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Search Results: 1 - 10 of 309785 matches for " Andrew J. Olaharski "
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Identification of a Kinase Profile that Predicts Chromosome Damage Induced by Small Molecule Kinase Inhibitors
Andrew J. Olaharski ,Nina Gonzaludo,Hans Bitter,David Goldstein,Stephan Kirchner,Hirdesh Uppal,Kyle Kolaja
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000446
Abstract: Kinases are heavily pursued pharmaceutical targets because of their mechanistic role in many diseases. Small molecule kinase inhibitors (SMKIs) are a compound class that includes marketed drugs and compounds in various stages of drug development. While effective, many SMKIs have been associated with toxicity including chromosomal damage. Screening for kinase-mediated toxicity as early as possible is crucial, as is a better understanding of how off-target kinase inhibition may give rise to chromosomal damage. To that end, we employed a competitive binding assay and an analytical method to predict the toxicity of SMKIs. Specifically, we developed a model based on the binding affinity of SMKIs to a panel of kinases to predict whether a compound tests positive for chromosome damage. As training data, we used the binding affinity of 113 SMKIs against a representative subset of all kinases (290 kinases), yielding a 113×290 data matrix. Additionally, these 113 SMKIs were tested for genotoxicity in an in vitro micronucleus test (MNT). Among a variety of models from our analytical toolbox, we selected using cross-validation a combination of feature selection and pattern recognition techniques: Kolmogorov-Smirnov/T-test hybrid as a univariate filter, followed by Random Forests for feature selection and Support Vector Machines (SVM) for pattern recognition. Feature selection identified 21 kinases predictive of MNT. Using the corresponding binding affinities, the SVM could accurately predict MNT results with 85% accuracy (68% sensitivity, 91% specificity). This indicates that kinase inhibition profiles are predictive of SMKI genotoxicity. While in vitro testing is required for regulatory review, our analysis identified a fast and cost-efficient method for screening out compounds earlier in drug development. Equally important, by identifying a panel of kinases predictive of genotoxicity, we provide medicinal chemists a set of kinases to avoid when designing compounds, thereby providing a basis for rational drug design away from genotoxicity.
Leucine-Rich Repeat Kinase 2 (LRRK2)-Deficient Rats Exhibit Renal Tubule Injury and Perturbations in Metabolic and Immunological Homeostasis
Daniel Ness, Zhao Ren, Shyra Gardai, Douglas Sharpnack, Victor J. Johnson, Richard J. Brennan, Elizabeth F. Brigham, Andrew J. Olaharski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066164
Abstract: Genetic evidence links mutations in the LRRK2 gene with an increased risk of Parkinson’s disease, for which no neuroprotective or neurorestorative therapies currently exist. While the role of LRRK2 in normal cellular function has yet to be fully described, evidence suggests involvement with immune and kidney functions. A comparative study of LRRK2-deficient and wild type rats investigated the influence that this gene has on the phenotype of these rats. Significant weight gain in the LRRK2 null rats was observed and was accompanied by significant increases in insulin and insulin-like growth factors. Additionally, LRRK2-deficient rats displayed kidney morphological and histopathological alterations in the renal tubule epithelial cells of all animals assessed. These perturbations in renal morphology were accompanied by significant decreases of lipocalin-2, in both the urine and plasma of knockout animals. Significant alterations in the cellular composition of the spleen between LRRK2 knockout and wild type animals were identified by immunophenotyping and were associated with subtle differences in response to dual infection with rat-adapted influenza virus (RAIV) and Streptococcus pneumoniae. Ontological pathway analysis of LRRK2 across metabolic and kidney processes and pathological categories suggested that the thioredoxin network may play a role in perturbing these organ systems. The phenotype of the LRRK2 null rat is suggestive of a complex biology influencing metabolism, immune function and kidney homeostasis. These data need to be extended to better understand the role of the kinase domain or other biological functions of the gene to better inform the development of pharmacological inhibitors.
The Flavoring Agent Dihydrocoumarin Reverses Epigenetic Silencing and Inhibits Sirtuin Deacetylases
Andrew J Olaharski ,Jasper Rine,Brett L Marshall,Joshua Babiarz,Luoping Zhang,Eric Verdin,Martyn T Smith
PLOS Genetics , 2005, DOI: 10.1371/journal.pgen.0010077
Abstract: Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC), a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases.
The Flavoring Agent Dihydrocoumarin Reverses Epigenetic Silencing and Inhibits Sirtuin Deacetylases.
