Circadian Clock Regulates Response to Pesticides in Drosophila via Conserved Pdp1 Pathway

PubMed Central

Beaver, Laura Michelle; Hooven, Louisa Ada; Butcher, Shawn Michael; Krishnan, Natraj; Sherman, Katherine Alice; Chow, Eileen Shin-Yeu; Giebultowicz, Jadwiga Maria

2010-01-01

Daily rhythms generated by the circadian clock regulate many life functions, including responses to xenobiotic compounds. In Drosophila melanogaster, the circadian clock consists of positive elements encoded by cycle (cyc) and Clock (Clk) and negative elements encoded by period (per) and timeless (tim) genes. The ϵ-isoform of the PAR-domain protein 1 (Pdp1ε) transcription factor is controlled by positive clock elements and regulates daily locomotor activity rhythms. Pdp1 target genes have not been identified, and its involvement in other clock output pathways is not known. Mammalian orthologs of Pdp1 have been implicated in the regulation of xenobiotic metabolism; therefore, we asked whether Pdp1 has a similar role in the fly. Using pesticides as model toxicants, we determined that disruption of Pdp1ε increased pesticide-induced mortality in flies. Flies deficient for cyc also showed increased mortality, while disruption of per and tim had no effect. Day/night and Pdp1-dependent differences in the expression of xenobiotic-metabolizing enzymes Cyp6a2, Cyp6g1, and α-Esterase-7 were observed and likely contribute to impaired detoxification. DHR96, a homolog of constitutive androstane receptor and pregnane X receptor, is involved in pesticide response, and DHR96 expression decreased when Pdp1 was suppressed. Taken together, our data uncover a pathway from the positive arm of the circadian clock through Pdp1 to detoxification effector genes, demonstrating a conserved role of the circadian system in modulating xenobiotic toxicity. PMID:20348229

Active muscle response using feedback control of a finite element human arm model.

PubMed

Östh, Jonas; Brolin, Karin; Happee, Riender

2012-01-01

Mathematical human body models (HBMs) are important research tools that are used to study the human response in car crash situations. Development of automotive safety systems requires the implementation of active muscle response in HBM, as novel safety systems also interact with vehicle occupants in the pre-crash phase. In this study, active muscle response was implemented using feedback control of a nonlinear muscle model in the right upper extremity of a finite element (FE) HBM. Hill-type line muscle elements were added, and the active and passive properties were assessed. Volunteer tests with low impact loading resulting in elbow flexion motions were performed. Simulations of posture maintenance in a gravity field and the volunteer tests were successfully conducted. It was concluded that feedback control of a nonlinear musculoskeletal model can be used to obtain posture maintenance and human-like reflexive responses in an FE HBM.

A single amino acid controls the functional switch of human constitutive androstane receptor (CAR) 1 to the xenobiotic-sensitive splicing variant CAR3.

PubMed

Chen, Tao; Tompkins, Leslie M; Li, Linhao; Li, Haishan; Kim, Gregory; Zheng, Yuxin; Wang, Hongbing

2010-01-01

The constitutive androstane receptor (CAR) is constitutively activated in immortalized cell lines independent of xenobiotic stimuli. This feature of CAR has limited its use as a sensor for xenobiotic-induced expression of drug-metabolizing enzymes. Recent reports, however, reveal that a splicing variant of human CAR (hCAR3), which contains an insertion of five amino acids (APYLT), exhibits low basal but xenobiotic-inducible activities in cell-based reporter assays. Nonetheless, the underlying mechanisms of this functional shift are not well understood. We have now generated chimeric constructs containing various residues of the five amino acids of hCAR3 and examined their response to typical hCAR activators. Our results showed that the retention of alanine (hCAR1+A) alone is sufficient to confer the constitutively activated hCAR1 to the xenobiotic-sensitive hCAR3. It is noteworthy that hCAR1+A was significantly activated by a series of known hCAR activators, and displayed activation superior to that of hCAR3. Moreover, intracellular localization assays revealed that hCAR1+A exhibits nuclear accumulation upon 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) treatment in COS1 cells, which differs from the spontaneous nuclear distribution of hCAR1 and the nontranslocatable hCAR3. Mammalian two-hybrid and glutathione S-transferase pull-down assays further demonstrated that hCAR1+A interacts with the coactivator SRC-1 and GRIP-1 at low level before activation, while at significantly enhanced level in the presence of CITCO. Thus, the alanine residue in the insertion of hCAR3 seems in charge of the xenobiotic response of hCAR3 through direct and indirect mechanisms. Activation of hCAR1+A may represent a sensitive avenue for the identification of hCAR activators.

A Single Amino Acid Controls the Functional Switch of Human Constitutive Androstane Receptor (CAR) 1 to the Xenobiotic-Sensitive Splicing Variant CAR3

PubMed Central

Chen, Tao; Tompkins, Leslie M.; Li, Linhao; Li, Haishan; Kim, Gregory; Zheng, Yuxin

2010-01-01

The constitutive androstane receptor (CAR) is constitutively activated in immortalized cell lines independent of xenobiotic stimuli. This feature of CAR has limited its use as a sensor for xenobiotic-induced expression of drug-metabolizing enzymes. Recent reports, however, reveal that a splicing variant of human CAR (hCAR3), which contains an insertion of five amino acids (APYLT), exhibits low basal but xenobiotic-inducible activities in cell-based reporter assays. Nonetheless, the underlying mechanisms of this functional shift are not well understood. We have now generated chimeric constructs containing various residues of the five amino acids of hCAR3 and examined their response to typical hCAR activators. Our results showed that the retention of alanine (hCAR1+A) alone is sufficient to confer the constitutively activated hCAR1 to the xenobiotic-sensitive hCAR3. It is noteworthy that hCAR1+A was significantly activated by a series of known hCAR activators, and displayed activation superior to that of hCAR3. Moreover, intracellular localization assays revealed that hCAR1+A exhibits nuclear accumulation upon 6-(4-chlorophenyl) imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) treatment in COS1 cells, which differs from the spontaneous nuclear distribution of hCAR1 and the nontranslocatable hCAR3. Mammalian two-hybrid and glutathione S-transferase pull-down assays further demonstrated that hCAR1+A interacts with the coactivator SRC-1 and GRIP-1 at low level before activation, while at significantly enhanced level in the presence of CITCO. Thus, the alanine residue in the insertion of hCAR3 seems in charge of the xenobiotic response of hCAR3 through direct and indirect mechanisms. Activation of hCAR1+A may represent a sensitive avenue for the identification of hCAR activators. PMID:19820207

Back to the future: transgenerational transmission of xenobiotic-induced epigenetic remodeling

PubMed Central

Jiménez-Chillarón, Josep C; Nijland, Mark J; Ascensão, António A; Sardão, Vilma A; Magalhães, José; Hitchler, Michael J; Domann, Frederick E; Oliveira, Paulo J

2015-01-01

Epigenetics, or regulation of gene expression independent of DNA sequence, is the missing link between genotype and phenotype. Epigenetic memory, mediated by histone and DNA modifications, is controlled by a set of specialized enzymes, metabolite availability, and signaling pathways. A mostly unstudied subject is how sub-toxic exposure to several xenobiotics during specific developmental stages can alter the epigenome and contribute to the development of disease phenotypes later in life. Furthermore, it has been shown that exposure to low-dose xenobiotics can also result in further epigenetic remodeling in the germ line and contribute to increase disease risk in the next generation (multigenerational and transgenerational effects). We here offer a perspective on current but still incomplete knowledge of xenobiotic-induced epigenetic alterations, and their possible transgenerational transmission. We also propose several molecular mechanisms by which the epigenetic landscape may be altered by environmental xenobiotics and hypothesize how diet and physical activity may counteract epigenetic alterations. PMID:25774863

Symposium overview: alterations in cytokine receptors by xenobiotics.

PubMed

Cohen, M D; Schook, L B; Oppenheim, J J; Freed, B M; Rodgers, K E

1999-04-01

A symposium entitled Alterations in Cytokine Receptors by Xenobiotics was held at the 37th Annual Meeting of the Society of Toxicology (SOT) in Seattle, Washington. The symposium was sponsored by the Immunotoxicology Specialty Section of SOT and was designed to present information on the effect of several different classes of xenobiotics on various aspects of receptor function (i.e., post-receptor signal transduction of receptor expression), or the involvement of cytokine receptors in the action of the toxicant under consideration. This symposium brought together scientists in the area of receptor immunobiology whose expertise in receptor modulation encompassed those major signaling agents involved in the normal immune response, i.e., proinflammatory cytokines, chemokines, interleukins, and interferons. The following is a summary of each of the individual presentations.

Current knowledge of detoxification mechanisms of xenobiotic in honey bees.

PubMed

Gong, Youhui; Diao, Qingyun

2017-01-01

The western honey bee Apis mellifera is the most important managed pollinator species in the world. Multiple factors have been implicated as potential causes or factors contributing to colony collapse disorder, including honey bee pathogens and nutritional deficiencies as well as exposure to pesticides. Honey bees' genome is characterized by a paucity of genes associated with detoxification, which makes them vulnerable to specific pesticides, especially to combinations of pesticides in real field environments. Many studies have investigated the mechanisms involved in detoxification of xenobiotics/pesticides in honey bees, from primal enzyme assays or toxicity bioassays to characterization of transcript gene expression and protein expression in response to xenobiotics/insecticides by using a global transcriptomic or proteomic approach, and even to functional characterizations. The global transcriptomic and proteomic approach allowed us to learn that detoxification mechanisms in honey bees involve multiple genes and pathways along with changes in energy metabolism and cellular stress response. P450 genes, is highly implicated in the direct detoxification of xenobiotics/insecticides in honey bees and their expression can be regulated by honey/pollen constitutes, resulting in the tolerance of honey bees to other xenobiotics or insecticides. P450s is also a key detoxification enzyme that mediate synergism interaction between acaricides/insecticides and fungicides through inhibition P450 activity by fungicides or competition for detoxification enzymes between acaricides. With the wide use of insecticides in agriculture, understanding the detoxification mechanism of insecticides in honey bees and how honeybees fight with the xenobiotis or insecticides to survive in the changing environment will finally benefit honeybees' management.

Review and evaluation of the effects of xenobiotic chemicals on microorganisms in soil. [139 references

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hicks, R.J.; Van Voris, P.

1988-02-01

The primary objective was to review and evaluate the relevance and quality of existing xenobiotic data bases and test methods for evaluating direct and indirect effects (both adverse and beneficial) of xenobiotics on the soil microbial community; direct and indirect effects of the soil microbial community on xenobiotics; and adequacy of test methods used to evaluate these effects and interactions. Xenobiotic chemicals are defined here as those compounds, both organic and inorganic, produced by man and introduced into the environment at concentrations that cause undesirable effects. Because soil serves as the main repository for many of these chemicals, it thereforemore » has a major role in determining their ultimate fate. Once released, the distribution of xenobiotics between environmental compartments depends on the chemodynamic properties of the compounds, the physicochemical properties of the soils, and the transfer between soil-water and soil-air interfaces and across biological membranes. Abiotic and biotic processes can transform the chemical compound, thus altering its chemical state and, subsequently, its toxicity and reactivity. Ideally, the conversion is to carbon dioxide, water, and mineral elements, or at least, to some harmless substance. However, intermediate transformation products, which can become toxic pollutants in their own right, can sometimes be formed. 139 refs., 6 figs., 11 tabs.« less

Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling.

PubMed

Hao, Nan; Lee, Kian Leong; Furness, Sebastian G B; Bosdotter, Cecilia; Poellinger, Lorenz; Whitelaw, Murray L

2012-12-01

The aryl hydrocarbon receptor (AhR) is a signal-regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a nonxenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand [isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439)]-treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic- and suspension-activated AhR signaling. Por and Cldnd1 were regulated predominantly by ligand treatments, whereas, in contrast, ApoER2 and Ganc were regulated predominantly by the suspension condition. Classic xenobiotic-metabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with chromatin immunoprecipitation assays and reporter gene analysis identified a functional xenobiotic response element (XRE) in the intron 1 of the mouse Tiparp gene, which was also bound by hypoxia-inducible factor-1α during hypoxia and features a concatemer of four XRE cores (GCGTG). Our data suggest that this XRE concatemer site concurrently regulates the expression of both the Tiparp gene and its cis antisense noncoding RNA after ligand- or suspension-induced AhR activation. This work provides novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation.

Optimized laser-induced breakdown spectroscopy for determination of xenobiotic silver in monosodium glutamate and its verification using ICP-AES.

PubMed

Rehan, I; Gondal, M A; Rehan, K

2018-04-20

Laser-induced breakdown spectroscopy (LIBS) was applied as a potential tool for the determination of xenobiotic metal in monosodium glutamate (MSG). In order to achieve a high-sensitivity LIBS system required to determine trace amounts of metallic silver in MSG and to attain the best detection limit, the parameters used in our experiment (impact of focusing laser energy on the intensity of LIBS emission signals, the influence of focusing lens distance on the intensity of LIBS signals, and time responses of the plasma emissions) were optimized. The spectra of MSG were obtained in air using a suitable detector with an optical resolution of 0.06 nm, covering a spectral region from 220 to 720 nm. Along with the detection of xenobiotic silver, other elements such as Ca, Mg, S, and Na were also detected in MSG. To determine the concentration of xenobiotic silver in MSG, the calibration curve was plotted by preparing standard samples having different silver abundances in an MSG matrix. The LIBS results of each sample were cross-verified by analyzing with a standard analytical technique such as inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Both (LIBS and ICP-AES) results were in mutual agreement. The limit of detection of the LIBS setup was found to be 0.57 ppm for silver present in MSG samples.

Research Resource: A Reference Transcriptome for Constitutive Androstane Receptor and Pregnane X Receptor Xenobiotic Signaling

PubMed Central

Ochsner, Scott A.; Tsimelzon, Anna; Dong, Jianrong; Coarfa, Cristian

2016-01-01

The pregnane X receptor (PXR) (PXR/NR1I3) and constitutive androstane receptor (CAR) (CAR/NR1I2) members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors are well-characterized mediators of xenobiotic and endocrine-disrupting chemical signaling. The Nuclear Receptor Signaling Atlas maintains a growing library of transcriptomic datasets involving perturbations of NR signaling pathways, many of which involve perturbations relevant to PXR and CAR xenobiotic signaling. Here, we generated a reference transcriptome based on the frequency of differential expression of genes across 159 experiments compiled from 22 datasets involving perturbations of CAR and PXR signaling pathways. In addition to the anticipated overrepresentation in the reference transcriptome of genes encoding components of the xenobiotic stress response, the ranking of genes involved in carbohydrate metabolism and gonadotropin action sheds mechanistic light on the suspected role of xenobiotics in metabolic syndrome and reproductive disorders. Gene Set Enrichment Analysis showed that although acetaminophen, chlorpromazine, and phenobarbital impacted many similar gene sets, differences in direction of regulation were evident in a variety of processes. Strikingly, gene sets representing genes linked to Parkinson's, Huntington's, and Alzheimer's diseases were enriched in all 3 transcriptomes. The reference xenobiotic transcriptome will be supplemented with additional future datasets to provide the community with a continually updated reference transcriptomic dataset for CAR- and PXR-mediated xenobiotic signaling. Our study demonstrates how aggregating and annotating transcriptomic datasets, and making them available for routine data mining, facilitates research into the mechanisms by which xenobiotics and endocrine-disrupting chemicals subvert conventional NR signaling modalities. PMID:27409825

Research Resource: A Reference Transcriptome for Constitutive Androstane Receptor and Pregnane X Receptor Xenobiotic Signaling.

PubMed

Ochsner, Scott A; Tsimelzon, Anna; Dong, Jianrong; Coarfa, Cristian; McKenna, Neil J

2016-08-01

The pregnane X receptor (PXR) (PXR/NR1I3) and constitutive androstane receptor (CAR) (CAR/NR1I2) members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors are well-characterized mediators of xenobiotic and endocrine-disrupting chemical signaling. The Nuclear Receptor Signaling Atlas maintains a growing library of transcriptomic datasets involving perturbations of NR signaling pathways, many of which involve perturbations relevant to PXR and CAR xenobiotic signaling. Here, we generated a reference transcriptome based on the frequency of differential expression of genes across 159 experiments compiled from 22 datasets involving perturbations of CAR and PXR signaling pathways. In addition to the anticipated overrepresentation in the reference transcriptome of genes encoding components of the xenobiotic stress response, the ranking of genes involved in carbohydrate metabolism and gonadotropin action sheds mechanistic light on the suspected role of xenobiotics in metabolic syndrome and reproductive disorders. Gene Set Enrichment Analysis showed that although acetaminophen, chlorpromazine, and phenobarbital impacted many similar gene sets, differences in direction of regulation were evident in a variety of processes. Strikingly, gene sets representing genes linked to Parkinson's, Huntington's, and Alzheimer's diseases were enriched in all 3 transcriptomes. The reference xenobiotic transcriptome will be supplemented with additional future datasets to provide the community with a continually updated reference transcriptomic dataset for CAR- and PXR-mediated xenobiotic signaling. Our study demonstrates how aggregating and annotating transcriptomic datasets, and making them available for routine data mining, facilitates research into the mechanisms by which xenobiotics and endocrine-disrupting chemicals subvert conventional NR signaling modalities.

Visualization of the Drosophila dKeap1-CncC interaction on chromatin illumines cooperative, xenobiotic-specific gene activation

PubMed Central

Deng, Huai; Kerppola, Tom K.

2014-01-01

Interactions among transcription factors control their physiological functions by regulating their binding specificities and transcriptional activities. We implement a strategy to visualize directly the genomic loci that are bound by multi-protein complexes in single cells in Drosophila. This method is based on bimolecular fluorescence complementation (BiFC) analysis of protein interactions on polytene chromosomes. Drosophila Keap1 (dKeap1)-CncC complexes localized to the nucleus and bound chromatin loci that were not bound preferentially by dKeap1 or CncC when they were expressed separately. dKeap1 and CncC binding at these loci was enhanced by phenobarbital, but not by tert-butylhydroquinone (tBHQ) or paraquat. Endogenous dKeap1 and CncC activated transcription of the Jheh (Jheh1, Jheh2, Jheh3) and dKeap1 genes at these loci, whereas CncC alone activated other xenobiotic response genes. Ectopic dKeap1 expression increased CncC binding at the Jheh and dKeap1 gene loci and activated their transcription, whereas dKeap1 inhibited CncC binding at other xenobiotic response gene loci and suppressed their transcription. The combinatorial chromatin-binding specificities and transcriptional activities of dKeap1-CncC complexes mediated the selective activation of different sets of genes by different xenobiotic compounds, in part through feed-forward activation of dKeap1 transcription. PMID:25063457

Epidermal Overexpression of Xenobiotic Receptor PXR Impairs the Epidermal Barrier and Triggers Th2 Immune Response.

PubMed

Elentner, Andreas; Schmuth, Matthias; Yannoutsos, Nikolaos; Eichmann, Thomas O; Gruber, Robert; Radner, Franz P W; Hermann, Martin; Del Frari, Barbara; Dubrac, Sandrine

2018-01-01

The skin is in daily contact with environmental pollutants, but the long-term effects of such exposure remain underinvestigated. Many of these toxins bind and activate the pregnane X receptor (PXR), a ligand-activated transcription factor that regulates genes central to xenobiotic metabolism. The objective of this work was to investigate the effect of constitutive activation of PXR in the basal layer of the skin to mimic repeated skin exposure to noxious molecules. We designed a transgenic mouse model that overexpresses the human PXR gene linked to the herpes simplex VP16 domain under the control of the keratin 14 promoter. We show that transgenic mice display increased transepidermal water loss and elevated skin pH, abnormal stratum corneum lipids, focal epidermal hyperplasia, activated keratinocytes expressing more thymic stromal lymphopoietin, a T helper type 2/T helper type 17 skin immune response, and increased serum IgE. Furthermore, the cutaneous barrier dysfunction precedes development of the T helper type 2/T helper type 17 inflammation in transgenic mice, thereby mirroring the time course of atopic dermatitis development in humans. Moreover, further experiments suggest increased PXR signaling in the skin of patients with atopic dermatitis when compared with healthy skin. Thus, PXR activation by environmental pollutants may compromise epidermal barrier function and favor an immune response resembling atopic dermatitis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Xenobiotic metabolizing enzyme (XME) expression in aging humans.

EPA Science Inventory

In the presence of foreign compounds, metabolic homeostasis of the organism is maintained by the liver’s ability to detoxify and eliminate these xenobiotics. This is accomplished, in part, by the expression of XMEs, which metabolize xenobiotics and determine whether exposure will...

A Global Genomic and Genetic Strategy to Identify, Validate and Use Gene Signatures of Xenobiotic-Responsive Transcription Factors in Prediction of Pathway Activation in the Mouse Liver

EPA Science Inventory

Many drugs and environmentally-relevant chemicals activate xenobiotic-responsive transcription factors. Identification of target genes of these factors would be useful in predicting pathway activation in in vitro chemical screening as well as their involvement in disease states. ...

Senescence responsive transcriptional element

DOEpatents

Campisi, Judith; Testori, Alessandro

1999-01-01

Recombinant polynucleotides have expression control sequences that have a senescence responsive element and a minimal promoter, and which are operatively linked to a heterologous nucleotide sequence. The molecules are useful for achieving high levels of expression of genes in senescent cells. Methods of inhibiting expression of genes in senescent cells also are provided.

Transgenic plants for enhanced biodegradation and phytoremediation of organic xenobiotics.

PubMed

Abhilash, P C; Jamil, Sarah; Singh, Nandita

2009-01-01

, PCBs etc. Another approach to enhancing phytoremediation ability is the construction of plants that secrete chemical degrading enzymes into the rhizosphere. Recent studies revealed that accelerated ethylene production in response to stress induced by contaminants is known to inhibit root growth and is considered as major limitation in improving phytoremediation efficiency. However, this can be overcome by the selective expression of bacterial ACC deaminase (which regulates ethylene levels in plants) in plants together with multiple genes for the different phases of xenobiotic degradation. This review examines the recent developments in use of transgenic-plants for the enhanced metabolism, degradation and phytoremediation of organic xenobiotics and its future directions.

Nuclear factor erythroid-derived 2-related factor 2 activates glutathione S-transferase expression in the midgut of Spodoptera litura (Lepidoptera: Noctuidae) in response to phytochemicals and insecticides.

PubMed

Chen, S; Lu, M; Zhang, N; Zou, X; Mo, M; Zheng, S

2018-05-10

Detoxication enzymes play an important role in insect resistance to xenobiotics such as insecticides and phytochemicals. We studied the pathway for activating the expression of glutathione S-transferases (GSTs) in response to selected xenobiotics. An assay of the promoter activity of GST epsilon 1 (Slgste1) of Spodoptera litura led to the discovery of a cis-regulating element. An antioxidant response element was activated in response to indole-3-carbinol (I3C) and chlorpyrifos (CPF) and was able to bind with the xenobiotic sensor protein nuclear factor erythroid-derived 2-related factor 2 (SlNrf2). SlNrf2 and Slgste1 were responsive to reactive oxygen species induced by I3C and CPF in a S. litura cell line, as well as in S. litura midguts. SlNrf2 RNA interference (RNAi) reduced the message RNA levels of Slgste1 and the peroxidase activity of GSTs in response to I3C, xanthotoxin, CPF and deltamethrin. SlNrf2 RNAi and inhibitor treatment of GST activity decreased the viability of I3C-treated cells. These results indicate that SlNrf2 activates the expression of GSTs in response to oxidative stresses caused by exposure to xenobiotics. © 2018 The Royal Entomological Society.

Hepatic Xenobiotic Metabolizing Enzyme Gene Expression Through the Life Stages of the Mouse

EPA Science Inventory

BACKGROUND: Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs). No comprehensive analysis of the mRNA expression of XMETs has been ca...

Xenobiotic Transporter Expression along the Male Genital Tract1

PubMed Central

Klein, David M.; Wright, Stephen H.; Cherrington, Nathan J.

2015-01-01

The male genital tract plays an important role in protecting sperm by forming a distinct compartment separate from the body which limits exposure to potentially toxic substrates. Transporters along this tract can influence the distribution of xenobiotics into the male genital tract through efflux back into the blood or facilitating the accumulation of toxicants. The aim of this study was to quantitatively determine the constitutive mRNA expression of 30 xenobiotic transporters in caput and cauda regions of the epididymis, vas deferens, prostate, and seminal vesicles from adult Sprague-Dawley rats. The epididymis was found to express at least moderate levels of 18 transporters, vas deferens 15, seminal vesicles 23, and prostate 18. Constitutive expression of these xenobiotic transporters in the male genital tract may provide insight into the xenobiotics that can potentially be transported into these tissues and may provide the molecular mechanism for site specific toxicity of select agents. PMID:24814985

The Chemically Inducible Plant Cytochrome P450 CYP76B1 Actively Metabolizes Phenylureas and Other Xenobiotics1

PubMed Central

Robineau, Tiburce; Batard, Yannick; Nedelkina, Svetlana; Cabello-Hurtado, Francisco; LeRet, Monique; Sorokine, Odile; Didierjean, Luc; Werck-Reichhart, Danièle

1998-01-01

Cytochrome P450s (P450s) constitute one of the major classes of enzymes that are responsible for detoxification of exogenous molecules both in animals and plants. On the basis of its inducibility by exogenous chemicals, we recently isolated a new plant P450, CYP76B1, from Jerusalem artichoke (Helianthus tuberosus) and showed that it was capable of dealkylating a model xenobiotic compound, 7-ethoxycoumarin. In the present paper we show that CYP76B1 is more strongly induced by foreign compounds than other P450s isolated from the same plant, and metabolizes with high efficiency a wide range of xenobiotics, including alkoxycoumarins, alkoxyresorufins, and several herbicides of the class of phenylureas. CYP76B1 catalyzes the double N-dealkylation of phenylureas with turnover rates comparable to those reported for physiological substrates and produces nonphytotoxic compounds. Potential uses for CYP76B1 thus include control of herbicide tolerance and selectivity, as well as soil and groundwater bioremediation. PMID:9808750

Genomic analysis of the aging rodent and human liver: impact on xenobiotic metabolism

EPA Science Inventory

Metabolic homeostasis of the organism is maintained by the liver’s ability to detoxify and eliminate xenobiotics. This is accomplished, in part, by xenobiotic metabolizing enzymes (XMEs), which metabolize xenobiotics and determine whether exposure will result in toxicity. Some ev...

Regulation of hepatic ABCC transporters by xenobiotics and in disease states

PubMed Central

Gu, Xinsheng; Manautou, Jose E.

2015-01-01

The subfamily of ABCC transporters consists of 13 members in mammals, including the multidrug resistance-associated proteins (MRPs), sulfonylurea receptors (SURs), and the cystic fibrosis transmembrane conductance regulator (CFTR). These proteins play roles in chemical detoxification, disposition, and normal cell physiology. ABCC transporters are expressed differentially in the liver and are regulated at the transcription and translation level. Their expression and function are also controlled by post-translational modification and membrane-trafficking events. These processes are tightly regulated. Information about alterations in the expression of hepatobiliary ABCC transporters could provide important insights into the pathogenesis of diseases and disposition of xenobiotics. In this review, we describe the regulation of hepatic ABCC transporters in humans and rodents by a variety of xenobiotics, under disease states and in genetically modified animal models deficient in transcription factors, transporters, and cell-signaling molecules. PMID:20233023

Spatio-temporal Model of Xenobiotic Distribution and Metabolism in an in Silico Mouse Liver Lobule

NASA Astrophysics Data System (ADS)

Fu, Xiao; Sluka, James; Clendenon, Sherry; Glazier, James; Ryan, Jennifer; Dunn, Kenneth; Wang, Zemin; Klaunig, James

Our study aims to construct a structurally plausible in silico model of a mouse liver lobule to simulate the transport of xenobiotics and the production of their metabolites. We use a physiologically-based model to calculate blood-flow rates in a network of mouse liver sinusoids and simulate transport, uptake and biotransformation of xenobiotics within the in silico lobule. Using our base model, we then explore the effects of variations of compound-specific (diffusion, transport and metabolism) and compound-independent (temporal alteration of blood flow pattern) parameters, and examine their influence on the distribution of xenobiotics and metabolites. Our simulations show that the transport mechanism (diffusive and transporter-mediated) of xenobiotics and blood flow both impact the regional distribution of xenobiotics in a mouse hepatic lobule. Furthermore, differential expression of metabolic enzymes along each sinusoid's portal to central axis, together with differential cellular availability of xenobiotics, induce non-uniform production of metabolites. Thus, the heterogeneity of the biochemical and biophysical properties of xenobiotics, along with the complexity of blood flow, result in different exposures to xenobiotics for hepatocytes at different lobular locations. We acknowledge support from National Institute of Health GM 077138 and GM 111243.

Adaptation to environmental stress in Daphnia magna simultaneously exposed to a xenobiotic.

PubMed

Coors, Anja; Hammers-Wirtz, Monika; Ratte, Hans Toni

2004-07-01

In standardized ecotoxicological testing chemicals are investigated under optimal conditions for the test organisms despite the fact that environmental factors such as predation pressure and food availability are important parameters regulating natural populations. Food limitation and predator presence can induce shifts in life-history traits in various Daphnia species, especially trade-offs in reproductive biomass allocation. These adaptive responses are thought to ensure survival of the population in a highly variable environment. A xenobiotic dispersant (used in textile dyeing processes) also shifted the biomass allocation of Daphnia magna. To assess whether the dispersant could hinder D. magna adaptation to varying environmental conditions, we conducted experiments with food level and presence of Chaoborus larvae as environmental factors and simultaneous exposure to the dispersant. At low food level and in presence of the predator, D. magna produced fewer but larger sized neonates, regardless of dispersant exposure. The dispersant shifted biomass allocation towards more but smaller sized offspring in all experiments. However, the adaptive response to the environmental factors and the dispersant effect cancelled each other out in that they induced independently from each other opposite shifts in biomass allocation. In summary, the dispersant exposure resulted not in an inhibition of the adaptive response but in a reduction of the value of the response. Our study with this model substance demonstrates that xenobiotics can affect the adaptation of organisms to environmental stress which can result in effects likely to be overlooked in standardized testing.

Do heavy metals and metalloids influence the detoxification of organic xenobiotics in plants?

PubMed

Schröder, Peter; Lyubenova, Lyudmila; Huber, Christian

2009-11-01

Mixed pollution with trace elements and organic industrial compounds is characteristic for many spill areas and dumping sites. The danger for the environment and human health from such sites is large, and sustainable remediation strategies are urgently needed. Phytoremediation seems to be a cheap and environmentally sound option for the removal of unwanted compounds, and the hyperaccumulation of trace elements and toxic metals is seemingly independent from the metabolism of organic xenobiotics. However, stress reactions, ROS formation and depletion of antioxidants will also cause alterations in xenobiotic detoxification. Here, we investigate the capability of plants to detoxify chlorophenols via glutathione conjugation in a mixed pollution situation. Typha latifolia and Phragmites australis plants for the present study were grown under greenhouse conditions in experimental ponds. A Picea abies L. suspension culture was grown in a growth chamber. Cadmium sulphate, sodium arsenate and lead chloride in concentrations from 10 to 500 microM were administered to plants. Enzymes of interest for the present study were: glutathione transferase (GST), glutathione reductase, ascorbate peroxidase and peroxidase. Measurements were performed according to published methods. GST spectrophotometric assays included the model substrates CDNB, DCNB, NBC, NBoC and the herbicide Fluorodifen. Heavy metals lead to visible stress symptoms in higher plants. Besides one long-term experiment of 72 days duration, the present study shows time and concentration-dependent plant alterations already after 24 and 72 h Cd incubation. P. abies spruce cell cultures react to CdSO(4) and Na(2)HAsO(4) with an oxidative burst, similar to that observed after pathogen attack or elicitor treatment. Cd application resulted in a reduction in GSH and GSSG contents. When a heavy metal mixture containing Na(2)HAsO(4), CdSO(4) and PbCl(2) was applied to cultures, both GSH and GSSG levels declined. Incubation with

Uncovering drug-responsive regulatory elements

PubMed Central

Luizon, Marcelo R; Ahituv, Nadav

2015-01-01

Nucleotide changes in gene regulatory elements can have a major effect on interindividual differences in drug response. For example, by reviewing all published pharmacogenomic genome-wide association studies, we show here that 96.4% of the associated single nucleotide polymorphisms reside in noncoding regions. We discuss how sequencing technologies are improving our ability to identify drug response-associated regulatory elements genome-wide and to annotate nucleotide variants within them. We highlight specific examples of how nucleotide changes in these elements can affect drug response and illustrate the techniques used to find them and functionally characterize them. Finally, we also discuss challenges in the field of drug-responsive regulatory elements that need to be considered in order to translate these findings into the clinic. PMID:26555224

Cytotoxic effects and aromatase inhibition by xenobiotic endocrine disrupters alone and in combination.

PubMed

Benachour, Nora; Moslemi, Safa; Sipahutar, Herbert; Seralini, Gilles-Eric

2007-07-15

Xenobiotics may cause long-term adverse effects in humans, especially at the embryonic level, raising questions about their levels of exposure, combined effects, and crucial endpoints. We are interested in the possible interactions between xenobiotic endocrine disrupters, cellular viability and androgen metabolism. Accordingly, we tested aroclor 1254 (A1254), atrazine (AZ), o,p'-DDT, vinclozolin (VZ), p,p'-DDE, bisphenol A (BPA), chlordecone (CD), nonylphenol (NP), tributylin oxide (TBTO), and diethylstilbestrol (DES) for cellular toxicity against human embryonic 293 cells, and activity against cellular aromatase, but also on placental microsomes and on the purified equine enzyme. Cellular viability was affected in 24 h by all the xenobiotics with a threshold at 50 microM (except for TBTO and DES, 10 microM threshold), and aromatase was inhibited at non-toxic doses. In combination synergism was observed reducing the threshold values of toxicity to 4-10 microM, and aromatase activity by 50% in some cases. In placental microsomes the most active xenobiotics rapidly inhibited microsomal aromatase in a manner independent of NADPH metabolism. Prolonged exposures to low doses in cells generally amplified by 50 times aromatase inhibition. These xenobiotics may act by inhibition of the active site or by allosteric effects on the enzyme. Bioaccumulation is a feature of some xenobiotics, especially chlordecone, DDT and DDE, and low level chronic exposures can also affect cell signaling mechanisms. This new information about the mechanism of action of these xenobiotics will assist in improved molecular design with a view to providing safer compounds for use in the (human) environment.

ADAPTATION OF AQUIFER MICROBIAL COMMUNITIES TO THE BIODEGRADATION OF XENOBIOTIC COMPOUNDS: INFLUENCE OF SUBSTRATE CONCENTRATION AND PREEXPOSURE

EPA Science Inventory

Studies were conducted to examine the adaptation response of aquifer microbial communities to xenobiotic compounds and the influence of chemical preexposure in the laboratory and in situ on adaptation. Adaptation and biodegradation were assessed as mineralization and cellular inc...

Coordinated Changes in Xenobiotic Metabolizing Enzyme Gene Expression in Aging Male Rats

EPA Science Inventory

In order to gain better insight on aging and susceptibility, we characterized the expression of xenobiotic metabolizing enzymes (XMEs) from the livers of rats to evaluate the change in capacity to respond to xenobiotics across the adult lifespan. Gene expression profiles for XMEs...

Organization of cis-acting regulatory elements in osmotic- and cold-stress-responsive promoters.

PubMed

Yamaguchi-Shinozaki, Kazuko; Shinozaki, Kazuo

2005-02-01

cis-Acting regulatory elements are important molecular switches involved in the transcriptional regulation of a dynamic network of gene activities controlling various biological processes, including abiotic stress responses, hormone responses and developmental processes. In particular, understanding regulatory gene networks in stress response cascades depends on successful functional analyses of cis-acting elements. The ever-improving accuracy of transcriptome expression profiling has led to the identification of various combinations of cis-acting elements in the promoter regions of stress-inducible genes involved in stress and hormone responses. Here we discuss major cis-acting elements, such as the ABA-responsive element (ABRE) and the dehydration-responsive element/C-repeat (DRE/CRT), that are a vital part of ABA-dependent and ABA-independent gene expression in osmotic and cold stress responses.

The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a "Central Dogma" for Toxic Mechanisms?

PubMed

Park, Yeong-Chul; Lee, Sundong; Cho, Myung-Haing

2014-09-01

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems.

Membrane Phospholipid Augments Cytochrome P4501a Enzymatic Activity by Modulating Structural Conformation during Detoxification of Xenobiotics

PubMed Central

Ghosh, Manik C.; Ray, Arun K.

