The Tec family kinase, Bruton’s Tyrosine Kinase (BTK), is one of the key intracellular signaling components proximal to the B cell receptor (BCR). In this study, we utilized an orally-accessible BTK inhibitor (BTKi) to study the functional effects blocking this signaling pathway has on antigen-driven B cell activation in vivo. We report that BTK is required for anti-IgD driven B cell activation in vivo as evidenced by suppression of the surface activation markers CD86 and mRNA transcripts (e.g. c-Myc, Bcl-xL, CCL3, CD98, EBI2, EGR1, EGR2 and IRF4) otherwise rapidly induced upon engagement of the BCR with antigen. Using the T-dependent protein PE and SRBCs as model antigens, we tested for a requirement of BTK in generating antigen-specific IgM and IgG antibody titers and germinal centers, and find that BTK is required for germinal center maintenance. Lastly, we tested for a role of BTK in long-lived PE-specific memory B cell re-activation and report that BTKi significantly suppressed the induction of PE-specific IgM and IgG titers upon antigen re-challenge. The use of BTKi allowed us to bypass the impact a genetically inactivated BTK gene has on B cell development and to assess BTK inactivation in both a wild-type setting and in a temporal manner. These results provide insight into the role of BTK in BCR-driven B cell activation in various antigen naïve and experienced B cell populations.

In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1 t(1/2) = 360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t(1/2) = 34 h. (C) 2010 Elsevier Ltd. All rights reserved.

Peter Pollack, The Picture History of Photography (Abrams, $25.00) David Simon, Fifty Classic Motion Pictures (Crown, $9.95) David Essoe's The Films of Clark Gable (Citadel, $10.00) John Springer's The Fondas (Citadel, $10.00) Pola Negri's Memoirs of a Star (Doubleday, $7.95) Alexander Walker's Stardom (Stein & Day, $10.00) T.J. Ross, Film and the Liberal Arts (Holt, Rinehart, and Winston, price unknown) Lewis Jacob's The Movies as Medium (Farrar Straus & Giroux, $8.95; or Noonday paporback, $3.95) Benjamin B. Hampton, A History of the Movies, originally published in 1931 and re-issued now as History of the American Film Industry (Dover paporbacks, $4.00) The Literature of Cinema Don Slay, Conversations: Volume I (Kaleidoscope Press (Albuquerque, New Mexico), $10.00) Raymond Durgnat, The Crazy Mirror: Hollywood Comedy and the American Imago (Horizon Press, $7.50) Harry M. Geduld and Ronald Gottesman's edited collection Serge Eisenstein and Upton Sinclair: Tho Making and Unmaking of “Quo Viva Mexico” (Iniana University gross, $15.00) Verne and Sylvia Carlson's Professional 16/35 mm Cameraman's Handbook (Hastings House, $15.00) Julius Bellone's edited collection, Rennaisance of the Film (Collier paperbacks, $2.95) Richard Randall's excellent Censorship of the Movies (University of Wisconsin Press, $7.95)