👤 Geoffrey G Hesketh

There is increasing interest in the importance of patterns of accumulation and overall daily time-use composition of physical activity (PA) and sedentary time (SED) for children's cardiometabolic health. This study examined cross-sectional associations between the time-use composition of PA and SED patterns with cardiometabolic risk factors in 4-year-olds. Data were drawn from the Barwon Infant Study 4-year review (n = 467). Accelerometer data were classified into short (≤ 1-minute) and long (> 1-min) SED, light-, moderate-, and vigorous-intensity PA (LPA, MPA, VPA) bouts. A waking time-use composition of eight distinct components (total volumes plus short and long bouts of SED, LPA MPA, VPA) was constructed using compositional data analysis. Linear mixed models examined associations between composition patterns and body mass index (BMI), percent body fat, triceps and subscapular skinfold thickness, blood pressure, heart rate, carotid-femoral pulse wave velocity, and aortic and carotid intima-media thickness. Adjusted models indicated a higher ratio of long versus short LPA bouts was associated with higher z-BMI (β = 1.69, SE = 0.83, p = 0.04), percent body fat (β = 10.72, SE = 3.71, p = 0.004), and z-triceps (β = 1.90, SE = 0.93, p = 0.04). A higher ratio of long versus short MPA bouts was associated with lower z-BMI (β = - 0.99, SE = 0.46, p = 0.03) and percent body fat (β = - 4.63, SE = 1.93, p = 0.02). A higher total volume of MPA versus VPA was associated with higher percent body fat (β = 4.07, SE = 1.63, p = 0.01) and z-triceps (β = 1.05, SE = 0.43, p = 0.01). Other outcomes showed no associations (p ≥   0.05). In preschoolers, accumulating LPA in shorter bursts, MPA in longer bursts, and maintaining a higher proportion of VPA may support healthier adiposity profiles. These findings underscore the importance of minimizing prolonged sedentary time and encouraging sustained, high-intensity PA from early childhood. Show less

MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Show less

Multi-subunit tethering complexes control membrane fusion events in eukaryotic cells. Class C core vacuole/endosome tethering (CORVET) and homotypic fusion and vacuole protein sorting (HOPS) are two such complexes, both containing the Sec1/Munc18 protein subunit VPS33A. Metazoans additionally possess VPS33B, which has considerable sequence similarity to VPS33A but does not integrate into CORVET or HOPS complexes and instead stably interacts with VIPAR. It has been recently suggested that VPS33B and VIPAR comprise two subunits of a novel multi-subunit tethering complex (named "CHEVI"), perhaps analogous in configuration to CORVET and HOPS. We utilized the BioID proximity biotinylation assay to compare and contrast the interactomes of VPS33A and VPS33B. Overall, few proteins were identified as associating with both VPS33A and VPS33B, suggesting that these proteins have distinct sub-cellular localizations. Consistent with previous reports, we observed that VPS33A was co-localized with many components of class III phosphatidylinositol 3-kinase (PI3KC3) complexes: PIK3C3, PIK3R4, NRBF2, UVRAG and RUBICON. Although VPS33A clearly co-localized with several subunits of CORVET and HOPS in this assay, no proteins with the canonical CORVET/HOPS domain architecture were found to co-localize with VPS33B. Instead, we identified that VPS33B interacts directly with CCDC22, a member of the CCC complex. CCDC22 does not co-fractionate with VPS33B and VIPAR in gel filtration of human cell lysates, suggesting that CCDC22 interacts transiently with VPS33B/VIPAR rather than forming a stable complex with these proteins in cells. We also observed that the protein complex containing VPS33B and VIPAR is considerably smaller than CORVET/HOPS, suggesting that the CHEVI complex comprises just VPS33B and VIPAR. Show less