2013-01-01

Cytochrome P450 is a superfamily of membrane-bound hemoprotein that gets involved with the degradation of xenobiotics and internal metabolites. Accumulated body of evidence indicates that phospholipids play a crucial role in determining the enzymatic activity of cytochrome P450 in the microenvironment by modulating its structure during detoxification; however, the structure-function relationship of cytochrome P4501A, a family of enzymes responsible for degrading lipophilic aromatic hydrocarbons, is still not well defined. Inducibility of cytochrome P4501A in cultured catfish hepatocytes in response to carbofuran, a widely used pesticide around the world, was studied earlier in our laboratory. In this present investigation, we observed that treating catfish with carbofuran augmented total phospholipid in the liver. We examined the role of phospholipid on the of cytochrome P4501A-marker enzyme which is known as ethoxyresorufin-O-deethylase (EROD) in the context of structure and function. We purified the carbofuran-induced cytochrome P4501A protein from catfish liver. Subsequently, we examined the enzymatic activity of purified P4501A protein in the presence of phospholipid, and studied how the structure of purified protein was influenced in the phospholipid environment. Membrane phospholipid appeared to accelerate the enzymatic activity of EROD by changing its structural conformation and thus controlling the detoxification of xenobiotics. Our study revealed the missing link of how the cytochrome P450 restores its enzymatic activity by changing its structural conformation in the phospholipid microenvironment. PMID:23469105

Membrane phospholipid augments cytochrome P4501a enzymatic activity by modulating structural conformation during detoxification of xenobiotics.

PubMed

Ghosh, Manik C; Ray, Arun K

2013-01-01

Cytochrome P450 is a superfamily of membrane-bound hemoprotein that gets involved with the degradation of xenobiotics and internal metabolites. Accumulated body of evidence indicates that phospholipids play a crucial role in determining the enzymatic activity of cytochrome P450 in the microenvironment by modulating its structure during detoxification; however, the structure-function relationship of cytochrome P4501A, a family of enzymes responsible for degrading lipophilic aromatic hydrocarbons, is still not well defined. Inducibility of cytochrome P4501A in cultured catfish hepatocytes in response to carbofuran, a widely used pesticide around the world, was studied earlier in our laboratory. In this present investigation, we observed that treating catfish with carbofuran augmented total phospholipid in the liver. We examined the role of phospholipid on the of cytochrome P4501A-marker enzyme which is known as ethoxyresorufin-O-deethylase (EROD) in the context of structure and function. We purified the carbofuran-induced cytochrome P4501A protein from catfish liver. Subsequently, we examined the enzymatic activity of purified P4501A protein in the presence of phospholipid, and studied how the structure of purified protein was influenced in the phospholipid environment. Membrane phospholipid appeared to accelerate the enzymatic activity of EROD by changing its structural conformation and thus controlling the detoxification of xenobiotics. Our study revealed the missing link of how the cytochrome P450 restores its enzymatic activity by changing its structural conformation in the phospholipid microenvironment.

The biochemistry and molecular biology of xenobiotic polymer degradation by microorganisms.

PubMed

Kawai, Fusako

2010-01-01

Research on microbial degradation of xenobiotic polymers has been underway for more than 40 years. It has exploited a new field not only in applied microbiology but also in environmental microbiology, and has greatly contributed to polymer science by initiating the design of biodegradable polymers. Owing to the development of analytical tools and technology, molecular biological and biochemical advances have made it possible to prospect for degrading microorganisms in the environment and to determine the mechanisms involved in biodegradation when xenobiotic polymers are introduced into the environment and are exposed to microbial attack. In this review, the molecular biological and biochemical aspects of the microbial degradation of xenobiotic polymers are summarized, and possible applications of potent microorganisms, enzymes, and genes in environmental biotechnology are suggested.

Xenobiotics: How the Environment Changes Your Body

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baker, Erin

Erin Baker studies how substances foreign to your body affect your health. To do so, her team at PNNL developed a rapid way to separate and study both xenobiotics and endogenous molecules using ion mobility.

Marine Invertebrate Xenobiotic-Activated Nuclear Receptors: Their Application as Sensor Elements in High-Throughput Bioassays for Marine Bioactive Compounds

PubMed Central

Richter, Ingrid; Fidler, Andrew E.

2014-01-01

Developing high-throughput assays to screen marine extracts for bioactive compounds presents both conceptual and technical challenges. One major challenge is to develop assays that have well-grounded ecological and evolutionary rationales. In this review we propose that a specific group of ligand-activated transcription factors are particularly well-suited to act as sensors in such bioassays. More specifically, xenobiotic-activated nuclear receptors (XANRs) regulate transcription of genes involved in xenobiotic detoxification. XANR ligand-binding domains (LBDs) may adaptively evolve to bind those bioactive, and potentially toxic, compounds to which organisms are normally exposed to through their specific diets. A brief overview of the function and taxonomic distribution of both vertebrate and invertebrate XANRs is first provided. Proof-of-concept experiments are then described which confirm that a filter-feeding marine invertebrate XANR LBD is activated by marine bioactive compounds. We speculate that increasing access to marine invertebrate genome sequence data, in combination with the expression of functional recombinant marine invertebrate XANR LBDs, will facilitate the generation of high-throughput bioassays/biosensors of widely differing specificities, but all based on activation of XANR LBDs. Such assays may find application in screening marine extracts for bioactive compounds that could act as drug lead compounds. PMID:25421319

PROXIMAL: a method for Prediction of Xenobiotic Metabolism.

PubMed

Yousofshahi, Mona; Manteiga, Sara; Wu, Charmian; Lee, Kyongbum; Hassoun, Soha

2015-12-22

Contamination of the environment with bioactive chemicals has emerged as a potential public health risk. These substances that may cause distress or disease in humans can be found in air, water and food supplies. An open question is whether these chemicals transform into potentially more active or toxic derivatives via xenobiotic metabolizing enzymes expressed in the body. We present a new prediction tool, which we call PROXIMAL (Prediction of Xenobiotic Metabolism) for identifying possible transformation products of xenobiotic chemicals in the liver. Using reaction data from DrugBank and KEGG, PROXIMAL builds look-up tables that catalog the sites and types of structural modifications performed by Phase I and Phase II enzymes. Given a compound of interest, PROXIMAL searches for substructures that match the sites cataloged in the look-up tables, applies the corresponding modifications to generate a panel of possible transformation products, and ranks the products based on the activity and abundance of the enzymes involved. PROXIMAL generates transformations that are specific for the chemical of interest by analyzing the chemical's substructures. We evaluate the accuracy of PROXIMAL's predictions through case studies on two environmental chemicals with suspected endocrine disrupting activity, bisphenol A (BPA) and 4-chlorobiphenyl (PCB3). Comparisons with published reports confirm 5 out of 7 and 17 out of 26 of the predicted derivatives for BPA and PCB3, respectively. We also compare biotransformation predictions generated by PROXIMAL with those generated by METEOR and Metaprint2D-react, two other prediction tools. PROXIMAL can predict transformations of chemicals that contain substructures recognizable by human liver enzymes. It also has the ability to rank the predicted metabolites based on the activity and abundance of enzymes involved in xenobiotic transformation.

The Simplest Flowchart Stating the Mechanisms for Organic Xenobiotics-induced Toxicity: Can it Possibly be Accepted as a “Central Dogma” for Toxic Mechanisms?

PubMed Central

Lee, Sundong; Cho, Myung-Haing

2014-01-01

Xenobiotics causing a variety of toxicity in biological systems could be classified as two types, inorganic and organic chemicals. It is estimated that the organic xenobiotics are responsible for approximately 80~90% of chemical-induced toxicity in human population. In the class for toxicology, we have encountered some difficulties in explaining the mechanisms of toxicity caused especially by organic chemicals. Here, a simple flowchart was introduced for explaining the mechanism of toxicity caused by organic xenobiotics, as the central dogma of molecular biology. This flowchart, referred to as a central dogma, was described based on a view of various aspects as follows: direct-acting chemicals vs. indirect-acting chemicals, cytochrome P450-dependent vs. cytochrome P450-independent biotransformation, reactive intermediates, reactivation, toxicokinetics vs. toxicodynamics, and reversibility vs. irreversibility. Thus, the primary objective of this flowchart is to help better understanding of the organic xenobiotics-induced toxic mechanisms, providing a major pathway for toxicity occurring in biological systems. PMID:25343011

NEUTRONIC REACTOR CONTROL ELEMENT

DOEpatents

Newson, H.W.

1960-09-13

A novel composite neutronic reactor control element is offered. The element comprises a multiplicity of sections arranged in end-to-end relationship, each of the sections having a markedly different neutron-reactive characteristic. For example, a three-section control element could contain absorber, moderator, and fuel sections. By moving such an element longitudinally through a reactor core, reactivity is decreased by the absorber, increased slightly by the moderator, or increased substantially by the fuel. Thus, control over a wide reactivity range is provided.

Xenobiotics enhance laccase activity in alkali-tolerant γ-proteobacterium JB.

PubMed

Singh, Gursharan; Batish, Mona; Sharma, Prince; Capalash, Neena

2009-01-01

Various genotoxic textile dyes, xenobiotics, substrates (10 µM) and agrochemicals (100 µg/ml) were tested for enhancement of alkalophilic laccase activity in γ-proteobacterium JB. Neutral Red, Indigo Carmine, Naphthol Base Bordears and Sulphast Ruby dyes increased the activity by 3.7, 2.7, 2.6 and 2.3 fold respectively. Xenobiotics/substrates like p-toluidine, 8-hydroxyquinoline and anthracine increased it by 3.4, 2.8 and 2.3 fold respectively. Atrazine and trycyclozole pesticides enhanced the activity by 1.95 and 1.5 fold respectively.

Xenobiotics enhance laccase activity in alkali-tolerant γ-proteobacterium JB

PubMed Central

Singh, Gursharan; Batish, Mona; Sharma, Prince; Capalash, Neena

2009-01-01

Various genotoxic textile dyes, xenobiotics, substrates (10 µM) and agrochemicals (100 µg/ml) were tested for enhancement of alkalophilic laccase activity in γ-proteobacterium JB. Neutral Red, Indigo Carmine, Naphthol Base Bordears and Sulphast Ruby dyes increased the activity by 3.7, 2.7, 2.6 and 2.3 fold respectively. Xenobiotics/substrates like p-toluidine, 8-hydroxyquinoline and anthracine increased it by 3.4, 2.8 and 2.3 fold respectively. Atrazine and trycyclozole pesticides enhanced the activity by 1.95 and 1.5 fold respectively. PMID:24031313

GENE EXPRESSION PROFILING IN AGING RATS AND MICE REVEALS CHANGES IN XENOBIOTIC METABOLISM GENES

EPA Science Inventory

Detoxification and elimination of xenobiotics are major functions of the liver and is important in maintaining the metabolic homeostasis of the organism. The degree to which aging affects hepatic metabolism is not known. The expression of xenobiotic metabolizing enzymes (XMEs), i...

Characterization of the Impact of Life Stage on Xenobiotic Metabolizing Enzyme Expression and Gene -Chemical Interactions in the Liver

EPA Science Inventory

Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs). We have carried out a comprehensive analysis of the mRNA expression of XMETs thro...

An in vitro bioassay for xenobiotics using the SXR-driven human CYP3A4/lacZ reporter gene.

PubMed

Lee, Mi R; Kim, Yeon J; Hwang, Dae Y; Kang, Tae S; Hwang, Jin H; Lim, Chae H; Kang, Hyung K; Goo, Jun S; Lim, Hwa J; Ahn, Kwang S; Cho, Jung S; Chae, Kap R; Kim, Yong K

2003-01-01

The dose and time effect of nine xenobiotics, including 17beta-estradiol, corticosterone, dexamethasone, progesterone, nifedipine, bisphenol A, rifampicin, methamphetamine, and nicotine were investigated, in vitro, using human steroid and xenobiotics receptor (SXR)-binding sites on the human CYP3A4 promoter, which can enhance the linked lacZ reporter gene transcription. To test this, liver-specific SAP (human serum amyloid P component)-SXR (SAP/SXR) and human CYP3A4 promoter-regulated lacZ (hCYP3A4/lacZ) constructs were transiently transfected into HepG2 and NIH3T3 cells to compare the xenobiotic responsiveness between human and nonhuman cell lines. In the HepG2 cells, rifampicin, followed by corticosterone, nicotine, methamphetamine, and dexamethasone, exhibited enhanced levels of the lacZ transcript, whereas those of bisphenol A and nifedipine were found to be reduced. No significant responses were observed with 17beta-estradiol or progesterone. In addition, 17beta-estradiol and progesterone did not change the levels of the lacZ transcripts in the HepG2 cells, but did induce significant increases in the transcripts of the NIH3T3 cells. Treatment with corticosterone and dexamethasone, which were highly expressed in the HepG2 cells, did not affect the levels of the lacZ transcript in NIH3T3 cells. These results show that lacZ transcripts can be measured, rapidly and reproducibly, using reverse transcriptase-polymerase chain reaction (RT-PCR) based on the expression of the hCYP3A4/lacZ reporter gene, and was mediated by the SXR. Thus, this in vitro reporter gene bioassay is useful for measuring xenobiotic activities, and is a means to a better relevant bioassay, using human cells, human genes and human promoters, in order to get a closer look at actual human exposure.

Filament condition-specific response elements control the expression of NRG1 and UME6, key transcriptional regulators of morphology and virulence in Candida albicans.

PubMed

Childers, Delma S; Kadosh, David

2015-01-01

Candida albicans is the most frequently isolated human fungal pathogen and can cause a range of mucosal and systemic infections in immunocompromised individuals. Morphogenesis, the ability to undergo a reversible transition from budding yeast to elongated filaments, is an essential virulence trait. The yeast-to-filament transition is associated with expression of genes specifically important for filamentation as well as other virulence-related processes, and is controlled, in part, by the key transcriptional regulators Nrg1 and Ume6. Both of these regulators are themselves controlled at the transcriptional level by filament-inducing environmental cues, although little is known about how this process occurs. In order to address this question and determine whether environmental signals regulate transcription of UME6 and NRG1 via distinct and/or common promoter elements, we performed promoter deletion analyses. Strains bearing promoter deletion constructs were induced to form filaments in YEPD plus 10% serum at 37°C, Spider medium (nitrogen and carbon starvation) and/or Lee's medium pH 6.8 (neutral pH) and reporter gene expression was measured. In the NRG1 promoter we identified several distinct condition-specific response elements for YEPD plus 10% serum at 37°C and Spider medium. In the UME6 promoter we also identified response elements for YEPD plus 10% serum at 37°C. While a few of these elements are distinct, others overlap with those which respond to Lee's pH 6.8 medium. Consistent with UME6 possessing a very long 5' UTR, many response elements in the UME6 promoter are located significantly upstream from the coding sequence. Our data indicate that certain distinct condition-specific elements can control expression of C. albicans UME6 and NRG1 in response to key filament-inducing environmental cues. Because C. albicans encounters a variety of host microenvironments during infection, our results suggest that UME6 and NRG1 expression can be differentially

Removal of xenobiotics from effluent discharge by adsorption on zeolite and expanded clay: an alternative to activated carbon?

PubMed

Tahar, A; Choubert, J M; Miège, C; Esperanza, M; Le Menach, K; Budzinski, H; Wisniewski, C; Coquery, M

2014-04-01

Xenobiotics such as pesticides and pharmaceuticals are an increasingly large problem in aquatic environments. A fixed-bed adsorption filter, used as tertiary stage of sewage treatment, could be a solution to decrease xenobiotics concentrations in wastewater treatment plants (WWTPs) effluent. The adsorption efficiency of two mineral adsorbent materials (expanded clay (EC) and zeolite (ZE)), both seen as a possible alternative to activated carbon (AC), was evaluated in batch tests. Experiments involving secondary treated domestic wastewater spiked with a cocktail of ten xenobiotics (eight pharmaceuticals and two pesticides) known to be poorly eliminated in conventional biological process were carried out. Removal efficiencies and partitions coefficients were calculated for two levels of initial xenobiotic concentration, i.e, concentrations lower to 10 μg/L and concentrations ranged from 100 to 1,000 μg/L. While AC was the most efficient adsorbent material, both alternative adsorbent materials showed good adsorption efficiencies for all ten xenobiotics (from 50 to 100 % depending on the xenobiotic/adsorbent material pair). For all the targeted xenobiotics, at lower concentrations, EC presented the best adsorption potential with higher partition coefficients, confirming the results in terms of removal efficiencies. Nevertheless, Zeolite presents virtually the same adsorption potential for both high and low xenobiotics concentrations to be treated. According to this first batch investigation, ZE and EC could be used as alternative absorbent materials to AC in WWTP.

Computer-aided prediction of xenobiotic metabolism in the human body

NASA Astrophysics Data System (ADS)

Bezhentsev, V. M.; Tarasova, O. A.; Dmitriev, A. V.; Rudik, A. V.; Lagunin, A. A.; Filimonov, D. A.; Poroikov, V. V.

2016-08-01

The review describes the major databases containing information about the metabolism of xenobiotics, including data on drug metabolism, metabolic enzymes, schemes of biotransformation and the structures of some substrates and metabolites. Computational approaches used to predict the interaction of xenobiotics with metabolic enzymes, prediction of metabolic sites in the molecule, generation of structures of potential metabolites for subsequent evaluation of their properties are considered. The advantages and limitations of various computational methods for metabolism prediction and the prospects for their applications to improve the safety and efficacy of new drugs are discussed. Bibliography — 165 references.

Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Last, Jerold A.; Gohil, Kishorchandra; Mathrani, Vivek C.

2005-10-15

Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkersmore » of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-{kappa}B in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.« less

Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes.

PubMed

Last, Jerold A; Gohil, Kishorchandra; Mathrani, Vivek C; Kenyon, Nicholas J

2005-10-15

Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-kappaB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.

An activated sludge modeling framework for xenobiotic trace chemicals (ASM-X): assessment of diclofenac and carbamazepine.

PubMed

Plósz, Benedek Gy; Langford, Katherine H; Thomas, Kevin V

2012-11-01

Conventional models for predicting the fate of xenobiotic organic trace chemicals, identified, and calibrated using data obtained in batch experiments spiked with reference substances, can be limited in predicting xenobiotic removal in wastewater treatment plants (WWTPs). At stake is the level of model complexity required to adequately describe a general theory of xenobiotic removal in WWTPs. In this article, we assess the factors that influence the removal of diclofenac and carbamazepine in activated sludge, and evaluate the complexity required for the model to effectively predict their removal. The results are generalized to previously published cases. Batch experimental results, obtained under anoxic and aerobic conditions, were used to identify extensions to, and to estimate parameter values of the activated sludge modeling framework for Xenobiotic trace chemicals (ASM-X). Measurement and simulation results obtained in the batch experiments, spiked with the diclofenac and carbamazepine content of preclarified municipal wastewater shows comparably high biotransformation rates in the presence of growth substrates. Forward dynamic simulations were performed using full-scale data obtained from Bekkelaget WWTP (Oslo, Norway) to evaluate the model and to estimate the level of re-transformable xenobiotics present in the influent. The results obtained in this study demonstrate that xenobiotic loading conditions can significantly influence the removal capacity of WWTPs. We show that the trace chemical retransformation in upstream sewer pipes can introduce considerable error in assessing the removal efficiency of a WWTP, based only on parent compound concentration measurements. The combination of our data with those from the literature shows that solids retention time (SRT) can enhance the biotransformation of diclofenac, which was not the case for carbamazepine. Model approximation of the xenobiotic concentration, detected in the solid phase, suggest that between

Mobile monolithic polymer elements for flow control in microfluidic devices

DOEpatents

Hasselbrink, Jr., Ernest F.; Rehm, Jason E.; Shepodd, Timothy J.

2004-08-31

A cast-in-place and lithographically shaped mobile, monolithic polymer element for fluid flow control in microfluidic devices and method of manufacture. Microfluid flow control devices, or microvalves that provide for control of fluid or ionic current flow can be made incorporating a cast-in-place, mobile monolithic polymer element, disposed within a microchannel, and driven by either fluid or gas pressure against a retaining or sealing surface. The polymer elements are made by the application of lithographic methods to monomer mixtures formulated in such a way that the polymer will not bond to microchannel walls. The polymer elements can seal against pressures greater than 5000 psi, and have a response time on the order of milliseconds. By the use of energetic radiation it is possible to depolymerize selected regions of the polymer element to form shapes that cannot be produced by conventional lithographic patterning and would be impossible to machine.

Two horizontally transferred xenobiotic resistance gene clusters associated with detoxification of benzoxazolinones by Fusarium species

USDA-ARS?s Scientific Manuscript database

Microbes encounter a broad spectrum of chemical compounds in their diverse environments. These xenobiotics may negatively impact growth or cause death. To counter such adverse effects, many microbes possess metabolic strategies to detoxify and biotransform xenobiotics. Fusarium verticillioides is a ...

Nontargeted analysis of the urine nonpolar sulfateome: a pathway to the nonpolar xenobiotic exposome

PubMed Central

Yao, Yuanyuan; Wang, Poguang; Shao, Gang; Anzalota Del Toro, Liza V.; Codero, Jose; Giese, Roger W.

2016-01-01

RATIONALE Testing the urine nonpolar sulfateome can enable discovery of xenobiotics that are most likely to be bioactive. This is based on the fact that nonpolar xenobiotics are more likely to enter cells where they tend to undergo metabolism, in part, to sulfates that are then largely excreted into the urine. METHODS The following sequence of steps, with conditions that achieve high reproducibility, was applied to large human urine samples: (1) competitive nonpolar extraction with a porous extraction paddle; (2) weak anion exchange extraction with strong organic washing; and (3) UHPLC/negative ion-MALDI-TOF/TOF-MS with recording of ions with S/N ≥ 20 that yielded M-1-80 (loss of SO3) or m/z 97 (HSO4−) upon fragmentation. RESULTS From a collection of urine samples from six pregnant women, the masses of 1129 putative sulfates were measured. Three lists of candidate compounds (preliminary hits) from these masses were formed by searching METLIN, especially via MATLAB, yielding putative xenobiotic contaminants (35 compounds), steroids (122), and flavonoids (1582). CONCLUSION A new way to reveal some of the nonpolar xenobiotic exposome has been developed that applies to urine samples. The value of the method is to suggest xenobiotics for subsequent targeted analysis in the population of people under study, in order to relate the environment to health and disease. PMID:27557133

Generation Z: Adolescent Xenobiotic Abuse in the 21st Century.

PubMed

Eggleston, William; Stork, Christine

2015-12-01

NMDA receptor antagonists include the prescription medication ketamine, the illicit xenobiotics PCP, MXE, and other novel PCP analogs, and the OTC medication DXM. The NMDA receptor antagonist most commonly abused by adolescents in the United States is DXM. These xenobiotics cause dissociative effects by non-competitively inhibiting the action of glutamate at the NMDA receptor. Additionally, these agents modulate the actions of monoamine neurotransmitters, agonize opioid receptors, and inhibit nitric oxide synthase. Patients typically present with sympathomimetic and neuropsychiatric clinical manifestations after abuse of NMDA receptor antagonists. Treatment is generally symptomatic and supportive. Interventions include benzodiazepines, propofol, fluids, antiemetics, aggressive cooling, and respiratory support.

Mobile Monolith Polymer Elements For Flow Control In Microfluidic Systems

DOEpatents

Hasselbrink, Jr., Ernest F.; Rehm, Jason E.; Shepodd, Timothy J.; Kirby, Brian J.

2006-01-24

A cast-in-place and lithographically shaped mobile, monolithic polymer element for fluid flow control in microfluidic devices and method of manufacture. Microfluid flow control devices, or microvalves that provide for control of fluid or ionic current flow can be made incorporating a cast-in-place, mobile monolithic polymer element, disposed within a microchannel, and driven by fluid pressure (either liquid or gas) against a retaining or sealing surface. The polymer elements are made by the application of lithographic methods to monomer mixtures formulated in such a way that the polymer will not bond to microchannel walls. The polymer elements can seal against pressures greater than 5000 psi, and have a response time on the order of milliseconds. By the use of energetic radiation it is possible to depolymerize selected regions of the polymer element to form shapes that cannot be produced by conventional lithographic patterning and would be impossible to machine.

Mobile monolithic polymer elements for flow control in microfluidic devices

DOEpatents

Hasselbrink, Jr., Ernest F.; Rehm, Jason E [Alameda, CA; Shepodd, Timothy J [Livermore, CA; Kirby, Brian J [San Francisco, CA

2005-11-11

A cast-in-place and lithographically shaped mobile, monolithic polymer element for fluid flow control in microfluidic devices and method of manufacture. Microfluid flow control devices, or microvalves that provide for control of fluid or ionic current flow can be made incorporating a cast-in-place, mobile monolithic polymer element, disposed within a microchannel, and driven by fluid pressure (either liquid or gas) against a retaining or sealing surface. The polymer elements are made by the application of lithographic methods to monomer mixtures formulated in such a way that the polymer will not bond to microchannel walls. The polymer elements can seal against pressures greater than 5000 psi, and have a response time on the order of milliseconds. By the use of energetic radiation it is possible to depolymerize selected regions of the polymer element to form shapes that cannot be produced by conventional lithographic patterning and would be impossible to machine.

Reappraisal of xenobiotic-induced, oxidative stress-mediated cellular injury in chronic pancreatitis: A systematic review

PubMed Central

Siriwardena, Ajith K

2014-01-01

AIM: To reappraise the hypothesis of xenobiotic induced, cytochrome P450-mediated, micronutrient-deficient oxidative injury in chronic pancreatitis. METHODS: Individual searches of the Medline and Embase databases were conducted for each component of the theory of oxidative-stress mediated cellular injury for the period from 1st January 1990 to 31st December 2012 using appropriate medical subject headings. Boolean operators were used. The individual components were drawn from a recent update on theory of oxidative stress-mediated cellular injury in chronic pancreatitis. RESULTS: In relation to the association between exposure to volatile hydrocarbons and chronic pancreatitis the studies fail to adequately control for alcohol intake. Cytochrome P450 (CYP) induction occurs as a diffuse hepatic and extra-hepatic response to xenobiotic exposure rather than an acinar cell-specific process. GSH depletion is not consistently confirmed. There is good evidence of superoxide dismutase depletion in acute phases of injury but less to support a chronic intra-acinar depletion. Although the liver is the principal site of CYP induction there is no evidence to suggest that oxidative by-products are carried in bile and reflux into the pancreatic duct to cause injury. CONCLUSION: Pancreatic acinar cell injury due to short-lived oxygen free radicals (generated by injury mediated by prematurely activated intra-acinar trypsin) is an important mechanism of cell damage in chronic pancreatitis. However, in contemporary paradigms of chronic pancreatitis this should be seen as one of a series of cell-injury mechanisms rather than a sole mediator. PMID:24659895

The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism

PubMed Central

Spanogiannopoulos, Peter; Bess, Elizabeth N.; Carmody, Rachel N.; Turnbaugh, Peter J.

2016-01-01

Although the significance of human genetic polymorphisms in therapeutic outcomes is well established, the importance of our “second genome” (the microbiome) has been largely overlooked. In this Review, we highlight recent studies that shed light on the mechanisms linking the human gut microbiome to the efficacy and toxicity of xenobiotics, including drugs, dietary compounds and environmental toxins. Continued progress in this area could enable more precise tools for predicting patient responses and the development of a next generation of therapeutics based on or targeted at the gut microbiome. Indeed, the admirable goal of precision medicine may require us to first understand the microbial pharmacists within. PMID:26972811

Xenobiotics removal by adsorption in the context of tertiary treatment: a mini review.

PubMed

Tahar, Alexandre; Choubert, Jean-Marc; Coquery, Marina

2013-08-01

Many xenobiotics, including several pharmaceuticals and pesticides, are poorly treated in domestic wastewater treatment plants. Adsorption processes, such as with activated carbons, could be a solution to curb their discharge into the aquatic environment. As adsorbent-like activated carbon is known to be expensive, identifying promising alternative adsorbent materials is a key challenge for efficient yet affordable xenobiotic removal from wastewaters. As part of the effort to address this challenge, we surveyed the literature on pharmaceutical and pesticide xenobiotics and built a database compiling data from 38 scientific publications covering 65 xenobiotics and 58 materials. Special focus was given to the relevance and comparability of the data to the characteristics of the adsorbent materials used and to the operating conditions of the batch tests inventoried. This paper gives an in-depth overview of the adsorption capacities of various adsorbents. The little data on alternative adsorbent materials, especially for the adsorption of pharmaceuticals, makes it difficult to single out any one activated carbon alternative capable of adsorbing pesticides and pharmaceuticals at the tertiary stage of treatment. There is a pressing need for further lab-scale experiments to investigate the tertiary treatment of discharged effluents. We conclude with recommendations on how future data should best be used and interpreted.

Embryonic treatment with xenobiotics disrupts steroid hormone profiles in hatchling red-eared slider turtles (Trachemys scripta elegans).

PubMed Central

Willingham, E; Rhen, T; Sakata, J T; Crews, D

2000-01-01

Many compounds in the environment capable of acting as endocrine disruptors have been assayed for their developmental effects on morphogenesis; however, few studies have addressed how such xenobiotics affect physiology. In the current study we examine the effects of three endocrine-disrupting compounds, chlordane, trans-nonachlor, and the polychlorinated biphenyl (PCB) mixture Aroclor 1242, on the steroid hormone concentrations of red-eared slider turtle (Trachemys scripta elegans) hatchlings treated in ovo. Basal steroid concentrations and steroid concentrations in response to follicle-stimulating hormone were examined in both male and female turtles treated with each of the three compounds. Treated male turtles exposed to Aroclor 1242 or chlordane exhibited significantly lower testosterone concentrations than controls, whereas chlordane-treated females had significantly lower progesterone, testosterone, and 5[alpha]-dihydrotestosterone concentrations relative to controls. The effects of these endocrine disruptors extend beyond embryonic development, altering sex-steroid physiology in exposed animals. Images Figure 1 Figure 2 PMID:10753091

Modulation of xenobiotic biotransformation system and hormonal responses in Atlantic salmon (Salmo salar) after exposure to tributyltin (TBT).

PubMed

Mortensen, Anne Skjetne; Arukwe, Augustine

2007-04-01

Multiple biological effects of tributyltin (TBT) on juvenile salmon have been investigated. Fish were exposed for 7 days to waterborne TBT at nominal concentrations of 50 and 250 microg/L dissolved in dimethyl sulfoxide (DMSO). Hepatic samples were analyzed for gene expression patterns in the hormonal and xenobiotic biotransformation pathways using validated real-time PCR method. Immunochemical and several cytochrome P450 (CYP)-mediated enzyme activity (ethoxyresorufin: EROD, benzyloxyresorufin: BROD, methoxyresorufin: MROD and pentoxyresorufin: PROD) assays were analyzed. Our data show that TBT produced concentration-specific decrease of estrogen receptor-alpha (ERalpha), vitellogenin (Vtg), zona radiata protein (Zr-protein) and increase of estrogen receptor-beta (ERbeta) and androgen receptor-beta (ARbeta) in the hormonal pathway. In the xenobiotic biotransformation pathway, TBT produced apparent increase and decrease at respective low and high concentration, on aryl hydrocarbon receptor-alpha (AhRalpha), AhR nuclear translocator (ARNT) and AhR repressor (AhRR) mRNA. The expression of CYP1A1 and GST showed a TBT concentration-dependent decrease. The AhRbeta, CYP3A and uridine diphosphoglucuronosyl transferase (UGT) mRNA expressions were significantly induced after exposure to TBT. Immunochemical analysis of CYP3A and CYP1A1 protein levels confirmed the TBT effects observed at the transcriptional levels. The effect of TBT on the biotransformation enzyme gene expressions partially co-related but did not directly parallel enzyme activity levels for EROD, BROD, MROD and PROD. In general, these findings confirm previous reports on the endocrine effects of TBT, in addition to effects on hepatic CYP1A isoenzyme at the transcriptional level that transcends to protein and enzymatic levels. The induced expression patterns of CYP3A and UGT mRNA after TBT exposure, suggest the involvement of CYP3A and UGT in TBT metabolism in fish. The effect of TBT on CYP3A is proposed to

Update on nandrolone and norsteroids: how endogenous or xenobiotic are these substances?

PubMed

Bricout, V; Wright, F

2004-06-01

Norsteroids are xenobiotics with androgenic and anabolic properties known since as far back as the 1930s. In doping controls, the use of the banned xenobiotic norsteroids is detected in the competitor's urines by the measurement of norandrosterone (19-NA) and noretiocholanolone (19-NE), which are the main metabolites for nandrolone (NT) and most norsteroids with anabolic properties. In 1996, the IOC subcommission "Doping and Biochemistry of Sport" informed the Heads of the "IOC Accredited Laboratories" that the recommended cut-off limit for reporting an offence was to be 1-2 ng ml(-1) urine for either 19-NA or 19-NE. We will discuss how technical progress in gas chromatography coupled to high-resolution mass spectrometry permitted a dramatic increase in sensitivity with a detection limit of 1 pg ml(-1) urine, or less, and an assay limit of 20-50 pg ml(-1) urine, for either 19-NA or 19-NE. As a paradox, norsteroids have been known for decades as not only xenobiotics but also obligatory endogenous intermediates in the biosynthesis of estrogens from androgens in all species, man included. It is this biochemical observation which fed the active scientific and medical controversy initiated in 1998 over the possibly endogenous production of nandrolone and metabolites well over the new IOC's recommended cut-off limit of 2 ng ml(-1) urine. Notwithstanding the particular technical difficulties attached, we will provide data and discuss the minute endogenous levels detected and measured in man either at rest, after performance or training and compare them to the relatively high levels reported in male athlete's doping controls today. We will also discuss data on the pharmacological effects of some contraceptive therapies containing norsteroids in women. In view of the well-documented noxious effects repeatedly observed after anabolic steroid misuse, the confirmation and implementation of technically proven procedures for reporting norsteroid abuse in sports seems an

Cross-induction of detoxification genes by environmental xenobiotics and insecticides in the mosquito Aedes aegypti: impact on larval tolerance to chemical insecticides.

PubMed

Poupardin, Rodolphe; Reynaud, Stéphane; Strode, Clare; Ranson, Hilary; Vontas, John; David, Jean-Philippe

2008-05-01

The effect of exposure of Aedes aegypti larvae to sub-lethal doses of the pyrethroid insecticide permethrin, the organophosphate temephos, the herbicide atrazine, the polycyclic aromatic hydrocarbon fluoranthene and the heavy metal copper on their subsequent tolerance to insecticides, detoxification enzyme activities and expression of detoxification genes was investigated. Bioassays revealed a moderate increase in larval tolerance to permethrin following exposure to fluoranthene and copper while larval tolerance to temephos increased moderately after exposure to atrazine, copper and permethrin. Cytochrome P450 monooxygenases activities were induced in larvae exposed to permethrin, fluoranthene and copper while glutathione S-transferase activities were induced after exposure to fluoranthene and repressed after exposure to copper. Microarray screening of the expression patterns of all detoxification genes following exposure to each xenobiotic with the Aedes Detox Chip identified multiple genes induced by xenobiotics and insecticides. Further expression studies using real-time quantitative PCR confirmed the induction of multiple CYP genes and one carboxylesterase gene by insecticides and xenobiotics. Overall, this study reveals the potential of xenobiotics found in polluted mosquito breeding sites to affect their tolerance to insecticides, possibly through the cross-induction of particular detoxification genes. Molecular mechanisms involved and impact on mosquito control strategies are discussed.

INTERINDIVIDUAL VARIANCE OF CYTOCHROME P450 FORMS IN HUMAN HEPATIC MICROSOMES: CORRELATION OF INDIVIDUAL FORMS WITH XENOBIOTIC METABOLISM AND IMPLICATIONS IN RISK ASSESSMENT

EPA Science Inventory

Differences in biotransformation activities may alter the bioavailability or efficacy of drugs, provide protection from certain xenobiotic and environmental agents, or increase toxicity of others. Cytochrome P450 (CYP450) enzymes are responsible for the majority of oxidation reac...

Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tocchetti, Guillermo Nicolás

The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a groupmore » of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs. - Highlights: • Intestinal MRP2 (ABCC2) expression and activity can be regulated by xenobiotics. • PXR and CAR are major MRP2 modulators through a transcriptional mechanism. �

Non-targeted, high resolution mass spectrometry strategy for simultaneous monitoring of xenobiotics and endogenous compounds in green sea turtles on the Great Barrier Reef.

