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This study aimed to provide an estimate of the prevalence of marijuana use among Guam's high-school youth and to explore the potential protective and risk factors associated with its use. Using a probability sample (n = 589), our findings revealed that 51 percent of respondents said that they had used marijuana at least once during their life. Males reported using marijuana more frequently than did female respondents. Higher grades and being female were each associated with significantly lower levels of marijuana use. Contrary to predictions, students that discussed their problems and worries with adults, and students that participated in high-school extracurricular activities, were more likely to have used marijuana. However, students who were members of intact families that discussed their worries and problems with adults were significantly less likely than others to say they used marijuana.

Tirzepatide (LY3298176) is a fatty-acid-modified, dual incretin receptor agonist that exhibits pharmacology similar to native GIP at the glucose-dependent insulinotropic polypeptide receptor (GIPR) but shows bias toward cyclic adenosine monophosphate signaling at the glucagon-like peptide-1 receptor (GLP-1R). In addition to GIPR signaling, the pathway bias at the GLP-1R may contribute to the efficacy of tirzepatide at improving glucose control and body weight regulation in type 2 diabetes mellitus. To investigate the structural basis for the differential signaling of tirzepatide, mechanistic pharmacology studies were allied with cryogenic electron microscopy. Here, we report high-resolution structures of tirzepatide in complex with the GIPR and GLP-1R. Similar to the native ligands, tirzepatide adopts an α-helical conformation with the N terminus reaching deep within the transmembrane core of both receptors. Analyses of the N-terminal tyrosine (Tyr1Tzp) of tirzepatide revealed a weak interaction with the GLP-1R. Molecular dynamics simulations indicated a greater propensity of intermittent hydrogen bonding between the lipid moiety of tirzepatide and the GIPR versus the GLP-1R, consistent with a more compact tirzepatide-GIPR complex. Informed by these analyses, tirzepatide was deconstructed, revealing a peptide structure-activity relationship that is influenced by acylation-dependent signal transduction. For the GIPR, Tyr1Tzp and other residues making strong interactions within the receptor core allow tirzepatide to tolerate fatty acid modification, yielding an affinity equaling that of GIP. Conversely, high-affinity binding with the extracellular domain of the GLP-1R, coupled with decreased stability from the Tyr1Tzp and the lipid moiety, foster biased signaling and reduced receptor desensitization. Together, these studies inform the structural determinants underlying the function of tirzepatide. [ABSTRACT FROM AUTHOR]

The characterization of a variant of Ras C118S is described. The structure of the mutant has been determined by multidimensional heteronuclear NMR methods. Analysis of the guanine-nucleotide exchange and the GTPase activity of the mutant showed that the mutation has not disrupted the structure of the protein. The results showed that the basis of Ras activation by NO is destabilization of a crucial interaction between residues in the GDP-binding pocket and the nucleotide.