Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy

Parkin, an E3 ubiquitin ligase implicated in Parkinson's disease, promotes degradation of dysfunctional mitochondria by autophagy. Using proteomic and cellular approaches, we show that upon translocation to mitochondria, Parkin activates the ubiquitin–proteasome system (UPS) for widespread degradation of outer membrane proteins. This is evidenced by an increase in K48-linked polyubiquitin on mitochondria, recruitment of the 26S proteasome and rapid degradation of multiple outer membrane proteins. The degradation of proteins by the UPS occurs independently of the autophagy pathway, and inhibition of the 26S proteasome completely abrogates Parkin-mediated mitophagy in HeLa, SH-SY5Y and mouse cells. Although the mitofusins Mfn1 and Mfn2 are rapid degradation targets of Parkin, we find that degradation of additional targets is essential for mitophagy. These results indicate that remodeling of the mitochondrial outer membrane proteome is important for mitophagy, and reveal a causal link between the UPS and autophagy, the major pathways for degradation of intracellular substrates

EXPERIMENTAL MEASUREMENT OF INTERNAL TEMPERATURE OF A TUBE IN COOLING ON A BED OF PASSAGECONTINUOUS UNDER NATURAL CONVECTION

The process behind manufacturing bars and profiles in the steel industry utilizes heating and cooling at controlled rates in order to facilitate changes in their geometries, as well as to obtain desired changes in mechanical steel properties.This work develops an experimental procedure to reproduce the thermal behavior tubes over a cooling bed. In literature the experimental results obtained by Damasceno (2004) do not take into account the temperature measurements of the sidewalls and the floor below the bed and storage temperatures within and outside the shed. These failures compromise the claim to validate the mathematical model of Souza (2015) and therefore new measurements were obtained with room temperatures controlled, order to validate the mathematical model of a cooling bed heat treatment of steel mill Vallourec Tubes, located in Belo Horizonte, Brazil

Numerical investigation of oil injection in a Roots blower operated as expander

The adoption of positive displacement machines as expanders in Organic Rankine Cycles (ORCs) is increasingly common, especially in the low to medium power range. At the same time, these devices often serve as compressor in Vapor-Compression Refrigeration Systems. In both cases, the application of Computation Fluid Dynamics (CFD) to optimize such machines has become an integrated tool in the design process. As a consequence, several challenges associated with the numerical simulation have to be taken into account. For example, the modeling of the gap represents a challenge for the stability of the numerical analysis. The dynamic of the process, combined with deformations of the clearances and of the working chamber has to be considered with extra care. To raise the efficiency of the machine, oil is typically injected. Its numerical modeling imply an extra challenge in the simulation of the actual operation of the machine. The present work is mainly focused on the multi-phase nature of the flow, with a particular analysis of the lubricant oil injected. In this work, a two-lobe Roots blower operated as expander has been simulated with the open-source software OpenFOAM-v1812, using the SCORG-V5.2.2. This analysis highlights the areas that are affected the most by the oil presence in order to highlight the sealing effect it provides

Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates Mitofusin

Loss of the E3 ubiquitin ligase Parkin causes early onset Parkinson's disease, a neurodegenerative disorder of unknown etiology. Parkin has been linked to multiple cellular processes including protein degradation, mitochondrial homeostasis, and autophagy; however, its precise role in pathogenesis is unclear. Recent evidence suggests that Parkin is recruited to damaged mitochondria, possibly affecting mitochondrial fission and/or fusion, to mediate their autophagic turnover. The precise mechanism of recruitment and the ubiquitination target are unclear. Here we show in Drosophila cells that PINK1 is required to recruit Parkin to dysfunctional mitochondria and promote their degradation. Furthermore, PINK1 and Parkin mediate the ubiquitination of the profusion factor Mfn on the outer surface of mitochondria. Loss of Drosophila PINK1 or parkin causes an increase in Mfn abundance in vivo and concomitant elongation of mitochondria. These findings provide a molecular mechanism by which the PINK1/Parkin pathway affects mitochondrial fission/fusion as suggested by previous genetic interaction studies. We hypothesize that Mfn ubiquitination may provide a mechanism by which terminally damaged mitochondria are labeled and sequestered for degradation by autophagy

Australia and Other Nations are Failing to Meet Sedentary Behaviour Guidelines for Children: Implications and a Way Forward

