2 channels is disrupted both by GBP and by the mutation in alpha(2)delta-2, which prevents GBP binding, and we find that GBP reduces cell-surface expression of alpha(2)delta-2 and Ca(V)2.1 subunits. Our evidence indicates that GBP may act chronically by displacing an endogenous ligand that is normally a positive modulator of alpha(2)delta subunit function, thereby impairing the trafficking function of the alpha(2)delta subunits to which it binds.
-
Proc. Natl. Acad. Sci. U.S.A. · Mar 2008
Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition.
Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. ⋯ IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.