Genetic-algorithm-based design of groundwater quality monitoring system

This research builds on the work of Meyer and Brill [I988] and subsequent work by Meyer et al. [1990], Meyer et al. [1992], and Meyer [I992] on the optimal location of a network of groundwater monitoring wells under conditions of uncertainty. A method of optimization is developed using genetic algorithms (GAS) which allows consideration of the two objectives of Meyer et al. [1992], maximizing reliability and minimizing contaminated area, separately yet simultaneously. The GA-based solution method can generate both convex and non-convex points of the tradeoff curve, can accommodate non-linearities in the two objective functions, and is not restricted to the peculiarities of a weighted objective function. Furthermore, GAS can generate large portions of the tradeoff curve in a single iteration and may be more efficient than methods that generate only a single point at a time.Four multi-objective GAS formulations are investigated and their performance in generating the multi-objective tradeoff curve is evaluated for the groundwater monitoring problem using two example data sets. The GA formulations are compared to each other and to simulated annealing on both performance and computational intensity.The simulated annealing based technique used by Meyer et al. [I992] relies on a weighted objective function which finds only a single point along the tradeoff curve for each iteration, while the multiple-objective GA formulations are able to find many convex and nonconvex points along the tradeoff curve in a single iteration. Each iteration of simulated annealing is approximately five times faster than an iteration of the genetic algorithm, but several simulated annealing iterations are required to generate the tradeoff curve. GAS are able to find a larger number of non-dominated points on the tradeoff curve in a single iteration, and are therefore just as computationally efficient as simulated annealing in terms of generating the tradeoff curves.None of the GA formulations demonstrate the ability to generate the entire tradeoff curve in a single iteration, but they yield either a good estimation of all regions of the tradeoff curve except the very highest and very lowest reliability ends or a good estimation of the high reliability end alone.U.S. Department of the InteriorU.S. Geological Surve

Detecting Determinism in High Dimensional Chaotic Systems

A method based upon the statistical evaluation of the differentiability of the measure along the trajectory is used to identify in high dimensional systems. The results show that the method is suitable for discriminating stochastic from deterministic systems even if the dimension of the latter is as high as 13. The method is shown to succeed in identifying determinism in electro-encephalogram signals simulated by means of a high dimensional system.Comment: 8 pages (RevTeX 3 style), 5 EPS figures, submitted to Phys. Rev. E (25 apr 2001

Multiple functional neurosteroid binding sites on GABAA receptors

Neurosteroids are endogenous modulators of neuronal excitability and nervous system development and are being developed as anesthetic agents and treatments for psychiatric diseases. While gamma amino-butyric acid Type A (GABAA) receptors are the primary molecular targets of neurosteroid action, the structural details of neurosteroid binding to these proteins remain ill defined. We synthesized neurosteroid analogue photolabeling reagents in which the photolabeling groups were placed at three positions around the neurosteroid ring structure, enabling identification of binding sites and mapping of neurosteroid orientation within these sites. Using middle-down mass spectrometry (MS), we identified three clusters of photolabeled residues representing three distinct neurosteroid binding sites in the human α1β3 GABAA receptor. Novel intrasubunit binding sites were identified within the transmembrane helical bundles of both the α1 (labeled residues α1-N408, Y415) and β3 (labeled residue β3-Y442) subunits, adjacent to the extracellular domains (ECDs). An intersubunit site (labeled residues β3-L294 and G308) in the interface between the β3(+) and α1(-) subunits of the GABAA receptor pentamer was also identified. Computational docking studies of neurosteroid to the three sites predicted critical residues contributing to neurosteroid interaction with the GABAA receptors. Electrophysiological studies of receptors with mutations based on these predictions (α1-V227W, N408A/Y411F, and Q242L) indicate that both the α1 intrasubunit and β3-α1 intersubunit sites are critical for neurosteroid action

The effects of nitroxyl (HNO) on soluble guanylate cyclase activity: interactions at ferrous heme and cysteine thiols

It has been previously proposed that nitric oxide (NO) is the only biologically relevant nitrogen oxide capable of activating the enzyme soluble guanylate cyclase (sGC). However, recent reports implicate HNO as another possible activator of sGC. Herein, we examine the affect of HNO donors on the activity of purified bovine lung sGC and find that, indeed, HNO is capable of activating this enzyme. Like NO, HNO activation appears to occur via interaction with the regulatory ferrous heme on sGC. Somewhat unexpectedly, HNO does not activate the ferric form of the enzyme. Finally, HNO-mediated cysteine thiol modification appears to also affect enzyme activity leading to inhibition. Thus, sGC activity can be regulated by HNO via interactions at both the regulatory heme and cysteine thiols

