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Institute
Damaged mitochondria are selectively eliminated by mitophagy. Parkin and PINK1, gene products mutated in familial Parkinson’s disease, play essential roles in mitophagy through ubiquitination of mitochondria. Cargo ubiquitination by E3 ubiquitin ligase Parkin is important to trigger selective autophagy. Although autophagy receptors recruit LC3-labeled autophagic membranes onto damaged mitochondria, how other essential autophagy units such as ATG9A-integrated vesicles are recruited remains unclear. Here, using mammalian cultured cells, we demonstrate that RABGEF1, the upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin. RABGEF1 directs the downstream Rab proteins, RAB5 and RAB7A, to damaged mitochondria, whose associations are further regulated by mitochondrial Rab-GAPs. Furthermore, depletion of RAB7A inhibited ATG9A vesicle assembly and subsequent encapsulation of the mitochondria by autophagic membranes. These results strongly suggest that endosomal Rab cycles on damaged mitochondria are a crucial regulator of mitophagy through assembling ATG9A vesicles.
Clustering of cardiovascular risk factors and carotid intima-media thickness : the USE-IMT study
(2017)
Background: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation.
Methods: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group.
Results: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women.
Conclusion: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.
At the Large Hadron Collider at CERN in Geneva, Switzerland, atomic nuclei are collided at ultra-relativistic energies. Many final-state particles are produced in each collision and their properties are measured by the ALICE detector. The detector signals induced by the produced particles are digitized leading to data rates that are in excess of 48 GB/s. The ALICE High Level Trigger (HLT) system pioneered the use of FPGA- and GPU-based algorithms to reconstruct charged-particle trajectories and reduce the data size in real time. The results of the reconstruction of the collision events, available online, are used for high level data quality and detector-performance monitoring and real-time time-dependent detector calibration. The online data compression techniques developed and used in the ALICE HLT have more than quadrupled the amount of data that can be stored for offline event processing.
At the Large Hadron Collider at CERN in Geneva, Switzerland, atomic nuclei are collided at ultra-relativistic energies. Many final-state particles are produced in each collision and their properties are measured by the ALICE detector. The detector signals induced by the produced particles are digitized leading to data rates that are in excess of 48 GB/s. The ALICE High Level Trigger (HLT) system pioneered the use of FPGA- and GPU-based algorithms to reconstruct charged-particle trajectories and reduce the data size in real time. The results of the reconstruction of the collision events, available online, are used for high level data quality and detector-performance monitoring and real-time time-dependent detector calibration. The online data compression techniques developed and used in the ALICE HLT have more than quadrupled the amount of data that can be stored for offline event processing.
At the Large Hadron Collider at CERN in Geneva, Switzerland, atomic nuclei are collided at ultra-relativistic energies. Many final-state particles are produced in each collision and their properties are measured by the ALICE detector. The detector signals induced by the produced particles are digitized leading to data rates that are in excess of 48 GB/s. The ALICE High Level Trigger (HLT) system pioneered the use of FPGA- and GPU-based algorithms to reconstruct charged-particle trajectories and reduce the data size in real time. The results of the reconstruction of the collision events, available online, are used for high level data quality and detector-performance monitoring and real-time time-dependent detector calibration. The online data compression techniques developed and used in the ALICE HLT have more than quadrupled the amount of data that can be stored for offline event processing.