Synthesis and evaluation of 3″- and 4″-deoxy and -fluoro analogs of the immunostimulatory glycolipid,KRN7000

Four 3″- and 4″-deoxy and -fluorogalactosyl ceramides were synthesized, and their ability to stimulate iNKT cells, based on levels of IL-2 production, was assessed in three NKT cell receptor hybridomas. In two of the hybridomas, 1.2 and 2H4, all of the analogs were immunostimulatory, while in the 1.4 hybridoma only the 4″-fluoro analog led to the production of significant levels of IL-2.     

Paroxysmal and cognitive phenotypes in Prrt2 mutant mice

Mutations in proline‐rich transmembrane protein 2 (PRRT2) cause a range of episodic disorders that include paroxysmal kinesigenic dyskinesia and benign familial infantile epilepsy. Mutations are generally loss of function and include the c649dupC frameshifting mutation that is present in around 80% of affected individuals. To investigate how Prrt2 loss of function mutations causes disease, we performed a phenotypic investigation of a transgenic Prrt2 knockout (Prrt2 KO) mouse. We observed spontaneous paroxysmal episodes with behavioural features of both seizure and movement disorders, as well as unexplained deaths in KO and HET animals. KO mice showed spatial learning deficits in the Morris water maze, as well as gait abnormalities in the quantitative Digigait analysis; both of which may be representative of the more severe phenotypes experienced by homozygous patients. These findings extend the described phenotypes of Prrt2 mutant mice, further confirming their utility for in vivo investigation of the role of Prrt2 mutations in episodic diseases.     

Habitat fragmentation in coastal southern California disrupts genetic connectivity in the cactus wren (Campylorhynchus brunneicapillus)

Achieving long‐term persistence of species in urbanized landscapes requires characterizing population genetic structure to understand and manage the effects of anthropogenic disturbance on connectivity. Urbanization over the past century in coastal southern California has caused both precipitous loss of coastal sage scrub habitat and declines in populations of the cactus wren (Campylorhynchus brunneicapillus). Using 22 microsatellite loci, we found that remnant cactus wren aggregations in coastal southern California comprised 20 populations based on strict exact tests for population differentiation, and 12 genetic clusters with hierarchical Bayesian clustering analyses. Genetic structure patterns largely mirrored underlying habitat availability, with cluster and population boundaries coinciding with fragmentation caused primarily by urbanization. Using a habitat model we developed, we detected stronger associations between habitat‐based distances and genetic distances than Euclidean geographic distance. Within populations, we detected a positive association between available local habitat and allelic richness and a negative association with relatedness. Isolation‐by‐distance patterns varied over the study area, which we attribute to temporal differences in anthropogenic landscape development. We also found that genetic bottleneck signals were associated with wildfire frequency. These results indicate that habitat fragmentation and alterations have reduced genetic connectivity and diversity of cactus wren populations in coastal southern California. Management efforts focused on improving connectivity among remaining populations may help to ensure population persistence.