PubMed

Heffernan, Amy L; Gómez-Ramos, Maria M; Gaus, Caroline; Vijayasarathy, Soumini; Bell, Ian; Hof, Christine; Mueller, Jochen F; Gómez-Ramos, Maria J

2017-12-01

Chemical contamination poses a threat to ecosystem, biota and human health, and identifying these hazards is a complex challenge. Traditional hazard identification relies on a priori-defined targets of limited chemical scope, and is generally inappropriate for exploratory studies such as explaining toxicological effects in environmental systems. Here we present a non-target high resolution mass spectrometry environmental monitoring study with multivariate statistical analysis to simultaneously detect biomarkers of exposure (e.g. xenobiotics) and biomarkers of effect in whole turtle blood. Borrowing the concept from clinical chemistry, a case-control sampling approach was used to investigate the potential influence of xenobiotics of anthropogenic origin on free-ranging green sea turtles (Chelonia mydas) from a remote, offshore 'control' site; and two coastal 'case' sites influenced by urban/industrial and agricultural activities, respectively, on the Great Barrier Reef in North Queensland, Australia. Multiple biomarkers of exposure, including sulfonic acids (n=9), a carbamate insecticide metabolite, and other industrial chemicals; and five biomarkers of effect (lipid peroxidation products), were detected in case sites. Additionally, two endogenous biomarkers of neuroinflammation and oxidative stress were identified, and showed moderate-to-strong correlations with clinical measures of inflammation and liver dysfunction. Our data filtering strategy overcomes limitations of traditional a priori selection of target compounds, and adds to the limited environmental xenobiotic metabolomics literature. To our knowledge this is the first case-control study of xenobiotics in marine megafauna, and demonstrates the utility of green sea turtles to link internal and external exposure, to explain potential toxicological effects in environmental systems. Copyright © 2017 Elsevier B.V. All rights reserved.

Xenobiotic effects on intestinal stem cell proliferation in adult honey bee (Apis mellifera L) workers.

PubMed

Forkpah, Cordelia; Dixon, Luke R; Fahrbach, Susan E; Rueppell, Olav

2014-01-01

The causes of the current global decline in honey bee health are unknown. One major group of hypotheses invokes the pesticides and other xenobiotics to which this important pollinator species is often exposed. Most studies have focused on mortality or behavioral deficiencies in exposed honey bees while neglecting other biological functions and target organs. The midgut epithelium of honey bees presents an important interface between the insect and its environment. It is maintained by proliferation of intestinal stem cells throughout the adult life of honey bees. We used caged honey bees to test multiple xenobiotics for effects on the replicative activity of the intestinal stem cells under laboratory conditions. Most of the tested compounds did not alter the replicative activity of intestinal stem cells. However, colchicine, methoxyfenozide, tetracycline, and a combination of coumaphos and tau-fluvalinate significantly affected proliferation rate. All substances except methoxyfenozide decreased proliferation rate. Thus, the results indicate that some xenobiotics frequently used in apiculture and known to accumulate in honey bee hives may have hitherto unknown physiological effects. The nutritional status and the susceptibility to pathogens of honey bees could be compromised by the impacts of xenobiotics on the maintenance of the midgut epithelium. This study contributes to a growing body of evidence that more comprehensive testing of xenobiotics may be required before novel or existing compounds can be considered safe for honey bees and other non-target species.

Xenobiotic Effects on Intestinal Stem Cell Proliferation in Adult Honey Bee (Apis mellifera L) Workers

PubMed Central

Forkpah, Cordelia; Dixon, Luke R.; Fahrbach, Susan E.; Rueppell, Olav

2014-01-01

The causes of the current global decline in honey bee health are unknown. One major group of hypotheses invokes the pesticides and other xenobiotics to which this important pollinator species is often exposed. Most studies have focused on mortality or behavioral deficiencies in exposed honey bees while neglecting other biological functions and target organs. The midgut epithelium of honey bees presents an important interface between the insect and its environment. It is maintained by proliferation of intestinal stem cells throughout the adult life of honey bees. We used caged honey bees to test multiple xenobiotics for effects on the replicative activity of the intestinal stem cells under laboratory conditions. Most of the tested compounds did not alter the replicative activity of intestinal stem cells. However, colchicine, methoxyfenozide, tetracycline, and a combination of coumaphos and tau-fluvalinate significantly affected proliferation rate. All substances except methoxyfenozide decreased proliferation rate. Thus, the results indicate that some xenobiotics frequently used in apiculture and known to accumulate in honey bee hives may have hitherto unknown physiological effects. The nutritional status and the susceptibility to pathogens of honey bees could be compromised by the impacts of xenobiotics on the maintenance of the midgut epithelium. This study contributes to a growing body of evidence that more comprehensive testing of xenobiotics may be required before novel or existing compounds can be considered safe for honey bees and other non-target species. PMID:24608542

In silico identification and construction of microbial gene clusters associated with biodegradation of xenobiotic compounds.

PubMed

Awasthi, Garima; Kumari, Anjani; Pant, Aditya Bhushan; Srivastava, Prachi

2018-01-01

Chemical substances not showing any importance in existence of biological systems and causing serious health hazards may be designated as Xenobiotic compound. Elimination or degradation of these unwanted substances is a major issue of concern for current time research. Process of biodegradation is a very important aspect of current research as discussed in current manuscript. Current study focuses on the detailed mining of data for the construction of microbial consortia for wide range of xenobiotics compounds. Intensive literature search was done for the construction of this library. Desired data was retrieved from NCBI in fasta format. Data was analysed through homology approaches by using BLAST. This homology based searched enriched with a great vision that not only bacterial population but many other cheap and potential sources are available for different xenobiotic degradation. Though it was focused that bacterial population covers a major part of biodegradation which is near about 90.6% but algae and fungi are also showing promising future in degradation of some important xenobiotic compounds. Analysis of data reveals that Pseudomonas putida has potential for degrading maximum compounds. Establishment of correlation through cluster analysis signifies that Pseudomonas putida, Aspergillus niger and Skeletonema costatum can have combined traits that can be used in finding out actual evolutionary relationship between these species. These findings may also givea new outcome in terms of much cheaper and eco-friendly source in the area of biodegradation of specified xenobiotic compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

Influence of xenobiotics on the microbiological and agrochemical parameters of soddy-podzolic soil

NASA Astrophysics Data System (ADS)

Vakkerov-Kouzova, N. D.

2010-08-01

We studied the influence of various chemical compounds, i.e., azobenzene (an insecticide and acaricide), nitrification inhibitors (DCD, dicyandiamide and DMPP, and 3,4-dimetylpyrazolphosphate), and inhibitors of urease activity (HQ-hydroquinone), on the agrochemical and microbiological parameters of a soddy-podzolic soil. It is proved that these xenobiotics are able to influence the agrochemical parameters (the pH and the content of NO{3/-} and NH{4/+}, the microbial activity (the basal respiration, the microbial mass carbon, and the microbial quotient), and the number of bacteria of different physiological groups in soddypodzolic soil. The influence of the xenobiotics was preserved for some time, which testified to their persistence in the soil. Upon cultivating the soil microorganisms in different media, the growth of the heterotrophic bacteria was inhibited, the radial growth velocity was slowed down, and the sporogenesis of the micromycetes was retarded. The toxic effect of the xenobiotics was higher with their increasing concentrations.

Free Radical Mechanisms of Xenobiotic Mammalian Cytotoxicities

DTIC Science & Technology

1991-06-30

injury process was mediated through biotransformation of the halocarbons to a free radical intermediate, similar to what happens in the liver . However...peroxidation) of antioxidant agents - is not limited to the liver , but also occurs in vascular cells as well. Unlike the liver , where most of the injury is...frequent mechanism of xenobiotic liver toxicity is biotransformation by cytochrome P,5o-enzymes to toxic free radical intermediates. The primary objective

Free Radical Mechanisms of Xenobiotic Mammalian Cytotoxicities

DTIC Science & Technology

1988-10-31

cytochrome P450 is small compared to that of the liver (about 0.1%), cardiovascular tissues may be more susceptible to oxidative injury because of the... injury participates in the pathogenic mechanisms of many lipophilic xenobiotic compounds). The most dramatic finding is our demonstration that five...UPID PEROXIDATION BETTER THAN THE INITIAL RADICAL OR HYDROPEROXIDE. INDIRECT IRP EFFECTS ON FREE RADICAL MEMBRANE INJURY : 4) POISONING OF THE ELECTRON

Development of an ATP measurement method suitable for xenobiotic treatment activated sludge biomass.

PubMed

Nguyen, Lan Huong; Chong, Nyuk-Min

2015-09-01

Activated sludge consumes a large amount of energy to degrade a xenobiotic organic compound. By tracking the energy inventory of activated sludge biomass during the sludge's degradation of a xenobiotic, any disadvantageous effect on the sludge's performance caused by energy deficiency can be observed. The purpose of this study was to develop a reliable and accurate method for measuring the ATP contents of activated sludge cells that were to degrade a xenobiotic organic. Cell disruption and cellular ATP extraction were performed by a protocol with which xenobiotic degrading activated sludge biomass was washed with SDS, treated by Tris and TCA, and followed by bead blasting. The suspension of disrupted cells was filtered before the filtrate was injected into HPLC that was set at optimal conditions to measure the ATP concentration therein. This extraction protocol and HPLC measurement of ATP was evaluated for its linearity, limits of detection, and reproducibility. Evaluation test results reported a R(2) of 0.999 of linear fit of ATP concentration versus activated sludge concentration, a LOD=0.00045mg/L, a LOQ=0.0015mg/L for HPLC measurement of ATP, a MDL=0.46mg/g SS for ATP extraction protocol, and a recovery efficiency of 96.4±2%. This method of ATP measurement was simple, rapid, reliable, and was unburdened of some limitations other methods may have. Copyright © 2015 Elsevier B.V. All rights reserved.

High hydrostatic pressure influences the in vitro response to xenobiotics in Dicentrarchus labrax liver.

PubMed

Lemaire, Benjamin; Mignolet, Eric; Debier, Cathy; Calderon, Pedro Buc; Thomé, Jean Pierre; Rees, Jean François

2016-04-01

Hydrostatic pressure (HP) increases by about 1 atmosphere (0.1MPa) for each ten-meter depth increase in the water column. This thermodynamical parameter could well influence the response to and effects of xenobiotics in the deep-sea biota, but this possibility remains largely overlooked. To grasp the extent of HP adaptation in deep-sea fish, comparative studies with living cells of surface species exposed to chemicals at high HP are required. We initially conducted experiments with precision-cut liver slices of a deep-sea fish (Coryphaenoides rupestris), co-exposed for 15h to the aryl hydrocarbon receptor (AhR) agonist 3-methylcholanthrene at HP levels representative of the surface (0.1MPa) and deep-sea (5-15MPa; i.e., 500-1500m depth) environments. The transcript levels of a suite of stress-responsive genes, such as the AhR battery CYP1A, were subsequently measured (Lemaire et al., 2012; Environ. Sci. Technol. 46, 10310-10316). Strikingly, the AhR agonist-mediated increase of CYP1A mRNA content was pressure-dependently reduced in C. rupestris. Here, the same co-exposure scenario was applied for 6 or 15h to liver slices of a surface fish, Dicentrarchus labrax, a coastal species presumably not adapted to high HP. Precision-cut liver slices of D. labrax were also used in 1h co-exposure studies with the pro-oxidant tert-butylhydroperoxide (tBHP) as to investigate the pressure-dependence of the oxidative stress response (i.e., reactive oxygen production, glutathione and lipid peroxidation status). Liver cells remained viable in all experiments (adenosine triphosphate content). High HP precluded the AhR agonist-mediated increase of CYP1A mRNA expression in D. labrax, as well as that of glutathione peroxidase, and significantly reduced that of heat shock protein 70. High HP (1h) also tended per se to increase the level of oxidative stress in liver cells of the surface fish. Trends to an increased resistance to tBHP were also noted. Whether the latter observation truly

Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes Modulated by ToxCast Chemicals

EPA Science Inventory

ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...

Effects of controlled element dynamics on human feedforward behavior in ramp-tracking tasks.

PubMed

Laurense, Vincent A; Pool, Daan M; Damveld, Herman J; van Paassen, Marinus René M; Mulder, Max

2015-02-01

In real-life manual control tasks, human controllers are often required to follow a visible and predictable reference signal, enabling them to use feedforward control actions in conjunction with feedback actions that compensate for errors. Little is known about human control behavior in these situations. This paper investigates how humans adapt their feedforward control dynamics to the controlled element dynamics in a combined ramp-tracking and disturbance-rejection task. A human-in-the-loop experiment is performed with a pursuit display and vehicle-like controlled elements, ranging from a single integrator through second-order systems with a break frequency at either 3, 2, or 1 rad/s, to a double integrator. Because the potential benefits of feedforward control increase with steeper ramp segments in the target signal, three steepness levels are tested to investigate their possible effect on feedforward control with the various controlled elements. Analyses with four novel models of the operator, fitted to time-domain data, reveal feedforward control for all tested controlled elements and both (nonzero) tested levels of ramp steepness. For the range of controlled element dynamics investigated, it is found that humans adapt to these dynamics in their feedforward response, with a close to perfect inversion of the controlled element dynamics. No significant effects of ramp steepness on the feedforward model parameters are found.

Laboratory procedure for estimating residue dynamics of xenobiotic contaminants in a freshwater food chain

USGS Publications Warehouse

Johnson, B. Thomas

1980-01-01

A laboratory method of measuring the accumulation, transfer, elimination, and degradation of xenobiotic contaminants is described for organisms in a freshwater food chain (microorganisms, filter-feeder, and fish). A flow-through diluter-system, 14C-labeled contaminants, gas and thin-layer chromatography, autoradiography, and liquid scintillation spectrometry are used in making residue determinations. Accumulation factors and various index values are developed for measuring and estimating potential accumulation of xenobiotic contaminants by aquatic organisms. The laboratory procedure is economical, simple, reproducible, and ecologically relevant.

Identification of an enhancer element of class Pi glutathione S-transferase gene required for expression by a co-planar polychlorinated biphenyl.

PubMed Central

Matsumoto, M; Imagawa, M; Aoki, Y

1999-01-01

3,3',4,4',5-Pentachlorobiphenyl (PenCB), one of the most toxic co-planar polychlorinated biphenyl congeners, specifically induces class Pi glutathione S-transferase (GSTP1) as well as cytochrome P-450 1A1 in primary cultured rat liver parenchymal cells [Aoki, Matsumoto and Suzuki (1993) FEBS Lett. 333, 114-118]. However, the 5'-flanking sequence of the GSTP1 gene does not contain a xenobiotic responsive element, to which arylhydrocarbon receptor binds. Using a chloramphenicol acetyltransferase assay we demonstrate here that the enhancer termed GSTP1 enhancer I (GPEI) is necessary for the stimulation by PenCB of GSTP1 gene expression in primary cultured rat liver parenchymal cells. GPEI is already known to contain a dyad of PMA responsive element-like elements oriented palindromically. It is suggested that a novel signal transduction pathway activated by PenCB contributes to the stimulation of GSTP1 expression. PMID:10051428

Do Candida spp. "read" Nietzsche? Can xenobiotics modulate their aggressiveness? Proposition that chemicals may interfere in their virulence attributes.

PubMed

Rosa, Edvaldo Antonio Ribeiro

2012-01-01

As well as the host, opportunist Candida spp. enface all sorts of exogenous chemicals, so-called xenobiotics. It is plausible that xenobiotics exert some effects on such microorganisms; among them, the modulation of virulence attributes.

Xenobiotic metal-induced autoimmunity: mercury and silver differentially induce antinucleolar autoantibody production in susceptible H-2s, H-2q and H-2f mice

PubMed Central

Hansson, M; Abedi-Valugerdi, M

2003-01-01

Xenobiotic-metals such as mercury (Hg) and silver (Ag) induce an H-2 linked antinucleolar autoantibody (ANolA) production in susceptible mice. The mechanism for induction of ANolA synthesis is not well understood. However, it has been suggested that both metals interact with nucleolar proteins and reveal cryptic self-peptides to nontolerant autoreactive T cells, which in turn stimulate specific autoreactive B cells. In this study, we considered this suggestion and asked if mercury and silver display, if not identical, similar cryptic self-peptides, they would induce comparable ANolA responses in H-2 susceptible mice. We analysed the development of ANolA production in mercury- and/or silver-treated mice of H-2s, H-2q and H-2f genotypes. We found that while mercury stimulated ANolA synthesis in all strains tested, silver induced ANolA responses of lower magnitudes in only H-2s and H-2q mice, but not in H-2f mice. Resistance to silver in H-2f mice was independent of the dosage/time-period of silver-treatment and non-H-2 genes. Further studies showed that F1 hybrid crosses between silver-susceptible A.SW (H-2s) and -resistant A.CA (H-2f) mice were resistant to silver, but not mercury with regard to ANolA production. Additionally, the magnitudes of mercury-induced ANolA responses in the F1 hybrids were lower than those of their parental strains. The above differential ANolA responses to mercury and silver can be explained by various factors, including the different display of nucleolar cryptic peptides by these xenobiotics, determinant capture and coexistence of different MHC molecules. Our findings also suggest that the ability of a xenobiotic metal merely to create cryptic self-peptides may not be sufficient for the induction of an ANolA response. PMID:12605692

An overview of transcriptional regulation in response to toxicological insult.

PubMed

Jennings, Paul; Limonciel, Alice; Felice, Luca; Leonard, Martin O

2013-01-01

The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.

Interaction of xenobiotics on the glucose-transport system and the Na+/K(+)-ATPase of human skin fibroblasts.

PubMed

Cascorbi, I; Forêt, M

1991-02-01

The effects of individual and combined xenobiotics on functional properties of the plasma membrane of human skin fibroblasts were investigated. Good correlations between toxic effects on the D-glucose transport system or the Na+/K(+)-ATPase and the lipophilicity of the substances could be observed. The linear regression coefficients plotting log EC20 values (doses, leading to 20% inhibition) versus log Pow (octanol/water partition coefficient) were r = 0.95 (P less than 0.05). The combination of lipophilic with less lipophilic xenobiotics, such as pentachlorophenol with 4-chloroaniline, leads to additional effects. However, when the detergent sodium dodecyl benzenesulfonate was combined with the herbicide 2,4-dichlorophenoxyacetate (2,4-D), the toxic effect of 2,4-D on the Na+/K(+)-ATPase decreased considerably. The results support in general the assumption that the inhibition of integral functional proteins is based on an accumulation of xenobiotics in the plasma membrane, probably due to the enhanced membrane fluidity. Thus, the basic toxicity of xenobiotics can be predicted by their physicochemical properties.

Tracing the evolution of degraders in activated sludge during the sludge’s acclimation to a xenobiotic organic

NASA Astrophysics Data System (ADS)

Chong, N. M.; Fan, C. H.; Yang, Y. C.

2017-01-01

The molecular biology method of high-throughput pyrosequencing was employed to examine the change of activated sludge community structures during the process in which activated sludge was acclimated to and degraded a target xenobiotic. The sample xenobiotic organic compound used as the activated sludge acclimation target was the herbicide 2,4-dichlorphenoxyacetic acid (2,4-D). Indigenous activated sludge microorganisms were acclimated to 2,4-D as the sole carbon source in both the batch and the continuous-flow reaction modes. Sludge masses at multiple time points during the course of acclimation were subjected to pyrosequencing targeting the microorganisms’ 16S rRNA genes. With the bacterial 16S rRNA sequencing results the genera that increased in abundance were checked with degradative pathway databases or literature to confirm that they are commonly seen as potent degraders of 2,4-D. From this systematic examination of degrader changes at time points during activated sludge acclimation and degradation of the target xenobiotic, the trend of degrader evolution in activated sludge over the sludge’s acclimation process to a xenobiotic was traced.

Modulation of Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes by ToxCast Chemicals

EPA Science Inventory

ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...

Live-cell imaging approaches for the investigation of xenobiotic-induced oxidant stress.

PubMed

Wages, Phillip A; Cheng, Wan-Yun; Gibbs-Flournoy, Eugene; Samet, James M

2016-12-01

Oxidant stress is arguably a universal feature in toxicology. Research studies on the role of oxidant stress induced by xenobiotic exposures have typically relied on the identification of damaged biomolecules using a variety of conventional biochemical and molecular techniques. However, there is increasing evidence that low-level exposure to a variety of toxicants dysregulates cellular physiology by interfering with redox-dependent processes. The study of events involved in redox toxicology requires methodology capable of detecting transient modifications at relatively low signal strength. This article reviews the advantages of live-cell imaging for redox toxicology studies. Toxicological studies with xenobiotics of supra-physiological reactivity require careful consideration when using fluorogenic sensors in order to avoid potential artifacts and false negatives. Fortunately, experiments conducted for the purpose of validating the use of these sensors in toxicological applications often yield unexpected insights into the mechanisms through which xenobiotic exposure induces oxidant stress. Live-cell imaging using a new generation of small molecule and genetically encoded fluorophores with excellent sensitivity and specificity affords unprecedented spatiotemporal resolution that is optimal for redox toxicology studies. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. Published by Elsevier B.V.

[THE SYSTEM OF XENOBIOTICS BIOTRANSFORMATION OF HELMINTHS. RESEMBLANCE AND DIFFERENSES FROM SIMILAR HOST SYSTEMS (REWEW)].

PubMed

Smirnov, L P; Borvinskaya, E V; Suhovskaya, I V

2016-01-01

The three phases system xenobiotic biotransformation in cells as prokaryotes as eukaryotes was formed during the process of evolution. Clear and managed function of all three links of this system guarantee the survival of living organisms at alteration of chemical component of environment. Oxidation, reduction or hydrolysis of xenobiotics realize in phase I by insertion or opening reactive and hydrophilic groups in structure of drug molecule. In phase II xenobiotics or their metabolites from phase I conjugate with endogenic compounds, main of there are glutathione, glucuronic acid, amino acids and sulphates. Active transport of substrata, metabolites and conjugates through cell lipid membranes special transport proteins carry out (phase III). The system of xenobiotics biotransformation of helminths has essential differences from the same of vertebrate hosts. In particular, parasites do not reveal the activity of prime oxidases of phase I, such as CYP or FMO, in spite of the genes of these enzymes in DNA. As this phenomenon displays mainly in adult helminths, living in guts of vertebrates, then the hypothesis was formulated that this effect is related with adaptation to conditions of strong deficiency of oxygen, arise in a process of evolution (Kotze et al., 2006). Literature data testify the existence in helminths of unique forms of enzymes of phase II, the investigation of which present doubtless interest in relation with possible role in adaptation to parasitic mode of life. Notwithstanding that many of helminths GST in greater or lesser degree similar with enzymes of M, P, S and О classes of other organisms, nevertheless they have essential structural differences as compared with enzymes of hosts that makes perspective the search of specific anthelminthics vaccines. Transport of xenobiotics is now considered phase III of biotransformation. It was shown that proteins of this phase (ATP binding cassette transporters (ABC ) of parasites) play a key role in efflux

Development of a human body finite element model with multiple muscles and their controller for estimating occupant motions and impact responses in frontal crash situations.

PubMed

Iwamoto, Masami; Nakahira, Yuko; Kimpara, Hideyuki; Sugiyama, Takahiko; Min, Kyuengbo

2012-10-01

A few reports suggest differences in injury outcomes between cadaver tests and real-world accidents under almost similar conditions. This study hypothesized that muscle activity could primarily cause the differences, and then developed a human body finite element (FE) model with individual muscles. Each muscle was modeled as a hybrid model of bar elements with active properties and solid elements with passive properties. The model without muscle activation was firstly validated against five series of cadaver test data on impact responses in the anterior-posterior direction. The model with muscle activation levels estimated based on electromyography (EMG) data was secondly validated against four series of volunteer test data on bracing effects for stiffness and thickness of an upper arm muscle, and braced driver's responses under a static environment and a brake deceleration. A muscle controller using reinforcement learning (RL), which is a mathematical model of learning process in the basal ganglia associated with human postural controls, were newly proposed to estimate muscle activity in various occupant conditions including inattentive and attentive conditions. Control of individual muscles predicted by RL reproduced more human like head-neck motions than conventional control of two groups of agonist and antagonist muscles. The model and the controller demonstrated that head-neck motions of an occupant under an impact deceleration of frontal crash were different in between a bracing condition with maximal braking force and an occupant condition predicted by RL. The model and the controller have the potential to investigate muscular effects in various occupant conditions during frontal crashes.

High temperature electrically conducting ceramic heating element and control system

NASA Technical Reports Server (NTRS)

Halbach, C. R.; Page, R. J.

1975-01-01

Improvements were made in both electrode technology and ceramic conductor quality to increase significantly the lifetime and thermal cycling capability of electrically conducting ceramic heater elements. These elements were operated in vacuum, inert and reducing environments as well as oxidizing atmospheres adding to the versatility of the conducting ceramic as an ohmic heater. Using stabilized zirconia conducting ceramic heater elements, a furnace was fabricated and demonstrated to have excellent thermal response and cycling capability. The furnace was used to melt platinum-20% rhodium alloy (melting point 1904 C) with an isothermal ceramic heating element having a nominal working cavity size of 2.5 cm diameter by 10.0 cm long. The furnace was operated to 1940 C with the isothermal ceramic heating element. The same furnace structure was fitted with a pair of main heater elements to provide axial gradient temperature control over a working cavity length of 17.8 cm.

ACTIVATION OF DIOXIN RESPONSE ELEMENT (DRE)-ASSOCIATED GENES BY BENZO(A)PYRENE 3,6-QUINONE AND BENZO(A)PYRENE 1,6-QUINONE IN MCF-10A HUMAN MAMMARY EPITHELIAL CELLS

PubMed Central

Burchiel, Scott W.; Thompson, Todd A.; Lauer, Fredine T.; Oprea, Tudor I.

2007-01-01

Benzo(a)pyrene (BaP) is a known human carcinogen and a suspected breast cancer complete carcinogen. BaP is metabolized by several metabolic pathways, some having bioactivation and others detoxification properties. BaP-quinones (BPQs) are formed via cytochrome P450 and peroxidase dependent pathways. Previous studies by our laboratory have shown that BPQs have significant growth promoting and anti-apoptotic activities in human MCF-10A mammary epithelial cells examined in vitro. Previous results suggest that BPQs act via redox-cycling and oxidative stress. However, because two specific BPQs (1,6-BPQ and 3,6-BPQ) differed in their ability to produce reactive oxygen species (ROS) and yet both had strong proliferative and EGF receptor activating activity, we utilized mRNA expression arrays and qRT-PCR to determine potential pathways and mechanisms of gene activation. The results of the present studies demonstrated that 1,6-BPQ and 3,6-BPQ activate dioxin response elements (DRE, also known as xenobiotic response elements, XRE) and anti-oxidant response elements (ARE, also known and electrophile response elements, EpRE). 3,6-BPQ had greater DRE activity than 1,6-BPQ, whereas the opposite was true for the activation of ARE. Both 3,6-BPQ and 1,6-BPQ induced oxidative stress associated genes (HMOX1, GCLC, GCLM, and SLC7A11), phase 2 enzyme genes (NQO1, NQO2, ALDH3A1) PAH metabolizing genes (CYP1B1, EPHX1, AKR1C1), and certain EGF receptor associated genes (EGFR, IER3, ING1, SQSTM1 and TRIM16). The results of these studies demonstrate that BPQs activate numerous pathways in human mammary epithelial cells associated with increased cell growth and survival that may play important roles in tumor promotion. PMID:17466351

A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene.

PubMed

Lee, M O; Liu, Y; Zhang, X K

1995-08-01

The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene

Centralized and Decentralized Control for Demand Response

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Shuai; Samaan, Nader A.; Diao, Ruisheng

2011-04-29

Demand response has been recognized as an essential element of the smart grid. Frequency response, regulation and contingency reserve functions performed traditionally by generation resources are now starting to involve demand side resources. Additional benefits from demand response include peak reduction and load shifting, which will defer new infrastructure investment and improve generator operation efficiency. Technical approaches designed to realize these functionalities can be categorized into centralized control and decentralized control, depending on where the response decision is made. This paper discusses these two control philosophies and compares their relative advantages and disadvantages in terms of delay time, predictability, complexity,more » and reliability. A distribution system model with detailed household loads and controls is built to demonstrate the characteristics of the two approaches. The conclusion is that the promptness and reliability of decentralized control should be combined with the predictability and simplicity of centralized control to achieve the best performance of the smart grid.« less

The Therapeutic Role of Xenobiotic Nuclear Receptors against Metabolic Syndrome.

PubMed

Pu, Shuqi; Wu, Xiaojie; Yang, Xiaoying; Zhang, Yunzhan; Dai, Yunkai; Zhang, Yueling; Wu, Xiaoting; Liu, Yan; Cui, Xiaona; Jin, Haiyong; Cao, Jianhong; Li, Ruliu; Cai, Jiazhong; Cao, Qizhi; Hu, Ling; Gao, Yong

2018-06-10

Xenobiotic nuclear receptors (XNRs) are nuclear receptors that characterized by coordinately regulating the expression of genes encoding drug-metabolizing enzymes and transporters to essentially eliminate and detoxify xenobiotics and endobiotics from the body, including the peroxisome proliferator-activated receptor (PPAR), the farnesoid X receptor (FXR), the liver X receptor (LXR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Heretofore, increasing evidences have suggested that these five XNRs are not only involved in the regulation of xeno-/endo-biotics detoxication but also the development of human diseases, such as cancer, obesity and diabetes. PPAR, FXR, LXR, PXR and CAR, as the receptors for numerous natural or synthetic compounds may be the most effective therapeutic targets in the treatment of metabolic diseases. In this review, we will focus on these five XNRs and their recently discovered functions in diabetes and its complications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Ablative Thermal Response Analysis Using the Finite Element Method

NASA Technical Reports Server (NTRS)

Dec John A.; Braun, Robert D.

2009-01-01

A review of the classic techniques used to solve ablative thermal response problems is presented. The advantages and disadvantages of both the finite element and finite difference methods are described. As a first step in developing a three dimensional finite element based ablative thermal response capability, a one dimensional computer tool has been developed. The finite element method is used to discretize the governing differential equations and Galerkin's method of weighted residuals is used to derive the element equations. A code to code comparison between the current 1-D tool and the 1-D Fully Implicit Ablation and Thermal Response Program (FIAT) has been performed.

Use of biomarkers to evaluate the ecological risk of xenobiotics associated with agriculture.

PubMed

Lima, Liana Bezerra Dias de; Morais, Paula Benevides de; Andrade, Ricardo Lopes Tortorela de; Mattos, Luciana Vieira; Moron, Sandro Estevan

2018-06-01

This research aimed to evaluate the ecological risk of xenobiotics associated with agricultural activities by determining metal contents and biomarker responses using tucunaré (Cichla sp.) as a bioindicator. The work was conducted in the southwest region of the state of Tocantins, in the cities of Lagoa da Confusão and Pium. Water samples and specimens of Cichla sp. were collected in the Javaés and Formoso Rivers at three collection points (A, B and C). The concentrations of Cd, Pb, Cu, Cr, Mn, Ni and Zn in water and fish were analyzed. In fish, genotoxic, biochemical (glucose serum levels, AST (aspartate aminotransferase) and ALT (alanine aminotransferase) and histological (gills and liver) biomarkers were assessed. In the water, the Cr and Mn concentrations at the three collection points exceeded the values for Class 1 rivers. In the muscle, Cr was above the maximum limit allowed for human consumption at the three collection points, although the values at Points B and C were not significantly different from that at Point A (p > 0.05). At the three collection points, the micronucleus test revealed a low frequency of micronuclei. Significant hyperglycemia and a decrease in the AST activity of the fish collected at Point C was observed. In the gills, the most frequent alterations were at Stages I and II, which indicated mild to moderate damage, and epithelial detachment was the most frequent variation. In the liver tissue, the most frequently observed histological changes were at Stages I and II and included cytoplasmic vacuolization, nuclear hypertrophy, dilated sinusoids and bile stagnation. The integrated evaluation of these biomarkers indicated that fish collected from areas with intense agricultural activities presented adaptive responses that were likely caused by the availability and bioaccumulation of certain xenobiotics in the environment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Rb and p53 Liver Functions Are Essential for Xenobiotic Metabolism and Tumor Suppression

PubMed Central

Nantasanti, Sathidpak; Toussaint, Mathilda J. M.; Youssef, Sameh A.; Tooten, Peter C. J.; de Bruin, Alain

2016-01-01

The tumor suppressors Retinoblastoma (Rb) and p53 are frequently inactivated in liver diseases, such as hepatocellular carcinomas (HCC) or infections with Hepatitis B or C viruses. Here, we discovered a novel role for Rb and p53 in xenobiotic metabolism, which represent a key function of the liver for metabolizing therapeutic drugs or toxins. We demonstrate that Rb and p53 cooperate to metabolize the xenobiotic 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). DDC is metabolized mainly by cytochrome P450 (Cyp)3a enzymes resulting in inhibition of heme synthesis and accumulation of protoporphyrin, an intermediate of heme pathway. Protoporphyrin accumulation causes bile injury and ductular reaction. We show that loss of Rb and p53 resulted in reduced Cyp3a expression decreased accumulation of protoporphyrin and consequently less ductular reaction in livers of mice fed with DDC for 3 weeks. These findings provide strong evidence that synergistic functions of Rb and p53 are essential for metabolism of DDC. Because Rb and p53 functions are frequently disabled in liver diseases, our results suggest that liver patients might have altered ability to remove toxins or properly metabolize therapeutic drugs. Strikingly the reduced biliary injury towards the oxidative stress inducer DCC was accompanied by enhanced hepatocellular injury and formation of HCCs in Rb and p53 deficient livers. The increase in hepatocellular injury might be related to reduce protoporphyrin accumulation, because protoporphrin is well known for its anti-oxidative activity. Furthermore our results indicate that Rb and p53 not only function as tumor suppressors in response to carcinogenic injury, but also in response to non-carcinogenic injury such as DDC. PMID:26967735

Steroid and xenobiotic receptor-mediated effects of bisphenol A on human osteoblasts.

PubMed

Miki, Yasuhiro; Hata, Shuko; Nagasaki, Shuji; Suzuki, Takashi; Ito, Kiyoshi; Kumamoto, Hiroyuki; Sasano, Hironobu

2016-06-15

Bisphenol A, one of the industrial chemicals used in plastics and in the coating of dishes and medical equipment, behaves as an endocrine disruptor in the human body. Bisphenol A can bind directly to several types of nuclear receptors, including steroid and xenobiotic receptor (SXR). SXR plays an important role in bone metabolism through the activation of osteoblasts in vitro, but SXR protein localization has not been reported in bone tissues. Additionally, it is not known whether bisphenol A acts on osteoblasts through SXR activation. Therefore, in this study, we first examined the immunolocalization of the SXR protein in human adult and fetal bone tissues. We then examined the effects of bisphenol A on human osteoblasts in vitro. SXR immunoreactivity was detected in osteoblasts, but not in osteoclasts, of both adult and fetal bone tissues. In fetal bone tissues, the mesenchymal cells or fetal connective tissue were also positive for SXR immunoreactivity. Expression of SXR target genes (tsukushi, matrilin-2, and CYP3A4) and SXR response element-luciferase activity were increased by bisphenol A treatment in normal osteoblasts transfected with SXR (hFOB/SXR) and in osteoblast-like cells (MG-63). Bisphenol A also stimulated cell proliferation and collagen accumulation in hFOB/SXR cells. These results suggest that, as in other tissues, SXR plays important roles in bone metabolism and fetal bone development and that bisphenol A may disturb bone homeostasis in both adult and fetus through SXR. Copyright © 2016 Elsevier Inc. All rights reserved.

Diffractive micro-optical element with nonpoint response

NASA Astrophysics Data System (ADS)

Soifer, Victor A.; Golub, Michael A.

1993-01-01

Common-use diffractive lenses have microrelief zones in the form of simple rings that provide only an optical power but do not contain any image information. They have a point-image response under point-source illumination. We must use a more complicated non-point response to focus a light beam into different light marks, letter-type images as well as for optical pattern recognition. The current presentation describes computer generation of diffractive micro- optical elements with complicated curvilinear zones of a regular piecewise-smooth structure and grey-level or staircase phase microrelief. The manufacture of non-point response elements uses the steps of phase-transfer calculation and orthogonal-scan masks generation or lithographic glass etching. Ray-tracing method is shown to be applicable in this task. Several working samples of focusing optical elements generated by computer and photolithography are presented. Using the experimental results we discuss here such applications as laser branding.

Passive rGE or developmental gene-environment cascade? An investigation of the role of xenobiotic metabolism genes in the association between smoke exposure during pregnancy and child birth weight

PubMed Central

Marceau, Kristine; Palmer, Rohan H.C.; Neiderhiser, Jenae M.; Smith, Taylor F.; McGeary, John E.; Knopik, Valerie S.

2016-01-01

There is considerable evidence that smoke exposure during pregnancy (SDP) environmentally influences birth weight after controlling for genetic influences and maternal characteristics. However, maternal smoking during pregnancy – the behavior that leads to smoke exposure during pregnancy – is also genetically-influenced, indicating the potential role of passive gene-environment correlation. An alternative to passive gene-SDP correlation is a cascading effect whereby maternal and child genetic influences are causally linked to prenatal exposures, which then have an ‘environmental’ effect on the development of the child’s biology and behavior. We describe and demonstrate a conceptual framework for disentangling passive rGE from this cascading GE effect using a systems-based polygenic scoring approach comprised of genes shown to be important in the xenobiotic (substances foreign to the body) metabolism pathway. Data were drawn from 5,044 families from the Avon Longitudinal Study of Parents and Children with information on maternal SDP, birth weight, and genetic polymorphisms in the xenobiotic pathway. Within a k-fold cross-validation approach (k=5), we created weighted maternal and child polygenic scores using 18 polymorphisms from 10 genes that have been implicated in the xenobiotic metabolism pathway. Mothers and children shared variation in xenobiotic metabolism genes. Amongst mothers who smoked during pregnancy, neither maternal nor child xenobiotic metabolism polygenic scores were associated with a higher likelihood of smoke exposure during pregnancy, or the severity of smoke exposure during pregnancy (and therefore, neither proposed mechanism was supported), or with child birth weight. SDP was consistently associated with lower child birth weight controlling for the polygenic scores, maternal educational attainment, social class, psychiatric problems, and age. Limitations of the study design and the potential of the framework using other designs are

Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein.

