Discovery of Small-Molecule CD33 Pre-mRNA Splicing Modulators.

CD33/Siglec 3 is a myeloid lineage cell surface receptor that is known to regulate microglia activity. Multiple genome-wide association studies (GWAS) have identified genetic variants in the CD33 gene that convey protection from late-onset Alzheimer's disease. Furthermore, mechanistic studies into GWAS-linked variants suggest that disease protection is attributed to the alternative splicing of exon 2 of the CD33 pre-mRNA. Using a phenomimetic screen, a series of compounds were found to enhance the exclusion of CD33 exon 2, acting as a chemomimetic of the GWAS-linked gene variants. Additional studies confirmed that meyloid lineage cells treated with several of these compounds have a reduced full-length V-domain containing CD33 protein, while targeted RNA-seq concordantly demonstrated that compound 1 increases exon 2 skipping in cellular mRNA pools. These studies demonstrate how pharmacological interventions can be used to manipulate disease-relevant pre-mRNA splicing and provide a starting point for future efforts to identify small molecules that alter neuroimmune function that is rooted in the human biology of neurodegenerative disease.

The impact of keels and tails on turtle swimming performance and their potential as models for biomimetic design.

Stability and turning performance are two key metrics of locomotor performance in animals, and performance in both of these metrics can be improved through a variety of morphological structures. Aquatic vehicles are often designed with keels and rudders to improve their stability and turning performance, but how keels and rudders function in rigid-bodied animals is less understood. Aquatic turtles are a lineage of rigid-bodied animals that have the potential to function similarly to engineered vehicles, and also might make use of keels and rudders to improve their stability and turning performance. To test these possibilities, we trained turtles to follow a mechanically controlled prey stimulus under three sets of conditions: with no structural modifications, with different sized and shaped keels, and with restricted tail use. We predicted that keels in turtles would function similarly to those in aquatic vehicles to reduce oscillations, and that turtles would use the tail like a rudder to reduce oscillations and improve turning performance. We found that the keel designs we tested did not reduce oscillations in turtles, but that the tail was used similarly to a rudder, with benefits to both the magnitude of oscillations they experienced and turning performance. These data show how variation in the accessory structures of rigid-bodied animals can impact swimming performance, and suggest that such variation among turtles could serve as a biomimetic model in designing aquatic vehicles that are stable as well as maneuverable and agile.