Olaharski,Rine,Marshall,Babiarz
PLOS Genetics , 2005,
Abstract: Sirtuins are a family of phylogenetically conserved nicotinamide adenine dinucleotide-dependent deacetylases that have a firmly established role in aging. Using a simple Saccharomyces cerevisiae yeast heterochromatic derepression assay, we tested a number of environmental chemicals to address the possibility that humans are exposed to sirtuin inhibitors. Here we show that dihydrocoumarin (DHC), a compound found in Melilotus officinalis (sweet clover) that is commonly added to food and cosmetics, disrupted heterochromatic silencing and inhibited yeast Sir2p as well as human SIRT1 deacetylase activity. DHC exposure in the human TK6 lymphoblastoid cell line also caused concentration-dependent increases in p53 acetylation and cytotoxicity. Flow cytometric analysis to detect annexin V binding to phosphatidylserine demonstrated that DHC increased apoptosis more than 3-fold over controls. Thus, DHC inhibits both yeast Sir2p and human SIRT1 deacetylases and increases p53 acetylation and apoptosis, a phenotype associated with senescence and aging. These findings demonstrate that humans are potentially exposed to epigenetic toxicants that inhibit sirtuin deacetylases.
Spatial and temporal variability of soil freeze-thaw cycling across Southern Alberta, Canada  [PDF]
Andrew J. Phillips, Nathaniel K. Newlands
Agricultural Sciences (AS) , 2011, DOI: 10.4236/as.2011.24051
Abstract: Soil freeze-thaw cycles play an important role in all aspects of agro-ecosystems, such as crop productivity, the evolution of the soil matrix, including trace-gas emissions. In regions that experience synoptic weather conditions throughout the winter, freeze-thaw cycles generally occur in one of two categories; seasonal or winter cycles. Current soil vegetation atmosphere models (SVAT’s) often include a heat-transport soil freeze-thaw algorithm, but lack detail on complex interactions between the main driving variables. Boundary conditions for these models are often based only on a few climate variables and typically lack regional context. A nested statistical analysis was applied to identify the optimal set of environmental variables (via a stepwise regression selection procedure) to track soil freeze-thaw dynamics. Historical data collected between the years 2006-2009, for 17 long-term climate stations distributed across southern Alberta Canada was utilized. Cross-correlation between wind speed and maximum air temperature identified Chinook-driven freeze-thaw events, with such interaction varying significantly across the region and by soil depth. Climate-soil interactions were most significant predictors of soil temperature during winter months. The seasonal freeze-thaw cycle is estimated to vary between 112 - 131 days, consisting of 12 - 20 winter cycles (1 cm depth), and 1-5 winter cycles (5 cm depth) with average lag time of 26 - 112 days. Freeze-thaw prediction was greatly improved when higher-order climate interaction terms were considered. Our findings highlight the importance for soil-water and more complex ecosystem, SVAT models to better resolve regional-driven climatic trends. Alongside improved representation of regional trends aimed at reducing model-based uncertainty, such efforts are expected to, in tandem, help advance the geostatistical design, and implementation of agroenvironmental monitoring systems that combine in-situ and satellite/remote-sensing derived estimates of near-surface soil moisture.
Emotions and Emotion Regulation in a Female Couple Undergoing in Vitro Fertilization Treatment  [PDF]
Tracey J. Devonport, Andrew M. Lane
Psychology (PSYCH) , 2013, DOI: 10.4236/psych.2013.46A1004
Abstract:

Research indicates that women undergoing In Vitro Fertilization (IVF) experience intense unwanted emotions, and that these emotions may result in the decision to abandon treatment. This case-study explored stressors, emotional responses and emotion regulation strategies of a female couple undergoing IVF procedures over a ten-week period. A mixed-method approach involved participants completing a daily open-ended diary and self-report scales to assess emotions and emotion regulation in relation to partner and self. Diary results indicated both partners experienced frequent stressors resulting from the IVF process, stressors that were intensified by perceptual and financial factors. Participants experienced a range of intense pleasant (e.g., happy, excited) and unpleasant emotions (e.g., depressed, anxious), and sought to down-regulate unpleasant emotions using a range of cognitive, behavioral, and social strategies. Questionnaire data indicated complementary styles of emotion regulation that appeared to help sustain pleasant emotions and down-regulate unpleasant emotions. Future research should test the effectiveness of interventions to help manage unwanted emotional responses to IVF treatment and corresponding regulatory efforts.

