Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt

Impairment of Akt phosphorylation, a critical survival signal, has been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. However, the mechanism underlying pAkt loss is unclear. In the current study, we demonstrate pAkt loss in ventral midbrain of mice treated with dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when compared to ventral midbrain of control mice treated with vehicle alone. Thiol residues of the critical cysteines in Akt are oxidized to a greater degree in mice treated with MPTP, which is reflected as a 40% loss of reduced Akt. Association of oxidatively modified Akt with the phosphatase PP2A, which can lead to enhanced dephosphorylation of pAkt, was significantly stronger after MPTP treatment. Maintaining the protein thiol homeostasis by thiol antioxidants prevented loss of reduced Akt, decreased association with PP2A, and maintained pAkt levels. Overexpression of glutaredoxin, a protein disulfide oxidoreductase, in human primary neurons helped sustain reduced state of Akt and abolished MPP+-mediated pAkt loss. We demonstrate for the first time the selective loss of Akt activity, in vivo, due to oxidative modification of Akt and provide mechanistic insight into oxidative stress-induced down-regulation of cell survival pathway in mouse midbrain following exposure to MPTP.-Durgadoss, L., Nidadavolu, P., Khader Valli, R., Saeed, U., Mishra, M., Seth, P., Ravindranath, R. Redox modification of Akt mediated by the dopaminergic neurotoxin MPTP, in mouse midbrain, leads to down-regulation of pAkt. FASEB J. 26, 1473-1483 (2012). www.fasebj.org

Thermal instability and the feedback regulation of hot haloes in clusters, groups and galaxies

We present global multidimensional numerical simulations of the plasma that pervades the dark matter haloes of clusters, groups and massive galaxies (the intracluster medium; ICM). Observations of clusters and groups imply that such haloes are roughly in global thermal equilibrium, with heating balancing cooling when averaged over sufficiently long time- and length-scales; the ICM is, however, very likely to be locally thermally unstable. Using simple observationally motivated heating prescriptions, we show that local thermal instability (TI) can produce a multiphase medium with similar to 104 K cold filaments condensing out of the hot ICM only when the ratio of the TI time-scale in the hot plasma (tTI) to the free-fall time-scale (tff) satisfies tTI/tff? 10. This criterion quantitatively explains why cold gas and star formation are preferentially observed in low-entropy clusters and groups. In addition, the interplay among heating, cooling and TI reduces the net cooling rate and the mass accretion rate at small radii by factors of similar to 100 relative to cooling-flow models. This dramatic reduction is in line with observations. The feedback efficiency required to prevent a cooling flow is similar to 10-3 for clusters and decreases for lower mass haloes; supernova heating may be energetically sufficient to balance cooling in galactic haloes. We further argue that the ICM self-adjusts so that tTI/tff? 10 at all radii. When this criterion is not satisfied, cold filaments condense out of the hot phase and reduce the density of the ICM. These cold filaments can power the black hole and/or stellar feedback required for global thermal balance, which drives tTI/tff? 10. In comparison to clusters, groups have central cores with lower densities and larger radii. This can account for the deviations from self-similarity in the X-ray luminositytemperature () relation. The high-velocity clouds observed in the Galactic halo can be due to local TI producing multiphase gas close to the virial radius if the density of the hot plasma in the Galactic halo is >rsim 10-5 cm-3 at large radii.

On-Chip Memory Architecture Exploration Framework for DSP Processor-Based Embedded System on Chip

Today's SoCs are complex designs with multiple embedded processors, memory subsystems, and application specific peripherals. The memory architecture of embedded SoCs strongly influences the power and performance of the entire system. Further, the memory subsystem constitutes a major part (typically up to 70%) of the silicon area for the current day SoC. In this article, we address the on-chip memory architecture exploration for DSP processors which are organized as multiple memory banks, where banks can be single/dual ported with non-uniform bank sizes. In this paper we propose two different methods for physical memory architecture exploration and identify the strengths and applicability of these methods in a systematic way. Both methods address the memory architecture exploration for a given target application by considering the application's data access characteristics and generates a set of Pareto-optimal design points that are interesting from a power, performance and VLSI area perspective. To the best of our knowledge, this is the first comprehensive work on memory space exploration at physical memory level that integrates data layout and memory exploration to address the system objectives from both hardware design and application software development perspective. Further we propose an automatic framework that explores the design space identifying 100's of Pareto-optimal design points within a few hours of running on a standard desktop configuration.

Regulation of lipid biosynthesis by phosphatidylinositol-specific phospholipase C through the transcriptional repression of upstream activating sequence inositol containing genes

The regulation of phospholipid biosynthesis in Saccharomyces cerevisiae through cis-acting upstream activating sequence inositol (UAS(ino)) and trans-acting elements, such as the INO2-INO4 complex and OPI1 by inositol supplementation in growth is thoroughly studied. In this study, we provide evidence for the regulation of lipid biosynthesis by phosphatidylinositol-specific phospholipase C (PLC) through UAS(ino) and the trans-acting elements. Gene expression analysis and radiolabelling experiments demonstrated that the overexpression of rice PLC in yeast cells altered phospholipid biosynthesis at the levels of transcriptional and enzyme activity. This is the first report implicating PLC in the direct regulation of lipid biosynthesis. (C) 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Rural electrification: Optimising the choice between decentralised renewable energy sources and grid extension

The study presents an analysis aimed at choosing between off-grid solar photovoltaic, biomass gasifier based power generation and conventional grid extension for remote village electrification. The model provides a relation between renewable energy systems and the economical distance limit (EDL) from the existing grid point, based on life cycle cost (LCC) analysis, where the LCC of energy for renewable energy systems and grid extension will match. The LCC of energy feed to the village is arrived at by considering grid availability and operating hours of the renewable energy systems. The EDL for the biomass gasifier system of 25 kW capacities is 10.5 km with 6 h of daily operation and grid availability. However, the EDL for a similar 25 kW capacity photovoltaic system is 35 km for the same number of hours of operation and grid availability. The analysis shows that for villages having low load demand situated far away from the existing grid line, biomass gasification based systems are more cost competitive than photovoltaic systems or even compared to grid extension. (C) 2012 Elsevier Inc. All rights reserved.

Cyclic AMP-induced Conformational Changes in Mycobacterial Protein Acetyltransferases

The activities of a number of proteins are regulated by the binding of cAMP and cGMP to cyclic nucleotide binding (CNB) domains that are found associated with one or more effector domains with diverse functions. Although the conserved architecture of CNB domains has been extensively studied by x-ray crystallography, the key to unraveling the mechanisms of cAMP action has been protein dynamics analyses. Recently, we have identified a novel cAMP-binding protein from mycobacteria, where cAMP regulates the activity of an associated protein acetyltransferase domain. In the current study, we have monitored the conformational changes that occur upon cAMP binding to the CNB domain in these proteins, using a combination of bioluminescence resonance energy transfer and amide hydrogen/deuterium exchange mass spectrometry. Coupled with mutational analyses, our studies reveal the critical role of the linker region (positioned between the CNB domain and the acetyltransferase domain) in allosteric coupling of cAMP binding to activation of acetyltransferase catalysis. Importantly, major differences in conformational change upon cAMP binding were accompanied by stabilization of the CNB and linker domain alone. This is in contrast to other cAMP-binding proteins, where cyclic nucleotide binding has been shown to involve intricate and parallel allosteric relays. Finally, this powerful convergence of results from bioluminescence resonance energy transfer and hydrogen/deuterium exchange mass spectrometry reaffirms the power of solution biophysical tools in unraveling mechanistic bases of regulation of proteins in the absence of high resolution structural information.