PubMed Central

Bain, L J; McLachlan, J B; LeBlanc, G A

1997-01-01

The multixenobiotic resistance phenotype is characterized by the reduced accumulation of xenobiotics by cells or organisms due to increased efflux of the compounds by P-glycoprotein (P-gp) or related transporters. An extensive xenobiotic database, consisting primarily of pesticides, was utilized in this study to identify molecular characteristics that render a xenobiotic susceptible to transport by or inhibition of P-gp. Transport substrates were differentiated by several molecular size/shape parameters, lipophilicity, and hydrogen bonding potential. Electrostatic features differentiated inhibitory ligands from compounds not catagorized as transport substrates and that did no interact with P-gp. A two-tiered system was developed using the derived structure-activity relationships to identify P-gp transport substrates and inhibitory ligands. Prediction accuracy of the approach was 82%. We then validated the system using six additional pesticides of which tow were predicted to be P-gp inhibitors and four were predicted to be noninteractors, based upon the structure-activity analyses. Experimental determinations using cells transfected with the human MDR1 gene demonstrated that five of the six pesticides were properly catagorized by the structure-activity analyses (83% accuracy). Finally, structure-activity analyses revealed that among P-gp inhibitors, relative inhibitory potency can be predicted based upon the surface area or volume of the compound. These results demonstrate that P-gp transport substrates and inhibitory ligands can be distinguished using molecular characteristics. Molecular characteristics of transport substrates suggest that P-gp may function in the elimination of hydroxylated metabolites of xenobiotics. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 1. E Figure 1. F Figure 1. G Figure 1. H Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 2. Figure 3. A Figure 3. B PMID:9347896

GENE EXPRESSION PROFILING OF XENOBIOTIC METABOLIZING ENZYMES (XMES) THROUGH THE LIFE STAGES OF THE MALE C57BL/6 MOUSE

EPA Science Inventory

In the presence of foreign compounds, metabolic homeostasis of the organism is maintained by the liver's ability to detoxify and eliminate these xenobiotics. This is accomplished, in part, by the expression of XMEs, which metabolize xenobiotics and determine whether exposure will...

The structure of distractor-response bindings: Conditions for configural and elemental integration.

PubMed

Moeller, Birte; Frings, Christian; Pfister, Roland

2016-04-01

Human action control is influenced by bindings between perceived stimuli and responses carried out in their presence. Notably, responses given to a target stimulus can also be integrated with additional response-irrelevant distractor stimuli that accompany the target (distractor-response binding). Subsequently reencountering such a distractor then retrieves the associated response. Although a large body of evidence supports the existence of this effect, the specific structure of distractor-response bindings is still unclear. Here, we test the predictions derived from 2 possible assumptions about the structure of bindings between distractors and responses. According to a configural approach, the entire distractor object is integrated with a response, and only upon repetition of the entire distractor object the associated response would be retrieved. According to an elemental approach, one would predict integration of individual distractor features with the response and retrieval due to the repetition of an individual distractor feature. Four experiments indicate that both, configural and elemental bindings exist and specify boundary conditions for each type of binding. These findings provide detailed insights into the architecture of bindings between response-irrelevant stimuli and actions and thus allow for specifying how distractor stimuli influence human behavior. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Active control of multi-element rotor blade airfoils

NASA Technical Reports Server (NTRS)

Torok, Michael S. (Inventor); Moffitt, Robert C. (Inventor); Bagai, Ashish (Inventor)

2005-01-01

A multi-element rotor blade includes an individually controllable main element and fixed aerodynamic surface in an aerodynamically efficient location relative to the main element. The main element is controlled to locate the fixed aerodynamic surface in a position to increase lift and/or reduce drag upon the main element at various azimuthal positions during rotation.

Daphnia HR96 is a Promiscuous Xenobiotic and Endobiotic Nuclear Receptor

PubMed Central

Karimullina, Elina; Li, Yangchun; Ginjupalli, Gautam; Baldwin, William S.

2012-01-01

Daphnia pulex is the first crustacean to have its genome sequenced. The genome project provides new insight and data into how an aquatic crustacean may respond to environmental stressors, including toxicants. We cloned Daphnia pulex HR96 (DappuHR96), a nuclear receptor orthologous to the CAR/PXR/VDR group of nuclear receptors. In Drosophila melanogaster, (hormone receptor 96) HR96 responds to phenobarbital exposure and has been hypothesized as a toxicant receptor. Therefore, we set up a transactivation assay to test whether DappuHR96 is a promiscuous receptor activated by xenobiotics and endobiotics similar to the constitutive androstane receptor (CAR) and the pregnane X-receptor (PXR). Transactivation assays performed with a GAL4-HR96 chimera demonstrate that HR96 is a promiscuous toxicant receptor activated by a diverse set of chemicals such as pesticides, hormones, and fatty acids. Several environmental toxicants activate HR96 including estradiol, pyriproxyfen, chlorpyrifos, atrazine, and methane arsonate. We also observed repression of HR96 activity by chemicals such as triclosan, androstanol, and fluoxetine. Nearly 50% of the chemicals tested activated or inhibited HR96. Interestingly, unsaturated fatty acids were common activators or inhibitors of HR96 activity, indicating a link between diet and toxicant response. The omega-6 and omega-9 unsaturated fatty acids linoleic and oleic acid activated HR96, but the omega-3 unsaturated fatty acids alpha-linolenic acid and docosahexaenoic acid inhibited HR96, suggesting that these two distinct sets of lipids perform opposing roles in Daphnia physiology. This also provides a putative mechanism by which the ratio of dietary unsaturated fats may affect the ability of an organism to respond to a toxic insult. In summary, HR96 is a promiscuous nuclear receptor activated by numerous endo- and xenobiotics. PMID:22466357

Compliance control with embedded neural elements

NASA Technical Reports Server (NTRS)

Venkataraman, S. T.; Gulati, S.

1992-01-01

The authors discuss a control approach that embeds the neural elements within a model-based compliant control architecture for robotic tasks that involve contact with unstructured environments. Compliance control experiments have been performed on actual robotics hardware to demonstrate the performance of contact control schemes with neural elements. System parameters were identified under the assumption that environment dynamics have a fixed nonlinear structure. A robotics research arm, placed in contact with a single degree-of-freedom electromechanical environment dynamics emulator, was commanded to move through a desired trajectory. The command was implemented by using a compliant control strategy.

Coordinated changes in xenobiotic metabolizing enzyme (XME) gene expression through the life stages of the male C57BL/6 mouse

EPA Science Inventory

Metabolic homeostasis of the organism is maintained by the liver's ability to detoxify and eliminate xenobiotics. This is accomplished, in part, by the expression of XMEs, which metabolize xenobiotics and determine whether exposure will result in toxicity. Some evidence indicates...

Hepatic Xenobiotic Metabolizing Enzyme Gene Expression ...

EPA Pesticide Factsheets

BACKGROUND: Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs). No comprehensive analysis of the mRNA expression of XMETs has been carried out through life stages in any species. RESULTS: Using full-genome arrays, the mRNA expression of all XMETs and their regulatory proteins was examined during fetal (gestation day (GD) 19), neonatal (postnatal day (PND) 7), prepubescent (PND32), middle age (12 months), and old age (18 and 24 months) in the C57BL/6J (C57) mouse liver and compared to adults. Fetal and neonatal life stages exhibited dramatic differences in XMET mRNA expression compared to the relatively minor effects of old age. The total number of XMET probe sets that differed from adults was 636, 500, 84, 5, 43, and 102 for GD19, PND7, PND32, 12 months, 18 months and 24 months, respectively. At all life stages except PND32, under-expressed genes outnumbered over-expressed genes. The altered XMETs included those in all of the major metabolic and transport phases including introduction of reactive or polar groups (Phase I), conjugation (Phase II) and excretion (Phase III). In the fetus and neonate, parallel increases in expression were noted in the dioxin receptor, Nrf2 components and their regulated genes while nuclear receptors and regulated genes were generally down-regulated. Suppression of male-specific XMETs w

Finite Element Modeling of the Buckling Response of Sandwich Panels

NASA Technical Reports Server (NTRS)

Rose, Cheryl A.; Moore, David F.; Knight, Norman F., Jr.; Rankin, Charles C.

2002-01-01

A comparative study of different modeling approaches for predicting sandwich panel buckling response is described. The study considers sandwich panels with anisotropic face sheets and a very thick core. Results from conventional analytical solutions for sandwich panel overall buckling and face-sheet-wrinkling type modes are compared with solutions obtained using different finite element modeling approaches. Finite element solutions are obtained using layered shell element models, with and without transverse shear flexibility, layered shell/solid element models, with shell elements for the face sheets and solid elements for the core, and sandwich models using a recently developed specialty sandwich element. Convergence characteristics of the shell/solid and sandwich element modeling approaches with respect to in-plane and through-the-thickness discretization, are demonstrated. Results of the study indicate that the specialty sandwich element provides an accurate and effective modeling approach for predicting both overall and localized sandwich panel buckling response. Furthermore, results indicate that anisotropy of the face sheets, along with the ratio of principle elastic moduli, affect the buckling response and these effects may not be represented accurately by analytical solutions. Modeling recommendations are also provided.

Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements.

PubMed

Hudson, William H; Vera, Ian Mitchelle S de; Nwachukwu, Jerome C; Weikum, Emily R; Herbst, Austin G; Yang, Qin; Bain, David L; Nettles, Kendall W; Kojetin, Douglas J; Ortlund, Eric A

2018-04-06

Glucocorticoids (GCs) are potent repressors of NF-κB activity, making them a preferred choice for treatment of inflammation-driven conditions. Despite the widespread use of GCs in the clinic, current models are inadequate to explain the role of the glucocorticoid receptor (GR) within this critical signaling pathway. GR binding directly to NF-κB itself-tethering in a DNA binding-independent manner-represents the standing model of how GCs inhibit NF-κB-driven transcription. We demonstrate that direct binding of GR to genomic NF-κB response elements (κBREs) mediates GR-driven repression of inflammatory gene expression. We report five crystal structures and solution NMR data of GR DBD-κBRE complexes, which reveal that GR recognizes a cryptic response element between the binding footprints of NF-κB subunits within κBREs. These cryptic sequences exhibit high sequence and functional conservation, suggesting that GR binding to κBREs is an evolutionarily conserved mechanism of controlling the inflammatory response.

Live-cell Imaging Approaches for the Investigation of Xenobiotic-Induced Oxidant Stress

EPA Science Inventory

BACKGROUND: Oxidant stress is arguably a universal feature in toxicology. Research studies on the role of oxidant stress induced by xenobiotic exposures have typically relied on the identification of damaged biomolecules using a variety of conventional biochemical and molecular t...

Activity of xenobiotic-metabolizing enzymes in the liver of rats with multi-vitamin deficiency.

PubMed

Tutelyan, Victor A; Kravchenko, Lidia V; Aksenov, Ilya V; Trusov, Nikita V; Guseva, Galina V; Kodentsova, Vera M; Vrzhesinskaya, Oksana A; Beketova, Nina A

2013-01-01

The purpose of the study was to determine how multi-vitamin deficiency affects xenobiotic-metabolizing enzyme (XME) activities in the rat liver. Vitamin levels and XME activities were studied in the livers of male Wistar rats who were fed for 4 weeks with semi-synthetic diets containing either adequate (100 % of recommended vitamin intake) levels of vitamins (control), or decreased vitamin levels (50 % or 20 % of recommended vitamin intake). The study results have shown that moderate vitamin deficiency (50 %) leads to a decrease of vitamin A levels only, and to a slight increase, as compared with the control, in the following enzyme activities: methoxyresorufin O-dealkylase (MROD) activity of CYP1 A2 - by 34 % (p < 0.05), UDP-glucuronosyl transferase - by 26 % (p < 0.05), and quinone reductase - by 55 % (p < 0.05). Profound vitamin deficiency (20 %) led to a decrease of vitamins A, E, B1, B2, and C, and enzyme activities in the liver: MROD - to 78 % of the control level (p < 0.05), 4-nitrophenol hydroxylase - to 74 % (p < 0.05), heme oxygenase-1 - to 83 % (p < 0.05), and quinone reductase - to 60 % (p < 0.05). At the same time, the UDP-glucuronosyl transferase activity and ethoxyresorufin O-dealkylase activity of CYP1A1, pentoxyresorufin O-dealkylase activity of CYP2B1/2 and 6β-testosterone hydroxylase, as well as the total activity of glutathione transferase did not differ from the control levels. The study has demonstrated that profound multi-vitamin deficiency is associated with a decrease in the expression of CYP1A2 and CYP3A1 mRNAs to 62 % and 79 %, respectively. These data indicated that a short-term but profound multi-vitamin deficiency in rats leads to a decrease in the activities and expression of the some XME that play an important role in detoxification of xenobiotics and metabolism of drugs and antioxidant protection.

Detoxification function of the Arabidopsis sulphotransferase AtSOT12 by sulphonation of xenobiotics.

PubMed

Chen, Jinhua; Gao, Liqiong; Baek, Dongwon; Liu, Chunlin; Ruan, Ying; Shi, Huazhong

2015-08-01

Cytosolic sulphotransferases have been implicated in inactivation of endogenous steroid hormones and detoxification of xenobiotics in human and animals. Yet, the function of plant sulphotransferases in xenobiotic sulphonation and detoxification has not been reported. In this study, we show that the Arabidopsis sulphotransferase AtSOT12 could sulphonate the bacterial-produced toxin cycloheximide. Loss-of-function mutant sot12 exhibited hypersensitive phenotype to cycloheximide, and expression of AtSOT12 protein in yeast cells conferred resistance to this toxic compound. AtSOT12 exhibited broad specificity and could sulphonate a variety of xenobiotics including phenolic and polycyclic compounds. Enzyme kinetics analysis indicated that AtSOT12 has different selectivity for simple phenolics with different side chains, and the position of the side chain in the simple phenolic compounds affects substrate binding affinity and catalytic efficiency. We proposed that the broad specificity and induced production of AtSOT12 may have rendered this enzyme to not only modify endogenous molecules such as salicylic acid as we previously reported, but also sulphonate pathogen-produced toxic small molecules to protect them from infection. Sulphonation of small molecules in plants may constitute a rapid way to inactivate or change the physiochemical properties of biologically active molecules that could have profound effects on plant growth, development and defence. © 2015 John Wiley & Sons Ltd.

Maternal drug abuse and human term placental xenobiotic and steroid metabolizing enzymes in vitro.

PubMed

Paakki, P; Stockmann, H; Kantola, M; Wagner, P; Lauper, U; Huch, R; Elovaara, E; Kirkinen, P; Pasanen, M

2000-02-01

We evaluated the impact of maternal drug abuse at term on human placental cytochrome P450 (CYP)-mediated (Phase I) xenobiotic and steroid-metabolizing activities [aromatase, 7-ethoxyresorufin O-deethylase (EROD), 7-ethoxycoumarin O-deethylase (ECOD), pyrene 1-hydroxylase (P1OH), and testosterone hydroxylase], and androstenedione-forming isomerase, NADPH quinone oxidoreductase (Phase II), UDP-glucuronosyltransferase (UGT), and glutathione S-transferase (GST) activities in vitro. Overall, the formation of androstenedione, P1OH, and testosterone hydroxylase was statistically significant between control and drug-abusing subjects; we observed no significant differences in any other of the phase I and II activities. In placentas from drug-abusing mothers, we found significant correlations between ECOD and P1OH activities (p < 0. 001), but not between ECOD and aromatase or P1OH and EROD activities; we also found significant correlations between blood cotinine and UGT activities (p < 0.01). In contrast, in controls (mothers who did not abuse drugs but did smoke cigarettes), the P1OH activity correlated with ECOD, EROD (p < 0.001), and testosterone hydroxylase (p < 0.001) activities. Our results (wider variation in ECOD activity among tissue from drug-abusing mothers and the significant correlation between P1OH and ECOD activities, but not with aromatase or EROD activities) indicate that maternal drug abuse results in an additive effect in enhancing placental xenobiotic metabolizing enzymes when the mother also smokes cigarettes; this may be due to enhancing a "silent" CYP form, or a new placental CYP form may be activated. The change in the steroid metabolism profile in vitro suggests that maternal drug abuse may alter normal hormonal homeostasis during pregnancy.

Quantitation of cytokine mRNA expression as an endpoint for prediction and diagnosis of xenobiotic-induced hypersensitivity reactions.

PubMed

Gaspard, I; Kerdine, S; Pallardy, M; Lebrec, H

1999-09-01

Xenobiotic-induced hypersensitivity reactions are immune-mediated effects that involve specific antibodies and/or effector and regulatory T lymphocytes. Cytokines are key mediators of such responses and must be considered as possible endpoints for predicting sensitizing potency of drugs and chemicals, as well as for helping diagnosis of allergy. Detecting cytokine production at the protein level has been shown to not be always sensitive enough. This paper describes three examples of the utilization of semiquantitative or competitive reverse transcription polymerase chain reaction analysis of interleukin-4, interferon gamma, and interleukin-1beta mRNAs as endpoints for assessing T-cell or dendritic cell responses to sensitizing drugs (beta-lactam antibiotics) or chemicals (dinitrochlorobenzene). Copyright 1999 Academic Press.

Retrofit Strategies for Incorporating Xenobiotic Metabolism into High Throughput Screening Assays (EMGS)

EPA Science Inventory

The US EPA’s ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...

Live-cell imaging approaches for the investigation of xenobiotic-induced oxidant stress☆,☆☆

PubMed Central

Wages, Phillip A.; Cheng, Wan-Yun; Gibbs-Flournoy, Eugene; Samet, James M.

2017-01-01

Background Oxidant stress is arguably a universal feature in toxicology. Research studies on the role of oxidant stress induced by xenobiotic exposures have typically relied on the identification of damaged biomolecules using a variety of conventional biochemical and molecular techniques. However, there is increasing evidence that low-level exposure to a variety of toxicants dysregulates cellular physiology by interfering with redox-dependent processes. Scope of review The study of events involved in redox toxicology requires methodology capable of detecting transient modifications at relatively low signal strength. This article reviews the advantages of live-cell imaging for redox toxicology studies. Major conclusions Toxicological studies with xenobiotics of supra-physiological reactivity require careful consideration when using fluorogenic sensors in order to avoid potential artifacts and false negatives. Fortunately, experiments conducted for the purpose of validating the use of these sensors in toxicological applications often yield unexpected insights into the mechanisms through which xenobiotic exposure induces oxidant stress. General significance Live-cell imaging using a new generation of small molecule and genetically encoded fluorophores with excellent sensitivity and specificity affords unprecedented spatiotemporal resolution that is optimal for redox toxicology studies. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu. PMID:27208426

Avian species differences in the intestinal absorption of xenobiotics (PCB, dieldrin, Hg2+)

USGS Publications Warehouse

Serafin, J.A.

1984-01-01

1. Intestinal absorption of a polychlorinated biphenyl, dieldrin, and mercury (from HgCl2) was measured in adult Northern bobwhites, Eastern screech owls, American kestrels, black-crowned night-herons and mallards in vivo by an in situ luminal perfusion technique.2. Bobwhites, screech owls and kestrels absorbed much more of each xenobiotic than black-crowned night-herons and mallards.3. Mallards absorbed less dieldrin and mercury than black-crowned night-herons.4. Mercury absorption by kestrels was more than twice that in screech owls and eight times that observed in mallards.5. Pronounced differences in xenobiotic absorption rates between bobwhites, screech owls and kestrels on the one hand, and black-crowned night-herons and mallards on the other, raise the possibility that absorptive ability may be associated with the phylogenetic classification of birds.

SAGE Analysis of Transcriptome Responses in Arabidopsis Roots Exposed to 2,4,6-Trinitrotoluene1

PubMed Central

Ekman, Drew R.; Lorenz, W. Walter; Przybyla, Alan E.; Wolfe, N. Lee; Dean, Jeffrey F.D.

2003-01-01

Serial analysis of gene expression was used to profile transcript levels in Arabidopsis roots and assess their responses to 2,4,6-trinitrotoluene (TNT) exposure. SAGE libraries representing control and TNT-exposed seedling root transcripts were constructed, and each was sequenced to a depth of roughly 32,000 tags. More than 19,000 unique tags were identified overall. The second most highly induced tag (27-fold increase) represented a glutathione S-transferase. Cytochrome P450 enzymes, as well as an ABC transporter and a probable nitroreductase, were highly induced by TNT exposure. Analyses also revealed an oxidative stress response upon TNT exposure. Although some increases were anticipated in light of current models for xenobiotic metabolism in plants, evidence for unsuspected conjugation pathways was also noted. Identifying transcriptome-level responses to TNT exposure will better define the metabolic pathways plants use to detoxify this xenobiotic compound, which should help improve phytoremediation strategies directed at TNT and other nitroaromatic compounds. PMID:14551330

[Hypothetical link between endometriosis and xenobiotics-associated genetically modified food].

PubMed

Aris, A; Paris, K

2010-12-01

Endometriosis is an oestrogen-dependent inflammatory disease affecting 10 % of reproductive-aged women. Often accompanied by chronic pelvic pain and infertility, endometriosis rigorously interferes with women's quality of life. Although the pathophysiology of endometriosis remains unclear, a growing body of evidence points to the implication of environmental toxicants. Over the last decade, an increase in the incidence of endometriosis has been reported and coincides with the introduction of genetically modified foods in our diet. Even though assessments of genetically modified food risk have not indicated any hazard on human health, xenobiotics-associated genetically modified food, such as pesticides residues and xenoproteins, could be harmful in the long-term. The "low-dose hypothesis", accumulation and biotransformation of pesticides-associated genetically modified food and the multiplied toxicity of pesticides-formulation adjuvants support this hypothesis. This review summarizes toxic effects (in vitro and on animal models) of some xenobiotics-associated genetically modified food, such as glyphosate and Cry1Ab protein, and extrapolates on their potential role in the pathophysiology of endometriosis. Their roles as immune toxicants, pro-oxidants, endocrine disruptors and epigenetic modulators are discussed. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Correlation of the lipophilicity of xenobiotics with their synergistic effects on DNA synthesis in human fibroblasts.

PubMed

Jacobi, H; Leier, G; Witte, I

1996-04-01

The binary combination effects of DNA synthesis of human fibroblasts were investigated using 2,4-D with 15 xenobiotics of different chemical substance classes. Results were compared with previous investigations on cell growth. Each of the 15 chemicals tested at their no effect concentrations (NOEC's) increased the effects of 2,4-D on DNA synthesis. Thereby, the EC20 value of 2,4-D was reduced by approximately 40% in the combinations. The NOEC's of the xenobiotics used in the combinations varied by a factor of 1,600 and depended strongly on the lipophilicity of the agents combined with 2,4-D. A significant statistical correlation of r = 0.90 was found between the NOEC's of the 15 combined xenobiotics and their lipophilicity. The combination effects on DNA synthesis were similar to those on cell growth. The regression lines of the relationship between the NOEC's and lipophilicity in both assays showed only slight differences in the slopes. This is an additional confirmation of our hypothesis on a facilitated uptake of 2,4-D in the binary combinations.

ACGT-containing abscisic acid response element (ABRE) and coupling element 3 (CE3) are functionally equivalent.

PubMed

Hobo, T; Asada, M; Kowyama, Y; Hattori, T

1999-09-01

ACGT-containing ABA response elements (ABREs) have been functionally identified in the promoters of various genes. In addition, single copies of ABRE have been found to require a cis-acting, coupling element to achieve ABA induction. A coupling element 3 (CE3) sequence, originally identified as such in the barley HVA1 promoter, is found approximately 30 bp downstream of motif A (ACGT-containing ABRE) in the promoter of the Osem gene. The relationship between these two elements was further defined by linker-scan analyses of a 55 bp fragment of the Osem promoter, which is sufficient for ABA-responsiveness and VP1 activation. The analyses revealed that both motif A and CE3 sequence were required not only for ABA-responsiveness but also for VP1 activation. Since the sequences of motif A and CE3 were found to be similar, motif-exchange experiments were carried out. The experiments demonstrated that motif A and CE3 were interchangeable by each other with respect to both ABA and VP1 regulation. In addition, both sequences were shown to be recognized by a VP1-interacting, ABA-responsive bZIP factor TRAB1. These results indicate that ACGT-containing ABREs and CE3 are functionally equivalent cis-acting elements. Furthermore, TRAB1 was shown to bind two other non-ACGT ABREs. Based on these results, all these ABREs including CE3 are proposed to be categorized into a single class of cis-acting elements.

Neurotoxicity Linked to Dysfunctional Metal Ion Homeostasis and Xenobiotic Metal Exposure: Redox Signaling and Oxidative Stress.

PubMed

Garza-Lombó, Carla; Posadas, Yanahi; Quintanar, Liliana; Gonsebatt, María E; Franco, Rodrigo

2018-06-20

Essential metals such as copper, iron, manganese, and zinc play a role as cofactors in the activity of a wide range of processes involved in cellular homeostasis and survival, as well as during organ and tissue development. Throughout our life span, humans are also exposed to xenobiotic metals from natural and anthropogenic sources, including aluminum, arsenic, cadmium, lead, and mercury. It is well recognized that alterations in the homeostasis of essential metals and an increased environmental/occupational exposure to xenobiotic metals are linked to several neurological disorders, including neurodegeneration and neurodevelopmental alterations. Recent Advances: The redox activity of essential metals is key for neuronal homeostasis and brain function. Alterations in redox homeostasis and signaling are central to the pathological consequences of dysfunctional metal ion homeostasis and increased exposure to xenobiotic metals. Both redox-active and redox-inactive metals trigger oxidative stress and damage in the central nervous system, and the exact mechanisms involved are starting to become delineated. In this review, we aim to appraise the role of essential metals in determining the redox balance in the brain and the mechanisms by which alterations in the homeostasis of essential metals and exposure to xenobiotic metals disturb the cellular redox balance and signaling. We focus on recent literature regarding their transport, metabolism, and mechanisms of toxicity in neural systems. Delineating the specific mechanisms by which metals alter redox homeostasis is key to understand the pathological processes that convey chronic neuronal dysfunction in neurodegenerative and neurodevelopmental disorders. Antioxid. Redox Signal. 28, 1669-1703.

Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism

PubMed Central

van Herwaarden, Antonius E.; Wagenaar, Els; van der Kruijssen, Cornelia M.M.; van Waterschoot, Robert A.B.; Smit, Johan W.; Song, Ji-Ying; van der Valk, Martin A.; van Tellingen, Olaf; van der Hoorn, José W.A.; Rosing, Hilde; Beijnen, Jos H.; Schinkel, Alfred H.

2007-01-01

Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications. To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a–/–) mice lacking all functional Cyp3a genes. Cyp3a–/– mice were viable, fertile, and without marked physiological abnormalities. However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration. These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification. To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a–/– mice expressing human CYP3A4 in either the intestine or the liver. Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance. These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner. The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems. PMID:17975676

It’s War Out There: Fighting for life with xenobiotic degrading enzymes

USDA-ARS?s Scientific Manuscript database

It’s War Out There: Fighting for life with xenobiotic degrading enzymes Beta-lactamase enzymes are well studied because of their tremendous impact on medicine. Their prominent role is in resistance to beta-lactam (four membered lactam ring) antibiotics including the first and most famous fungally d...

Estimation of maximum transdermal flux of nonionized xenobiotics from basic physicochemical determinants

PubMed Central

Milewski, Mikolaj; Stinchcomb, Audra L.

2012-01-01

An ability to estimate the maximum flux of a xenobiotic across skin is desirable both from the perspective of drug delivery and toxicology. While there is an abundance of mathematical models describing the estimation of drug permeability coefficients, there are relatively few that focus on the maximum flux. This article reports and evaluates a simple and easy-to-use predictive model for the estimation of maximum transdermal flux of xenobiotics based on three common molecular descriptors: logarithm of octanol-water partition coefficient, molecular weight and melting point. The use of all three can be justified on the theoretical basis of their influence on the solute aqueous solubility and the partitioning into the stratum corneum lipid domain. The model explains 81% of the variability in the permeation dataset comprised of 208 entries and can be used to obtain a quick estimate of maximum transdermal flux when experimental data is not readily available. PMID:22702370

Substrate specificity of xenobiotic metabolizing esterases in the liver of two catfish species

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jaiswal, R.G.; Huang, T.L.; Obih, P.O.

1994-12-31

The preliminary studies were conducted on the characterization of substrate specificity in the liver microsomes and cytosol of two catfish species, Ictalurus punctatus and Ictalurus natalie. A series of five esters of p-nitrophenol were used as calorimetric substrates to assay the carboxylesterases. The substrate specificity of liver microsomal and cytosolic carboxylesterases were remarkably different from each other. The valerate ester of p-nitrophenol was most rapidly hydrolyzed by the microsomal carboxylesterases, whereas the prioponate ester was the best substrate for cytosolic carboxylesterases. The Ictalurus natalie catfish species were obtained from the Devil Swamp site of the Mississippi River Basin which ismore » known to be heavily contaminated with toxic and hazardous industrial wastes. These results will be discussed in relation to the responses of xenobiotic metabolizing esterases to environmental pollutants and their possible use as biomarkers.« less

Damper mechanism for nuclear reactor control elements

DOEpatents

Taft, William Elwood

1976-01-01

A damper mechanism which provides a nuclear reactor control element decelerating function at the end of the scram stroke. The total damping function is produced by the combination of two assemblies, which operate in sequence. First, a tapered dashram assembly decelerates the control element to a lower velocity, after which a spring hydraulic damper assembly takes over to complete the final damping.

Comparative investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family among fungi

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes well-characterized in several bacteria and higher eukaryotes. The role of NATs in fungal biology has only recently been investigated. The NAT1 gene of Gibberella moniliformis was the first NAT cloned and characterized from fun...

Comparative genomic and phylogenetic investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes characterized in several bacteria and eukaryotic organisms. We report a comprehensive phylogenetic analysis employing an exhaustive dataset of NAT-homologous sequences recovered through inspection of 2445 genomes. We describe ...

Monobromobimane occupies a distinct xenobiotic substrate site in glutathione S-transferase π

PubMed Central

Ralat, Luis A.; Colman, Roberta F.

2003-01-01

Monobromobimane (mBBr), functions as a substrate of porcine glutathione S-transferase π (GST π): The enzyme catalyzes the reaction of mBBr with glutathione. S-(Hydroxyethyl)bimane, a nonreactive analog of monobromobimane, acts as a competitive inhibitor with respect to mBBr as substrate but does not affect the reaction of GST π with another substrate, 1-chloro-2,4-dinitrobenzene (CDNB). In the absence of glutathione, monobromobimane inactivates GST π at pH 7.0 and 25°C as assayed using mBBr as substrate, with a lesser effect on the enzyme’s use of CDNB as substrate. These results indicate that the sites occupied by CDNB and mBBr are not identical. Inactivation is proportional to the incorporation of 2 moles of bimane/mole of subunit. Modification of GST π with mBBr does not interfere with its binding of 8-anilino-1-naphthalene sulfonate, indicating that this hydrophobic site is not the target of monobromobimane. S-Methylglutathione and S-(hydroxyethyl)bimane each yield partial protection against inactivation and decrease reagent incorporation, while glutathionyl-bimane protects completely against inactivation. Peptide analysis after trypsin digestion indicates that mBBr modifies Cys45 and Cys99 equally. Modification of Cys45 is reduced in the presence of S-methylglutathione, indicating that this residue is at or near the glutathione binding region. In contrast, modification of Cys99 is reduced in the presence of S-(hydroxyethyl)bimane, suggesting that this residue is at or near the mBBr xenobiotic substrate binding site. Modification of Cys99 can best be understood by reaction with monobromobimane while it is bound to its xenobiotic substrate site in an alternate orientation. These results support the concept that glutathione S-transferase accomplishes its ability to react with a diversity of substrates in part by harboring distinct xenobiotic substrate sites. PMID:14573868

Monobromobimane occupies a distinct xenobiotic substrate site in glutathione S-transferase pi.

PubMed

Ralat, Luis A; Colman, Roberta F

2003-11-01

Monobromobimane (mBBr), functions as a substrate of porcine glutathione S-transferase pi (GST pi): The enzyme catalyzes the reaction of mBBr with glutathione. S-(Hydroxyethyl)bimane, a nonreactive analog of monobromobimane, acts as a competitive inhibitor with respect to mBBr as substrate but does not affect the reaction of GST pi with another substrate, 1-chloro-2,4-dinitrobenzene (CDNB). In the absence of glutathione, monobromobimane inactivates GST pi at pH 7.0 and 25 degrees C as assayed using mBBr as substrate, with a lesser effect on the enzyme's use of CDNB as substrate. These results indicate that the sites occupied by CDNB and mBBr are not identical. Inactivation is proportional to the incorporation of 2 moles of bimane/mole of subunit. Modification of GST pi with mBBr does not interfere with its binding of 8-anilino-1-naphthalene sulfonate, indicating that this hydrophobic site is not the target of monobromobimane. S-Methylglutathione and S-(hydroxyethyl)bimane each yield partial protection against inactivation and decrease reagent incorporation, while glutathionyl-bimane protects completely against inactivation. Peptide analysis after trypsin digestion indicates that mBBr modifies Cys45 and Cys99 equally. Modification of Cys45 is reduced in the presence of S-methylglutathione, indicating that this residue is at or near the glutathione binding region. In contrast, modification of Cys99 is reduced in the presence of S-(hydroxyethyl)bimane, suggesting that this residue is at or near the mBBr xenobiotic substrate binding site. Modification of Cys99 can best be understood by reaction with monobromobimane while it is bound to its xenobiotic substrate site in an alternate orientation. These results support the concept that glutathione S-transferase accomplishes its ability to react with a diversity of substrates in part by harboring distinct xenobiotic substrate sites.

Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification

NASA Astrophysics Data System (ADS)

Kugel, Susann; Baunach, Martin; Baer, Philipp; Ishida-Ito, Mie; Sundaram, Srividhya; Xu, Zhongli; Groll, Michael; Hertweck, Christian

2017-06-01

Terpenoid natural products comprise a wide range of molecular architectures that typically result from C-C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2 (at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.

Disentangling controls on element impurities of bivalve shells

NASA Astrophysics Data System (ADS)

Zhao, Liqiang; Schöne, Bernd R.; Mertz-Kraus, Regina

2017-04-01

Trace and minor elements of bivalve shells can potentially serve as proxies of past environmental change. However, retrieving environmental information from element impurities of bivalve shells remains an extremely challenging task. A central difficulty concerns the fact that extrinsic and intrinsic factors governing the element incorporation are poorly constrained. Within the framework of the ARAMACC project, we aim to decipher the complexity of the incorporation of trace and minor elements into bivalve shells and explore their full potential as proxies of environmental change. More specifically, the following questions were tackled. (1) How are trace and minor elements transported from the ambient environment to the calcifying front? (2) How is their incorporation into the shells affected by environmental and physiological variables? Our findings lend support to the general assumption that divalent ions (e.g., Cu2+, Mn2+, Zn2+ and Pb2+) share the same transport pathways as Ca2+ because of similar ionic radii and electrochemical properties. However, results obtained for Mg2+, Sr2+ and Ba2+ are particularly interesting as they are at odds with existing hypotheses on the incorporation of these three elements, i.e., intracellular Ca2+ pathways (via Ca2+ channels and Ca2+-ATPase) are likely not responsible for their incorporation. Despite the existence of strong physiological interference, some encouraging results were found, in particular (1) strong, positive relationships between the Sr, Ba and Mn contents of the shells and concentrations in the ambient water, (2) only minor effects of growth rate (which is closely linked to the rate of crystal growth and hence, kinetics) on the amounts of Na, Sr, Ba and Mn incorporation into the shells. Overall, our findings demonstrate that environmental and physiological controls on the element incorporation do not have to be mutually exclusive, i.e., if environmental changes outweigh physiological influences, one could still

Intermolecular Forces as a Key to Understanding the Environmental Fate of Organic Xenobiotics

ERIC Educational Resources Information Center

Casey, Ryan E.; Pittman, Faith A.

2005-01-01

A module that can be incorporated into chemistry or environmental science classes at the high school or undergraduate level is described. The module is divided into a series of segments, each of which incorporates several concepts and results in students making significant predictions about the behavior of organic xenobiotics.

