Proceedings of the National Academy of Sciences of the United States of America
-
Proc. Natl. Acad. Sci. U.S.A. · Feb 2005
Combinatorial theory of Macdonald polynomials I: proof of Haglund's formula.
Haglund recently proposed a combinatorial interpretation of the modified Macdonald polynomials H(mu). We give a combinatorial proof of this conjecture, which establishes the existence and integrality of H(mu). As corollaries, we obtain the cocharge formula of Lascoux and Schutzenberger for Hall-Littlewood polynomials, a formula of Sahi and Knop for Jack's symmetric functions, a generalization of this result to the integral Macdonald polynomials J(mu), a formula for H(mu) in terms of Lascoux-Leclerc-Thibon polynomials, and combinatorial expressions for the Kostka-Macdonald coefficients K(lambda,mu) when mu is a two-column shape.
-
Proc. Natl. Acad. Sci. U.S.A. · Feb 2005
CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids.
CB(2) cannabinoid receptor-selective agonists are promising candidates for the treatment of pain. CB(2) receptor activation inhibits acute, inflammatory, and neuropathic pain responses but does not cause central nervous system (CNS) effects, consistent with the lack of CB(2) receptors in the normal CNS. To date, there has been virtually no information regarding the mechanism of CB(2) receptor-mediated inhibition of pain responses. ⋯ These data suggest that CB(2) receptor activation stimulates release from keratinocytes of beta-endorphin, which acts at local neuronal mu-opioid receptors to inhibit nociception. Supporting this possibility, CB(2) immunolabeling was detected on beta-endorphin-containing keratinocytes in stratum granulosum throughout the epidermis of the hindpaw. This mechanism allows for the local release of beta-endorphin, where CB(2) receptors are present, leading to anatomical specificity of opioid effects.
-
Proc. Natl. Acad. Sci. U.S.A. · Feb 2005
A non-ATP-competitive inhibitor of BCR-ABL overrides imatinib resistance.
Imatinib, which is an inhibitor of the BCR-ABL tyrosine kinase, has been a remarkable success for the treatment of Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemias (CMLs). However, a significant proportion of patients chronically treated with imatinib develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Mutations occur at residues directly implicated in imatinib binding or, more commonly, at residues important for the ability of the kinase to adopt the specific closed (inactive) conformation to which imatinib binds. ⋯ Kinetic studies demonstrate that this compound is not ATP-competitive but is substrate-competitive and works synergistically with imatinib in wild-type BCR-ABL inhibition. More importantly, ON012380 was found to induce apoptosis of all of the known imatinib-resistant mutants at concentrations of <10 nM concentration in vitro and cause regression of leukemias induced by i.v. injection of 32Dcl3 cells expressing the imatinib-resistant BCR-ABL isoform T315I. Daily i.v. dosing for up to 3 weeks with a >100 mg/kg concentration of this agent is well tolerated in rodents, without any hematotoxicity.
-
Proc. Natl. Acad. Sci. U.S.A. · Feb 2005
Brain correlates of subjective reality of physically and psychologically induced pain.
Meaningful behavior requires successful differentiation of events surfacing from one's mind from those arising from the external world. Such judgements may be especially demanding during pain because of the strong contribution from psychological factors to this experience. It is unknown how the subjective reality of pain (SRP) is constructed in the human brain, and neuronal mechanisms of the subjective reality are poorly understood in general. ⋯ These findings support the view that information about sensory-discriminative characteristics of pain contributes to the SRP. Differences in such information between physically and psychologically induced pain, however, could be quantitative rather than qualitative and therefore insufficient for judging the reality of pain without knowledge about the source of this information. The medial prefrontal cortex is a likely area to contribute to such source monitoring.