Baxter, L. L. | Search bioRxiv

bioRxiv2026

Anti-inflammatory and pro-proliferative effects of fasudil in human trisomy 21 neural progenitor cells

Down syndrome (DS) results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. No effective treatments currently exist that improve neurodevelopment and cognition. Atypical brain development in individuals with DS is apparent before birth, which suggests that the optimal time to begin administration of therapies is prenatally. Human neural progenitor cell (NPC) cultures provide a tractable in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the effects of pharmacological interventions. Here we report the results of preclinical studies evaluating 24 candidate therapies. RNA-Seq analyses found that euploid and T21 NPCs showed different transcriptomic responses to five candidate pharmacotherapies. The Rho-associated coiled-coil kinase (ROCK) inhibitor fasudil increased proliferation of T21 NPCs, reduced expression of inflammatory pathway genes in T21 NPCs, and reduced markers of inflammation in LPS-stimulated microglia model systems. These results demonstrate that fasudil can alter multiple T21-associated abnormalities in a beneficial manner, suggesting that fasudil warrants further study as a candidate prenatal pharmacotherapy for DS.

pharmacology and toxicology↗

bioRxiv2020

Sexual selection theory meets disease vector control: Testing harmonic convergence as a "good genes" signal in Aedes aegypti mosquitoes

The mosquito Aedes aegypti is a medically important, globally distributed vector of the viruses that cause dengue, yellow fever, chikungunya, and Zika. Although reproduction and mate choice are key components of vector population dynamics and control, our understanding of the mechanisms of sexual selection in mosquitoes remains poor. In "good genes" models of sexual selection, females use male cues as an indicator of both mate and offspring inherent genetic quality. Recent studies in Ae. aegypti provide evidence that male wingbeat acoustics signal aspects of offspring quality and performance during mate selection in a process known as harmonic convergence. However, the extent to which harmonic convergence may signal overall inherent quality of mates and their offspring remains unknown. To examine this, we measured the potential acoustic signaling and heritability of a broad panel of parent and offspring fitness traits in two generations of field-derived Ae. aegypti originating from dengue endemic field sites in Thailand. Our data show that in this population of mosquitoes, harmonic convergence does not signal male fertility, female fecundity, and male flight performance traits, which despite displaying robust variability in both parents and their offspring were only weakly heritable. Together with previous work, our findings suggest that vector reproductive control programs should treat harmonic convergence as an indicator of some, but not all aspects of inherent quality, and that multiple forms of sexual selection are likely at play in Ae. aegypti in a trait, population, and environment dependent manner.

ecology↗