Virtual Screening as a Strategy for the Identification of Xenobiotics Disrupting Corticosteroid Action

PubMed Central

Praxmarer, Lukas; Chantong, Boonrat; Cereghetti, Diego; Winiger, Rahel; Schuster, Daniela; Odermatt, Alex

2012-01-01

Background Impaired corticosteroid action caused by genetic and environmental influence, including exposure to hazardous xenobiotics, contributes to the development and progression of metabolic diseases, cardiovascular complications and immune disorders. Novel strategies are thus needed for identifying xenobiotics that interfere with corticosteroid homeostasis. 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) and mineralocorticoid receptors (MR) are major regulators of corticosteroid action. 11β-HSD2 converts the active glucocorticoid cortisol to the inactive cortisone and protects MR from activation by glucocorticoids. 11β-HSD2 has also an essential role in the placenta to protect the fetus from high maternal cortisol concentrations. Methods and Principal Findings We employed a previously constructed 3D-structural library of chemicals with proven and suspected endocrine disrupting effects for virtual screening using a chemical feature-based 11β-HSD pharmacophore. We tested several in silico predicted chemicals in a 11β-HSD2 bioassay. The identified antibiotic lasalocid and the silane-coupling agent AB110873 were found to concentration-dependently inhibit 11β-HSD2. Moreover, the silane AB110873 was shown to activate MR and stimulate mitochondrial ROS generation and the production of the proinflammatory cytokine interleukin-6 (IL-6). Finally, we constructed a MR pharmacophore, which successfully identified the silane AB110873. Conclusions Screening of virtual chemical structure libraries can facilitate the identification of xenobiotics inhibiting 11β-HSD2 and/or activating MR. Lasalocid and AB110873 belong to new classes of 11β-HSD2 inhibitors. The silane AB110873 represents to the best of our knowledge the first industrial chemical shown to activate MR. Furthermore, the MR pharmacophore can now be used for future screening purposes. PMID:23056542

Structure of genes for Hsp30 from the white-rot fungus Coriolus versicolor and the increase of their expression by heat shock and exposure to a hazardous chemical.

PubMed

Iimura, Yosuke; Tatsumi, Kenji

2002-07-01

We isolated and analysed two genomic DNAs that encode the heat-shock protein Hsp30 from Coriolus versicolor. The amino acid sequences substitute only three amino acid substitutions. The promoter regions contain the consensus heat-shock element, a xenobiotic-response element, a stress-response element, and a metal-response element. The levels of mRNAs for Hsp30 increased markedly after exposure of C. versicolor to pentachlorophenol and levels were higher than those after heat shock.

DEVELOPMENT OF MOLECULAR INDICATORS OF EXPOSURE TO ENDOCRINE DISRUPTING COMPOUNDS, PESTICIDES & OTHER XENOBIOTIC AGENTS

EPA Science Inventory

A great deal of uncertainty exists regarding the extent to which humans and wildlife are exposed to chemical stressors in aquatic resources. Scientific literature is replete with studies of xenobiotics in surface waters, including a recent national USGS survey of endocrine disrup...

Active magnetic bearing control loop modeling for a finite element rotordynamics code

NASA Technical Reports Server (NTRS)

Genta, Giancarlo; Delprete, Cristiana; Carabelli, Stefano

1994-01-01

A mathematical model of an active electromagnetic bearing which includes the actuator, the sensor and the control system is developed and implemented in a specialized finite element code for rotordynamic analysis. The element formulation and its incorporation in the model of the machine are described in detail. A solution procedure, based on a modal approach in which the number of retained modes is controlled by the user, is then shown together with other procedures for computing the steady-state response to both static and unbalance forces. An example of application shows the numerical results obtained on a model of an electric motor suspended on a five active-axis magnetic suspension. The comparison of some of these results with the experimental characteristics of the actual system shows the ability of the present model to predict its performance.

Risk assessment for selected xenobiotics by bioassay methods with higher plants

NASA Astrophysics Data System (ADS)

Günther, Petra; Pestemer, Wilfried

1990-05-01

Different bioassays with higher plants were approved for use in a bioassay procedure for testing of xenobiotics according to the German Chemicals Act. Selected environmental pollutants (atrazine, cadmium chloride, 2,6-dichlorobenzonitrile, pentachlorophenol, potassium dichromate, thiourea), all from a list of reference chemicals, were tested with these methods. Dose-response curves for growth of oats and turnips were evaluated in soil and vermiculite (nonsorptive substrate), and availability to plants was calculated by comparing the EC50 values for one chemical in both substrates. The most active chemical was atrazine, followed by 2,6-dichlorobenzonitrile, pentachlorophenol, potassium dichromate, cadmium chloride, and thiourea. The least available compound to plants was pentachlorophenol, tested with turnips ( Brassica rapa var. rapa). The strongest inhibition of germination, demonstrated in an in vitro assay with garden cress ( Lepidium sativum), was found with 2,6-dichlorobenzonitrile, the lowest with atrazine. The effect of an extended exposure of the plants to the chemicals was evaluated in a long-term bioassay with oats ( Avena sativa) in hydroponic culture. Several dose-response curves during the growing period were derived. It was found that the EC50 values for atrazine and thiourea decreased markedly during the first four weeks; thereafter the changes were much smaller. As an overall conclusion, a bioassay procedure is proposed that can be included in the graduated plan recommended by the German Chemicals Act.

Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements

PubMed Central

Morrissey, Kari M.; Luizon, Marcelo R.; Hoffmann, Thomas J.; Sun, Xuefeng; Jones, Stacy L.; Force Aldred, Shelley; Ramamoorthy, Anuradha; Desta, Zeruesenay; Liu, Yunlong; Skaar, Todd C.; Trinklein, Nathan D.; Giacomini, Kathleen M.; Ahituv, Nadav

2014-01-01

Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements. PMID:25275310

GENE EXPRESSION PROFILING OF XENOBIOTIC METABOLIZING ENZYMES (XMES) IN THE AGING MALE FISHER RAT

EPA Science Inventory

Detoxification and elimination of xenobiotics is a major function of the liver and is important in maintaining the metabolic homeostasis of the organism. The degree to which aging affects hepatic metabolism is not known. The expression of XMEs, in part, determines the fate of the...

Epigenetic Programming of Breast Cancer and Nutrition Prevention

DTIC Science & Technology

2011-05-01

is to test the role of xenobiotics and food compounds that bind the aromatic hydrocarbon receptor (AhR). AhR-ligands include the dioxin -like and...tumor promoter 2,3,7,8 tetrachlorobenzo-p- dioxin (TCDD). The activated AhR regulates transcription through binding to xenobiotic response elements (XRE...phytoalexin resveratrol, selected as a prototype dietary AhR antagonist, antagonizes at physiologically relevant doses (1  mol /L) the TCDD-induced

[Construction of a general AAV vector regulated by minimal and artificial hypoxic-responsive element].

PubMed

Nie, Xiao-wei; Sun, Li-jun; Hao, Yue-wen; Yang, Guang-xiao; Wang, Quan-ying

2011-03-01

To synthesize the minimal and artificial HRE, and to insert it into the anterior extremity of CMV promoter of a AAV plasmid, and then to construct the AAV regulated by hypoxic-responsive element which was introduced into 293 cell by method of Ca3(PO4)2 using three plasmids. Thus obtaining the adenoassociated virus vector regulated by hypoxic-responsive element was possibly used for gene therapy in ischemia angiocardiopathy and cerebrovascular disease. Artificially synthesize the 36 bp nucleotide sequences of four connection in series HIF-binding sites A/GCGTG(4×HBS)and a 35 bp nucleotide sequences spacing inserted into anterior extremity of CMV promoter TATA Box, then amplified by PCR. The cDNA fragment was confirmed to be right by DNA sequencing. Molecular biology routine method was used to construct a AAV vector regulated by minimal hypoxic-responsive element after the normal CMV promoter in AAV vector was replaced by the CMV promoter included minimal hypoxic-responsive element. Then, NT4-6His-PR39 fusogenic peptide was inserted into MCS of the plasmid, the recombinant AAV vector was obtained by three plasmid co-transfection in 293 cells, in which we can also investigate the expression of 6×His using immunochemistry in hypoxia environment. Artificial HRE was inserted into anterior extremity of CMV promoter and there was a correct spacing between the HRE and the TATA-box. The DNA sequencing and restriction enzyme digestion results indicated that the AAV regulated by hypoxic-responsive element was successfully constructed. Compared to the control group, the expressions of 6×His was significantly increased in the experimental groups in hypoxia environment, which confirmed that the AAV effectually regulated by the minimal HRE was inserted into anterior extremity of CMV promoter. The HRE is inserted into anterior extremity of CMV promoter to lack incision enzyme recognition site by PCR. And eukaryotic expression vector regulated by hypoxic-responsive is constructed

High-Fat Diets Alter the Modulatory Effects of Xenobiotics on Cytochrome P450 Activities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sadler, Natalie C.; Webb-Robertson, Bobbie-Jo M.; Clauss, Therese R.

Cytochrome P450 monooxygenases (P450) are key to the metabolism of myriad endogenous chemicals and xenobiotics, including the majority of therapeutic drugs. Dysregulated P450 activities can lead to altered drug metabolism and toxicity, oxidative stress, and inflammation; all physiological states frequently charged as the impetus for various chronic pathologies. We characterized the impact of common xenobiotic exposures, specifically high-fat diet and active or passive cigarette smoke, on the functional capacity of hepatic and pulmonary P450s. We employed an activity-based protein profiling approach to characterize the identity and activity level of measured individual P450 isoforms. Our results confirm expectations of significant alterationsmore » in pulmonary P450s due to cigarette smoke, but now reveal the repressive impact of high-fat diet-induced obesity on many hepatic P450s activities, and the dynamic alterations due to concomitant diet and smoke exposures on liver and lung P450 activities impacting drug metabolism and pathways of inflammation.« less

Temperature control system for optical elements in astronomical instrumentation

NASA Astrophysics Data System (ADS)

Verducci, Orlando; de Oliveira, Antonio C.; Ribeiro, Flávio F.; Vital de Arruda, Márcio; Gneiding, Clemens D.; Fraga, Luciano

2014-07-01

Extremely low temperatures may damage the optical components assembled inside of an astronomical instrument due to the crack in the resin or glue used to attach lenses and mirrors. The environment, very cold and dry, in most of the astronomical observatories contributes to this problem. This paper describes the solution implemented at SOAR for remotely monitoring and controlling temperatures inside of a spectrograph, in order to prevent a possible damage of the optical parts. The system automatically switches on and off some heat dissipation elements, located near the optics, as the measured temperature reaches a trigger value. This value is set to a temperature at which the instrument is not operational to prevent malfunction and only to protect the optics. The software was developed with LabVIEWTM and based on an object-oriented design that offers flexibility and ease of maintenance. As result, the system is able to keep the internal temperature of the instrument above a chosen limit, except perhaps during the response time, due to inertia of the temperature. This inertia can be controlled and even avoided by choosing the correct amount of heat dissipation and location of the thermal elements. A log file records the measured temperature values by the system for operation analysis.

Elements of active vibration control for rotating machinery

NASA Technical Reports Server (NTRS)

Ulbrich, Heinz

1990-01-01

The success or failure of active vibration control is determined by the availability of suitable actuators, modeling of the entire system including all active elements, positioning of the actuators and sensors, and implementation of problem-adapted control concepts. All of these topics are outlined and their special problems are discussed in detail. Special attention is given to efficient modeling of systems, especially for considering the active elements. Finally, design methods for and the application of active vibration control on rotating machinery are demonstrated by several real applications.

Disposition of xenobiotic chemicals and metabolites in marine organisms.

PubMed Central

Varanasi, U; Stein, J E

1991-01-01

Studies with several bottom fish species from urban waterways show that of the identified xenobiotic chemicals in bottom sediments, polycylic aromatic hydrocarbons (PAHs) are the most strongly associated with the prevalence of liver lesions, including neoplasms. Accordingly, there is concern about the transfer of contaminants, such as PAHs, from aquatic species to humans. Because PAHs exert their toxicity only after being biotransformed, increasing attention has been focused on the ability of aquatic organisms to metabolize these chemicals. Overall, the results of both laboratory and field studies show that generally low levels (nanograms per gram wet weight) of a few low molecular weight PAHs may be present in edible tissue of fish from contaminated areas and that high molecular weight PAHs, such as the carcinogen benzo(a)pyrene, will rarely be detected because of extensive metabolism. Additionally, the results from a few studies suggest that even though interactions between xenobiotics can affect both biochemical and physiological systems to alter the disposition of PAHs in fish, these interactions do not markedly change the relative proportions of metabolites to parent PAH in tissues. Thus, these studies clearly demonstrate that to obtain some insight into the questions of whether there is any risk to human health from consuming fish and crustaceans from urban areas, techniques must be developed that measure metabolites of carcinogens, such as PAHs, in edible tissue. Initial attempts may focus on semiquantitative methods that permit rapid assessment of the level of metabolites in edible tissues of fish and crustaceans from many urban areas.(ABSTRACT TRUNCATED AT 250 WORDS) Images FIGURE 4. FIGURE 4. FIGURE 4. PMID:2050086

An assigned responsibility system for robotic teleoperation control.

PubMed

Small, Nicolas; Lee, Kevin; Mann, Graham

2018-01-01

This paper proposes an architecture that explores a gap in the spectrum of existing strategies for robot control mode switching in adjustable autonomy. In situations where the environment is reasonably known and/or predictable, pre-planning these control changes could relieve robot operators of the additional task of deciding when and how to switch. Such a strategy provides a clear division of labour between the automation and the human operator(s) before the job even begins, allowing for individual responsibilities to be known ahead of time, limiting confusion and allowing rest breaks to be planned. Assigned Responsibility is a new form of adjustable autonomy-based teleoperation that allows the selective inclusion of automated control elements at key stages of a robot operation plan's execution. Progression through these stages is controlled by automatic goal accomplishment tracking. An implementation is evaluated through engineering tests and a usability study, demonstrating the viability of this approach and offering insight into its potential applications.

Targeting xenobiotic receptors PXR and CAR in human diseases

PubMed Central

Banerjee, Monimoy; Robbins, Delira; Chen, Taosheng

2014-01-01

Nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenobiotic receptors regulating not only drug metabolism and disposition but also various human diseases such as cancer, diabetes, inflammatory disease, metabolic disease and liver diseases, suggesting that PXR and CAR are promising targets for drug discovery. Consequently, there is an urgent need to discover and develop small molecules that target these PXR- and/or CAR-mediated human-disease-related pathways for relevant therapeutic applications. This review proposes approaches to target PXR and CAR, either individually or simultaneously, in the context of various human diseases, taking into consideration the structural differences between PXR and CAR. PMID:25463033

Multiple resistance to carcinogens and xenobiotics: P-glycoproteins as universal detoxifiers.

PubMed

Efferth, Thomas; Volm, Manfred

2017-07-01

The detoxification of toxic substances is of general relevance in all biological systems. The plethora of exogenous xenobiotic compounds and endogenous toxic metabolic products explains the evolutionary pressure of all organisms to develop molecular mechanisms to detoxify and excrete harmful substances from the body. P-glycoprotein and other members of the ATP-binding cassette (ABC) transporter family extrude innumerous chemical compounds out of cells. Their specific expression in diverse biological contexts cause different phenotypes: (1) multidrug resistance (MDR) and thus failure of cancer chemotherapy, (2) avoidance of accumulation of carcinogens and prevention of carcinogenesis in healthy tissues, (3) absorption, distribution, metabolization and excretion (ADME) of pharmacological drugs in human patients, (4) protection from environmental toxins in aquatic organisms (multi-xenobiotic resistance, MXR). Hence ABC-transporters may have opposing effects for organismic health reaching from harmful in MDR of tumors to beneficial for maintenance of health in MXR. While their inhibition by specific inhibitors may improve treatment success in oncology and avoid carcinogenesis, blocking of ABC-transporter-driven efflux by environmental pollutants leads to ecotoxicological consequences in marine biotopes. Poisoned seafood may enter the food-chain and cause intoxications in human beings. As exemplified with ABC-transporters, joining forces in interdisciplinary research may, therefore, be a wise strategy to fight problems in human medicine and environmental sciences.

Phylogenetic and biological investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family among fungi

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes well-characterized in several bacteria and eukaryotic organisms. The role of NATs in fungal biology has only recently been investigated. The NAT1 (FDB2) gene of Fusarium verticillioides was the first NAT cloned and character...

Finite element modelling to assess the effect of surface mounted piezoelectric patch size on vibration response of a hybrid beam

NASA Astrophysics Data System (ADS)

Rahman, N.; Alam, M. N.

2018-02-01

Vibration response analysis of a hybrid beam with surface mounted patch piezoelectric layer is presented in this work. A one dimensional finite element (1D-FE) model based on efficient layerwise (zigzag) theory is used for the analysis. The beam element has eight mechanical and a variable number of electrical degrees of freedom. The beams are also modelled in 2D-FE (ABAQUS) using a plane stress piezoelectric quadrilateral element for piezo layers and a plane stress quadrilateral element for the elastic layers of hybrid beams. Results are presented to assess the effect of size of piezoelectric patch layer on the free and forced vibration responses of thin and moderately thick beams under clamped-free and clamped-clamped configurations. The beams are subjected to unit step loading and harmonic loading to obtain the forced vibration responses. The vibration control using in phase actuation potential on piezoelectric patches is also studied. The 1D-FE results are compared with the 2D-FE results.

Transcriptome Analysis of the Carmine Spider Mite, Tetranychus cinnabarinus (Boisduval, 1867) (Acari: Tetranychidae), and Its Response to β-Sitosterol

PubMed Central

Bu, Chunya; Li, Jinling; Wang, Xiao-Qin; Shi, Guanglu; Peng, Bo; Han, Jingyu; Gao, Pin; Wang, Younian

2015-01-01

Tetranychus cinnabarinus (Acari: Tetranychidae) is a worldwide polyphagous agricultural pest that has the title of resistance champion among arthropods. We reported previously the identification of the acaricidal compound β-sitosterol from Mentha piperita and Inula japonica. However, the acaricidal mechanism of β-sitosterol is unclear. Due to the limited genetic research carried out, we de novo assembled the transcriptome of T. cinnabarinus using Illumina sequencing and conducted a differential expression analysis of control and β-sitosterol-treated mites. In total, we obtained >5.4 G high-quality bases for each sample with unprecedented sequencing depth and assembled them into 22,941 unigenes. We identified 617 xenobiotic metabolism-related genes involved in detoxification, binding, and transporting of xenobiotics. A highly expanded xenobiotic metabolic system was found in mites. T. cinnabarinus detoxification genes—including carboxyl/cholinesterase and ABC transporter class C—were upregulated after β-sitosterol treatment. Defense-related proteins, such as Toll-like receptor, legumain, and serine proteases, were also activated. Furthermore, other important genes—such as the chloride channel protein, cytochrome b, carboxypeptidase, peritrophic membrane chitin binding protein, and calphostin—may also play important roles in mites' response to β-sitosterol. Our results demonstrate that high-throughput-omics tool facilitates identification of xenobiotic metabolism-related genes and illustration of the acaricidal mechanisms of β-sitosterol. PMID:26078964

Infrasound-array-element frequency response: in-situ measurement and modeling

NASA Astrophysics Data System (ADS)

Gabrielson, T.

2011-12-01

Most array elements at the infrasound stations of the International Monitoring System use some variant of a multiple-inlet pipe system for wind-noise suppression. These pipe systems have a significant impact on the overall frequency response of the element. The spatial distribution of acoustic inlets introduces a response dependence that is a function of frequency and of vertical and horizontal arrival angle; the system of inlets, pipes, and summing junctions further shapes that response as the signal is ducted to the transducer. In-situ measurements, using a co-located reference microphone, can determine the overall frequency response and diagnose problems with the system. As of July 2011, the in-situ frequency responses for 25 individual elements at 6 operational stations (I10, I53, I55, I56, I57, and I99) have been measured. In support of these measurements, a fully thermo-viscous model for the acoustics of these multiple-inlet pipe systems has been developed. In addition to measurements at operational stations, comparative analyses have been done on experimental systems: a multiple-inlet radial-pipe system with varying inlet hole size; a one-quarter scale model of a 70-meter rosette system; and vertical directionality of a small rosette system using aircraft flyovers. [Funded by the US Army Space and Missile Defense Command

Xenobiotic-metabolizing enzymes in plants and their role in uptake and biotransformation of veterinary drugs in the environment.

PubMed

Bártíková, Hana; Skálová, Lenka; Stuchlíková, Lucie; Vokřál, Ivan; Vaněk, Tomáš; Podlipná, Radka

2015-08-01

Many various xenobiotics permanently enter plants and represent potential danger for their organism. For that reason, plants have evolved extremely sophisticated detoxification systems including a battery of xenobiotic-metabolizing enzymes. Some of them are similar to those in humans and animals, but there are several plant-specific ones. This review briefly introduces xenobiotic-metabolizing enzymes in plants and summarizes present information about their action toward veterinary drugs. Veterinary drugs are used worldwide to treat diseases and protect animal health. However, veterinary drugs are also unwantedly introduced into environment mostly via animal excrements, they persist in the environment for a long time and may impact on the non-target organisms. Plants are able to uptake, transform the veterinary drugs to non- or less-toxic compounds and store them in the vacuoles and cell walls. This ability may protect not only plant themselves but also other organisms, predominantly invertebrates and wild herbivores. The aim of this review is to emphasize the importance of plants in detoxification of veterinary drugs in the environment. The results of studies, which dealt with transport and biotransformation of veterinary drugs in plants, are summarized and evaluated. In conclusion, the risks and consequences of veterinary drugs in the environment and the possibilities of phytoremediation technologies are considered and future perspectives are outlined.

Proteomic analysis of drought resistance in crabapple seedlings primed by the xenobiotic Beta-aminobutyric acid

USDA-ARS?s Scientific Manuscript database

In a variety of annual crops and model plants, the xenobiotic DL-Beta-aminobutyric acid (BABA) has been shown to enhance disease resistance and increase salt, drought and thermotolerance. BABA does not activate stress genes directly, but sensitizes plants to respond more quickly and strongly to biot...

Inhalation exposure of rats to asphalt fumes generated at paving temperatures alters pulmonary xenobiotic metabolism pathways without lung injury.

PubMed Central

Ma, Jane Y C; Rengasamy, Apavoo; Frazer, Dave; Barger, Mark W; Hubbs, Ann F; Battelli, Lori; Tomblyn, Seith; Stone, Samuel; Castranova, Vince

2003-01-01

Asphalt fumes are complex mixtures of various organic compounds, including polycyclic aromatic hydrocarbons (PAHs). PAHs require bioactivation by the cytochrome P-450 monooxygenase system to exert toxic/carcinogenic effects. The present study was carried out to characterize the acute pulmonary inflammatory responses and the alterations of pulmonary xenobiotic pathways in rats exposed to asphalt fumes by inhalation. Rats were exposed at various doses and time periods to air or to asphalt fumes generated at paving temperatures. To assess the acute damage and inflammatory responses, differential cell counts, acellular lactate dehydrogenase (LDH) activity, and protein content of bronchoalveolar lavage fluid were determined. Alveolar macrophage (AM) function was assessed by monitoring generation of chemiluminescence and production of tumor necrosis factor-alpha and interleukin-1. Alteration of pulmonary xenobiotic pathways was determined by monitoring the protein levels and activities of P-450 isozymes (CYP1A1 and CYP2B1), glutathioneS-transferase (GST), and NADPH:quinone oxidoreductase (QR). The results show that acute asphalt fume exposure did not cause neutrophil infiltration, alter LDH activity or protein content, or affect AM function, suggesting that short-term asphalt fume exposure did not induce acute lung damage or inflammation. However, acute asphalt fume exposure significantly increased the activity and protein level of CYP1A1 whereas it markedly reduced the activity and protein level of CYP2B1 in the lung. The induction of CYP1A1 was localized in nonciliated bronchiolar epithelial (Clara) cells, alveolar septa, and endothelial cells by immunofluorescence microscopy. Cytosolic QR activity was significantly elevated after asphalt fume exposure, whereas GST activity was not affected by the exposure. This induction of CYP1A1 and QR with the concomitant down-regulation of CYP2B1 after asphalt fume exposure could alter PAH metabolism and may lead to potential

Vitreous humor analysis for the detection of xenobiotics in forensic toxicology: a review.

PubMed

Bévalot, Fabien; Cartiser, Nathalie; Bottinelli, Charline; Fanton, Laurent; Guitton, Jérôme

2016-01-01

Vitreous humor (VH) is a gelatinous substance contained in the posterior chamber of the eye, playing a mechanical role in the eyeball. It has been the subject of numerous studies in various forensic applications, primarily for the assessment of postmortem interval and for postmortem chemical analysis. Since most of the xenobiotics present in the bloodstream are detected in VH after crossing the selective blood-retinal barrier, VH is an alternative matrix useful for forensic toxicology. VH analysis offers particular advantages over other biological matrices: it is less prone to postmortem redistribution, is easy to collect, has relatively few interfering compounds for the analytical process, and shows sample stability over time after death. The present study is an overview of VH physiology, drug transport and elimination. Collection, storage, analytical techniques and interpretation of results from qualitative and quantitative points of view are dealt with. The distribution of xenobiotics in VH samples is thus discussed and illustrated by a table reporting the concentrations of 106 drugs from more than 300 case reports. For this purpose, a survey was conducted of publications found in the MEDLINE database from 1969 through April 30, 2015.

Metagenomic analysis of the pinewood nematode microbiome reveals a symbiotic relationship critical for xenobiotics degradation

PubMed Central

Cheng, Xin-Yue; Tian, Xue-Liang; Wang, Yun-Sheng; Lin, Ren-Miao; Mao, Zhen-Chuan; Chen, Nansheng; Xie, Bing-Yan

2013-01-01

Our recent research revealed that pinewood nematode (PWN) possesses few genes encoding enzymes for degrading α-pinene, which is the main compound in pine resin. In this study, we examined the role of PWN microbiome in xenobiotics detoxification by metagenomic and bacteria culture analyses. Functional annotation of metagenomes illustrated that benzoate degradation and its related metabolisms may provide the main metabolic pathways for xenobiotics detoxification in the microbiome, which is obviously different from that in PWN that uses cytochrome P450 metabolism as the main pathway for detoxification. The metabolic pathway of degrading α-pinene is complete in microbiome, but incomplete in PWN genome. Experimental analysis demonstrated that most of tested cultivable bacteria can not only survive the stress of 0.4% α-pinene, but also utilize α-pinene as carbon source for their growth. Our results indicate that PWN and its microbiome have established a potentially mutualistic symbiotic relationship with complementary pathways in detoxification metabolism. PMID:23694939

COMPARISON OF MICROBIAL TRANSFORMATION RATE COEFFICIENTS OF XENOBIOTIC CHEMICALS BETWEEN FIELD-COLLECTED AND LABORATORY MICROCOSM MICROBIOTA

EPA Science Inventory

Two second-order transformation rate coefficients--kb, based on total plate counts, and kA, based on periphyton-colonized surface areas--were used to compare xenobiotic chemical transformation by laboratory-developed (microcosm) and by field-collected microbiota. Similarity of tr...

Ternary Complex Factors and Cofactors Are Essential for Human T-Cell Leukemia Virus Type 1 Tax Transactivation of the Serum Response Element

PubMed Central

Shuh, Maureen; Derse, David

2000-01-01

The human T-cell leukemia virus type 1 Tax protein activates the expression of cellular immediate early genes controlled by the serum response element (SRE), which contains both the serum response factor (SRF) binding element (CArG box) and the ternary complex factor (TCF) binding element (Ets box). We show that TCF binding is necessary for Tax activation of the SRE and that Tax directly interacts with TCFs in vitro. In addition, Tax interactions with CREB binding protein (CBP) and p300- and CBP-associated factor were found to be essential for Tax activation of SRF-mediated transcription. PMID:11070040

Disposition of xenobiotic chemicals and metabolites in marine organisms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varanasi, U.; Stein, J.E.

1991-01-01

Studies with several bottom fish species from urban waterways show that of the identified xenobiotic chemicals in bottom sediments, polycyclic aromatic hydrocarbons (PAHs) are the most strongly associated with the prevalence of liver lesions, including neoplasms. Accordingly, there is concern about the transfer of contaminants, such as PAHs, from aquatic species to humans. Because PAHs exert their toxicity only after being biotransformed, increasing attention has been focused on the ability of aquatic organisms to metabolize these chemicals. Overall, the results of both laboratory and field studies show that generally low levels of a few low molecular weight PAHs may bemore » present in edible tissue of fish from contaminated areas and that high molecular weight PAHs, such as the carcinogen benzo(a)pyrene, will rarely be detected because of extensive metabolism. Additionally, the results from a few studies suggest that even though interactions between xenobiotics can affect both biochemical and physiological systems to alter the disposition of PAHs in fish, these interactions do not markedly change the relative proportions of metabolites to parent PAH in tissues. Thus, these studies clearly demonstrate that to obtain some insight into the questions of whether there is any risk to human health from consuming fish and crustaceans from urban areas, techniques must be developed that measure metabolites of carcinogens, such as PAHs, in edible tissue. Initial attempts may focus on semiquantitative methods that permit rapid assessment of the level of metabolites in edible tissues of fish and crustaceans from many urban areas. Based on information from such screening studies, further refinement in methodology leading to identification of specific compounds may be needed because certain metabolites may not be as toxic or carcinogenic as others.« less

Prediction of transcriptional regulatory elements for plant hormone responses based on microarray data

PubMed Central

2011-01-01

Background Phytohormones organize plant development and environmental adaptation through cell-to-cell signal transduction, and their action involves transcriptional activation. Recent international efforts to establish and maintain public databases of Arabidopsis microarray data have enabled the utilization of this data in the analysis of various phytohormone responses, providing genome-wide identification of promoters targeted by phytohormones. Results We utilized such microarray data for prediction of cis-regulatory elements with an octamer-based approach. Our test prediction of a drought-responsive RD29A promoter with the aid of microarray data for response to drought, ABA and overexpression of DREB1A, a key regulator of cold and drought response, provided reasonable results that fit with the experimentally identified regulatory elements. With this succession, we expanded the prediction to various phytohormone responses, including those for abscisic acid, auxin, cytokinin, ethylene, brassinosteroid, jasmonic acid, and salicylic acid, as well as for hydrogen peroxide, drought and DREB1A overexpression. Totally 622 promoters that are activated by phytohormones were subjected to the prediction. In addition, we have assigned putative functions to 53 octamers of the Regulatory Element Group (REG) that have been extracted as position-dependent cis-regulatory elements with the aid of their feature of preferential appearance in the promoter region. Conclusions Our prediction of Arabidopsis cis-regulatory elements for phytohormone responses provides guidance for experimental analysis of promoters to reveal the basis of the transcriptional network of phytohormone responses. PMID:21349196

Androgen receptor stimulates bone sialoprotein (BSP) gene transcription via cAMP response element and activator protein 1/glucocorticoid response elements.

PubMed

Takai, Hideki; Nakayama, Youhei; Kim, Dong-Soon; Arai, Masato; Araki, Shouta; Mezawa, Masaru; Nakajima, Yu; Kato, Naoko; Masunaga, Hiroshi; Ogata, Yorimasa

2007-09-01

Bone sialoprotein (BSP) is an early marker of osteoblast differentiation. Androgens are steroid hormones that are essential for skeletal development. The androgen receptor (AR) is a transcription factor and a member of the steroid receptor superfamily that plays an important role in male sexual differentiation and prostate cell proliferation. To determine the molecular mechanism involved in the stimulation of bone formation, we have analyzed the effects of androgens and AR effects on BSP gene transcription. AR protein levels were increased after AR overexpression in ROS17/2.8 cells. BSP mRNA levels were increased by AR overexpression. However, the endogenous and overexpressed BSP mRNA levels were not changed by DHT (10(-8) M, 24 h). Whereas luciferase (LUC) activities in all constructs, including a short construct (nts -116 to +60), were increased by AR overexpression, the basal and LUC activities enhanced by AR overexpression were not induced by DHT (10(-8)M, 24 h). The effect of AR overexpression was abrogated by 2 bp mutations in either the cAMP response element (CRE) or activator protein 1 (AP1)/glucocorticoid response element (GRE). Gel shift analyses showed that AR overexpression increased binding to the CRE and AP1/GRE elements. Notably, the CRE-protein complexes were supershifted by phospho-CREB antibody, and CREB, c-Fos, c-Jun, and AR antibodies disrupted the complexes formation. The AP1/GRE-protein complexes were supershifted by c-Fos antibody and c-Jun, and AR antibodies disrupted the complexes formation. These studies demonstrate that AR stimulates BSP gene transcription by targeting the CRE and AP1/GRE elements in the promoter of the rat BSP gene.

[Carbohydrate metabolism in acute poisoning with xenobiotics].

PubMed

Pach, Dorota; Szurkowska, Magdalena; Szafraniec, Krystyna; Targosz, Dorota; Sułek, Monika; Kamenczak, Aleksandra; Huszno, Bohdan

2007-01-01

The aim of the study was to evaluate carbohydrate metabolism in patients hospitalised because of acute intoxication with xenobiotics. An analysis of 3628 patients (1553 females and 2075 males; age: 40.6 +/- 15.9 y) hospitalized at the Ward of Toxicology and Environmental Diseases because of acute poisoning in 2004-2006 was done. The patients with diabetes mellitus diagnosed prior to hospitalisation were excluded from the analysis. The blood ethanol concentration was measured, medication drugs and/or psychoactive substance screening test were performed in all patients on admission. Fasting glucose level on admission and control level on second or third day of hospitalisation were determined. Risk ratio of hyperglycaemia according to toxic agent was assessed using multiple regression model considering age, gender, and the patient education. In 18.2% (398 males and 254 females) of the patients the blood glucose level on admission was > or = 7.8 mmol/l; in u 3.6% (78 males and 50 females) > or = 11.1 mmol/l. In 24 (0.6%) of the patients glycaemia on admission was < or = 3.5 mmol/l. Control fasting glucose level of > or = 7.0 mmol/l was determined in 115 males and 76 female patients. 42% elevation in risk of hyperglycaemia was noted in acute carbon monoxide poisoning (OR = 1.42; 95% PU: 1.11-1.82). In ethanol intoxicated patients 12% drop in risk of hyperglycaemia was noted (OR = 0.88; 95% PU: 0.72-1.07). Benzodiazepine poisoning diminished risk of hyperglycaemia in 36% (OR=0.64; 95%PU: 0.48-0.84). Risk of hyperglycaemia in poisoning by medicines co-ingested with ethanol was always lower compared to poisoning with the single agent. A higher risk of hyperglycaemia was related to acute carbon monoxide poisoning whereas lower risk of hyperglycaemia was attributed to benzodiazepines and alcohol. A frequency of hypoglycaemia in the group of poisoned patients was much more lower compared to hyperglycaemia.

ABFs, a family of ABA-responsive element binding factors.

PubMed

Choi, H; Hong, J; Ha, J; Kang, J; Kim, S Y

2000-01-21

Abscisic acid (ABA) plays an important role in environmental stress responses of higher plants during vegetative growth. One of the ABA-mediated responses is the induced expression of a large number of genes, which is mediated by cis-regulatory elements known as abscisic acid-responsive elements (ABREs). Although a number of ABRE binding transcription factors have been known, they are not specifically from vegetative tissues under induced conditions. Considering the tissue specificity of ABA signaling pathways, factors mediating ABA-dependent stress responses during vegetative growth phase may thus have been unidentified so far. Here, we report a family of ABRE binding factors isolated from young Arabidopsis plants under stress conditions. The factors, isolated by a yeast one-hybrid system using a prototypical ABRE and named as ABFs (ABRE binding factors) belong to a distinct subfamily of bZIP proteins. Binding site selection assay performed with one ABF showed that its preferred binding site is the strong ABRE, CACGTGGC. ABFs can transactivate an ABRE-containing reporter gene in yeast. Expression of ABFs is induced by ABA and various stress treatments, whereas their induction patterns are different from one another. Thus, a new family of ABRE binding factors indeed exists that have the potential to activate a large number of ABA/stress-responsive genes in Arabidopsis.

Extrachromosomal genetic elements in Micrococcus.

PubMed

Dib, Julián Rafael; Liebl, Wolfgang; Wagenknecht, Martin; Farías, María Eugenia; Meinhardt, Friedhelm

2013-01-01

Micrococci are Gram-positive G + C-rich, nonmotile, nonspore-forming actinomycetous bacteria. Micrococcus comprises ten members, with Micrococcus luteus being the type species. Representatives of the genus play important roles in the biodegradation of xenobiotics, bioremediation processes, production of biotechnologically important enzymes or bioactive compounds, as test strains in biological assays for lysozyme and antibiotics, and as infective agents in immunocompromised humans. The first description of plasmids dates back approximately 28 years, when several extrachromosomal elements ranging in size from 1.5 to 30.2 kb were found in Micrococcus luteus. Up to the present, a number of circular plasmids conferring antibiotic resistance, the ability to degrade aromatic compounds, and osmotolerance are known, as well as cryptic elements with unidentified functions. Here, we review the Micrococcus extrachromosomal traits reported thus far including phages and the only quite recently described large linear extrachromosomal genetic elements, termed linear plasmids, which range in size from 75 kb (pJD12) to 110 kb (pLMA1) and which confer putative advantageous capabilities, such as antibiotic or heavy metal resistances (inferred from sequence analyses and curing experiments). The role of the extrachromosomal elements for the frequently proven ecological and biotechnological versatility of the genus will be addressed as well as their potential for the development and use as genetic tools.

