We have measured the spin structure functions g p 2 and g d 2 and the virtual photon asymmetries A p 2 and A d 2 over the kinematic range 0.02 ≤ x ≤ 0.8 and 0.7 ≤ Q 2 ≤ 20 GeV 2 by scattering 29.1 and 32.3 GeV longitudinally polarized electrons from transversely polarized NH3 and 6 LiD targets. Our measured g2 approximately follows the twist-2 Wandzura-Wilczek calculation. The twist-3 reduced matrix elements d p 2 and d n 2 are less than two standard deviations from zero. The data are inconsistent with the Burkhardt-Cottingham sum rule if there is no pathological behavior as x → 0. The Efremov-Leader-Teryaev integral is consistent with zero within our measured kinematic range. The absolute value of A2 is significantly smaller than the A2 < R(1 + A1)/2 limit.
Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d 3 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.