A Possible Novel Anti-Inflammatory Mechanism for the Pharmacological Prolyl Hydroxylase Inhibitor 3,4-Dihydroxybenzoate: Implications for Use as a Therapeutic for Parkinson's Disease

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized in part by the preferential loss of nigrostriatal dopaminergic neurons. Although the precise etiology of PD is unknown, accumulating evidence suggests that PD involves microglial activation that exerts neurotoxic effects through production of proinflammatory cytokines and increased oxidative and nitrosative stress. Thus, controlling microglial activation has been suggested as a therapeutic target for combating PD. Previously we demonstrated that pharmacological inhibition of a class of enzymes known as prolyl hydroxylases via 3,4-dihydroxybenzoate administration protected against MPTP-induced neurotoxicity, however the exact mechanisms involved were not elucidated. Here we show that this may be due to DHB's ability to inhibit microglial activation. DHB significantly attenuated LPS-mediated induction of nitric oxide synthase and pro-inflammatory cytokines in murine BV2 microglial cells in vitro in conjunction with reduced ROS production and activation of NFκB and MAPK pathways possibly due to up-regulation of HO-1 levels. HO-1 inhibition partially abrogates LPS-mediated NFκB activity and subsequent NO induction. In vivo, DHB pre-treatment suppresses microglial activation elicited by MPTP treatment. Our results suggest that DHB's neuroprotective properties could be due to its ability to dampen induction of microglial activation via induction of HO-1

Batch Adsorber based PSA Model for Rapid and Efficient Screening of Adsorbents in Post-Combustion CO2 Capture

The adsorption-based CO capture has shown promising potential overcoming the limitations posed by commercialised solvent amine-based systems. The choice of an adsorbent is critical to the design of pressure swing adsorption (PSA) processes. Since adsorption processes are cyclic, their design and optimization are computationally challenging. Hence, simple models that capture the essential process characteristics are required for rapid screening of adsorbents. The objective of this work is to come up with a simplified process design model for PSA process which could reliably screen the adsorbents at a faster rate. The model considers only a batch adsorber thereby significantly reducing the complexity, allowing for rapid computation. The model is used to estimate CO purity, recovery and energy consumption. The model results are compared with detailed process optimizations to develop a classification metric to identify adsorbents that satisfy U. S. Department of Energy’s requirement for CO capture processes. The model is then used to screen favourable adsorbents from a set of 100+ real and hypothetical adsorbents. The results indicate that the batch adsorber model can be used for screening a large database of adsorbents in a fast and efficient manner.Fil: Subramanian Balashankar, V.. University of Alberta; CanadáFil: De Pauw, R.. University of Alberta; CanadáFil: Rajagopalan, A. K.. University of Alberta; CanadáFil: Avila, Adolfo María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Química del Noroeste. Universidad Nacional de Tucumán. Facultad de Bioquímica, Química y Farmacia. Instituto de Química del Noroeste; ArgentinaFil: Rajendran, A.. University of Alberta; CanadáXXIX Interamerican Congress of Chemical EngineeringTorontoCanadáCanadian Society for Chemical Engineerin

Experiences in the development of magnesium cell technology at Central Electrochemical Research Institute, Karaikudi

Research activities on the preparation of magnesium metal by molten salt electrolytic process were initiated in CECRI as early as in 1958. CECRI started its experiments on a bench scale level and further developed into pilot plant scale and finally to the scale of semicommercial unit. Various types of electrolytic cells were developed at CECRI which include externally heated cells with different design modifications, modular cells, bipolar/multipolar cells and new modified monopolar ceUs. The primary aim of each development was aimed at high current efficiencies energy efficiencies and space time yields. Various types of raw materials like magnesite, sea bitterns, and byproduct MgCl2 from ZrrTi plants etc. were utilised during the investigations. These studies were carried out with financial grants from Govt. of Tamil Nadu, CSIR, DRDO and Nuclear Fuel Complex. The paper illustrates the design and operational features of different electrolytic cells with consequent gradual decrease in specific energy consumption for magnesium production and increased space time yields with improvement in cell design and operational parameters

Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson's Disease

Exposure to the herbicide paraquat (PQ) is associated with an increased risk of idiopathic Parkinson’s disease (PD). Therapies based on PQ’s presumed mechanisms of action have not, however, yielded effective disease therapies. Cellular senescence is an anticancer mechanism that arrests proliferation of replication-competent cells and results in a pro-inflammatory senescence-associated secretory phenotype (SASP) capable of damaging neighboring tissues. Here, we demonstrate that senescent cell markers are preferentially present within astrocytes in PD brain tissues. Additionally, PQ was found to induce astrocytic senescence and an SASP in vitro and in vivo, and senescent cell depletion in the latter protects against PQ-induced neuropathology. Our data suggest that exposure to certain environmental toxins promotes accumulation of senescent cells in the aging brain, which can contribute to dopaminergic neurodegeneration. Therapies that target senescent cells may constitute a strategy for treatment of sporadic PD, for which environmental exposure is a major risk factor

Metabolic Control Analysis in a Cellular Model of Elevated MAO-B: Relevance to Parkinson’s Disease

We previously demonstrated that spare respiratory capacity of the TCA cycle enzyme alpha-ketoglutarate dehydrogenase (KGDH) was completely abolished upon increasing levels of MAO-B activity in a dopaminergic cell model system (Kumar et al., J Biol Chem 278:46432–46439, 2003). MAO-B mediated increases in H2O2 also appeared to result in direct oxidative inhibition of both mitochondrial complex I and aconitase. In order to elucidate the contribution that each of these components exerts over metabolic respiratory control as well as the impact of MAO-B elevation on their spare respiratory capacities, we performed metabolic respiratory control analysis. In addition to KGDH, we assessed the activities and substrate-mediated respiration of complex I, pyruvate dehydrogenase (PDH), succinate dehydrogenase (SDH), and mitochondrial aconitase in the absence and presence of complex-specific inhibitors in specific and mixed substrate conditions in mitochondria from our MAO-B elevated cells versus controls. Data from this study indicates that Complex I and KGDH are the most sensitive to inhibition by MAO-B mediated H2O2 generation, and could be instrumental in determining the fate of mitochondrial metabolism in this cellular PD model system

An integer linear programming approach for finding deregulated subgraphs in regulatory networks

Deregulation of cell signaling pathways plays a crucial role in the development of tumors. The identification of such pathways requires effective analysis tools that facilitate the interpretation of expression differences. Here, we present a novel and highly efficient method for identifying deregulated subnetworks in a regulatory network. Given a score for each node that measures the degree of deregulation of the corresponding gene or protein, the algorithm computes the heaviest connected subnetwork of a specified size reachable from a designated root node. This root node can be interpreted as a molecular key player responsible for the observed deregulation. To demonstrate the potential of our approach, we analyzed three gene expression data sets. In one scenario, we compared expression profiles of non-malignant primary mammary epithelial cells derived from BRCA1 mutation carriers and of epithelial cells without BRCA1 mutation. Our results suggest that oxidative stress plays an important role in epithelial cells of BRCA1 mutation carriers and that the activation of stress proteins may result in avoidance of apoptosis leading to an increased overall survival of cells with genetic alterations. In summary, our approach opens new avenues for the elucidation of pathogenic mechanisms and for the detection of molecular key players

Discovering Networks of Perturbed Biological Processes in Hepatocyte Cultures

The liver plays a vital role in glucose homeostasis, the synthesis of bile acids and the detoxification of foreign substances. Liver culture systems are widely used to test adverse effects of drugs and environmental toxicants. The two most prevalent liver culture systems are hepatocyte monolayers (HMs) and collagen sandwiches (CS). Despite their wide use, comprehensive transcriptional programs and interaction networks in these culture systems have not been systematically investigated. We integrated an existing temporal transcriptional dataset for HM and CS cultures of rat hepatocytes with a functional interaction network of rat genes. We aimed to exploit the functional interactions to identify statistically significant linkages between perturbed biological processes. To this end, we developed a novel approach to compute Contextual Biological Process Linkage Networks (CBPLNs). CBPLNs revealed numerous meaningful connections between different biological processes and gene sets, which we were successful in interpreting within the context of liver metabolism. Multiple phenomena captured by CBPLNs at the process level such as regulation, downstream effects, and feedback loops have well described counterparts at the gene and protein level. CBPLNs reveal high-level linkages between pathways and processes, making the identification of important biological trends more tractable than through interactions between individual genes and molecules alone. Our approach may provide a new route to explore, analyze, and understand cellular responses to internal and external cues within the context of the intricate networks of molecular interactions that control cellular behavior