Responses of trace elements to aerobic maximal exercise in elite sportsmen.

PubMed

Otag, Aynur; Hazar, Muhsin; Otag, Ilhan; Gürkan, Alper Cenk; Okan, Ilyas

2014-02-21

Trace elements are chemical elements needed in minute quantities for the proper growth, development, and physiology of the organism. In biochemistry, a trace element is also referred to as a micronutrient. Trace elements, such as nickel, cadmium, aluminum, silver, chromium, molybdenum, germanium, tin, titanium, tungsten, scandium, are found naturally in the environment and human exposure derives from a variety of sources, including air, drinking water and food. The Purpose of this study was investigated the effect of aerobic maximal intensity endurance exercise on serum trace elements as well-trained individuals of 28 wrestlers (age (year) 19.64±1.13, weight (Kg) 70.07 ± 15.69, height (cm) 176.97 ± 6.69) during and after a 2000 meter Ergometer test protocol was used to perform aerobic (75 %) maximal endurance exercise. Trace element serum levels were analyzed from blood samples taken before, immediately after and one hour after the exercise. While an increase was detected in Chromium (Cr), Nickel (Ni), Molybdenum (Mo) and Titanium (Ti) serum levels immediately after the exercise, a decrease was detected in Aluminum (Al), Scandium (Sc) and Tungsten (W) serum levels. Except for aluminum, the trace elements we worked on showed statistically meaningful responses (P < 0.05 and P < 0.001). According to the responses of trace elements to the exercise showed us the selection and application of the convenient sport is important not only in terms of sportsman performance but also in terms of future healthy life plans and clinically.

Molecular insights into the association of obesity with breast cancer risk: relevance to xenobiotic metabolism and CpG island methylation of tumor suppressor genes.

PubMed

Naushad, Shaik Mohammad; Hussain, Tajamul; Al-Attas, Omar S; Prayaga, Aruna; Digumarti, Raghunadha Rao; Gottumukkala, Suryanarayana Raju; Kutala, Vijay Kumar

2014-07-01

Obesity, genetic polymorphisms of xenobiotic metabolic pathway, hypermethylation of tumor suppressor genes, and hypomethylation of proapoptotic genes are known to be independent risk factors for breast cancer. The objective of this study is to evaluate the combined effect of these environmental, genetic, and epigenetic risk factors on the susceptibility to breast cancer. PCR-RFLP and multiplex PCR were used for the genetic analysis of six variants of xenobiotic metabolic pathway. Methylation-specific PCR was used for the epigenetic analysis of four genetic loci. Multifactor dimensionality reduction analysis revealed a significant interaction between the body mass index (BMI) and catechol-O-methyl transferase H108L variant alone or in combination with cytochrome P450 (CYP) 1A1m1 variant. Women with "Luminal A" breast cancer phenotype had higher BMI compared to other phenotypes and healthy controls. There was no association between the BMI and tumor grade. The post-menopausal obese women exhibited lower glutathione levels. BMI showed a positive association with the methylation of extracellular superoxide dismutase (r = 0.21, p < 0.05), Ras-association (RalGDS/AF-6) domain family member 1 (RASSF1A) (r = 0.31, p < 0.001), and breast cancer type 1 susceptibility protein (r = 0.19, p < 0.05); and inverse association with methylation of BNIP3 (r = -0.48, p < 0.0001). To conclude based on these results, obesity increases the breast cancer susceptibility by two possible mechanisms: (i) by interacting with xenobiotic genetic polymorphisms in inducing increased oxidative DNA damage and (ii) by altering the methylome of several tumor suppressor genes.

Structural Elements Regulating AAA+ Protein Quality Control Machines.

PubMed

Chang, Chiung-Wen; Lee, Sukyeong; Tsai, Francis T F

2017-01-01

Members of the ATPases Associated with various cellular Activities (AAA+) superfamily participate in essential and diverse cellular pathways in all kingdoms of life by harnessing the energy of ATP binding and hydrolysis to drive their biological functions. Although most AAA+ proteins share a ring-shaped architecture, AAA+ proteins have evolved distinct structural elements that are fine-tuned to their specific functions. A central question in the field is how ATP binding and hydrolysis are coupled to substrate translocation through the central channel of ring-forming AAA+ proteins. In this mini-review, we will discuss structural elements present in AAA+ proteins involved in protein quality control, drawing similarities to their known role in substrate interaction by AAA+ proteins involved in DNA translocation. Elements to be discussed include the pore loop-1, the Inter-Subunit Signaling (ISS) motif, and the Pre-Sensor I insert (PS-I) motif. Lastly, we will summarize our current understanding on the inter-relationship of those structural elements and propose a model how ATP binding and hydrolysis might be coupled to polypeptide translocation in protein quality control machines.

Assessment of hypoxia and TNF-alpha response by a vector with HRE and NF-kappaB response elements.

PubMed

Chen, Zhilin; Eadie, Ashley L; Hall, Sean R; Ballantyne, Laurel; Ademidun, David; Tse, M Yat; Pang, Stephen C; Melo, Luis G; Ward, Christopher A; Brunt, Keith R

2017-01-01

Hypoxia and inflammatory cytokine activation (H&I) are common processes in many acute and chronic diseases. Thus, a single vector that responds to both hypoxia and inflammatory cytokines, such as TNF-alpha, is useful for assesing the severity of such diseases. Adaptation to hypoxia is regulated primarily by hypoxia inducible transcription factor (HIF alpha) nuclear proteins that engage genes containing a hypoxia response element (HRE). Inflammation activates a multitude of cytokines, including TNF-alpha, that invariably modulate activation of the nuclear factor kappa B (NF-kB) transcription factor. We constructed a vector that encompassed both a hypoxia response element (HRE), and a NF-kappaB responsive element. We show that this vector was functionally responsive to both hypoxia and TNF-alpha, in vitro and in vivo . Thus, this vector might be suitable for the detection and assessment of hypoxia or TNF-alpha.

Cytochrome P450 peroxidase/peroxygenase mediated xenobiotic metabolic activation and cytotoxicity in isolated hepatocytes.

PubMed

Anari, M R; Khan, S; Liu, Z C; O'Brien, P J

1995-12-01

Cytochrome P450 (P450) can utilize organic hydroperoxides and peracids to support hydroxylation and dealkylation of various P450 substrates. However, the biological significance of this P450 peroxygenase/peroxidase activity in the bioactivation of xenobiotics in intact cells has not been demonstrated. We have shown that tert-butyl hydroperoxide (tBHP) markedly enhances 3-20-fold the cytotoxicity of various aromatic hydrocarbons and their phenolic metabolites. The tBHP-enhanced hepatocyte cytotoxicity of 4-nitroanisole (4-NA) and 4-hydroxyanisole (4-HA) was also accompanied by an increase in the hepatocyte O-demethylation of 4-NA and 4-HA up to 7.5- and 21-fold, respectively. Hepatocyte GSH conjugation by 4-HA was also markedly increased by tBHP. An LC/MS analysis of the GSH conjugates identified hydroquinone-GSH and 4-methoxy-catechol:GSH conjugates as the predominant adducts. Pretreatment of hepatocytes with P450 inhibitors, e.g., phenylimidazole, prevented tBHP-enhanced 4-HA metabolism, GSH depletion, and cytotoxicity. In conclusion, hydroperoxides can therefore be used by intact cells to support the bioactivation of xenobiotics through the P450 peroxidase/peroxygenase system.

Development of an invitro technique to use mouse embryonic stem cell in evaluating effects of xenobiotics

EPA Science Inventory

Our goal has been to develop a high-throughput, in vitro technique for evaluating the effects of xenobiotics using mouse embryonic stem cells (mESCs). We began with the Embryonic Stem Cell Test (EST), which is used to predict the embryotoxic potential of a test compound by combin...

Homologues of xenobiotic metabolizing N-acetyltransferases in plant-associated fungi: Novel functions for an old enzyme family

USDA-ARS?s Scientific Manuscript database

Plant-pathogenic fungi and their hosts engage in chemical warfare, attacking each other with toxic products of secondary metabolism and defending themselves via an arsenal of xenobiotic metabolizing enzymes. One such enzyme is homologous to arylamine N-acetyltransferase (NAT) and has been identified...

Oxidation and adduct formation of xenobiotics in a microfluidic electrochemical cell with boron doped diamond electrodes and an integrated passive gradient rotation mixer.

PubMed

van den Brink, Floris T G; Wigger, Tina; Ma, Liwei; Odijk, Mathieu; Olthuis, Wouter; Karst, Uwe; van den Berg, Albert

2016-10-05

Reactive xenobiotic metabolites and their adduct formation with biomolecules such as proteins are important to study as they can be detrimental to human health. Here, we present a microfluidic electrochemical cell with integrated micromixer to study phase I and phase II metabolism as well as protein adduct formation of xenobiotics in a purely instrumental approach. The newly developed microfluidic device enables both the generation of reactive metabolites through electrochemical oxidation and subsequent adduct formation with biomolecules in a chemical microreactor. This allows us to study the detoxification of reactive species with glutathione and to predict potential toxicity of xenobiotics as a result of protein modification. Efficient mixing in microfluidic systems is a slow process due to the typically laminar flow conditions in shallow channels. Therefore, a passive gradient rotation micromixer has been designed that is capable of mixing liquids efficiently in a 790 pL volume within tens of milliseconds. The mixing principle relies on turning the concentration gradient that is initially established by bringing together two streams of liquid, to take advantage of the short diffusion distances in the shallow microchannels of thin-layer flow cells. The mixer is located immediately downstream of the working electrode of an electrochemical cell with integrated boron doped diamond electrodes. In conjunction with mass spectrometry, the two microreactors integrated in a single device provide a powerful tool to study the metabolism and toxicity of xenobiotics, which was demonstrated by the investigation of the model compound 1-hydroxypyrene.

Functional Response of NiTi Elements for Smart Micro-actuation Applications

NASA Astrophysics Data System (ADS)

Biffi, C. A.; Nespoli, A.; Previtali, B.; Villa, E.; Tuissi, A.

2014-07-01

Shape memory alloys (SMAs) can be considered a good candidate for actuation applications in the current micro-technology field. In the micro-scale, the temporal response of the SMA actuators can be improved, because of faster cooling during the austenite-martensite transformation. One of the most investigated geometries for this purpose has been the snake-like arrangement, which allows high strokes with considerable forces to be obtained. In this work, SMA elements for micro-actuators were patterned by laser machining in a snake-like shape. Subsequent surface chemical etching was adopted to improve the functional properties of the micro-elements. Calorimetric analysis and thermo-mechanical response of 90 μm thick SMA elements were reported for the evaluation of their functional performances. Moreover, the effect of post-thermal treatment and grain orientation were also evaluated on the final performances.

Impact of environmental exposures on ovarian function and role of xenobiotic metabolism during ovotoxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhattacharya, Poulomi; Keating, Aileen F., E-mail: akeating@iastate.edu

2012-06-15

The mammalian ovary is a heterogeneous organ and contains oocyte-containing follicles at varying stages of development. The most immature follicular stage, the primordial follicle, comprises the ovarian reserve and is a finite number, defined at the time of birth. Depletion of all follicles within the ovary leads to reproductive senescence, known as menopause. A number of chemical classes can destroy follicles, thus hastening entry into the menopausal state. The ovarian response to chemical exposure can determine the extent of ovotoxicity that occurs. Enzymes capable of bioactivating as well as detoxifying xenobiotics are expressed in the ovary and their impact onmore » ovotoxicity has been partially characterized for trichloroethylene, 7,12-dimethylbenz[a]anthracene, and 4-vinylcyclohexene. This review will discuss those studies, as well as illustrate where knowledge gaps remain for chemicals that have also been established as ovotoxicants. -- Highlights: ► Summary of ovotoxicant action during ovotoxicity. ► Discussion of impact of biotransformation on chemical toxicity. ► Identification of knowledge gaps in chemical metabolism.« less

Effects of Brown Rice and White Rice on Expression of Xenobiotic Metabolism Genes in Type 2 Diabetic Rats

PubMed Central

Imam, Mustapha Umar; Ismail, Maznah

2012-01-01

Xenobiotics constantly influence biological systems through several means of interaction. These interactions are disturbed in type 2 diabetes, with implications for disease outcome. We aimed to study the implications of such disturbances on type 2 diabetes and rice consumption, the results of which could affect management of the disease in developing countries. In a type 2 diabetic rat model induced through a combination of high fat diet and low dose streptozotocin injection, up-regulation of xenobiotic metabolism genes in the diabetic untreated group was observed. Xenobiotic metabolism genes were upregulated more in the white rice (WR) group than the diabetic untreated group while the brown rice (BR) group showed significantly lower expression values, though not as effective as metformin, which gave values closer to the normal non-diabetic group. The fold changes in expression in the WR group compared to the BR group for Cyp2D4, Cyp3A1, Cyp4A1, Cyp2B1, Cyp2E1, Cyp2C11, UGT2B1, ALDH1A1 and Cyp2C6 were 2.6, 2, 1.5, 4, 2.8, 1.5, 1.8, 3 and 5, respectively. Our results suggest that WR may upregulate these genes in type 2 diabetes more than BR, potentially causing faster drug metabolism, less drug efficacy and more toxicity. These results may have profound implications for rice eating populations, constituting half the world’s population. PMID:22942722

Comparative genomic, phylogenetic, and functional investigation of the xenobiotic metabolizing arylamine N-acetyltransferase enzyme family among fungi

USDA-ARS?s Scientific Manuscript database

Arylamine N-acetyltransferases (NATs) are xenobiotic metabolizing enzymes well-characterized in several bacteria and higher eukaryotes. The role of NATs in fungal biology has only recently been investigated (Glenn and Bacon, 2009; Glenn et al., 2010). The NAT1 gene of Gibberella moniliformis was the...

Control of adaptive optic element displacement with the help of a magnetic rheology drive

NASA Astrophysics Data System (ADS)

Deulin, Eugeni A.; Mikhailov, Valeri P.; Sytchev, Victor V.

2000-10-01

The control system of adaptive optic of a large astronomical segmentated telescope was designed and tested. The dynamic model and the amplitude-frequency analysis of the new magnetic rheology (MR) drive are presented. The loop controlled drive consists of hydrostatic carrier, MR hydraulic loop controlling system, elastic thin wall seal, stainless seal which are united in a single three coordinate manipulator. This combination ensures short positioning error (delta) (phi) response. The main feature of a large astronomical telescope (diameter 25 m) is the large number (in our case 512) of primary mirror segments usage, which are united in one reflecting system. This design makes easier the problem of the primary mirror manufacturing but brings another problem to ensure precise movement of every mirror segment movement and to provides a perfect coincidence of the mirror segments constantly. Suggested parameters of the drive, based on magnetic rheology (MR) liquid are: precision (delta) (phi) response Tcontrolled MR drive may be expressed: (delta) (phi) equals (delta) r + (delta) db + (delta) f + (delta) i, where (delta) r -- 'reproduction' error (depends on drive structure and controlling system, and in our case the drive ensures (delta) r equals 0); (delta) db -- 'disturbance' error ((delta) db equals 5...10 nm); (delta) f -- error, because of static friction forces action ((delta) f equals kt (DOT) Fst equals 2 (DOT) Is/ki equals 30 nm, where kt -- transformation coefficient of the drive; Fst -- static force in the drive; Is -- 'starting' current in the drive; ki -- transformation coefficient of the measuring system); (delta) i -- 'instrumental' error. In case of a laser interferometer usage (delta) i equals 10 nm and the summarized error is (delta) (phi) response T of the drive depends mainly on the combination of time constants of the next elements: MR-valve Tm

Xenobiotic-metabolizing enzymes in Bacillus anthracis: molecular and functional analysis of a truncated arylamine N-acetyltransferase isozyme.

PubMed

Kubiak, Xavier; Duval, Romain; Pluvinage, Benjamin; Chaffotte, Alain F; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

2017-07-01

The arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes that play an important role in the detoxification and/or bioactivation of arylamine drugs and xenobiotics. In bacteria, NATs may contribute to the resistance against antibiotics such as isoniazid or sulfamides through their acetylation, which makes this enzyme family a possible drug target. Bacillus anthracis, a bacterial species of clinical significance, expresses three NAT isozymes with distinct structural and enzymatic properties, including an inactive isozyme ((BACAN)NAT3). (BACAN)NAT3 features both a non-canonical Glu residue in its catalytic triad and a truncated C-terminus domain. However, the role these unusual characteristics play in the lack of activity of the (BACAN)NAT3 isozyme remains unclear. Protein engineering, recombinant expression, enzymatic analyses with aromatic amine substrates and phylogenetic analysis approaches were conducted. The deletion of guanine 580 (G580) in the nat3 gene was shown to be responsible for the expression of a truncated (BACAN)NAT3 isozyme. Artificial re-introduction of G580 in the nat3 gene led to a functional enzyme able to acetylate several arylamine drugs displaying structural characteristics comparable with its functional Bacillus cereus homologue ((BACCR)NAT3). Phylogenetic analysis of the nat3 gene in the B. cereus group further indicated that nat3 may constitute a pseudogene of the B. anthracis species. The existence of NATs with distinct properties and evolution in Bacillus species may account for their adaptation to their diverse chemical environments. A better understanding of these isozymes is of importance for their possible use as drug targets. This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc. © 2016 The British Pharmacological Society.

Response of hot element flush wall gauges in oscillating laminar flow

NASA Technical Reports Server (NTRS)

Giddings, T. A.; Cook, W. J.

1986-01-01

The time dependent response characteristics of flush-mounted hot element gauges used as instruments to measure wall shear stress in unsteady periodic air flows were investigated. The study was initiated because anomalous results were obtained from the gauges in oscillating turbulent flows for the phase relation of the wall shear stress variation, indicating possible gauge response problems. Flat plate laminar oscillating turbulent flows characterized by a mean free stream velocity with a superposed sinusoidal variation were performed. Laminar rather than turbulent flows were studied, because a numerical solution for the phase angle between the free stream velocity and the wall shear stress variation that is known to be correct can be obtained. The focus is on comparing the phase angle indicated by the hot element gauges with corresponding numerical prediction for the phase angle, since agreement would indicate that the hot element gauges faithfully follow the true wall shear stress variation.

Natural allelic variations of xenobiotic-metabolizing enzymes affect sexual dimorphism in Oryzias latipes.

PubMed

Katsumura, Takafumi; Oda, Shoji; Nakagome, Shigeki; Hanihara, Tsunehiko; Kataoka, Hiroshi; Mitani, Hiroshi; Kawamura, Shoji; Oota, Hiroki

2014-12-22

Sexual dimorphisms, which are phenotypic differences between males and females, are driven by sexual selection. Interestingly, sexually selected traits show geographical variations within species despite strong directional selective pressures. This paradox has eluded many evolutionary biologists for some time, and several models have been proposed (e.g. 'indicator model' and 'trade-off model'). However, disentangling which of these theories explains empirical patterns remains difficult, because genetic polymorphisms that cause variation in sexual differences are still unknown. In this study, we show that polymorphisms in cytochrome P450 (CYP) 1B1, which encodes a xenobiotic-metabolizing enzyme, are associated with geographical differences in sexual dimorphism in the anal fin morphology of medaka fish (Oryzias latipes). Biochemical assays and genetic cross experiments show that high- and low-activity CYP1B1 alleles enhanced and declined sex differences in anal fin shapes, respectively. Behavioural and phylogenetic analyses suggest maintenance of the high-activity allele by sexual selection, whereas the low-activity allele possibly has experienced positive selection due to by-product effects of CYP1B1 in inferred ancestral populations. The present data can elucidate evolutionary mechanisms behind genetic variations in sexual dimorphism and indicate trade-off interactions between two distinct mechanisms acting on the two alleles with pleiotropic effects of xenobiotic-metabolizing enzymes. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Environmental controls on the elemental composition of a Southern Hemisphere strain of the coccolithophore Emiliania huxleyi

NASA Astrophysics Data System (ADS)

Feng, Yuanyuan; Roleda, Michael Y.; Armstrong, Evelyn; Law, Cliff S.; Boyd, Philip W.; Hurd, Catriona L.

2018-01-01

A series of semi-continuous incubation experiments were conducted with the coccolithophore Emiliania huxleyi strain NIWA1108 (Southern Ocean isolate) to examine the effects of five environmental drivers (nitrate and phosphate concentrations, irradiance, temperature, and partial pressure of CO2 (pCO2)) on both the physiological rates and elemental composition of the coccolithophore. Here, we report the alteration of the elemental composition of E. huxleyi in response to the changes in these environmental drivers. A series of dose-response curves for the cellular elemental composition of E. huxleyi were fitted for each of the five drivers across an environmentally representative gradient. The importance of each driver in regulating the elemental composition of E. huxleyi was ranked using a semi-quantitative approach. The percentage variations in elemental composition arising from the change in each driver between present-day and model-projected conditions for the year 2100 were calculated. Temperature was the most important driver controlling both cellular particulate organic and inorganic carbon content, whereas nutrient concentrations were the most important regulator of cellular particulate nitrogen and phosphorus of E. huxleyi. In contrast, elevated pCO2 had the greatest influence on cellular particulate inorganic carbon to organic carbon ratio, resulting in a decrease in the ratio. Our results indicate that the different environmental drivers play specific roles in regulating the elemental composition of E. huxleyi with wide-reaching implications for coccolithophore-related marine biogeochemical cycles, as a consequence of the regulation of E. huxleyi physiological processes.

Ethanol Extract of Cirsium japonicum var. ussuriense Kitamura Exhibits the Activation of Nuclear Factor Erythroid 2-Related Factor 2-dependent Antioxidant Response Element and Protects Human Keratinocyte HaCaT Cells Against Oxidative DNA Damage.

PubMed

Yoo, Ok-Kyung; Choi, Bu Young; Park, Jin-Oh; Lee, Ji-Won; Park, Byoung-Kwon; Joo, Chul Gue; Heo, Hyo-Jung; Keum, Young-Sam

2016-03-01

Keratinocytes are constantly exposed to extracellular insults, such as ultraviolet B, toxic chemicals and mechanical stress, all of which can facilitate the aging of keratinocytes via the generation of intracellular reactive oxygen species (ROS). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting keratinocytes against oxidants and xenobiotics by binding to the antioxidant response element (ARE), a cis-acting element existing in the promoter of most phase II cytoprotective genes. In the present study, we have attempted to find novel ethanol extract(s) of indigenous plants of Jeju island, Korea that can activate the Nrf2/ARE-dependent gene expression in human keratinocyte HaCaT cells. As a result, we identified that ethanol extract of Cirsium japonicum var. ussuriense Kitamura (ECJUK) elicited strong stimulatory effect on the ARE-dependent gene expression. Supporting this observation, we found that ECJUK induced the expression of Nrf2, hemoxygenase-1, and quinone oxidoreductase-1 and this event was correlated with Akt1 phosphorylation. We also found that ECJUK increased the intracellular reduced glutathione level and suppressed 12-O-tetradecanoylphorbol acetate-induced 8-hydroxyguanosine formation without affecting the overall viability. Collectively, our results provide evidence that ECJUK can protect against oxidative stress-mediated damages through the activation of Nrf2/ARE-dependent phase II cytoprotective gene expression.

Development of an hp-version finite element method for computational optimal control

NASA Technical Reports Server (NTRS)

Hodges, Dewey H.; Warner, Michael S.

1993-01-01

The purpose of this research effort was to begin the study of the application of hp-version finite elements to the numerical solution of optimal control problems. Under NAG-939, the hybrid MACSYMA/FORTRAN code GENCODE was developed which utilized h-version finite elements to successfully approximate solutions to a wide class of optimal control problems. In that code the means for improvement of the solution was the refinement of the time-discretization mesh. With the extension to hp-version finite elements, the degrees of freedom include both nodal values and extra interior values associated with the unknown states, co-states, and controls, the number of which depends on the order of the shape functions in each element. One possible drawback is the increased computational effort within each element required in implementing hp-version finite elements. We are trying to determine whether this computational effort is sufficiently offset by the reduction in the number of time elements used and improved Newton-Raphson convergence so as to be useful in solving optimal control problems in real time. Because certain of the element interior unknowns can be eliminated at the element level by solving a small set of nonlinear algebraic equations in which the nodal values are taken as given, the scheme may turn out to be especially powerful in a parallel computing environment. A different processor could be assigned to each element. The number of processors, strictly speaking, is not required to be any larger than the number of sub-regions which are free of discontinuities of any kind.

Adaptive beam shaping by controlled thermal lensing in optical elements

NASA Astrophysics Data System (ADS)

Arain, Muzammil A.; Quetschke, Volker; Gleason, Joseph; Williams, Luke F.; Rakhmanov, Malik; Lee, Jinho; Cruz, Rachel J.; Mueller, Guido; Tanner, D. B.; Reitze, David. H.

2007-04-01

We describe an adaptive optical system for use as a tunable focusing element. The system provides adaptive beam shaping via controlled thermal lensing in the optical elements. The system is agile, remotely controllable, touch free, and vacuum compatible; it offers a wide dynamic range, aberration-free focal length tuning, and can provide both positive and negative lensing effects. Focusing is obtained through dynamic heating of an optical element by an external pump beam. The system is especially suitable for use in interferometric gravitational wave interferometers employing high laser power, allowing for in situ control of the laser modal properties and compensation for thermal lensing of the primary laser. Using CO2 laser heating of fused-silica substrates, we demonstrate a focal length variable from infinity to 4.0 m, with a slope of 0.082 diopter/W of absorbed heat. For on-axis operation, no higher-order modes are introduced by the adaptive optical element. Theoretical modeling of the induced optical path change and predicted thermal lens agrees well with measurement.

Adaptive beam shaping by controlled thermal lensing in optical elements.

PubMed

Arain, Muzammil A; Quetschke, Volker; Gleason, Joseph; Williams, Luke F; Rakhmanov, Malik; Lee, Jinho; Cruz, Rachel J; Mueller, Guido; Tanner, D B; Reitze, David H

2007-04-20

We describe an adaptive optical system for use as a tunable focusing element. The system provides adaptive beam shaping via controlled thermal lensing in the optical elements. The system is agile, remotely controllable, touch free, and vacuum compatible; it offers a wide dynamic range, aberration-free focal length tuning, and can provide both positive and negative lensing effects. Focusing is obtained through dynamic heating of an optical element by an external pump beam. The system is especially suitable for use in interferometric gravitational wave interferometers employing high laser power, allowing for in situ control of the laser modal properties and compensation for thermal lensing of the primary laser. Using CO(2) laser heating of fused-silica substrates, we demonstrate a focal length variable from infinity to 4.0 m, with a slope of 0.082 diopter/W of absorbed heat. For on-axis operation, no higher-order modes are introduced by the adaptive optical element. Theoretical modeling of the induced optical path change and predicted thermal lens agrees well with measurement.

33 CFR Appendix C to Part 155 - Training Elements for Oil Spill Response Plans

Code of Federal Regulations, 2010 CFR

2010-07-01

... Response Plans C Appendix C to Part 155 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND.... 155, App. C Appendix C to Part 155—Training Elements for Oil Spill Response Plans 1. General 1.1The....3The material in this appendix C is not all-inclusive and is provided for guidance only. 2. Elements To...

Effects of Sublethal Exposure to a Glyphosate-Based Herbicide Formulation on Metabolic Activities of Different Xenobiotic-Metabolizing Enzymes in Rats.

PubMed

Larsen, Karen; Najle, Roberto; Lifschitz, Adrián; Maté, María L; Lanusse, Carlos; Virkel, Guillermo L

2014-07-01

The activities of different xenobiotic-metabolizing enzymes in liver subcellular fractions from Wistar rats exposed to a glyphosate (GLP)-based herbicide (Roundup full II) were evaluated in this work. Exposure to the herbicide triggered protective mechanisms against oxidative stress (increased glutathione peroxidase activity and total glutathione levels). Liver microsomes from both male and female rats exposed to the herbicide had lower (45%-54%, P < 0.01) hepatic cytochrome P450 (CYP) levels compared to their respective control animals. In female rats, the hepatic 7-ethoxycoumarin O-deethylase (a general CYP-dependent enzyme activity) was 57% higher (P < 0.05) in herbicide-exposed compared to control animals. Conversely, this enzyme activity was 58% lower (P < 0.05) in male rats receiving the herbicide. Lower (P < 0.05) 7-ethoxyresorufin O-deethlyase (EROD, CYP1A1/2 dependent) and oleandomycin triacetate (TAO) N-demethylase (CYP3A dependent) enzyme activities were observed in liver microsomes from exposed male rats. Conversely, in females receiving the herbicide, EROD increased (123%-168%, P < 0.05), whereas TAO N-demethylase did not change. A higher (158%-179%, P < 0.01) benzyloxyresorufin O-debenzylase (a CYP2B-dependent enzyme activity) activity was only observed in herbicide-exposed female rats. In herbicide-exposed rats, the hepatic S-oxidation of methimazole (flavin monooxygenase dependent) was 49% to 62% lower (P < 0.001), whereas the carbonyl reduction of menadione (a cytosolic carbonyl reductase-dependent activity) was higher (P < 0.05). Exposure to the herbicide had no effects on enzymatic activities dependent on carboxylesterases, glutathione transferases, and uridinediphospho-glucuronosyltransferases. This research demonstrated certain biochemical modifications after exposure to a GLP-based herbicide. Such modifications may affect the metabolic fate of different endobiotic and xenobiotic substances. The pharmacotoxicological significance of these

Functioning of Microsomal Cytochrome P450s: Murburn Concept Explains the Metabolism of Xenobiotics in Hepatocytes.

PubMed

Manoj, Kelath Murali; Parashar, Abhinav; Gade, Sudeep K; Venkatachalam, Avanthika

2016-01-01

Using oxygen and NADPH, the redox enzymes cytochrome P450 (CYP) and its reductase (CPR) work in tandem to carry out the phase I metabolism of a vast majority of drugs and xenobiotics. As per the erstwhile understanding of the catalytic cycle, binding of the substrate to CYP's heme distal pocket allows CPR to pump electrons through a CPR-CYP complex. In turn, this trigger (a thermodynamic push of electrons) leads to the activation of oxygen at CYP's heme-center, to give Compound I, a two-electron deficient enzyme reactive intermediate. The formation of diffusible radicals and reactive oxygen species (DROS, hitherto considered an undesired facet of the system) was attributed to the heme-center. Recently, we had challenged these perceptions and proposed the murburn ("mured burning" or "mild unrestricted burning") concept to explain heme enzymes' catalytic mechanism, electron-transfer phenomena and the regulation of redox equivalents' consumption. Murburn concept incorporates a one-electron paradigm, advocating obligatory roles for DROS. The new understanding does not call for high-affinity substrate-binding at the heme distal pocket of the CYP (the first and the most crucial step of the erstwhile paradigm) or CYP-CPR protein-protein complexations (the operational backbone of the erstwhile cycle). Herein, the dynamics of reduced nicotinamide nucleotides' consumption, peroxide formation and depletion, product(s) formation, etc. was investigated with various controls, by altering reaction variables, environments and through the incorporation of diverse molecular probes. In several CYP systems, control reactions lacking the specific substrate showed comparable or higher peroxide in milieu, thereby discrediting the foundations of the erstwhile hypothesis. The profiles obtained by altering CYP:CPR ratios and the profound inhibitions observed upon the incorporation of catalytic amounts of horseradish peroxidase confirm the obligatory roles of DROS in milieu, ratifying

Development of an hp-version finite element method for computational optimal control

NASA Technical Reports Server (NTRS)

Hodges, Dewey H.; Warner, Michael S.

1993-01-01

The purpose of this research effort is to develop a means to use, and to ultimately implement, hp-version finite elements in the numerical solution of optimal control problems. The hybrid MACSYMA/FORTRAN code GENCODE was developed which utilized h-version finite elements to successfully approximate solutions to a wide class of optimal control problems. In that code the means for improvement of the solution was the refinement of the time-discretization mesh. With the extension to hp-version finite elements, the degrees of freedom include both nodal values and extra interior values associated with the unknown states, co-states, and controls, the number of which depends on the order of the shape functions in each element.

Finite Element Analysis of Adaptive-Stiffening and Shape-Control SMA Hybrid Composites

NASA Technical Reports Server (NTRS)

Gao, Xiujie; Burton, Deborah; Turner, Travis L.; Brinson, Catherine

2005-01-01

Shape memory alloy hybrid composites with adaptive-stiffening or morphing functions are simulated using finite element analysis. The composite structure is a laminated fiber-polymer composite beam with embedded SMA ribbons at various positions with respect to the neutral axis of the beam. Adaptive stiffening or morphing is activated via selective resistance heating of the SMA ribbons or uniform thermal loads on the beam. The thermomechanical behavior of these composites was simulated in ABAQUS using user-defined SMA elements. The examples demonstrate the usefulness of the methods for the design and simulation of SMA hybrid composites. Keywords: shape memory alloys, Nitinol, ABAQUS, finite element analysis, post-buckling control, shape control, deflection control, adaptive stiffening, morphing, constitutive modeling, user element

Molecular analysis of UAS(E), a cis element containing stress response elements responsible for ethanol induction of the KlADH4 gene of Kluyveromyces lactis.

PubMed

Mazzoni, C; Santori, F; Saliola, M; Falcone, C

2000-01-01

KlADH4 is a gene of Kluyveromyces lactis encoding a mitochondrial alcohol dehydrogenase activity, which is specifically induced by ethanol and insensitive to glucose repression. In this work, we report the molecular analysis of UAS(E), an element of the KlADH4 promoter which is essential for the induction of KlADH4 in the presence of ethanol. UAS(E) contains five stress response elements (STREs), which have been found in many genes of Saccharomyces cerevisiae involved in the response of cells to conditions of stress. Whereas KlADH4 is not responsive to stress conditions, the STREs present in UAS(E) seem to play a key role in the induction of the gene by ethanol, a situation that has not been observed in the related yeast S. cerevisiae. Gel retardation experiments showed that STREs in the KlADH4 promoter can bind factor(s) under non-inducing conditions. Moreover, we observed that the RAP1 binding site present in UAS(E) binds KlRap1p.

Key metabolic pathways involved in xenobiotic biotransformation and stress responses revealed by transcriptomics of the mangrove oyster Crassostrea brasiliana.

PubMed

Lüchmann, Karim H; Clark, Melody S; Bainy, Afonso C D; Gilbert, Jack A; Craft, John A; Chipman, J Kevin; Thorne, Michael A S; Mattos, Jacó J; Siebert, Marília N; Schroeder, Declan C

2015-09-01

The Brazilian oyster Crassostrea brasiliana was challenged to three common environmental contaminants: phenanthrene, diesel fuel water-accommodated fraction (WAF) and domestic sewage. Total RNA was extracted from the gill and digestive gland, and cDNA libraries were sequenced using the 454 FLX platform. The assembled transcriptome resulted in ̃20,000 contigs, which were annotated to produce the first de novo transcriptome for C. brasiliana. Sequences were screened to identify genes potentially involved in the biotransformation of xenobiotics and associated antioxidant defence mechanisms. These gene families included those of the cytochrome P450 (CYP450), 70kDa heat shock, antioxidants, such as glutathione S-transferase, superoxide dismutase, catalase and also multi-drug resistance proteins. Analysis showed that the massive expansion of the CYP450 and HSP70 family due to gene duplication identified in the Crassostrea gigas genome also occurred in C. brasiliana, suggesting these processes form the base of the Crassostrea lineage. Preliminary expression analyses revealed several candidates biomarker genes that were up-regulated during each of the three treatments, suggesting the potential for environmental monitoring. Copyright © 2015 Elsevier B.V. All rights reserved.

Involvement of the sieve element cytoskeleton in electrical responses to cold shocks.

PubMed

Hafke, Jens B; Ehlers, Katrin; Föller, Jens; Höll, Sabina-Roxana; Becker, Stefanie; van Bel, Aart J E

2013-06-01

This study dealt with the visualization of the sieve element (SE) cytoskeleton and its involvement in electrical responses to local cold shocks, exemplifying the role of the cytoskeleton in Ca(2+)-triggered signal cascades in SEs. High-affinity fluorescent phalloidin as well as immunocytochemistry using anti-actin antibodies demonstrated a fully developed parietal actin meshwork in SEs. The involvement of the cytoskeleton in electrical responses and forisome conformation changes as indicators of Ca(2+) influx was investigated by the application of cold shocks in the presence of diverse actin disruptors (latrunculin A and cytochalasin D). Under control conditions, cold shocks elicited a graded initial voltage transient, ΔV1, reduced by external La(3+) in keeping with the involvement of Ca(2+) channels, and a second voltage transient, ΔV2. Cytochalasin D had no effect on ΔV1, while ΔV1 was significantly reduced with 500 nm latrunculin A. Forisome dispersion was triggered by cold shocks of 4°C or greater, which was indicative of an all-or-none behavior. Forisome dispersion was suppressed by incubation with latrunculin A. In conclusion, the cytoskeleton controls cold shock-induced Ca(2+) influx into SEs, leading to forisome dispersion and sieve plate occlusion in fava bean (Vicia faba).

