The conserved Pkh–Ypk kinase cascade is required for endocytosis in yeast

Internalization of activated signaling receptors by endocytosis is one way cells downregulate extracellular signals. Like many signaling receptors, the yeast α-factor pheromone receptor is downregulated by hyperphosphorylation, ubiquitination, and subsequent internalization and degradation in the lysosome-like vacuole. In a screen to detect proteins involved in ubiquitin-dependent receptor internalization, we identified the sphingoid base–regulated serine–threonine kinase Ypk1. Ypk1 is a homologue of the mammalian serum– and glucocorticoid-induced kinase, SGK, which can substitute for Ypk1 function in yeast. The kinase activity of Ypk1 is required for receptor endocytosis because mutations in two residues important for its catalytic activity cause a severe defect in α-factor internalization. Ypk1 is required for both receptor-mediated and fluid-phase endocytosis, and is not necessary for receptor phosphorylation or ubiquitination. Ypk1 itself is phosphorylated by Pkh kinases, homologues of mammalian PDK1. The threonine in Ypk1 that is phosphorylated by Pkh1 is required for efficient endocytosis, and pkh mutant cells are defective in α-factor internalization and fluid-phase endocytosis. These observations demonstrate that Ypk1 acts downstream of the Pkh kinases to control endocytosis by phosphorylating components of the endocytic machinery

Hemodynamic evaluation in patients with transposition of the great arteries after the arterial switch operation:4D flow and 2D phase contrast cardiovascular magnetic resonance compared with Doppler echocardiography

Background: Peak velocity measurements are used to evaluate the significance of stenosis in patients with transposition of the great arteries after the arterial switch operation (TGA after ASO). 4D flow cardiovascular magnetic resonance (CMR) provides 3-directional velocity encoding and full volumetric coverage of the great arteries and may thus improve the hemodynamic evaluation in these patients. The aim of this study was to compare peak velocities measured by 4D flow CMR with 2D phase contrast (PC) CMR and the gold standard Doppler echocardiography (echo) in patients with TGA after ASO. Methods: Nineteen patients (mean age 13 +/- 9 years, range 1-25 years) with TGA after ASO who underwent 2D PC CMR and 4D flow CMR were included in this study. Peak velocities were measured with 4D flow CMR in the aorta and pulmonary arteries and compared to peak velocities measured with 2D PC CMR and Doppler echo. 2D PC CMR data were available in the ascending aorta, main, right and left pulmonary arteries (AAO/MPA/RPA/LPA) for 19/18/ 17/17 scans, respectively, and Doppler echo data were available for 13/9/6/6 scans, respectively. Peak velocities were measured with: 1) a single cross section for 2D PC CMR, 2) velocity maximum intensity projections (MIPs) for 4D flow CMR and 3) Doppler echo. Results: Significantly higher peak velocities were found with 4D flow CMR than 2D PC CMR in the AAO (p = 0.003), MPA (p = 0.002) and RPA (p = 0.005) but not in the LPA (p = 0.200). No difference in peak velocity was found between 4D flow CMR and Doppler echo (p > 0.46) or 2D PC CMR and echo (p > 0.11) for all analyzed vessel segments. Conclusions: 4D flow CMR evaluation of patients with TGA after ASO detected higher peak velocities than 2D PC CMR, indicating the potential of 4D flow CMR to provide improved stenosis assessment in these patients

Hemodynamic evaluation in patients with transposition of the great arteries after the arterial switch operation: 4D flow and 2D phase contrast cardiovascular magnetic resonance compared with Doppler echocardiography

Background: Peak velocity measurements are used to evaluate the significance of stenosis in patients with transposition of the great arteries after the arterial switch operation (TGA after ASO). 4D flow cardiovascular magnetic resonance (CMR) provides 3-directional velocity encoding and full volumetric coverage of the great arteries and may thus improve the hemodynamic evaluation in these patients. The aim of this study was to compare peak velocities measured by 4D flow CMR with 2D phase contrast (PC) CMR and the gold standard Doppler echocardiography (echo) in patients with TGA after ASO. Methods: Nineteen patients (mean age 13 +/- 9 years, range 1-25 years) with TGA after ASO who underwent 2D PC CMR and 4D flow CMR were included in this study. Peak velocities were measured with 4D flow CMR in the aorta and pulmonary arteries and compared to peak velocities measured with 2D PC CMR and Doppler echo. 2D PC CMR data were available in the ascending aorta, main, right and left pulmonary arteries (AAO/MPA/RPA/LPA) for 19/18/ 17/17 scans, respectively, and Doppler echo data were available for 13/9/6/6 scans, respectively. Peak velocities were measured with: 1) a single cross section for 2D PC CMR, 2) velocity maximum intensity projections (MIPs) for 4D flow CMR and 3) Doppler echo. Results: Significantly higher peak velocities were found with 4D flow CMR than 2D PC CMR in the AAO (p = 0.003), MPA (p = 0.002) and RPA (p = 0.005) but not in the LPA (p = 0.200). No difference in peak velocity was found between 4D flow CMR and Doppler echo (p > 0.46) or 2D PC CMR and echo (p > 0.11) for all analyzed vessel segments. Conclusions: 4D flow CMR evaluation of patients with TGA after ASO detected higher peak velocities than 2D PC CMR, indicating the potential of 4D flow CMR to provide improved stenosis assessment in these patients

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3–90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to examine age‐related trajectories inferred from cross‐sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter‐individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age‐related morphometric patterns

Cortical thickness across the lifespan: Data from 17,075 healthy individuals aged 3-90 years

Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large‐scale studies. In response, we used cross‐sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) Consortium to infer age‐related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta‐analysis and one‐way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes