The Structure of the Thioredoxin-Triosephosphate Isomerase Complex Provides Insights into the Reversible Glutathione-Mediated Regulation of Triosephosphate Isomerase

Protein-protein interactions are crucial for many biological functions. The redox interactome encompasses numerous weak transient interactions in which thioredoxin plays a central role. Proteomic studies have shown that thioredoxin binds to numerous proteins belonging to various cellular processes, including energy metabolism. Thioredoxin has cross talk with other redox mechanisms involving glutathionylation and has functional overlap with glutaredoxin in deglutathionylation reactions. In this study, we have explored the structural and biochemical interactions of thioredoxin with the glycolytic enzyme, triosephosphate isomerase. Nuclear magnetic resonance chemical shift mapping methods and molecular dynamics-based docking have been applied in deriving a structural model of the thioredoxin-triosephosphate isomerase complex. The spatial proximity of active site cysteine residues of thioredoxin to reactive thiol groups on triosephosphate isomerase provides a direct link to the observed deglutathionylation of cysteine 217 in triosephosphate isomerase, thereby reversing the inhibitory effect of S-glutathionylation of triosephosphate isomerase.

The Structure of the Thioredoxin−Triosephosphate Isomerase Complex Provides Insights into the Reversible Glutathione-Mediate Regulation of Triosephosphate Isomerase

Protein−protein interactions are crucial for many biological functions. The redox interactome encompasses numerous weak transient interactions in which thioredoxin plays a central role. Proteomic studies have shown that thioredoxin binds to numerous proteins belonging to various cellular processes, including energy metabolism. Thioredoxin has cross talk with other redox mechanisms involving glutathionylation and has functional overlap with glutaredoxin in deglutathionylation reactions. In this study, we have explored the structural and biochemical interactions of thioredoxin with the glycolytic enzyme, triosephosphate isomerase. Nuclear magnetic resonance chemical shift mapping methods and molecular dynamics-based docking have been applied in deriving a structural model of the thioredoxin−triosephosphate isomerase complex. The spatial proximity of active site cysteine residues of thioredoxin to reactive thiol groups on triosephosphate isomerase provides a direct link to the observed deglutathionylation of cysteine 217 in triosephosphate isomerase, thereby reversing the inhibitory effect of S-glutathionylation of triosephosphate isomerase.

Functional regulation of PVBV Nuclear Inclusion protein-a protease activity upon interaction with Viral Protein genome-linked and phosphorylation

Regulation of NIa-Pro is crucial for polyprotein processing and hence, for successful infection of potyviruses. We have examined two novel mechanisms that could regulate NIa-Pro activity. Firstly, the influence of VPg domain on the proteolytic activity of NIa-Pro was investigated. It was shown that the turnover number of the protease increases when these two domains interact (as: two-fold; trans: seven-fold) with each other. Secondly, the protease activity of NIa-Pro could also be modulated by phosphorylation at Ser129. A mutation of this residue either to aspartate (phosphorylation-mimic) or alanine (phosphorylation-deficient) drastically reduces the protease activity. Based on these observations and molecular modeling studies, we propose that interaction with VPg as well as phosphorylation of Ser129 could relay a signal through Trp143 present at the protein surface to the active site pocket by subtle conformational changes, thus modulating protease activity of NIa-Pro. (C) 2011 Elsevier Inc. All rights reserved.

Network pricing for QoS: A 'Regulation' approach

V. S. Borkar’s work was supported in part by grant number III.5(157)/99-ET from the Department of Science and Technology, Government of India. D. Manjunath’s work was supported in part by grant number 1(1)/2004-E-Infra from the Ministry of Information Technology, Government of India.

