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The muscarinic acetylcholine receptor subtype 1 (M 1 ) receptors play an important role in cognition and memory, and are considered to be attractive targets for the development of novel medications to treat cognitive impairments seen in schizophrenia and Alzheimer's disease. Indeed, the M 1 agonist xanomeline has been shown to produce beneficial cognitive effects in both Alzheimer's disease and schizophrenia patients. Unfortunately, the therapeutic utility of xanomeline was limited by cholinergic side effects (sweating, salivation, gastrointestinal distress), which are believed to result from nonselective activation of other muscarinic receptor subtypes such as M 2 and M 3 . Therefore, drug discovery efforts targeting the M 1 receptor have focused on the discovery of compounds with improved selectivity profiles. Recently, allosteric M 1 receptor ligands have been described, which exhibit excellent selectivity for M 1 over other muscarinic receptor subtypes. In the current study, the following three compounds with mixed agonist/positive allosteric modulator activities that are highly functionally selective for the M 1 receptor were tested in rats, dogs, and cynomologous monkeys: (3-((1S,2S)-2-hydrocyclohexyl)-6-((6-(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl)methyl)benzo[h]quinazolin-4(3H)-one; 1-((4-cyano-4-(pyridin-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; and (R)-ethyl 3-(2-methylbenzamido)-[1, 49-bipiperidine]-19-carboxylate). Despite their selectivity for the M 1 receptor, all three compounds elicited cholinergic side effects such as salivation, diarrhea, and emesis. These effects could not be explained by activity at other muscarinic receptor subtypes, or by activity at other receptors tested. Together, these results suggest that activation of M 1 receptors alone is sufficient to produce unwanted cholinergic side effects such as those seen with xanomeline. This has important implications for the development of M 1 receptor-targeted therapeutics since it suggests that dose-limiting cholinergic side effects still reside in M 1 receptor selective activators.

During early July 1968, a severe food shortage occurred on Cayo Santiago, an island colony of free-ranging rhesus monkeys (AMacaca muEatta). The food shortage produced striking changes in the behavior of the monkeys. Within the one social group intensively studied, the total frequencies of grooming, play and fights decreased significantly; the frequency of matings also dropped; body contact, displacements by other groups, and non-displacement movements decreased, but not in statistically significant amounts. Changes in the percentage of total grooming attributable to related and unrelated monkeys reflected the stability of the rhesus matriline. Comparisons made between Cay0 Santiago and other primate groups under analogous situations reveal similar responses to food shortage.

This paper describes a project that was undertaken using naturalistic driving data collected via Global Positioning System (GPS) devices to demonstrate a proof-of-concept for proactive safety assessments of crash-prone locations. The main hypothesis for the study is that the segments where drivers have to apply hard braking (higher jerks) more frequently might be the "unsafe" segments with more crashes over a long-term. The linear referencing methodology in ArcMap was used to link the GPS data with roadway characteristic data of US Highway 101 northbound (NB) and southbound (SB) in San Luis Obispo, California. The process used to merge GPS data with quarter-mile freeway segments for traditional crash frequency analysis is also discussed in the paper. A negative binomial regression analyses showed that proportion of high magnitude jerks while decelerating on freeway segments (from the driving data) was significantly related with the long-term crash frequency of those segments. A random parameter negative binomial model with uniformly distributed parameter for ADT and a fixed parameter for jerk provided a statistically significant estimate for quarter-mile segments. The results also indicated that roadway curvature and the presence of auxiliary lane are not significantly related with crash frequency for the highway segments under consideration. The results from this exploration are promising since the data used to derive the explanatory variable(s) can be collected using most off-the-shelf GPS devices, including many smartphones.

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