Inverse agonism of histamine H2 antagonist accounts for upregulation of spontaneously active histamine H2 receptors.

Histamine H2 receptors transfected in Chinese hamster ovary (CHO) cells are time- and dose-dependently upregulated upon exposure to the H2 antagonists cimetidine and ranitidine. This effect appears to be H2 receptor-mediated as no change in receptor density was observed after H1 or H3 antagonist treatment or after incubation with the structural analogue of cimetidine, VUF 8299, which has no H2 antagonistic effects. By using transfected CHO cells expressing different densities of wild-type H2 receptors or an uncoupled H2Leu124Ala receptor, the histamine H2 receptor was found to display considerable agonist-independent H2 receptor activity. Cimetidine and ranitidine, which both induce H2 receptor upregulation, actually functioned as inverse agonists in those cell lines displaying spontaneous agonist-independent H2 receptor activity. Burimamide, on the other hand, was shown to act as a neutral antagonist and did as expected not induce H2 receptor upregulation after long-term exposure. The displayed inverse agonism of H2 antagonists appears to be a mechanistic basis for the observed H2 antagonist-induced H2 receptor upregulation in transfected CHO cells. These observations shed new light on the pharmacological classification of the H2 antagonists and may offer a plausible explanation for the observed development of tolerance after prolonged clinical use.

A structural model for a homeotic protein-extradenticle-DNA complex accounts for the choice of HOX protein in the heterodimer.

The genes of the homeotic complex (HOX) encode DNA binding homeodomain proteins that control developmental fates by differentially regulating the transcription of downstream target genes. Despite their unique in vivo functions, disparate HOX proteins often bind to very similar DNA sequences in vitro. Thus, a critical question is how HOX proteins select the correct sets of target genes in vivo. The homeodomain proteins encoded by the Drosophila extradenticle gene and its mammalian homologues, the pbx genes, contribute to HOX specificity by cooperatively binding to DNA with HOX proteins. For example, the HOX protein labial cooperatively binds with extradenticle protein to a 20-bp oligonucleotide that is sufficient to direct a labial-like expression pattern in Drosophila embryos. Here we have analyzed the protein-DNA interactions that are important for forming the labial-extradenticle-DNA complex. The data suggest a model in which labial and extradenticle, separated by only 4 bp, bind this DNA as a heterodimer in a head-to-tail orientation. We have confirmed several aspects of this model by characterizing extradenticle-HOX binding to mutant oligonucleotides. Most importantly, mutations in base pairs predicted to contact the HOX N-terminal arm resulted in a change in HOX preference in the heterodimer, from labial to Ultrabithorax. These results demonstrate that extradenticle prefers to bind cooperatively with different HOX proteins depending on subtle differences in the heterodimer binding site.

Notebook describing scholars' and church fathers' accounts of the Resurrection, undated

This notebook contains prose entries about many different scholars' accounts of Jesus Christ's Resurrection. Prince apparently studied over fifty authors' writings concerning the Resurrection and recorded in this notebook what he considered to be the significant details of each authors' interpretation.

Butler's accounts for the Classes of 1789-1794, 1789-1799

The marbled-paper-covered book contains two sections written by Butlers Thomas Adams and Samuel Shapleigh: a two column debit and credit entry section for students in the Classes of 1789 through 1794, with additions made through June 1791, and at the end of the volume a two page "Account of monies paid out as Atty. to T. Adams" for 1791 with lenders' names and amounts.

The entomologist's useful compendium; or, An introduction to the knowledge of British insects, comprising the best means of obtaining and preserving them, and a description of the apparatus generally used; together with the genera of Linné, and the modern method of arranging the classes...according to the views of Dr. Leach...with instructions for collecting and fitting up objects for the microscope.

1821

Reports of the Committee of commons, 1800

This collection contains two handwritten committee reports that provide a brief financial overview of the Harvard College Steward's accounts for the quarters ending February 27, 1800 and May 29, 1800. The February 27th statement is dated March 4, 1800, and the May 29th statement is dated June 2, 1800.