Evolutionary Algorithm for the Determination of Optimal Mode of Bioreactor Operation

Stirred tank bioreactors, employed in the production of a variety of biologically active chemicals, are often operated in batch, fed-batch, and continuous modes of operation. The optimal design of bioreactor is dependent on the kinetics of the biological process, as well as the performance criteria (yield, productivity, etc.) under consideration. In this paper, a general framework is proposed for addressing the two key issues related to the optimal design of a bioreactor, namely, (i) choice of the best operating mode and (ii) the corresponding flow rate trajectories. The optimal bioreactor design problem is formulated with initial conditions and inlet and outlet flow rate trajectories as decision variables to maximize more than one performance criteria (yield, productivity, etc.) as objective functions. A computational methodology based on genetic algorithm approach is developed to solve this challenging multiobjective optimization problem with multiple decision variables. The applicability of the algorithm is illustrated by solving two challenging problems from the bioreactor optimization literature.

New Insights into Optimal Discrete Rate Adaptation for Average Power Constrained Single and Multi-Node Systems

The throughput-optimal discrete-rate adaptation policy, when nodes are subject to constraints on the average power and bit error rate, is governed by a power control parameter, for which a closed-form characterization has remained an open problem. The parameter is essential in determining the rate adaptation thresholds and the transmit rate and power at any time, and ensuring adherence to the power constraint. We derive novel insightful bounds and approximations that characterize the power control parameter and the throughput in closed-form. The results are comprehensive as they apply to the general class of Nakagami-m (m >= 1) fading channels, which includes Rayleigh fading, uncoded and coded modulation, and single and multi-node systems with selection. The results are appealing as they are provably tight in the asymptotic large average power regime, and are designed and verified to be accurate even for smaller average powers.

Optimal static voltage stability improvement using a numerically stable SLP algorithm, for real time applications

A numerically stable sequential Primal–Dual LP algorithm for the reactive power optimisation (RPO) is presented in this article. The algorithm minimises the voltage stability index C 2 [1] of all the load buses to improve the system static voltage stability. Real time requirements such as numerical stability, identification of the most effective subset of controllers for curtailing the number of controllers and their movement can be handled effectively by the proposed algorithm. The algorithm has a natural characteristic of selecting the most effective subset of controllers (and hence curtailing insignificant controllers) for improving the objective. Comparison with transmission loss minimisation objective indicates that the most effective subset of controllers and their solution identified by the static voltage stability improvement objective is not the same as that of the transmission loss minimisation objective. The proposed algorithm is suitable for real time application for the improvement of the system static voltage stability.

Optimal placement of Distributed Generation for a projected load increase using Relative Electrical Distance approach

There is a lot of pressure on all the developed and second world countries to produce low emission power and distributed generation (DG) is found to be one of the most viable ways to achieve this. DG generally makes use of renewable energy sources like wind, micro turbines, photovoltaic, etc., which produce power with minimum green house gas emissions. While installing a DG it is important to define its size and optimal location enabling minimum network expansion and line losses. In this paper, a methodology to locate the optimal site for a DG installation, with the objective to minimize the net transmission losses, is presented. The methodology is based on the concept of relative electrical distance (RED) between the DG and the load points. This approach will help to identify the new DG location(s), without the necessity to conduct repeated power flows. To validate this methodology case studies are carried out on a 20 node, 66kV system, a part of Karnataka Transco and results are presented.

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.

Optimal multi-layered congestion based pricing schemes for enhanced QoS

Pricing is an effective tool to control congestion and achieve quality of service (QoS) provisioning for multiple differentiated levels of service. In this paper, we consider the problem of pricing for congestion control in the case of a network of nodes with multiple queues and multiple grades of service. We present a closed-loop multi-layered pricing scheme and propose an algorithm for finding the optimal state dependent price levels for individual queues, at each node. This is different from most adaptive pricing schemes in the literature that do not obtain a closed-loop state dependent pricing policy. The method that we propose finds optimal price levels that are functions of the queue lengths at individual queues. Further, we also propose a variant of the above scheme that assigns prices to incoming packets at each node according to a weighted average queue length at that node. This is done to reduce frequent price variations and is in the spirit of the random early detection (RED) mechanism used in TCP/IP networks. We observe in our numerical results a considerable improvement in performance using both of our schemes over that of a recently proposed related scheme in terms of both throughput and delay performance. In particular, our first scheme exhibits a throughput improvement in the range of 67-82% among all routes over the above scheme. (C) 2011 Elsevier B.V. All rights reserved.