A Compilation of In Vitro Rate and Affinity Values for Xenobiotic Biotransformation in Fish, Measured Under Physiological Conditions

EPA Science Inventory

This manuscript presents a summary of in vitro rate and affinity data for xenobiotic biotransformation enzymes in fish...One potential use of this data summary is to support in vitro to in vivo metabolism extrapolations which can be used as inputs to chemical kinetic models for f...

Characterization of the small heat shock protein Hsp27 gene in Chironomus riparius (Diptera) and its expression profile in response to temperature changes and xenobiotic exposures.

PubMed

Martínez-Paz, Pedro; Morales, Mónica; Martín, Raquel; Martínez-Guitarte, José Luis; Morcillo, Gloria

2014-07-01

Small heat shock proteins constitute the most diverse and least conserved group within the large family of heat shock proteins, which play a crucial role in cell response to environmental insults. Chironomus riparius larvae are widely used in environmental research for testing pollutant toxicity in sediments and freshwater environments. Different genes, such as Hsp70, Hsc70, Hsp90, and Hsp40, have been identified in this species as sensitive biomarkers for xenobiotics, but small Hsps genes remain largely unknown. In this study, the Hsp27 has been characterized in C. riparius and its transcriptional response evaluated under several environmental stimuli. The Hsp27 gene was mapped by FISH on polytene chromosomes at region I-C4 and was found to encode a 195 aa protein, which contains an α-crystallin domain bounded by three conserved regions. This protein shows homology with Drosophila melanogaster HSP27, Ceratitis capitata HSP27, and Sarcophaga crassipalpis HSP25. Real-time reverse transcriptase-polymerase chain reaction analysis showed that heat shock (35 °C) and cadmium dramatically upregulate this gene. Moreover, exposures to triclosan and bisphenol A were able to significantly increase mRNA levels. However, neither nonylphenol nor tributyltin altered Hsp27 gene expression. The transcriptional activity of Hsp27 gene was modulated during cold stress. Interestingly, cold shock (4 °C) significantly reduced Hsp27 transcripts, but this gene was significantly overexpressed during the recovery time at the normal growing temperature. These results show that the Hsp27 gene is sensitive to different environmental stimuli, including endocrine-disrupting pollutants, suggesting its potential as a suitable biomarker for ecotoxicological studies in aquatic systems.

Selection of Reference Genes for Expression Studies of Xenobiotic Adaptation in Tetranychus urticae.

PubMed

Morales, Mariany Ashanty; Mendoza, Bianca Marie; Lavine, Laura Corley; Lavine, Mark Daniel; Walsh, Douglas Bruce; Zhu, Fang

2016-01-01

Quantitative real-time PCR (qRT-PCR) is an extensively used, high-throughput method to analyze transcriptional expression of genes of interest. An appropriate normalization strategy with reliable reference genes is required for calculating gene expression across diverse experimental conditions. In this study, we aim to identify the most stable reference genes for expression studies of xenobiotic adaptation in Tetranychus urticae, an extremely polyphagous herbivore causing significant yield reduction of agriculture. We chose eight commonly used housekeeping genes as candidates. The qRT-PCR expression data for these genes were evaluated from seven populations: a susceptible and three acaricide resistant populations feeding on lima beans, and three other susceptible populations which had been shifted host from lima beans to three other plant species. The stability of the candidate reference genes was then assessed using four different algorithms (comparative ΔCt method, geNorm, NormFinder, and BestKeeper). Additionally, we used an online web-based tool (RefFinder) to assign an overall final rank for each candidate gene. Our study found that CycA and Rp49 are best for investigating gene expression in acaricide susceptible and resistant populations. GAPDH, Rp49, and Rpl18 are best for host plant shift studies. And GAPDH and Rp49 were the most stable reference genes when investigating gene expression under changes in both experimental conditions. These results will facilitate research in revealing molecular mechanisms underlying the xenobiotic adaptation of this notorious agricultural pest.

Selection of Reference Genes for Expression Studies of Xenobiotic Adaptation in Tetranychus urticae

PubMed Central

Morales, Mariany Ashanty; Mendoza, Bianca Marie; Lavine, Laura Corley; Lavine, Mark Daniel; Walsh, Douglas Bruce; Zhu, Fang

2016-01-01

Quantitative real-time PCR (qRT-PCR) is an extensively used, high-throughput method to analyze transcriptional expression of genes of interest. An appropriate normalization strategy with reliable reference genes is required for calculating gene expression across diverse experimental conditions. In this study, we aim to identify the most stable reference genes for expression studies of xenobiotic adaptation in Tetranychus urticae, an extremely polyphagous herbivore causing significant yield reduction of agriculture. We chose eight commonly used housekeeping genes as candidates. The qRT-PCR expression data for these genes were evaluated from seven populations: a susceptible and three acaricide resistant populations feeding on lima beans, and three other susceptible populations which had been shifted host from lima beans to three other plant species. The stability of the candidate reference genes was then assessed using four different algorithms (comparative ΔCt method, geNorm, NormFinder, and BestKeeper). Additionally, we used an online web-based tool (RefFinder) to assign an overall final rank for each candidate gene. Our study found that CycA and Rp49 are best for investigating gene expression in acaricide susceptible and resistant populations. GAPDH, Rp49, and Rpl18 are best for host plant shift studies. And GAPDH and Rp49 were the most stable reference genes when investigating gene expression under changes in both experimental conditions. These results will facilitate research in revealing molecular mechanisms underlying the xenobiotic adaptation of this notorious agricultural pest. PMID:27570487

Nonlinear finite element modeling of vibration control of plane rod-type structural members with integrated piezoelectric patches

NASA Astrophysics Data System (ADS)

Chróścielewski, Jacek; Schmidt, Rüdiger; Eremeyev, Victor A.

2018-05-01

This paper addresses modeling and finite element analysis of the transient large-amplitude vibration response of thin rod-type structures (e.g., plane curved beams, arches, ring shells) and its control by integrated piezoelectric layers. A geometrically nonlinear finite beam element for the analysis of piezolaminated structures is developed that is based on the Bernoulli hypothesis and the assumptions of small strains and finite rotations of the normal. The finite element model can be applied to static, stability, and transient analysis of smart structures consisting of a master structure and integrated piezoelectric actuator layers or patches attached to the upper and lower surfaces. Two problems are studied extensively: (i) FE analyses of a clamped semicircular ring shell that has been used as a benchmark problem for linear vibration control in several recent papers are critically reviewed and extended to account for the effects of structural nonlinearity and (ii) a smart circular arch subjected to a hydrostatic pressure load is investigated statically and dynamically in order to study the shift of bifurcation and limit points, eigenfrequencies, and eigenvectors, as well as vibration control for loading conditions which may lead to dynamic loss of stability.

Xenobiotic Compounds Degradation by Heterologous Expression of a Trametes sanguineus Laccase in Trichoderma atroviride

PubMed Central

Balcázar-López, Edgar; Méndez-Lorenzo, Luz Helena; Batista-García, Ramón Alberto; Esquivel-Naranjo, Ulises; Ayala, Marcela; Kumar, Vaidyanathan Vinoth; Savary, Olivier; Cabana, Hubert; Herrera-Estrella, Alfredo; Folch-Mallol, Jorge Luis

2016-01-01

Fungal laccases are enzymes that have been studied because of their ability to decolorize and detoxify effluents; they are also used in paper bleaching, synthesis of polymers, bioremediation, etc. In this work we were able to express a laccase from Trametes (Pycnoporus) sanguineus in the filamentous fungus Trichoderma atroviride. For this purpose, a transformation vector was designed to integrate the gene of interest in an intergenic locus near the blu17 terminator region. Although monosporic selection was still necessary, stable integration at the desired locus was achieved. The native signal peptide from T. sanguineus laccase was successful to secrete the recombinant protein into the culture medium. The purified, heterologously expressed laccase maintained similar properties to those observed in the native enzyme (Km and kcat and kcat/km values for ABTS, thermostability, substrate range, pH optimum, etc). To determine the bioremediation potential of this modified strain, the laccase-overexpressing Trichoderma strain was used to remove xenobiotic compounds. Phenolic compounds present in industrial wastewater and bisphenol A (an endocrine disruptor) from the culture medium were more efficiently removed by this modified strain than with the wild type. In addition, the heterologously expressed laccase was able to decolorize different dyes as well as remove benzo[α]pyrene and phenanthrene in vitro, showing its potential for xenobiotic compound degradation. PMID:26849129

Identification and Characterization of Pathogen-Response Genes (repat) in Spodoptera frugiperda (Lepidoptera: Noctuidae).

PubMed

Machado, Vilmar; Serrano, Jose; Galián, Jose

2016-01-01

The fall armyworm (Spodoptera frugiperda, Noctuidae, Lepidoptera) is one of the most important crop pests in the Americas, causing significant damage to maize, rice and sorghum. The mechanisms that determine its defences against pathogens are particularly relevant for the development of management and control strategies. We used an in silico approach to identify and characterize pathogen response genes (repat) present in different tissue libraries of S. fugiperda. The analyses revealed complete cDNA for nine repat genes; of these, repat15 and repat39 were found in libraries from a specific tissue--the midgut of larvae fed with xenobiotic substances. High expression levels of some genes were found in different libraries: 39 hits in repat30 in challenged hemocytes, 16 hits in repat31 in fat body, 10 hits in repat32 in fat body and 10 in challenged hemocytes, and 10 hits in repat38 in midgut of non-treated larvae and midgut of larvae fed with natural and xenobiotic substances. The genes corresponded to two ontology categories, stress response and immune response, and their phylogenetic relationships, nucleotide similarity, number of amino acid residues and molecular weights agree with what has been described for repat genes. It is noteworthy that proteins encoded by the repat genes of S. frugiperda have important defence functions in other tissues beyond midgut and that their functional categories are likely diverse, as they are related to cell envelope structure, energy metabolism, transport and binding.

Xenobiotic interaction with and alteration of channel catfish estrogen receptor.

PubMed

Nimrod, A C; Benson, W H

1997-12-01

In teleostean in vivo studies, the vitellogenin response to environmental estrogens is not completely predicted by mammalian literature. One possible explanation for differences is heterogeneity of the estrogen receptor (ER) structure between species. Therefore, ER from channel catfish (Ictalurus punctatus) hepatic tissue was characterized by binding affinity for several compounds. Affinity was indirectly measured as potency of the chemical for inhibiting binding of radiolabeled estradiol (E2) to specific binding sites. The order of potency among therapeutic chemicals was ethinylestradiol > unlabeled E2 = diethylstilbestrol > mestranol > tamoxifen > testosterone. Unlabeled E2 had an IC50 of 2.2 nM. Several environmentally relevant chemicals were evaluated in a similar manner and the order of potency established was the o-demethylated metabolite of methoxychlor (MXC) > nonylphenol (NP) > chlordecone > MXC > o,p'-DDT > o,p'-DDE > beta-hexachlorocyclohexane. Demethylated MXC had an IC50 1000-fold greater than that of E2. Of the most potent inhibitors, NP appeared to be a competitive inhibitor for the same binding site as E2, while o-demethylated MXC had a more complex interaction with the receptor protein. ER from nonvitellogenic females was determined to have a Kd value of 1.0 to 1.3 nM. Because E2 has been reported to up-regulate teleostean ER, the hepatic ER population following in vivo xenobiotic exposure was assessed. NP significantly increased ER per milligram hepatic protein almost to the same extent as E2, but did not increase Kd to the same extent as E2.

Efficient techniques for forced response involving linear modal components interconnected by discrete nonlinear connection elements

NASA Astrophysics Data System (ADS)

Avitabile, Peter; O'Callahan, John

2009-01-01

Generally, response analysis of systems containing discrete nonlinear connection elements such as typical mounting connections require the physical finite element system matrices to be used in a direct integration algorithm to compute the nonlinear response analysis solution. Due to the large size of these physical matrices, forced nonlinear response analysis requires significant computational resources. Usually, the individual components of the system are analyzed and tested as separate components and their individual behavior may essentially be linear when compared to the total assembled system. However, the joining of these linear subsystems using highly nonlinear connection elements causes the entire system to become nonlinear. It would be advantageous if these linear modal subsystems could be utilized in the forced nonlinear response analysis since much effort has usually been expended in fine tuning and adjusting the analytical models to reflect the tested subsystem configuration. Several more efficient techniques have been developed to address this class of problem. Three of these techniques given as: equivalent reduced model technique (ERMT);modal modification response technique (MMRT); andcomponent element method (CEM); are presented in this paper and are compared to traditional methods.

SUPPRESSION OF ALLERGIC IMMUNE RESPONSES TO HOUSE DUST MITE (HDM) IN RATS EXPOSED TO 2,3,7,8-TCDD

EPA Science Inventory

Abstract
Exposure to various xenobiotics, including oxidant gases, diesel exhaust and certain pesticides, has been reported to exacerbate pulmonary allergic hypersensitivity responses. Increased lymphocyte proliferative responses to parasite antigens or increased antibody r...

High-throughput metagenomic analysis of petroleum-contaminated soil microbiome reveals the versatility in xenobiotic aromatics metabolism.

PubMed

Bao, Yun-Juan; Xu, Zixiang; Li, Yang; Yao, Zhi; Sun, Jibin; Song, Hui

2017-06-01

The soil with petroleum contamination is one of the most studied soil ecosystems due to its rich microorganisms for hydrocarbon degradation and broad applications in bioremediation. However, our understanding of the genomic properties and functional traits of the soil microbiome is limited. In this study, we used high-throughput metagenomic sequencing to comprehensively study the microbial community from petroleum-contaminated soils near Tianjin Dagang oilfield in eastern China. The analysis reveals that the soil metagenome is characterized by high level of community diversity and metabolic versatility. The metageome community is predominated by γ-Proteobacteria and α-Proteobacteria, which are key players for petroleum hydrocarbon degradation. The functional study demonstrates over-represented enzyme groups and pathways involved in degradation of a broad set of xenobiotic aromatic compounds, including toluene, xylene, chlorobenzoate, aminobenzoate, DDT, methylnaphthalene, and bisphenol. A composite metabolic network is proposed for the identified pathways, thus consolidating our identification of the pathways. The overall data demonstrated the great potential of the studied soil microbiome in the xenobiotic aromatics degradation. The results not only establish a rich reservoir for novel enzyme discovery but also provide putative applications in bioremediation. Copyright © 2016. Published by Elsevier B.V.

Classification and modelling of non-extractable residue (NER) formation from xenobiotics in soil - a synthesis

NASA Astrophysics Data System (ADS)

Kaestner, Matthias; Nowak, Karolina; Miltner, Anja; Trapp, Stefan; Schaeffer, Andreas

2014-05-01

This presentation provides a comprehensive overview about the formation of non-extractable residues (NER) from organic pesticides and contaminants in soil and tries classifying the different types. Anthropogenic organic chemicals are deliberately (e.g. pesticides) or unintentionally (e.g. polyaromatic hydrocarbons [PAH], chlorinated solvents, pharmaceuticals) released in major amounts to nearly all compartments of the environment. Soils and sediments as complex matrices provide a wide variety of binding sites and are the major sinks for these compounds. Many of the xenobiotics entering soil undergo turnover processes and can be volatilised, leached to the groundwater, degraded by microorganisms or taken up and enriched by living organisms. Xenobiotic NER may be derived from parent compounds and primary metabolites that are sequestered (sorbed or entrapped) within the soil organic matter (type I NER) or can be covalently bound (type II NER). Especially type I NER may pose a considerably environmental risk of potential release. However, NER resulting from productive biodegradation, which means the conversion of carbon (or nitrogen) from the compounds into microbial biomass molecules during microbial degradation (type III, bioNER), do not pose any risk. Experimental and analytical approaches to clearly distinguish between the types are provided and a model to prospectively estimate their fate in soil is proposed.

Molecular cloning of a family of xenobiotic-inducible drosophilid cytochrome P450s: Evidence for involvement in host-plant allelochemical resistance

PubMed Central

Danielson, Phillip B.; MacIntyre, Ross J.; Fogleman, James C.

1997-01-01

Cytochrome P450s constitute a superfamily of genes encoding mostly microsomal hemoproteins that play a dominant role in the metabolism of a wide variety of both endogenous and foreign compounds. In insects, xenobiotic metabolism (i.e., metabolism of insecticides and toxic natural plant compounds) is known to involve members of the CYP6 family of cytochrome P450s. Use of a 3′ RACE (rapid amplification of cDNA ends) strategy with a degenerate primer based on the conserved cytochrome P450 heme-binding decapeptide loop resulted in the amplification of four cDNA sequences representing another family of cytochrome P450 genes (CYP28) from two species of isoquinoline alkaloid-resistant Drosophila and the cosmopolitan species Drosophila hydei. The CYP28 family forms a monophyletic clade with strong regional homologies to the vertebrate CYP3 family and the insect CYP6 family (both of which are involved in xenobiotic metabolism) and to the insect CYP9 family (of unknown function). Induction of mRNA levels for three of the CYP28 cytochrome P450s by toxic host-plant allelochemicals (up to 11.5-fold) and phenobarbital (up to 49-fold) corroborates previous in vitro metabolism studies and suggests a potentially important role for the CYP28 family in determining patterns of insect–host-plant relationships through xenobiotic detoxification. PMID:9380713

Environmental Factors and Bioremediation of Xenobiotics Using White Rot Fungi

PubMed Central

Fragoeiro, Silvia; Bastos, Catarina

2010-01-01

This review provides background information on the importance of bioremediation approaches. It describes the roles of fungi, specifically white rot fungi, and their extracellular enzymes, laccases, ligninases, and peroxidises, in the degradation of xenobiotic compounds such as single and mixtures of pesticides. We discuss the importance of abiotic factors such as water potential, temperature, and pH stress when considering an environmental screening approach, and examples are provided of the differential effect of white rot fungi on the degradation of single and mixtures of pesticides using fungi such as Trametes versicolor and Phanerochaete chrysosporium. We also explore the formulation and delivery of fungal bioremedial inoculants to terrestrial ecosystems as well as the use of spent mushroom compost as an approach. Future areas for research and potential exploitation of new techniques are also considered. PMID:23956663

Male Germline Control of Transposable Elements1

PubMed Central

Bao, Jianqiang; Yan, Wei

2012-01-01

ABSTRACT Repetitive sequences, especially transposon-derived interspersed repetitive elements, account for a large fraction of the genome in most eukaryotes. Despite the repetitive nature, these transposable elements display quantitative and qualitative differences even among species of the same lineage. Although transposable elements contribute greatly as a driving force to the biological diversity during evolution, they can induce embryonic lethality and genetic disorders as a result of insertional mutagenesis and genomic rearrangement. Temporary relaxation of the epigenetic control of retrotransposons during early germline development opens a risky window that can allow retrotransposons to escape from host constraints and to propagate abundantly in the host genome. Because germline mutations caused by retrotransposon activation are heritable and thus can be deleterious to the offspring, an adaptive strategy has evolved in host cells, especially in the germline. In this review, we will attempt to summarize general defense mechanisms deployed by the eukaryotic genome, with an emphasis on pathways utilized by the male germline to confer retrotransposon silencing. PMID:22357546

Characteristics of a newly isolated fungus Geotrichum candidum Dec 1 with broad degradation spectrum of xenobiotic compounds.

PubMed

Shoda, M

2003-01-01

A newly isolated fungus, Geotrichum candidum Dec 1 (abbreviated as Dec 1), was found to have the ability to degrade many xenobiotic compounds such as synthetic dyes, food coloring agents, molasses, organic halogens, lignin and kraft pulp effluents. The broad spectrum of the degradation of these compounds are associated mainly with peroxidases produced by the fungus.

Weak Hamiltonian finite element method for optimal control problems

NASA Technical Reports Server (NTRS)

Hodges, Dewey H.; Bless, Robert R.

1991-01-01

A temporal finite element method based on a mixed form of the Hamiltonian weak principle is developed for dynamics and optimal control problems. The mixed form of Hamilton's weak principle contains both displacements and momenta as primary variables that are expanded in terms of nodal values and simple polynomial shape functions. Unlike other forms of Hamilton's principle, however, time derivatives of the momenta and displacements do not appear therein; instead, only the virtual momenta and virtual displacements are differentiated with respect to time. Based on the duality that is observed to exist between the mixed form of Hamilton's weak principle and variational principles governing classical optimal control problems, a temporal finite element formulation of the latter can be developed in a rather straightforward manner. Several well-known problems in dynamics and optimal control are illustrated. The example dynamics problem involves a time-marching problem. As optimal control examples, elementary trajectory optimization problems are treated.

Regulatory elements in vivo in the promoter of the abscisic acid responsive gene rab17 from maize.

PubMed

Busk, P K; Jensen, A B; Pagès, M

1997-06-01

The rab17 gene from maize is transcribed in late embryonic development and is responsive to abscisic acid and water stress in embryo and vegetative tissues. In vivo footprinting and transient transformation of rab17 were performed in embryos and vegetative tissues to characterize the cis-elements involved in regulation of the gene. By in vivo footprinting, protein binding was observed to nine elements in the promoter, which correspond to five putative ABREs (abscisic acid responsive elements) and four other sequences. The footprints indicated that distinct proteins interact with these elements in the two developmental stages. In transient transformation, six of the elements were important for high level expression of the rab17 promoter in embryos, whereas only three elements were important in leaves. The cis-acting sequences can be divided in embryo-specific, ABA-specific and leaf-specific elements on the basis of protein binding and the ability to confer expression of rab17. We found one positive, new element, called GRA, with the sequence CACTGGCCGCCC. This element was important for transcription in leaves but not in embryos. Two other non-ABRE elements that stimulated transcription from the rab17 promoter resemble previously described abscisic acid and drought-inducible elements. There were differences in protein binding and function of the five ABREs in the rab17 promoter. The possible reasons for these differences are discussed. The in vivo data obtained suggest that an embryo-specific pathway regulates transcription of the rab genes during development, whereas another pathway is responsible for induction in response to ABA and drought in vegetative tissues.

Genome-wide analysis of ABA-responsive elements ABRE and CE3 reveals divergent patterns in Arabidopsis and rice

PubMed Central

Gómez-Porras, Judith L; Riaño-Pachón, Diego Mauricio; Dreyer, Ingo; Mayer, Jorge E; Mueller-Roeber, Bernd

2007-01-01

Background In plants, complex regulatory mechanisms are at the core of physiological and developmental processes. The phytohormone abscisic acid (ABA) is involved in the regulation of various such processes, including stomatal closure, seed and bud dormancy, and physiological responses to cold, drought and salinity stress. The underlying tissue or plant-wide control circuits often include combinatorial gene regulatory mechanisms and networks that we are only beginning to unravel with the help of new molecular tools. The increasing availability of genomic sequences and gene expression data enables us to dissect ABA regulatory mechanisms at the individual gene expression level. In this paper we used an in-silico-based approach directed towards genome-wide prediction and identification of specific features of ABA-responsive elements. In particular we analysed the genome-wide occurrence and positional arrangements of two well-described ABA-responsive cis-regulatory elements (CREs), ABRE and CE3, in thale cress (Arabidopsis thaliana) and rice (Oryza sativa). Results Our results show that Arabidopsis and rice use the ABA-responsive elements ABRE and CE3 distinctively. Earlier reports for various monocots have identified CE3 as a coupling element (CE) associated with ABRE. Surprisingly, we found that while ABRE is equally abundant in both species, CE3 is practically absent in Arabidopsis. ABRE-ABRE pairs are common in both genomes, suggesting that these can form functional ABA-responsive complexes (ABRCs) in Arabidopsis and rice. Furthermore, we detected distinct combinations, orientation patterns and DNA strand preferences of ABRE and CE3 motifs in rice gene promoters. Conclusion Our computational analyses revealed distinct recruitment patterns of ABA-responsive CREs in upstream sequences of Arabidopsis and rice. The apparent absence of CE3s in Arabidopsis suggests that another CE pairs with ABRE to establish a functional ABRC capable of interacting with transcription

Genome-wide analysis of ABA-responsive elements ABRE and CE3 reveals divergent patterns in Arabidopsis and rice.

PubMed

Gómez-Porras, Judith L; Riaño-Pachón, Diego Mauricio; Dreyer, Ingo; Mayer, Jorge E; Mueller-Roeber, Bernd

2007-08-01

In plants, complex regulatory mechanisms are at the core of physiological and developmental processes. The phytohormone abscisic acid (ABA) is involved in the regulation of various such processes, including stomatal closure, seed and bud dormancy, and physiological responses to cold, drought and salinity stress. The underlying tissue or plant-wide control circuits often include combinatorial gene regulatory mechanisms and networks that we are only beginning to unravel with the help of new molecular tools. The increasing availability of genomic sequences and gene expression data enables us to dissect ABA regulatory mechanisms at the individual gene expression level. In this paper we used an in-silico-based approach directed towards genome-wide prediction and identification of specific features of ABA-responsive elements. In particular we analysed the genome-wide occurrence and positional arrangements of two well-described ABA-responsive cis-regulatory elements (CREs), ABRE and CE3, in thale cress (Arabidopsis thaliana) and rice (Oryza sativa). Our results show that Arabidopsis and rice use the ABA-responsive elements ABRE and CE3 distinctively. Earlier reports for various monocots have identified CE3 as a coupling element (CE) associated with ABRE. Surprisingly, we found that while ABRE is equally abundant in both species, CE3 is practically absent in Arabidopsis. ABRE-ABRE pairs are common in both genomes, suggesting that these can form functional ABA-responsive complexes (ABRCs) in Arabidopsis and rice. Furthermore, we detected distinct combinations, orientation patterns and DNA strand preferences of ABRE and CE3 motifs in rice gene promoters. Our computational analyses revealed distinct recruitment patterns of ABA-responsive CREs in upstream sequences of Arabidopsis and rice. The apparent absence of CE3s in Arabidopsis suggests that another CE pairs with ABRE to establish a functional ABRC capable of interacting with transcription factors. Further studies will be

Dynamic control of spin states in interacting magnetic elements

DOEpatents

Jain, Shikha; Novosad, Valentyn

2014-10-07

A method for the control of the magnetic states of interacting magnetic elements comprising providing a magnetic structure with a plurality of interacting magnetic elements. The magnetic structure comprises a plurality of magnetic states based on the state of each interacting magnetic element. The desired magnetic state of the magnetic structure is determined. The active resonance frequency and amplitude curve of the desired magnetic state is determined. Each magnetic element of the magnetic structure is then subjected to an alternating magnetic field or electrical current having a frequency and amplitude below the active resonance frequency and amplitude curve of said desired magnetic state and above the active resonance frequency and amplitude curve of the current state of the magnetic structure until the magnetic state of the magnetic structure is at the desired magnetic state.

Specificity determinants for the abscisic acid response element.

PubMed

Sarkar, Aditya Kumar; Lahiri, Ansuman

2013-01-01

Abscisic acid (ABA) response elements (ABREs) are a group of cis-acting DNA elements that have been identified from promoter analysis of many ABA-regulated genes in plants. We are interested in understanding the mechanism of binding specificity between ABREs and a class of bZIP transcription factors known as ABRE binding factors (ABFs). In this work, we have modeled the homodimeric structure of the bZIP domain of ABRE binding factor 1 from Arabidopsis thaliana (AtABF1) and studied its interaction with ACGT core motif-containing ABRE sequences. We have also examined the variation in the stability of the protein-DNA complex upon mutating ABRE sequences using the protein design algorithm FoldX. The high throughput free energy calculations successfully predicted the ability of ABF1 to bind to alternative core motifs like GCGT or AAGT and also rationalized the role of the flanking sequences in determining the specificity of the protein-DNA interaction.

Dynamic response of a sensor element made of magnetic hybrid elastomer with controllable properties

NASA Astrophysics Data System (ADS)

Becker, T. I.; Zimmermann, K.; Borin, D. Yu.; Stepanov, G. V.; Storozhenko, P. A.

2018-03-01

Smart materials like magnetic hybrid elastomers (MHEs) are based on an elastic composite with a complex hybrid filler of magnetically hard and soft particles. Due to their unique magnetic field depending characteristics, these elastomers offer great potential for designing sensor systems with a complex adaptive behaviour and operating sensitivity. The present paper deals with investigations of the material properties and motion behaviour displayed by synthesised MHE beams in the presence of a uniform magnetic field. The distribution and structure formation of the magnetic components inside the elastic matrix depending on the manufacturing conditions are examined. The specific magnetic features of the MHE material during the magnetising process are revealed. Experimental investigations of the in-plane free vibrational behaviour displayed by the MHE beams with the fixed-free end conditions are performed for various magnitudes of an imposed uniform magnetic field. For the samples pre-magnetised along the length axis, it is demonstrated that the deflection of the beam can be identified unambiguously by magnetic field distortion measurements. It is shown that the material properties of the vibrating MHE element can be specifically adjusted by means of an external magnetic field control. The dependence of the first eigenfrequency of free bending vibrations of the MHE beams on the strength of an imposed uniform magnetic field is obtained. The results are aimed to assess the potential of MHEs to design acceleration sensor systems with an adaptive magnetically controllable sensitivity range.

Two Horizontally Transferred Xenobiotic Resistance Gene Clusters Associated with Detoxification of Benzoxazolinones by Fusarium Species

PubMed Central

Glenn, Anthony E.; Davis, C. Britton; Gao, Minglu; Gold, Scott E.; Mitchell, Trevor R.; Proctor, Robert H.; Stewart, Jane E.; Snook, Maurice E.

2016-01-01

Microbes encounter a broad spectrum of antimicrobial compounds in their environments and often possess metabolic strategies to detoxify such xenobiotics. We have previously shown that Fusarium verticillioides, a fungal pathogen of maize known for its production of fumonisin mycotoxins, possesses two unlinked loci, FDB1 and FDB2, necessary for detoxification of antimicrobial compounds produced by maize, including the γ-lactam 2-benzoxazolinone (BOA). In support of these earlier studies, microarray analysis of F. verticillioides exposed to BOA identified the induction of multiple genes at FDB1 and FDB2, indicating the loci consist of gene clusters. One of the FDB1 cluster genes encoded a protein having domain homology to the metallo-β-lactamase (MBL) superfamily. Deletion of this gene (MBL1) rendered F. verticillioides incapable of metabolizing BOA and thus unable to grow on BOA-amended media. Deletion of other FDB1 cluster genes, in particular AMD1 and DLH1, did not affect BOA degradation. Phylogenetic analyses and topology testing of the FDB1 and FDB2 cluster genes suggested two horizontal transfer events among fungi, one being transfer of FDB1 from Fusarium to Colletotrichum, and the second being transfer of the FDB2 cluster from Fusarium to Aspergillus. Together, the results suggest that plant-derived xenobiotics have exerted evolutionary pressure on these fungi, leading to horizontal transfer of genes that enhance fitness or virulence. PMID:26808652

Effects of frying oil and Houttuynia cordata thunb on xenobiotic-metabolizing enzyme system of rodents

PubMed Central

Chen, Ya-Yen; Chen, Chiao-Ming; Chao, Pi-Yu; Chang, Tsan-Ju; Liu, Jen-Fang

2005-01-01

AIM: To evaluate the effects of frying oil and Houttuynia cordata Thunb (H. cordata), a vegetable traditionally consumed in Taiwan, on the xenobiotic-metabolizing enzyme system of rodents. METHODS: Forty-eight Sprague-Dawley rats were fed with a diet containing 0%, 2% or 5% H. cordata powder and 15% fresh soybean oil or 24-h oxidized frying oil (OFO) for 28 d respectively. The level of microsomal protein, total cytochrome 450 content (CYP450) and enzyme activities including NADPH reductase, ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-dealkylase (PROD), aniline hydroxylase (ANH), aminopyrine demethylase (AMD), and quinone reductase (QR) were determined. QR represented phase II enzymes, the rest of the enzymes tested represented phase I enzymes. RESULTS: The oxidized frying oil feeding produced a significant increase in phase I and II enzyme systems, including the content of CYP450 and microsomal protein, and the activities of NADPH reductase, EROD, PROD, ANH, AMD and QR in rats (P<0.05). In addition, the activities of EROD, ANH and AMD decreased and QR increased after feeding with H. cordata in OFO-fed group (P<0.05). The feeding with 2% H. cordata diet showed the most significant effect. CONCLUSION: The OFO diet induces phases I and II enzyme activity, and the 2% H. cordata diet resulted in a better regulation of the xenobiotic-metabolizing enzyme system. PMID:15637750

Application of the control volume mixed finite element method to a triangular discretization

USGS Publications Warehouse

Naff, R.L.

2012-01-01

A two-dimensional control volume mixed finite element method is applied to the elliptic equation. Discretization of the computational domain is based in triangular elements. Shape functions and test functions are formulated on the basis of an equilateral reference triangle with unit edges. A pressure support based on the linear interpolation of elemental edge pressures is used in this formulation. Comparisons are made between results from the standard mixed finite element method and this control volume mixed finite element method. Published 2011. This article is a US Government work and is in the public domain in the USA. ?? 2012 John Wiley & Sons, Ltd. This article is a US Government work and is in the public domain in the USA.

Monocrotophos Induces the Expression and Activity of Xenobiotic Metabolizing Enzymes in Pre-Sensitized Cultured Human Brain Cells

PubMed Central

Tripathi, Vinay K.; Kumar, Vivek; Singh, Abhishek K.; Kashyap, Mahendra P.; Jahan, Sadaf; Pandey, Ankita; Alam, Sarfaraz; Khan, Feroz; Khanna, Vinay K.; Yadav, Sanjay; Lohani, Mohtshim; Pant, Aditya B.

2014-01-01

The expression and metabolic profile of cytochrome P450s (CYPs) is largely missing in human brain due to non-availability of brain tissue. We attempted to address the issue by using human brain neuronal (SH-SY5Y) and glial (U373-MG) cells. The expression and activity of CYP1A1, 2B6 and 2E1 were carried out in the cells exposed to CYP inducers viz., 3-methylcholanthrene (3-MC), cyclophosphamide (CPA), ethanol and known neurotoxicant- monocrotophos (MCP), a widely used organophosphorous pesticide. Both the cells show significant induction in the expression and CYP-specific activity against classical inducers and MCP. The induction level of CYPs was comparatively lower in MCP exposed cells than cells exposed to classical inducers. Pre-exposure (12 h) of cells to classical inducers significantly added the MCP induced CYPs expression and activity. The findings were concurrent with protein ligand docking studies, which show a significant modulatory capacity of MCP by strong interaction with CYP regulators-CAR, PXR and AHR. Similarly, the known CYP inducers- 3-MC, CPA and ethanol have also shown significantly high docking scores with all the three studied CYP regulators. The expression of CYPs in neuronal and glial cells has suggested their possible association with the endogenous physiology of the brain. The findings also suggest the xenobiotic metabolizing capabilities of these cells against MCP, if received a pre-sensitization to trigger the xenobiotic metabolizing machinery. MCP induced CYP-specific activity in neuronal cells could help in explaining its effect on neurotransmission, as these CYPs are known to involve in the synthesis/transport of the neurotransmitters. The induction of CYPs in glial cells is also of significance as these cells are thought to be involved in protecting the neurons from environmental insults and safeguard them from toxicity. The data provide better understanding of the metabolizing capability of the human brain cells against xenobiotics

Ecologically Appropriate Xenobiotics Induce Cytochrome P450s in Apis mellifera

PubMed Central

Johnson, Reed M.; Mao, Wenfu; Pollock, Henry S.; Niu, Guodong; Schuler, Mary A.; Berenbaum, May R.

2012-01-01

Background Honey bees are exposed to phytochemicals through the nectar, pollen and propolis consumed to sustain the colony. They may also encounter mycotoxins produced by Aspergillus fungi infesting pollen in beebread. Moreover, bees are exposed to agricultural pesticides, particularly in-hive acaricides used against the parasite Varroa destructor. They cope with these and other xenobiotics primarily through enzymatic detoxificative processes, but the regulation of detoxificative enzymes in honey bees remains largely unexplored. Methodology/Principal Findings We used several approaches to ascertain effects of dietary toxins on bee susceptibility to synthetic and natural xenobiotics, including the acaricide tau-fluvalinate, the agricultural pesticide imidacloprid, and the naturally occurring mycotoxin aflatoxin. We administered potential inducers of cytochrome P450 enzymes, the principal biochemical system for Phase 1 detoxification in insects, to investigate how detoxification is regulated. The drug phenobarbital induces P450s in many insects, yet feeding bees with phenobarbital had no effect on the toxicity of tau-fluvalinate, a pesticide known to be detoxified by bee P450s. Similarly, no P450 induction, as measured by tau-fluvalinate tolerance, occurred in bees fed xanthotoxin, salicylic acid, or indole-3-carbinol, all of which induce P450s in other insects. Only quercetin, a common pollen and honey constituent, reduced tau-fluvalinate toxicity. In microarray comparisons no change in detoxificative gene expression was detected in phenobarbital-treated bees. However, northern blot analyses of guts of bees fed extracts of honey, pollen and propolis showed elevated expression of three CYP6AS P450 genes. Diet did not influence tau-fluvalinate or imidacloprid toxicity in bioassays; however, aflatoxin toxicity was higher in bees consuming sucrose or high-fructose corn syrup than in bees consuming honey. Conclusions/Significance These results suggest that regulation of

Alterations of serum macro-minerals and trace elements are associated with major depressive disorder: a case-control study.

