Lipid droplets and lipotoxicity during autophagy.

Lipid droplets (LDs) are neutral lipid storage organelles that provide a rapidly accessible source of fatty acids (FAs) for energy during periods of nutrient deprivation. Surprisingly, lipids released by the macroautophagic/autophagic breakdown of membranous organelles are packaged and stored in new LDs during periods of prolonged starvation. Why cells would store FAs during an energy crisis was unknown. In our recent study, we demonstrated that FAs released during MTORC1-regulated autophagy are selectively channeled by DGAT1 (diacylglycerol O-acyltransferase 1) into triacylglycerol (TAG)-rich LDs. These DGAT1-dependent LDs sequester FAs and prevent the accumulation of acylcarnitines, which otherwise directly disrupt mitochondrial integrity. Our findings establish LD biogenesis as a general cellular response to periods of high autophagic flux that provide a lipid buffering system to mitigate lipotoxic cellular damage

Getting a handle on lipid droplets: Insights into ER-lipid droplet tethering.

Lipid droplets (LDs) are hubs for lipid metabolism that form membrane contact sites with multiple organelles. In this issue, Hariri et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201808119) reveal the functions of Mdm1-mediated endoplasmic reticulum (ER)-LD tethering in yeast and Datta et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201808133) identify a role for the Mdm1 orthologue, Snx14, as an ER-LD tether that regulates lipid metabolism in human cells

Problem Solving and Memory: Investigating the Solvability and Memorability of Remote Associates Problems

Honors (Bachelor's)Brain, Behavior, and Cognitive SciencesUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/91798/1/aolzmann.pd

PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1.

Mutations in the PTEN induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). So far, no substrates of PINK1 have been reported, and the mechanism by which PINK1 mutations lead to neurodegeneration is unknown. Here we report the identification of TNF receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone also known as heat shock protein 75 (Hsp75), as a cellular substrate for PINK1 kinase. PINK1 binds and colocalizes with TRAP1 in the mitochondria and phosphorylates TRAP1 both in vitro and in vivo. We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. Moreover, we find that the ability of PINK1 to promote TRAP1 phosphorylation and cell survival is impaired by PD-linked PINK1 G309D, L347P, and W437X mutations. Our findings suggest a novel pathway by which PINK1 phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis and implicate the dysregulation of this mitochondrial pathway in PD pathogenesis

A New Conceptual and Operational Framework for the Switching of IT Outsourcing Providers

The switching of information technology (IT) providers is a subject of considerable significance, since the IT outsourcing (ITO) market is still growing and ITO deals are regularly reaching the end of their contract period, whilst other ITO contracts are prematurely discontinued. The transitional phase to a new provider is a highly complex, resource intensive and critical phase of strategic importance. The objective of this phase is that the contract with the new provider is implemented and the incumbent provider is replaced. Existing literature suggests that an unsuccessful transition can endanger the business continuity of the ITO client. Yet, to date, no research has holistically focused on how successful ITO transitions can be performed. This research seeks to contribute to the understanding and knowledge of which factors support the successful transition of ITO providers for the switching client. It does so by identifying critical success factors, secondary success factors, key risks, and then develops a conceptual framework and a practical operational guide. This qualitative research is conducted within a constructivist paradigm. Twenty-one practitioners from seven different organisations were interviewed. The interviewed practitioners represent three different groups - IT outsourcing client (8), incumbent provider (6) and new provider (7). The focus is on complex ITO deals, where ‘complex’ is considered to comprise large ITO deals with total contract value of more than €100 million, and where at least two IT services have been outsourced and need to be switched. All interviews were transcribed and the data analysis was conducted based on a modified grounded theory approach and the NVivo software tool facilitated the coding process. The results of the analysis and the development of the conceptual and operational framework were subject to validation procedures and verification strategies, such as member checking. The thesis provides a comprehensive critical review of the literature on switching ITO providers and related relevant literature on IT outsourcing to act as the basis of this research. This is refined and augmented through the empirical work to present a final holistic framework that details the success factors and risks involved. This framework provides a holistic view of the management capabilities and business activities that are necessary to ensure a successful switching of ITO providers. For each management capability or business activity a RACI table is provided, which outlines key tasks and responsibilities. Collectively, the new conceptual framework and associated analysis and materials will provide a significant contribution to both literature and practice in the ITO field

The unimolecular decomposition of dimethoxymethane: channel switching as a function of temperature and pressure

Branching ratios of competing unimolecular reactions often exhibit a complicated temperature and pressure dependence that makes modelling of complex reaction systems in the gas phase difficult. In particular, the competition between steps proceeding via tight and loose transition states is known to present a problem. A recent example from the field of combustion chemistry is the unimolecular decomposition of CH$_3$OCH$_2$OCH$_3$ (DMM), which is discussed as an alternative fuel accessible from sustainable sources. It is shown by a detailed master equation analysis with energy- and angular-momentum-resolved specific rate coefficients from RRKM theory and from the simplified statistical adiabatic channel model, how channel switching of DMM depends on temperature and pressure, and under which experimental conditions which channels prevail. The necessary molecular and energy data were obtained from quantum-chemical calculations at the CCSD(F12*)(T*)/cc-pVQZ-F12//B2PLYP-D3/def2-TZVPP level of theory. A parameterization describing the channel branching over extended ranges of temperature and pressure is derived, and the model is used to simulate shock tube experiments with detection by atomic resonance absorption spectroscopy and time-of-flight mass spectrometry. The agreement between the simulated and experimental concentration–time profiles is very good. The temperature and pressure dependence of the channel branching is rationalized, and the data are presented in a form that can be readily implemented into DMM combustion models

The interaction of an incident shock wave with liquid fuel drops

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76252/1/AIAA-1971-206-999.pd