Background:The mechanisms by which ligands activate TAM receptors (TYRO3, AXL, and MER) are not well understood. Results:We created a series of TAM reporter cell lines and interrogated ligand-inducible TAM activation. Conclusion: TAMs are differentially activated by GAS6 and protein S and have distinct requirements for phosphatidylserine. Significance: Results reveal molecular mechanisms and rationale for non-overlapping functions of TAMs.

T ransthoracic echocardiography (TTE) is the standard clinical tool for initial assessment and longitudinal evaluation of patients with valvular heart disease.1 Current clinical guidelines for the management of adults with chronic valve regurgitation include clear recommendations for measuring regurgitant severity.1,2 Quantification is recommended as a tool to identify patients at risk of adverse long-term physiological consequences, including irreversible left ventricular (LV) contractile dysfunction, and to prevent adverse clinical outcomes, including heart failure, sudden death, and cardiovascular mortality. Clinical Perspective on p 57TTE allows measurement of regurgitant volume (RVol), fraction, and orifice area and has been well validated in both experimental and clinical studies. 2 In addition, regurgitant orifice area (ROA) has been shown to be predictive of clinical outcome for both aortic regurgitation (AR) and mitral regurgitation (MR). 3 However, echocardiographic quantification of valve regurgitation can be challenging because of poor acoustic windows, dynamic or eccentric jets, and geometric assumptions. 2,4,5 Cardiovascular magnetic resonance (CMR) is an alternative modality for assessing patients with chronic valve regurgitation based on measurement of LV volumes and phase-contrast velocity mapping.6-8 CMR has several potential advantages compared with TTE, including improved endocardial definition, fewer geometric assumptions, and less angle dependence for flow measurements. However there are few data on direct systematic comparisons, including reproducibility, between TTE and CMR for quantitation of AR and MR. Thus, we hypothesized that CMR has less interobserver variability when quantifying chronic AR and MR and thus may be preferable for longitudinal follow-up in individual patients.Background-Both transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) imaging allow quantification of chronic aortic regurgitation (AR) and mitral regurgitation (MR). We hypothesized that CMR measurement of regurgitant volume (RVol) is more reproducible than TTE.Methods and Results-TTE and CMR performed on the same day in 57 prospectively enrolled adults (31 with AR, 26 with MR) were measured by 2 independent physicians. TTE RVol AR was calculated as Doppler left ventricular outflow minus inflow stroke volume. RVol MR was calculated by both the proximal isovelocity surface area method and Doppler volume flow at 2 sites. CMR RVol AR was calculated by phase-contrast velocity mapping at the aortic sinuses and RVol MR as total left ventricular minus forward stroke volume. Intraobserver and interobserver variabilities were similar. For AR, the Bland-Altman mean interobserver difference in RVol was −0.7 mL (95% confidence interval [CI], −5 to 4) for CMR and −9 mL (95% CI, −53 to −36) for TTE. The Pearson correlation was higher (P=0.001) between CMR (0.99) than TTE readers (0.89). For MR, the Bland-Altman mean difference in RVol between observers was −4 mL (95% CI, −21 to 13) for CMR compared with 0....

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species.