Identification and characterization of maize microRNAs involved in the very early stage of seed germination

<p>Abstract</p> <p>Background</p> <p>MicroRNAs (miRNAs) are a new class of endogenous small RNAs that play essential regulatory roles in plant growth, development and stress response. Extensive studies of miRNAs have been performed in model plants such as rice, <it>Arabidopsis thaliana </it>and other plants. However, the number of miRNAs discovered in maize is relatively low and little is known about miRNAs involved in the very early stage during seed germination.</p> <p>Results</p> <p>In this study, a small RNA library from maize seed 24 hours after imbibition was sequenced by the Solexa technology. A total of 11,338,273 reads were obtained. 1,047,447 total reads representing 431 unique sRNAs matched to known maize miRNAs. Further analysis confirmed the authenticity of 115 known miRNAs belonging to 24 miRNA families and the discovery of 167 novel miRNAs in maize. Both the known and the novel miRNAs were confirmed by sequencing of a second small RNA library constructed the same way as the one used in the first sequencing. We also found 10 miRNAs that had not been reported in maize, but had been reported in other plant species. All novel sequences had not been earlier described in other plant species. In addition, seven miRNA* sequences were also obtained. Putative targets for 106 novel miRNAs were successfully predicted. Our results indicated that miRNA-mediated gene expression regulation is present in maize imbibed seed.</p> <p>Conclusions</p> <p>This study led to the confirmation of the authenticity of 115 known miRNAs and the discovery of 167 novel miRNAs in maize. Identification of novel miRNAs resulted in significant enrichment of the repertoire of maize miRNAs and provided insights into miRNA regulation of genes expressed in imbibed seed.</p

Geographic and ecologic heterogeneity in elimination thresholds for the major vector-borne helminthic disease, lymphatic filariasis

<p>Abstract</p> <p>Background</p> <p>Large-scale intervention programmes to control or eliminate several infectious diseases are currently underway worldwide. However, a major unresolved question remains: what are reasonable stopping points for these programmes? Recent theoretical work has highlighted how the ecological complexity and heterogeneity inherent in the transmission dynamics of macroparasites can result in elimination thresholds that vary between local communities. Here, we examine the empirical evidence for this hypothesis and its implications for the global elimination of the major macroparasitic disease, lymphatic filariasis, by applying a novel Bayesian computer simulation procedure to fit a dynamic model of the transmission of this parasitic disease to field data from nine villages with different ecological and geographical characteristics. Baseline lymphatic filariasis microfilarial age-prevalence data from three geographically distinct endemic regions, across which the major vector populations implicated in parasite transmission also differed, were used to fit and calibrate the relevant vector-specific filariasis transmission models. Ensembles of parasite elimination thresholds, generated using the Bayesian fitting procedure, were then examined in order to evaluate site-specific heterogeneity in the values of these thresholds and investigate the ecological factors that may underlie such variability</p> <p>Results</p> <p>We show that parameters of density-dependent functions relating to immunity, parasite establishment, as well as parasite aggregation, varied significantly between the nine different settings, contributing to locally varying filarial elimination thresholds. Parasite elimination thresholds predicted for the settings in which the mosquito vector is anopheline were, however, found to be higher than those in which the mosquito is culicine, substantiating our previous theoretical findings. The results also indicate that the probability that the parasite will be eliminated following six rounds of Mass Drug Administration with diethylcarbamazine and albendazole decreases markedly but non-linearly as the annual biting rate and parasite reproduction number increases.</p> <p>Conclusions</p> <p>This paper shows that specific ecological conditions in a community can lead to significant local differences in population dynamics and, consequently, elimination threshold estimates for lymphatic filariasis. These findings, and the difficulty of measuring the key local parameters (infection aggregation and acquired immunity) governing differences in transmission thresholds between communities, mean that it is necessary for us to rethink the utility of the current anticipatory approaches for achieving the elimination of filariasis both locally and globally.</p