A Novel Approach for Sugarcane Yield Prediction Using Landsat Time Series Imagery: A Case Study on Bundaberg Region  [PDF]
Muhammad Moshiur Rahman, Andrew J. Robson
Advances in Remote Sensing (ARS) , 2016, DOI: 10.4236/ars.2016.52008
Abstract: Quantifying sugarcane production is critical for a wide range of applications, including crop management and decision making processes such as harvesting, storage, and forward selling. This study explored a novel model for predicting sugarcane yield in Bundaberg region from time series Landsat data. From the freely available Landsat archive, 98 cloud free (<40%) Landsat Thematic Mapper (TM) and Enhanced Thematic Mapper (ETM+) images, acquired between November 15th to July 31st (2001-2015) were sourced for this study. The images were masked using the field boundary layer vector files of each year and the GNDVI was calculated. An analysis of average green normalized difference vegetation index (GNDVI) values from all sugarcane crops grown within the Bundaberg region over the 15 year period identified the beginning of April as the peak growth stage and, therefore, the optimum time for satellite image based yield forecasting. As the GNDVI is an indicator of crop vigor, the model derived maximum GNDVI was regressed against historical sugarcane yield data, which showed a significant correlation with R2 = 0.69 and RMSE = 4.2 t/ha. Results showed that the model derived maximum GNDVI from Landsat imagery would be a feasible and a modest technique to predict sugarcane yield in Bundaberg region.
Estimating a Falsified Model  [PDF]
Andrew J. Buck, George M. Lady
Advances in Pure Mathematics (APM) , 2016, DOI: 10.4236/apm.2016.68040
Abstract: It is common econometric practice to propose a system of equations, termed the “structure,” estimate each endogenous variable in the structure via a linear regression with all of the exogenous variables as arguments, and then employ one of variety of regression techniques to recapture the coefficients in the (Jacobian) arrays of the structure. A recent literature, e.g., [1], has shown that a qualitative analysis of a model’s structural and estimated reduced form arrays can provide a robust procedure for assessing if a model’s hypothesized structure has been falsified. This paper shows that the even weaker statement of the model’s structure provided by zero restrictions on the structural arrays can be falsified, independent of the proposed nonzero entries. When this takes place, multi-stage least squares, or any procedure for estimating the structural arrays with the zero restrictions imposed, will present estimates that could not possibly have generated the data upon which the estimated reduced form is based. The examples given in the paper are based upon a Monte Carlo sampling procedure.
Epidural Blood Patch for Treatment of Postdural Puncture Headache in a Patient with Spinal Fusion and Recent Implantation of Intrathecal Pain Pump  [PDF]
Chistopher J. Burnett,Andrew J. White,Marius D. Vulcan
Open Journal of Anesthesiology (OJAnes) , 2013, DOI: 10.4236/ojanes.2013.33039
Abstract: We present an interesting case report of a 49-year-old female who presented with symptoms of post-dural puncture headache following implantation of an intrathecal pain pump. Her history was complicated by previous multi-level spinal fusion with hardware. The patient was evaluated and felt to be a candidate for epidural blood patch, which she elected to proceed with. Under fluoroscopic guidance epidural blood patch was successfully performed. Immediately following the procedure the patient noted significant improvement in the headache and six hours following the procedure was headache free and remained so at follow up three weeks later.
Lattice Boltzmann modeling for tracer test analysis in a fractured Gneiss aquifer  [PDF]
Ramadan Abdelaziz, Andrew J. Pearson, Broder J. Merkel
Natural Science (NS) , 2013, DOI: 10.4236/ns.2013.53050
Abstract:

Fractured Gneiss aquifers present a challenge to hydrogeologists because of their geological complexity. Interpretation methods which can be applied to porous media cannot be applied to fractured Gneiss aquifers because flow and transport occur in fractures, joints, and conduits. In contrast, the rock matrix contribution to groundwater flow is not very important in Gneiss aquifers. Sodium chloride was injected into groundwater flow under steady state condition as tracer to determine transport parameters which are needed for transport modeling. QTRACER2 was used to evaluate the tracer test data. Lattice Boltzmann method was applied to simulate flow and tracer transport through a fracture zone in Gneiss. Experimental tracer data and the numerical solution by lattice Boltzmann method are compared. In general, the results indicate that a 2D Lattice Boltzmann model is able to simulate solute transport in fractured gneiss aquifer at field scale level.

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