The dynein regulatory complex is required for ciliary motility and otolith biogenesis in the inner ear

In teleosts, proper balance and hearing depend on mechanical sensors in the inner ear. These sensors include actin-based microvilli and microtubule-based cilia that extend from the surface of sensory hair cells and attach to biomineralized 'ear stones' (or otoliths) 1. Otolith number, size and placement are under strict developmental control, but the mechanisms that ensure otolith assembly atop specific cells of the sensory epithelium are unclear. Here we demonstrate that cilia motility is required for normal otolith assembly and localization. Using in vivo video microscopy, we show that motile tether cilia at opposite poles of the otic vesicle create fluid vortices that attract otolith precursor particles, thereby biasing an otherwise random distribution to direct localized otolith seeding on tether cilia. Independent knockdown of subunits for the dynein regulatory complex and outer-arm dynein disrupt cilia motility, leading to defective otolith biogenesis. These results demonstrate a requirement for the dynein regulatory complex in vertebrates and show that cilia-driven flow is a key epigenetic factor in controlling otolith biomineralization

High triglyceride to HDL cholesterol ratio is associated with increased coronary heart disease among White but not Black adults

Objective: Black adults are less likely than White adults to present with adverse lipid profiles and more likely to present with low-grade inflammation. The impact of race on the association between atherogenic lipid profiles, inflammation, and coronary heart disease (CHD) is unknown. Methods: We evaluated the association between high levels (>50th percentile) of high-sensitivity C-reactive protein (hsCRP) and of triglycerides to high density lipoprotein ratio (TG/HDL-C) and CHD events by race in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort with 30,239 Black and White participants aged 45 and older. Results: Participants with both high hsCRP and high TG/HDL-C had highest rates of CHD (HR 1.84; 95% CI: 1.48, 2.29 vs HR 1.52; 95% CI: 1.19, 1.94 in White vs Black participants respectively). Whereas isolated high hsCRP was associated with increased CHD risk in both races (HR 1.68; 95% CI: 1.31, 2.15 and HR 1.43; 95% CI: 1.13, 1.81 for White and Black participants respectively), isolated high TG/HDL was associated with increased CHD risk only in White participants (HR 1.44; 95% CI: 1.15, 1.79 vs HR 1.01; 95% CI: 0.74, 1.38). Further, the effects of high hsCRP and high TG/HDL-C were additive, with inflammation being the driving variable for the association in both races. Conclusion: In both races, higher inflammation combined with adverse lipid profile is associated with greater CHD risk. Therefore, inflammation increases CHD risk in both races whereas dyslipidemia alone is associated with a greater risk in White but not in Black adults. hsCRP testing should be a standard feature of CHD risk assessment, particularly in Black patients

The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with abnormal function of motile cilia. Approximately half of PCD patients also have alterations in the left-right organization of internal organ positioning including situs inversus and situs ambiguous (Kartagener’s Syndrome, KS). Here we identify an uncharacterized coiled-coil domain containing protein (CCDC40) essential for correct left-right patterning in mouse, zebrafish and humans. Ccdc40 is expressed in tissues that contain motile cilia and mutation of Ccdc40 results in cilia with reduced ranges of motility. Importantly, we demonstrate that CCDC40 deficiency causes a novel PCD variant characterized by misplacement of central pair microtubules and defective axonemal assembly of inner dynein arms (IDAs) and dynein regulator complexes (DRCs). CCDC40 localizes to motile cilia and the apical cytoplasm and is responsible for axonemal recruitment of CCDC39, which is also mutated in a similar PCD variant