MS170

The social amoeba, Dictyostelium discoideum, produces a multicellular fruiting body and has become a model system for cell-cell interactions such as signalling, adhesion and development. However, unlike most multicellular organisms, it forms by aggregation of cells and, in the laboratory, forms genetic chimeras where there may be competition among clones. Here we show that chimera formation is also likely in nature, because different clones commonly co-occur on a very small scale. This suggests that D. discoideum will likely have evolved strategies for competing in chimeras, and that the function of some developmental genes will be competitive. Natural chimerism also makes D. discoideum a good model organism for the investigation of issues relating to coexistence and conflict between cells.

The geographic ranges of rhesus (Macaca mulatta) and cynomolgus (M. fascicularis) macaques adjoin in Indochina where they appear to hybridize. We used published and newly generated DNA sequences from 19 loci spanning approximately 20 kb to test whether introgression has occurred between these macaque species. We studied introgression at the level of nuclear DNA and distinguished between incomplete lineage sorting of ancestral polymorphisms or interspecific gene flow. We implemented a divergence population genetics approach by fitting our data to an isolation model implemented in the software IMa. The model that posits no gene flow from the rhesus into the cynomolgus macaque was rejected (P = 1.99 x 10(-8)). Gene flow in this direction was estimated as 2Nm approximately 1.2, while gene flow in the reverse direction was nonsignificantly different from zero (P = 0.16). The divergence time between species was estimated as approximately 1.3 million years. Balancing selection, a special case of incomplete sorting, was taken into consideration, as well as potential crossbreeding in captivity. Parameter estimates varied between analyses of subsets of data, although we still rejected isolation models. Geographic sampling of the data, where samples of cynomolgus macaques derived from Indochina were excluded, revealed a lost signature of gene flow, indicating that interspecific gene flow is restricted to mainland Indochina. Our results, in conjunction with those by others, justify future detailed analyses into the genetics of reproductive barriers and reticulate evolution in these two genome-enabled primates. Future studies of the natural hybridization between rhesus and cynomolgus macaques would expand the repertoire of systems available for speciation studies in primates.

The serine/threonine kinase AKT functions as a critical node of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (m-TOR) signaling pathway. Aberrant activation and overexpression of AKT are strongly correlated with numerous human cancers. To date, only two AKT degraders with no structure-activity relationship (SAR) results have been reported. Through extensive SAR studies on various linkers, E3 ligase ligands, and AKT binding moieties, we identified two novel and potent AKT proteolysis targeting chimera (PROTAC) degraders: von Hippel-Lindau (VHL)-recruiting degrader13(MS98) and cereblon (CRBN)-recruiting degrader25(MS170). These two compounds selectively induced robust AKT protein degradation, inhibited downstream signaling, and suppressed cancer cell proliferation. Moreover, these two degraders exhibited good plasma exposure levels in mice through intraperitoneal injection. Overall, our comprehensive SAR studies led to the discovery of degraders13and25, which are potentially useful chemical tools to investigate biological and pathogenic functions of AKT in vitro and in vivo.