BACKGROUND: Australia has joined a growing number of nations which have evaluated the physical activity and sedentary behaviour status of their children. Australia received a 'D minus' in the first Active Healthy Kids Australia Physical Activity Report Card. METHODS: An expert subgroup of the Australian Report Card Research Working Group iteratively reviewed available evidence to answer three questions: 1) What are the main sedentary behaviours of children?, 2) What are the potential mechanisms for sedentary behaviour to impact on child health and development? and, 3) What are the effects of different types of sedentary behaviours on child health and development? RESULTS: Neither sedentary time nor screen time are homogeneous activities likely to result in homogenous effects. There are several mechanisms by which various sedentary behaviours may positively or negatively affect cardiometabolic, neuro-musculoskeletal, and psycho-social health, though the strength of evidence varies. National surveillance systems, and mechanistic, longitudinal and experimental studies are needed for Australia and other nations to improve their grade. CONCLUSIONS: Despite limitations, available evidence is sufficiently convincing that the total exposure and pattern of exposure to sedentary behaviours are critical to the healthy growth, development and wellbeing of children. Nations therefore need strategies to address these common behaviours

Development and a Validation of a Charge Sensitive Organic Rankine Cycle (ORC) Simulation Tool

Despite the increasing interest in organic Rankine cycle (ORC) systems and the large number of cycle models proposed in the literature, charge-based ORC models are still almost absent. In this paper, a detailed overall ORC simulation model is presented based on two solution strategies: condenser subcooling and total working fluid charge of the system. The latter allows the subcooling level to be predicted rather than specified as an input. The overall cycle model is composed of independent models for pump, expander, line sets, liquid receiver and heat exchangers. Empirical and semi-empirical models are adopted for the pump and expander, respectively. A generalized steady-state moving boundary method is used to model the heat exchangers. The line sets and liquid receiver are used to better estimate the total charge of the system and pressure drops. Finally, the individual components are connected to form a cycle model in an object-oriented fashion. The solution algorithm includes a preconditioner to guess reasonable values for the evaporating and condensing temperatures and a main cycle solver loop which drives to zero a set of residuals to ensure the convergence of the solution. The model has been developed in the Python programming language. A thorough validation is then carried out against experimental data obtained from two test setups having different nominal size, working fluids and individual components: (i) a regenerative ORC with a 5 kW scroll expander and an oil flooding loop; (ii) a regenerative ORC with a 11 kW single-screw expander. The computer code is made available through open-source dissemination

Culling sick mitochondria from the herd

The PINK1–Parkin pathway plays a critical role in mitochondrial quality control by selectively targeting damaged mitochondria for autophagy. In this issue, Tanaka et al. (2010. J. Cell Biol. doi: 10.1083/jcb.201007013) demonstrate that the AAA-type ATPase p97 acts downstream of PINK1 and Parkin to segregate fusion-incompetent mitochondria for turnover. p97 acts by targeting the mitochondrial fusion-promoting factor mitofusin for degradation through an endoplasmic reticulum–associated degradation (ERAD)-like mechanism

Performance Analysis of Available Bandwidth Estimation Tools for Grid Networks

Abstract Modern large-scale grid computing systems for processing advanced science and engineering applications rely on geographically distributed clusters. In such highly distributed environments, estimating the available bandwidth between clusters is a key issue for efficient task scheduling. We analyze the performance of two well known available bandwidth estimation tools, pathload and abget, with the aim of using them in grid environments. Our experiments consider the accuracy of the estimation, the convergence time, their level of intrusion in the grid links, and the ability to handle multiple simultaneous estimations. Overall, pathload represents a good solution to estimate available bandwidth in grid environments

Guidelines for the Selection of Physical Literacy Measures in Physical Education in Australia

Assessment of physical literacy poses a dilemma of what instrument to use. There is currently no guide regarding the suitability of common assessment approaches. The purpose of this brief communication is to provide a user's guide for selecting physical literacy assessment instruments appropriate for use in school physical education and sport settings. While recommendations regarding specific instruments are not provided, the guide offers information about key attributes and considerations for the use. A decision flow chart has been developed to assist teachers and affiliated school practitioners to select appropriate methods of assessing physical literacy. School PE and sport scenarios are presented to illustrate this process. It is important that practitioners are empowered to select the most appropriate instrument/s to suit their needs

Defining Physical Literacy for Application in Australia: A Modified Delphi Method

Purpose. The development of a physical literacy definition and standards framework suitable for implementation in Australia. Method. Modified Delphi methodology. Results . Consensus was established on four defining statements: Core – Physical literacy is lifelong holistic learning acquired and applied in movement and physical activity contexts; Composition – Physical literacy reflects ongoing changes integrating physical, psychological, cognitive and social capabilities; Importance – Physical literacy is vital in helping us lead healthy and fulfilling lives through movement and physical activity; Aspiration – A physically literate person is able to draw on their integrated physical, psychological, cognitive, and social capacities to support health promoting and fulfilling movement and physical activity, relative to their situation and context, throughout the lifespan. The standards framework addressed four learning domains (physical, psychological, cognitive, and social), spanning five learning configurations/levels. Conclusion. The development of a bespoke program for a new context has important implications for both existing and future program