Using Topological Statistics to Detect Determinism in Time Series

Statistical differentiability of the measure along the reconstructed trajectory is a good candidate to quantify determinism in time series. The procedure is based upon a formula that explicitly shows the sensitivity of the measure to stochasticity. Numerical results for partially surrogated time series and series derived from several stochastic models, illustrate the usefulness of the method proposed here. The method is shown to work also for high--dimensional systems and experimental time seriesComment: 23 RevTeX pages, 14 eps figures. To appear in Physical Review

Metabolic changes in schizophrenia and human brain evolution.

BACKGROUND: Despite decades of research, the molecular changes responsible for the evolution of human cognitive abilities remain unknown. Comparative evolutionary studies provide detailed information about DNA sequence and mRNA expression differences between humans and other primates but, in the absence of other information, it has proved very difficult to identify molecular pathways relevant to human cognition. RESULTS: Here, we compare changes in gene expression and metabolite concentrations in the human brain and compare them to the changes seen in a disorder known to affect human cognitive abilities, schizophrenia. We find that both genes and metabolites relating to energy metabolism and energy-expensive brain functions are altered in schizophrenia and, at the same time, appear to have changed rapidly during recent human evolution, probably as a result of positive selection. CONCLUSION: Our findings, along with several previous studies, suggest that the evolution of human cognitive abilities was accompanied by adaptive changes in brain metabolism, potentially pushing the human brain to the limit of its metabolic capabilities.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Impact of the California Lead Ammunition Ban on Reducing Lead Exposure in Golden Eagles and Turkey Vultures

Predatory and scavenging birds may be exposed to high levels of lead when they ingest shot or bullet fragments embedded in the tissues of animals injured or killed with lead ammunition. Lead poisoning was a contributing factor in the decline of the endangered California condor population in the 1980s, and remains one of the primary factors threatening species recovery. In response to this threat, a ban on the use of lead ammunition for most hunting activities in the range of the condor in California was implemented in 2008. Monitoring of lead exposure in predatory and scavenging birds is essential for assessing the effectiveness of the lead ammunition ban in reducing lead exposure in these species. In this study, we assessed the effectiveness of the regulation in decreasing blood lead concentration in two avian sentinels, golden eagles and turkey vultures, within the condor range in California. We compared blood lead concentration in golden eagles and turkey vultures prior to the lead ammunition ban and one year following implementation of the ban. Lead exposure in both golden eagles and turkey vultures declined significantly post-ban. Our findings provide evidence that hunter compliance with lead ammunition regulations was sufficient to reduce lead exposure in predatory and scavenging birds at our study sites

Controlled Radical Polymerization of Vinyl Acetate Mediated by a Bis(imino)pyridine Vanadium Complex

Source type: Prin

Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells

A major challenge associated with biochemical and cellular analysis of pseudokinases is a lack of target-validated small-molecule compounds with which to probe function. Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, including the canonical AKT signaling module. There is substantial evidence that human TRIB2 promotes survival and drug resistance in solid tumors and blood cancers and therefore is of interest as a therapeutic target. The unusual TRIB2 pseudokinase domain contains a unique cysteine-rich C-helix and interacts with a conserved peptide motif in its own carboxyl-terminal tail, which also supports its interaction with E3 ubiquitin ligases. We found that TRIB2 is a target of previously described small-molecule protein kinase inhibitors, which were originally designed to inhibit the canonical kinase domains of epidermal growth factor receptor tyrosine kinase family members. Using a thermal shift assay, we discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS) and used a drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro. TRIB2 destabilizing agents, including the covalent drug afatinib, led to rapid TRIB2 degradation in human AML cancer cells, eliciting tractable effects on signaling and survival. Our data reveal new drug leads for the development of TRIB2-degrading compounds, which will also be invaluable for unraveling the cellular mechanisms of TRIB2-based signaling. Our study highlights that small molecule–induced protein down-regulation through drug “off-targets” might be relevant for other inhibitors that serendipitously target pseudokinases