Resonant and nonresonant D+ -> K- pi+ l+ nu(l) semileptonic decays

We analyse the semileptonic decay D+ -> K- pi+ l+ nu(l) using an effective Lagrangian developed previously to describe the decays D -> P l nu(l) and D -> V l nu(l). Light vector mesons are included in the model which combines the heavy quark effective Lagrangian and chiral perturbation theory approach. The nonresonant and resonant contributions are compared. With no new parameters the model correctly reproduces the measured ratio Gamma(nres)/Gamma(nres + res). We also present useful nonresonant decay distributions. Finally, a similar model, but with a modified current which satisfies the soft pion theorems at the expense of introducing another parameter, is analyzed and the results of the models are compared.Comment: 17 pages, 3 Postscript figures, standard Latex, extended revision, title, abstract and text (especially Sec. IV) changed, results unchange

Identification and characterization of mechanistically distinct inducers of gamma-globin transcription

Inhibition of HbS polymerization is a major target for therapeutic approaches in sickle cell anemia. Toward this goal, initial efforts at pharmacological elevation of fetal hemoglobin (HbF) has shown therapeutic efficacy. In order to identify well-tolerated, novel agents that induce HbF in patients, we developed a high-throughput screening approach based on induction of gamma-globin gene expression in erythroid cells. We measured gamma-globin transcription in K562 cells transfected with either gamma promoter elements fused with the locus control region hypersensitivity site 2 and luciferase reporter gene (HS2 gamma) or a beta-yeast artificial chromosome in which the luciferase reporter gene was recombined into the gamma-globin coding sequences (gamma YAC). Corresponding pharmacological increases in HbF protein were confirmed in both K562 cells and in human primary erythroid progenitor cells. Approximately 186,000 defined chemicals and fungal extracts were evaluated for their ability to increase gamma gene transcription in either HS2 gamma or gamma YAC models. Eleven distinct classes of compounds were identified, the majority of which were active within 24-48 hr. The short chain hydroxamate-containing class generally exhibited delayed maximal activity, which continued to increase transcription up to 120 hr. The cyclic tetrapeptide OSI-2040 and the hydroxamates were shown to have histone deacetylase inhibitory activity. In primary hematopoietic progenitor cell cultures, OSI-2040 increased HbF by 4.5-fold at a concentration of only 40 nM, comparable to the effects of hydroxyurea at 100 microM. This screening methodology successfully identifies active compounds for further mec