PubMed

Islam, Md Rabiul; Islam, Md Reazul; Shalahuddin Qusar, M M A; Islam, Mohammad Safiqul; Kabir, Md Humayun; Mustafizur Rahman, G K M; Islam, Md Saiful; Hasnat, Abul

2018-04-10

Major depressive disorder (MDD) is a mixed disorder with the highly irregular course, inconsistent response to treatment and has no well-known mechanism for the pathophysiology. Major causes of depression are genetic, neurobiological, and environmental. However, over the past few years, altered serum levels of macro-minerals (MM) and trace elements (TE) have been recognized as major causative factors to the pathogenesis of many mental disorders. The purpose of this study was to determine the serum levels of MM (calcium and magnesium) and TE (copper, iron, manganese, selenium, and zinc) in MDD patients and find out their associations with depression risk. This prospective case-control study recruited 247 patients and 248 healthy volunteers matched by age and sex. The serum levels of MM and TE were analyzed by atomic absorption spectroscopy (AAS). Statistical analysis was performed with independent sample t-tests and Pearson's correlation test. We found significantly decreased concentrations of calcium and magnesium, iron, manganese, selenium, and zinc in MDD patients compared with control subjects (p < 0.05). But the concentration of copper was significantly increased in the patients than control subjects (p < 0.05). Data obtained from different inter-element relations in MDD patients and control subjects strongly suggest that there is a disturbance in the element homeostasis. Our study suggests that altered serum concentrations of MM and TE are major contributing factors for the pathogenesis of MDD. Alterations of these elements in serum levels of MDD patients arise independently and they may provide a prognostic tool for the assessment of depression risk.

International Space Station Environmental Control and Life Support Emergency Response Verification for Node 1

NASA Technical Reports Server (NTRS)

Williams, David E.

2008-01-01

The International Space Station (ISS) Node 1 Environmental Control and Life Support (ECLS) System is comprised of five subsystems: Atmosphere Control and Supply (ACS), Atmosphere Revitalization (AR), Fire Detection and Suppression (FDS), Temperature and Humidity Control (THC), and Water Recovery and Management (WRM). This paper provides a summary of the Node 1 Emergency Response capability, which includes nominal and off-nominal FDS operation, off nominal ACS operation, and off-nominal THC operation. These subsystems provide the capability to help aid the crew members during an emergency cabin depressurization, a toxic spill, or a fire. The paper will also provide a discussion of the detailed Node 1 ECLS Element Verification methodologies for operation of the Node 1 Emergency Response hardware operations utilized during the Qualification phase.

Active Vibration Control of a Railway Vehicle Carbody Using Piezoelectric Elements

NASA Astrophysics Data System (ADS)

Molatefi, Habibollah; Ayoubi, Pejman; Mozafari, Hozhabr

2017-07-01

In recent years and according to modern transportation development, rail vehicles are manufactured lighter to achieve higher speed and lower transportation costs. On the other hand, weight reduction of rail vehicles leads to increase the structural vibration. In this study, Active Vibration Control of a rail vehicle using piezoelectric elements is investigated. The optimal control employed as the control approach regard to the first two modes of vibration. A simplified Car body structure is modeled in Matlab using the finite element theory by considering six DOF beam element and then the Eigen functions and mode shapes are derived. The surface roughness of different classes of rail tracks have been obtained using random vibration theory and applied to the secondary suspension as the excitation of the structure; Then piezoelectric mounted where the greatest moments were captured. The effectiveness of Piezoelectric in structural vibrations attenuation of car body is demonstrated through the state space equations and its effect on modal coefficient.

Polymorphisms in xenobiotic metabolizing enzymes and diet influence colorectal adenoma risk.

PubMed

Northwood, Emma L; Elliott, Faye; Forman, David; Barrett, Jennifer H; Wilkie, Murray J V; Carey, Francis A; Steele, Robert J C; Wolf, Roland; Bishop, Timothy; Smith, Gillian

2010-05-01

We have earlier shown that diet and xenobiotic metabolizing enzyme genotypes influence colorectal cancer risk, and now investigate whether similar associations are seen in patients with premalignant colorectal adenomas (CRA), recruited during the pilot phase of the Scottish Bowel Screening Programme. Nineteen polymorphisms in 13 genes [cytochrome P450 (P450), glutathione S-transferase (GST), N-acetyl transferase, quinone reductase (NQ01) and microsomal epoxide hydrolase (EPHX1) genes] were genotyped using multiplex PCR or Taqman-based allelic discrimination assays and analyzed in conjunction with diet, assessed by food frequency questionnaire, in a case-control study [317 CRA cases (308 cases genotyped), 296 controls]. Findings significant at a nominal 5% level are reported. CRA risk was inversely associated with fruit (P=0.02, test for trend) and vegetable (P=0.001, test for trend) consumption. P450 CYP2C9*3 heterozygotes had reduced CRA risk compared with homozygotes for the reference allele [odds ratio (OR): 0.60; 95% confidence interval (CI): 0.36-0.99], whereas CYP2D6*4 homozygotes (OR: 2.72; 95% CI: 1.18-6.27) and GSTM1 'null' individuals (OR: 1.43; 95% CI: 1.04-1.98) were at increased risk. The protective effect of fruit consumption was confined to GSTP1 (Ala114Val) reference allele homozygotes (OR: 0.49; 95% CI: 0.34-0.71, P=0.03 for interaction). CRA risk was not associated with meat consumption, although a significant interaction between red meat consumption and EPHX1 (His139Arg) genotype was noted (P=0.02 for interaction). We report the novel associations between P450 genotype and CRA risk, and highlight the risk association with GSTM1 genotype, common to our CRA and cancer case-control series. In addition, we report a novel modifying influence of GSTP1 genotype on dietary chemoprevention. These novel findings require independent confirmation.

Transcriptomic analysis of rice aleurone cells identified a novel abscisic acid response element.

PubMed

Watanabe, Kenneth A; Homayouni, Arielle; Gu, Lingkun; Huang, Kuan-Ying; Ho, Tuan-Hua David; Shen, Qingxi J

2017-09-01

Seeds serve as a great model to study plant responses to drought stress, which is largely mediated by abscisic acid (ABA). The ABA responsive element (ABRE) is a key cis-regulatory element in ABA signalling. However, its consensus sequence (ACGTG(G/T)C) is present in the promoters of only about 40% of ABA-induced genes in rice aleurone cells, suggesting other ABREs may exist. To identify novel ABREs, RNA sequencing was performed on aleurone cells of rice seeds treated with 20 μM ABA. Gibbs sampling was used to identify enriched elements, and particle bombardment-mediated transient expression studies were performed to verify the function. Gene ontology analysis was performed to predict the roles of genes containing the novel ABREs. This study revealed 2443 ABA-inducible genes and a novel ABRE, designated as ABREN, which was experimentally verified to mediate ABA signalling in rice aleurone cells. Many of the ABREN-containing genes are predicted to be involved in stress responses and transcription. Analysis of other species suggests that the ABREN may be monocot specific. This study also revealed interesting expression patterns of genes involved in ABA metabolism and signalling. Collectively, this study advanced our understanding of diverse cis-regulatory sequences and the transcriptomes underlying ABA responses in rice aleurone cells. © 2017 John Wiley & Sons Ltd.

Xenobiotic metabolism in human skin and 3D human skin reconstructs: a review.

PubMed

Gibbs, Sue; van de Sandt, Johannes J M; Merk, Hans F; Lockley, David J; Pendlington, Ruth U; Pease, Camilla K

2007-12-01

In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental chemical exposure, it is also a potential target organ for adverse health effects. Occupational, accidental or intended-use exposure to toxic chemicals could result in acute or delayed injury to the skin (e.g. inflammation, allergy, cancer). Skin metabolism may play a role in the manifestation or amelioration of adverse effects via the topical route. Today, we have robust testing strategies to assess the potential for local skin toxicity of chemical exposure. Such methods (e.g. the local lymph node assay for assessing skin sensitisation; skin painting carcinogenicity studies) incorporate skin metabolism implicitly in the in vivo model system used. In light of recent European legislation (i.e. 7(th) Amendment to the Cosmetics Directive and Registration Evaluation and Authorisation of existing Chemicals (REACH)), non-animal approaches will be required to reduce and replace animal experiments for chemical risk assessment. It is expected that new models and approaches will need to account for skin metabolism explicitly, as the mechanisms of adverse effects in the skin are deconvoluted. 3D skin models have been proposed as a tool to use in new in vitro alternative approaches. In order to be able to use 3D skin models in this context, we need to understand their metabolic competency in relation to xenobiotic biotransformation and whether functional activity is representative of that seen in human skin.

Finite element solution of optimal control problems with state-control inequality constraints

NASA Technical Reports Server (NTRS)

Bless, Robert R.; Hodges, Dewey H.

1992-01-01

It is demonstrated that the weak Hamiltonian finite-element formulation is amenable to the solution of optimal control problems with inequality constraints which are functions of both state and control variables. Difficult problems can be treated on account of the ease with which algebraic equations can be generated before having to specify the problem. These equations yield very accurate solutions. Owing to the sparse structure of the resulting Jacobian, computer solutions can be obtained quickly when the sparsity is exploited.

Xenobiotics that affect oxidative phosphorylation alter differentiation of human adipose-derived stem cells at concentrations that are found in human blood

PubMed Central

Llobet, Laura; Toivonen, Janne M.; Montoya, Julio; Ruiz-Pesini, Eduardo; López-Gallardo, Ester

2015-01-01

ABSTRACT Adipogenesis is accompanied by differentiation of adipose tissue-derived stem cells to adipocytes. As part of this differentiation, biogenesis of the oxidative phosphorylation system occurs. Many chemical compounds used in medicine, agriculture or other human activities affect oxidative phosphorylation function. Therefore, these xenobiotics could alter adipogenesis. We have analyzed the effects on adipocyte differentiation of some xenobiotics that act on the oxidative phosphorylation system. The tested concentrations have been previously reported in human blood. Our results show that pharmaceutical drugs that decrease mitochondrial DNA replication, such as nucleoside reverse transcriptase inhibitors, or inhibitors of mitochondrial protein synthesis, such as ribosomal antibiotics, diminish adipocyte differentiation and leptin secretion. By contrast, the environmental chemical pollutant tributyltin chloride, which inhibits the ATP synthase of the oxidative phosphorylation system, can promote adipocyte differentiation and leptin secretion, leading to obesity and metabolic syndrome as postulated by the obesogen hypothesis. PMID:26398948

A weak Hamiltonian finite element method for optimal control problems

NASA Technical Reports Server (NTRS)

Hodges, Dewey H.; Bless, Robert R.

1989-01-01

A temporal finite element method based on a mixed form of the Hamiltonian weak principle is developed for dynamics and optimal control problems. The mixed form of Hamilton's weak principle contains both displacements and momenta as primary variables that are expanded in terms of nodal values and simple polynomial shape functions. Unlike other forms of Hamilton's principle, however, time derivatives of the momenta and displacements do not appear therein; instead, only the virtual momenta and virtual displacements are differentiated with respect to time. Based on the duality that is observed to exist between the mixed form of Hamilton's weak principle and variational principles governing classical optimal control problems, a temporal finite element formulation of the latter can be developed in a rather straightforward manner. Several well-known problems in dynamics and optimal control are illustrated. The example dynamics problem involves a time-marching problem. As optimal control examples, elementary trajectory optimization problems are treated.

A weak Hamiltonian finite element method for optimal control problems

NASA Technical Reports Server (NTRS)

Hodges, Dewey H.; Bless, Robert R.

1990-01-01

A temporal finite element method based on a mixed form of the Hamiltonian weak principle is developed for dynamics and optimal control problems. The mixed form of Hamilton's weak principle contains both displacements and momenta as primary variables that are expanded in terms of nodal values and simple polynomial shape functions. Unlike other forms of Hamilton's principle, however, time derivatives of the momenta and displacements do not appear therein; instead, only the virtual momenta and virtual displacements are differentiated with respect to time. Based on the duality that is observed to exist between the mixed form of Hamilton's weak principle and variational principles governing classical optimal control problems, a temporal finite element formulation of the latter can be developed in a rather straightforward manner. Several well-known problems in dynamics and optimal control are illustrated. The example dynamics problem involves a time-marching problem. As optimal control examples, elementary trajectory optimization problems are treated.

Two-point method uncertainty during control and measurement of cylindrical element diameters

NASA Astrophysics Data System (ADS)

Glukhov, V. I.; Shalay, V. V.; Radev, H.

2018-04-01

The topic of the article is devoted to the urgent problem of the reliability of technical products geometric specifications measurements. The purpose of the article is to improve the quality of parts linear sizes control by the two-point measurement method. The article task is to investigate methodical extended uncertainties in measuring cylindrical element linear sizes. The investigation method is a geometric modeling of the element surfaces shape and location deviations in a rectangular coordinate system. The studies were carried out for elements of various service use, taking into account their informativeness, corresponding to the kinematic pairs classes in theoretical mechanics and the number of constrained degrees of freedom in the datum element function. Cylindrical elements with informativity of 4, 2, 1 and θ (zero) were investigated. The uncertainties estimation of in two-point measurements was made by comparing the results of of linear dimensions measurements with the functional diameters maximum and minimum of the element material. Methodical uncertainty is formed when cylindrical elements with maximum informativeness have shape deviations of the cut and the curvature types. Methodical uncertainty is formed by measuring the element average size for all types of shape deviations. The two-point measurement method cannot take into account the location deviations of a dimensional element, so its use for elements with informativeness less than the maximum creates unacceptable methodical uncertainties in measurements of the maximum, minimum and medium linear dimensions. Similar methodical uncertainties also exist in the arbitration control of the linear dimensions of the cylindrical elements by limiting two-point gauges.

Activation of the carbohydrate response element binding protein (ChREBP) in response to anoxia in the turtle Trachemys scripta elegans.

PubMed

Krivoruchko, Anastasia; Storey, Kenneth B

2014-10-01

ChREBP (carbohydrate response element binding protein) is a glucose-responsive transcription factor that is known to be an important regulator of glycolytic and lipogenic genes in response to glucose. We hypothesized that activation of ChREBP could be relevant to anoxia survival by the anoxia-tolerant turtle, Trachemys scripta elegans. Expression of ChREBP in response to 5 and 20h of anoxia was examined using RT-PCR and Western immunoblotting. In addition, subcellular localization and DNA-binding activity of ChREBP protein were assessed and transcript levels of liver pyruvate kinase (LPK), a downstream gene under ChREBP control were quantified using RT-PCR. ChREBP was anoxia-responsive in kidney and liver, with transcript levels increasing by 1.2-1.8 fold in response to anoxia and protein levels increasing by 1.8-1.9 fold. Enhanced nuclear presence under anoxia was also observed in both tissues by 2.2-2.8 fold. A 4.2 fold increase in DNA binding activity of ChREBP was also observed in liver in response to 5h of anoxia. In addition, transcript levels of LPK increased by 2.1 fold in response to 5h of anoxia in the liver. The results suggest that activation of ChREBP in response to anoxia might be a crucial factor for anoxia survival in turtle liver by contributing to elevated glycolytic flux in the initial phases of oxygen limitation. This study provides the first demonstration of activation of ChREBP in response to anoxia in a natural model of anoxia tolerance, further improving our understanding of the molecular nature of anoxia tolerance. Copyright © 2014 Elsevier B.V. All rights reserved.

Regulation of insulin-like growth factor I transcription by cyclic adenosine 3',5'-monophosphate (cAMP) in fetal rat bone cells through an element within exon 1: protein kinase A-dependent control without a consensus AMP response element

NASA Technical Reports Server (NTRS)

McCarthy, T. L.; Thomas, M. J.; Centrella, M.; Rotwein, P.

1995-01-01

Insulin-like growth factor I (IGF-I) is a locally synthesized anabolic growth factor for bone. IGF-I synthesis by primary fetal rat osteoblasts (Ob) is stimulated by agents that increase the intracellular cAMP concentration, including prostaglandin E2 (PGE2). Previous studies with Ob cultures demonstrated that PGE2 enhanced IGF-I transcription through selective use of IGF-I promoter 1, with little effect on IGF-I messenger RNA half-life. Transient transfection of Ob cultures with an array of promoter 1-luciferase reporter fusion constructs has now allowed localization of a potential cis-acting promoter element(s) responsible for cAMP-stimulated gene expression to the 5'-untranslated region (5'-UTR) of IGF-I exon 1, within a segment lacking a consensus cAMP response element. Our evidence derives from three principal observations: 1) a transfection construct containing only 122 nucleotides (nt) of promoter 1 and 328 nt of the 5'-UTR retained full PGE2-stimulated reporter expression; 2) maximal PGE2-driven reporter expression required the presence of nt 196 to 328 of exon 1 when tested within the context of IGF-I promoter 1; 3) cotransfection of IGF-I promoter-luciferase-reporter constructs with a plasmid encoding the alpha-isoform of the catalytic subunit of murine cAMP-dependent protein kinase (PKA) produced results comparable to those seen with PGE2 treatment, whereas cotransfection with a plasmid encoding a mutant regulatory subunit of PKA that cannot bind cAMP blocked PGE2-induced reporter expression. Deoxyribonuclease I footprinting of the 5'-UTR of exon 1 demonstrated protected sequences at HS3A, HS3B, and HS3D, three of six DNA-protein binding sites previously characterized with rat liver nuclear extracts. Of these three regions, only the HS3D binding site is located within the functionally identified hormonally responsive segment of IGF-I exon 1. These results directly implicate PKA in the control of IGF-I gene transcription by PGE2 and identify a segment of

Node-controlled allocation of mineral elements in Poaceae.

PubMed

Yamaji, Naoki; Ma, Jian Feng

2017-10-01

Mineral elements taken up by the roots will be delivered to different organs and tissues depending on their requirements. In Poaceae, this selective distribution is mainly mediated in the nodes, which have highly developed and fully organized vascular systems. Inter-vascular transfer of mineral elements from enlarged vascular bundles to diffuse vascular bundles is required for their preferential distribution to developing tissues and reproductive organs. A number of transporters involved in this inter-vascular transfer processes have been identified mainly in rice. They are localized at the different cell layers and form an efficient machinery within the node. Furthermore, some these transporters show rapid response to the environmental changes of mineral elements at the protein level. In addition to the node-based transporters, distinct nodal structures including enlarged xylem area, folded plasma membrane of xylem transfer cells and presence of an apoplastic barrier are also required for the efficient inter-vascular transfer. Manipulation of node-based transporters will provide a novel breeding target to improve nutrient use efficiency, productivity, nutritional value and safety in cereal crops. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cadmium, cobalt and lead cause stress response, cell cycle deregulation and increased steroid as well as xenobiotic metabolism in primary normal human bronchial epithelial cells which is coordinated by at least nine transcription factors.

PubMed

Glahn, Felix; Schmidt-Heck, Wolfgang; Zellmer, Sebastian; Guthke, Reinhard; Wiese, Jan; Golka, Klaus; Hergenröder, Roland; Degen, Gisela H; Lehmann, Thomas; Hermes, Matthias; Schormann, Wiebke; Brulport, Marc; Bauer, Alexander; Bedawy, Essam; Gebhardt, Rolf; Hengstler, Jan G; Foth, Heidi

2008-08-01

Workers occupationally exposed to cadmium, cobalt and lead have been reported to have increased levels of DNA damage. To analyze whether in vivo relevant concentrations of heavy metals cause systematic alterations in RNA expression patterns, we performed a gene array study using primary normal human bronchial epithelial cells. Cells were incubated with 15 microg/l Cd(II), 25 microg/l Co(II) and 550 microg/l Pb(II) either with individual substances or in combination. Differentially expressed genes were filtered out and used to identify enriched GO categories as well as KEGG pathways and to identify transcription factors whose binding sites are enriched in a given set of promoters. Interestingly, combined exposure to Cd(II), Co(II) and Pb(II) caused a coordinated response of at least seven stress response-related transcription factors, namely Oct-1, HIC1, TGIF, CREB, ATF4, SRF and YY1. A stress response was further corroborated by up regulation of genes involved in glutathione metabolism. A second major response to heavy metal exposure was deregulation of the cell cycle as evidenced by down regulation of the transcription factors ELK-1 and the Ets transcription factor GABP, as well as deregulation of genes involved in purine and pyrimidine metabolism. A third and surprising response was up regulation of genes involved in steroid metabolism, whereby promoter analysis identified up regulation of SRY that is known to play a role in sex determination. A forth response was up regulation of xenobiotic metabolising enzymes, particularly of dihydrodiol dehydrogenases 1 and 2 (AKR1C1, AKR1C2). Incubations with individual heavy metals showed that the response of AKR1C1 and AKR1C2 was predominantly caused by lead. In conclusion, we have shown that in vivo relevant concentrations of Cd(II), Co(II) and Pb(II) cause a complex and coordinated response in normal human bronchial epithelial cells. This study gives an overview of the most responsive genes.

Involvement of the Sieve Element Cytoskeleton in Electrical Responses to Cold Shocks1[W

PubMed Central

Hafke, Jens B.; Ehlers, Katrin; Föller, Jens; Höll, Sabina-Roxana; Becker, Stefanie; van Bel, Aart J.E.

2013-01-01

This study dealt with the visualization of the sieve element (SE) cytoskeleton and its involvement in electrical responses to local cold shocks, exemplifying the role of the cytoskeleton in Ca2+-triggered signal cascades in SEs. High-affinity fluorescent phalloidin as well as immunocytochemistry using anti-actin antibodies demonstrated a fully developed parietal actin meshwork in SEs. The involvement of the cytoskeleton in electrical responses and forisome conformation changes as indicators of Ca2+ influx was investigated by the application of cold shocks in the presence of diverse actin disruptors (latrunculin A and cytochalasin D). Under control conditions, cold shocks elicited a graded initial voltage transient, ΔV1, reduced by external La3+ in keeping with the involvement of Ca2+ channels, and a second voltage transient, ΔV2. Cytochalasin D had no effect on ΔV1, while ΔV1 was significantly reduced with 500 nm latrunculin A. Forisome dispersion was triggered by cold shocks of 4°C or greater, which was indicative of an all-or-none behavior. Forisome dispersion was suppressed by incubation with latrunculin A. In conclusion, the cytoskeleton controls cold shock-induced Ca2+ influx into SEs, leading to forisome dispersion and sieve plate occlusion in fava bean (Vicia faba). PMID:23624858

Phytoestrogens modulate hepcidin expression by Nrf2: Implications for dietary control of iron absorption.

PubMed

Bayele, Henry K; Balesaria, Sara; Srai, Surjit K S

2015-12-01

Hepcidin is a liver-derived antimicrobial peptide that regulates iron absorption and is also an integral part of the acute phase response. In a previous report, we found evidence that this peptide could also be induced by toxic heavy metals and xenobiotics, thus broadening its teleological role as a defensin. However it remained unclear how its sensing of disparate biotic and abiotic stressors might be integrated at the transcriptional level. We hypothesized that its function in cytoprotection may be regulated by NFE2-related factor 2 (Nrf2), the master transcriptional controller of cellular stress defenses. In this report, we show that hepcidin regulation is inextricably linked to the acute stress response through Nrf2 signaling. Nrf2 regulates hepcidin expression from a prototypical antioxidant response element in its promoter, and by synergizing with other basic leucine-zipper transcription factors. We also show that polyphenolic small molecules or phytoestrogens commonly found in fruits and vegetables including the red wine constituent resveratrol can induce hepcidin expression in vitro and post-prandially, with concomitant reductions in circulating iron levels and transferrin saturation by one such polyphenol quercetin. Furthermore, these molecules derepress hepcidin promoter activity when its transcription by Nrf2 is repressed by Keap1. Taken together, the data show that hepcidin is a prototypical antioxidant response or cytoprotective gene within the Nrf2 transcriptional circuitry. The ability of phytoestrogens to modulate hepcidin expression in vivo suggests a novel mechanism by which diet may impact iron homeostasis. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Low levels of graphene and graphene oxide inhibit cellular xenobiotic defense system mediated by efflux transporters.

PubMed

Liu, Su; Jiang, Wei; Wu, Bing; Yu, Jing; Yu, Haiyan; Zhang, Xu-Xiang; Torres-Duarte, Cristina; Cherr, Gary N

2016-01-01

Low levels of graphene and graphene oxide (GO) are considered to be environmentally safe. In this study, we analyzed the potential effects of graphene and GO at relatively low concentrations on cellular xenobiotic defense system mediated by efflux transporters. The results showed that graphene (<0.5 μg/mL) and GO (<20 μg/mL) did not decrease cell viability, generate reactive oxygen species, or disrupt mitochondrial function. However, graphene and GO at the nontoxic concentrations could increase calcein-AM (CAM, an indicator of membrane ATP-binding cassette (ABC) transporter) activity) accumulation, indicating inhibition of ABC transporters' efflux capabilities. This inhibition was observed even at 0.005 μg/mL graphene and 0.05 μg/mL GO, which are 100 times and 400 times lower than their lowest toxic concentration from cytotoxicity experiments, respectively. The inhibition of ABC transporters significantly increased the toxicity of paraquat and arsenic, known substrates of ABC transporters. The inhibition of ABC transporters was found to be based on graphene and GO damaging the plasma membrane structure and fluidity, thus altering functions of transmembrane ABC transporters. This study demonstrates that low levels of graphene and GO are not environmentally safe since they can significantly make cell more susceptible to other xenobiotics, and this chemosensitizing activity should be considered in the risk assessment of graphene and GO.

Automatic control of finite element models for temperature-controlled radiofrequency ablation.

PubMed

Haemmerich, Dieter; Webster, John G

2005-07-14

The finite element method (FEM) has been used to simulate cardiac and hepatic radiofrequency (RF) ablation. The FEM allows modeling of complex geometries that cannot be solved by analytical methods or finite difference models. In both hepatic and cardiac RF ablation a common control mode is temperature-controlled mode. Commercial FEM packages don't support automating temperature control. Most researchers manually control the applied power by trial and error to keep the tip temperature of the electrodes constant. We implemented a PI controller in a control program written in C++. The program checks the tip temperature after each step and controls the applied voltage to keep temperature constant. We created a closed loop system consisting of a FEM model and the software controlling the applied voltage. The control parameters for the controller were optimized using a closed loop system simulation. We present results of a temperature controlled 3-D FEM model of a RITA model 30 electrode. The control software effectively controlled applied voltage in the FEM model to obtain, and keep electrodes at target temperature of 100 degrees C. The closed loop system simulation output closely correlated with the FEM model, and allowed us to optimize control parameters. The closed loop control of the FEM model allowed us to implement temperature controlled RF ablation with minimal user input.

Automatic control of finite element models for temperature-controlled radiofrequency ablation

PubMed Central

Haemmerich, Dieter; Webster, John G

2005-01-01

Background The finite element method (FEM) has been used to simulate cardiac and hepatic radiofrequency (RF) ablation. The FEM allows modeling of complex geometries that cannot be solved by analytical methods or finite difference models. In both hepatic and cardiac RF ablation a common control mode is temperature-controlled mode. Commercial FEM packages don't support automating temperature control. Most researchers manually control the applied power by trial and error to keep the tip temperature of the electrodes constant. Methods We implemented a PI controller in a control program written in C++. The program checks the tip temperature after each step and controls the applied voltage to keep temperature constant. We created a closed loop system consisting of a FEM model and the software controlling the applied voltage. The control parameters for the controller were optimized using a closed loop system simulation. Results We present results of a temperature controlled 3-D FEM model of a RITA model 30 electrode. The control software effectively controlled applied voltage in the FEM model to obtain, and keep electrodes at target temperature of 100°C. The closed loop system simulation output closely correlated with the FEM model, and allowed us to optimize control parameters. Discussion The closed loop control of the FEM model allowed us to implement temperature controlled RF ablation with minimal user input. PMID:16018811

Pharmacogenetic profile of xenobiotic enzyme metabolism in survivors of the Spanish toxic oil syndrome.

PubMed Central

Ladona, M G; Izquierdo-Martinez, M; Posada de la Paz, M P; de la Torre, R; Ampurdanés, C; Segura, J; Sanz, E J

2001-01-01

In 1981, the Spanish toxic oil syndrome (TOS) affected more than 20,000 people, and over 300 deaths were registered. Assessment of genetic polymorphisms on xenobiotic metabolism would indicate the potential metabolic capacity of the victims at the time of the disaster. Thus, impaired metabolic pathways may have contributed to the clearance of the toxicant(s) leading to a low detoxification or accumulation of toxic metabolites contributing to the disease. We conducted a matched case-control study using 72 cases (54 females, 18 males) registered in the Official Census of Affected Patients maintained by the Spanish government. Controls were nonaffected siblings (n =72) living in the same household in 1981 and nonaffected nonrelatives (n = 70) living in the neighborhood at that time, with no ties to TOS. Genotype analyses were performed to assess the metabolic capacity of phase I [cytochrome P450 1A1 (CYP1A1), CYP2D6] and phase II [arylamine N-acetyltransferase-2 (NAT2), GSTM1 (glutathione S-transferase M1) and GSTT1] enzyme polymorphisms. The degree of association of the five metabolic pathways was estimated by calculating their odds ratios (ORs) using conditional logistic regression analysis. In the final model, cases compared with siblings (72 pairs) showed no differences either in CYP2D6 or CYP1A1 polymorphisms, or in conjugation enzyme polymorphisms, whereas cases compared with the unrelated controls (70 pairs) showed an increase in NAT2 defective alleles [OR = 6.96, 95% confidence interval (CI), 1.46-33.20] adjusted by age and sex. Glutathione transferase genetic polymorphisms (GSTM1, GSTT1) showed no association with cases compared with their siblings or unrelated controls. These findings suggest a possible role of impaired acetylation mediating susceptibility in TOS. PMID:11335185

Mechanical Stress Induces Biotic and Abiotic Stress Responses via a Novel cis-Element

PubMed Central

Walley, Justin W; Coughlan, Sean; Hudson, Matthew E; Covington, Michael F; Kaspi, Roy; Banu, Gopalan; Harmer, Stacey L; Dehesh, Katayoon

2007-01-01

Plants are continuously exposed to a myriad of abiotic and biotic stresses. However, the molecular mechanisms by which these stress signals are perceived and transduced are poorly understood. To begin to identify primary stress signal transduction components, we have focused on genes that respond rapidly (within 5 min) to stress signals. Because it has been hypothesized that detection of physical stress is a mechanism common to mounting a response against a broad range of environmental stresses, we have utilized mechanical wounding as the stress stimulus and performed whole genome microarray analysis of Arabidopsis thaliana leaf tissue. This led to the identification of a number of rapid wound responsive (RWR) genes. Comparison of RWR genes with published abiotic and biotic stress microarray datasets demonstrates a large overlap across a wide range of environmental stresses. Interestingly, RWR genes also exhibit a striking level and pattern of circadian regulation, with induced and repressed genes displaying antiphasic rhythms. Using bioinformatic analysis, we identified a novel motif overrepresented in the promoters of RWR genes, herein designated as the Rapid Stress Response Element (RSRE). We demonstrate in transgenic plants that multimerized RSREs are sufficient to confer a rapid response to both biotic and abiotic stresses in vivo, thereby establishing the functional involvement of this motif in primary transcriptional stress responses. Collectively, our data provide evidence for a novel cis-element that is distributed across the promoters of an array of diverse stress-responsive genes, poised to respond immediately and coordinately to stress signals. This structure suggests that plants may have a transcriptional network resembling the general stress signaling pathway in yeast and that the RSRE element may provide the key to this coordinate regulation. PMID:17953483

Finite element solution of optimal control problems with inequality constraints

NASA Technical Reports Server (NTRS)

Bless, Robert R.; Hodges, Dewey H.

1990-01-01

A finite-element method based on a weak Hamiltonian form of the necessary conditions is summarized for optimal control problems. Very crude shape functions (so simple that element numerical quadrature is not necessary) can be used to develop an efficient procedure for obtaining candidate solutions (i.e., those which satisfy all the necessary conditions) even for highly nonlinear problems. An extension of the formulation allowing for discontinuities in the states and derivatives of the states is given. A theory that includes control inequality constraints is fully developed. An advanced launch vehicle (ALV) model is presented. The model involves staging and control constraints, thus demonstrating the full power of the weak formulation to date. Numerical results are presented along with total elapsed computer time required to obtain the results. The speed and accuracy in obtaining the results make this method a strong candidate for a real-time guidance algorithm.

33 CFR Appendix D to Part 154 - Training Elements for Oil Spill Response Plans

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 2 2014-07-01 2014-07-01 false Training Elements for Oil Spill... Appendix D to Part 154—Training Elements for Oil Spill Response Plans 1. General 1.1The portion of the plan... contracted oil spill removal organizations and the procedures to notify the activate such organizations. 2.2...

33 CFR Appendix D to Part 154 - Training Elements for Oil Spill Response Plans

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Training Elements for Oil Spill... Appendix D to Part 154—Training Elements for Oil Spill Response Plans 1. General 1.1The portion of the plan... contracted oil spill removal organizations and the procedures to notify the activate such organizations. 2.2...

33 CFR Appendix D to Part 154 - Training Elements for Oil Spill Response Plans

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 2 2012-07-01 2012-07-01 false Training Elements for Oil Spill... Appendix D to Part 154—Training Elements for Oil Spill Response Plans 1. General 1.1The portion of the plan... contracted oil spill removal organizations and the procedures to notify the activate such organizations. 2.2...

33 CFR Appendix D to Part 154 - Training Elements for Oil Spill Response Plans

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Training Elements for Oil Spill... Appendix D to Part 154—Training Elements for Oil Spill Response Plans 1. General 1.1The portion of the plan... contracted oil spill removal organizations and the procedures to notify the activate such organizations. 2.2...

Development of an adaptive hp-version finite element method for computational optimal control

NASA Technical Reports Server (NTRS)

Hodges, Dewey H.; Warner, Michael S.

1994-01-01

In this research effort, the usefulness of hp-version finite elements and adaptive solution-refinement techniques in generating numerical solutions to optimal control problems has been investigated. Under NAG-939, a general FORTRAN code was developed which approximated solutions to optimal control problems with control constraints and state constraints. Within that methodology, to get high-order accuracy in solutions, the finite element mesh would have to be refined repeatedly through bisection of the entire mesh in a given phase. In the current research effort, the order of the shape functions in each element has been made a variable, giving more flexibility in error reduction and smoothing. Similarly, individual elements can each be subdivided into many pieces, depending on the local error indicator, while other parts of the mesh remain coarsely discretized. The problem remains to reduce and smooth the error while still keeping computational effort reasonable enough to calculate time histories in a short enough time for on-board applications.

The Yeast Anaerobic Response Element AR1b Regulates Aerobic Antifungal Drug-dependent Sterol Gene Expression*

PubMed Central

Gallo-Ebert, Christina; Donigan, Melissa; Liu, Hsing-Yin; Pascual, Florencia; Manners, Melissa; Pandya, Devanshi; Swanson, Robert; Gallagher, Denise; Chen, WeiWei; Carman, George M.; Nickels, Joseph T.

2013-01-01

Saccharomyces cerevisiae ergosterol biosynthesis, like cholesterol biosynthesis in mammals, is regulated at the transcriptional level by a sterol feedback mechanism. Yeast studies defined a 7-bp consensus sterol-response element (SRE) common to genes involved in sterol biosynthesis and two transcription factors, Upc2 and Ecm22, which direct transcription of sterol biosynthetic genes. The 7-bp consensus SRE is identical to the anaerobic response element, AR1c. Data indicate that Upc2 and Ecm22 function through binding to this SRE site. We now show that it is two novel anaerobic AR1b elements in the UPC2 promoter that direct global ERG gene expression in response to a block in de novo ergosterol biosynthesis, brought about by antifungal drug treatment. The AR1b elements are absolutely required for auto-induction of UPC2 gene expression and protein and require Upc2 and Ecm22 for function. We further demonstrate the direct binding of recombinant expressed S. cerevisiae ScUpc2 and pathogenic Candida albicans CaUpc2 and Candida glabrata CgUpc2 to AR1b and SRE/AR1c elements. Recombinant endogenous promoter studies show that the UPC2 anaerobic AR1b elements act in trans to regulate ergosterol gene expression. Our results indicate that Upc2 must occupy UPC2 AR1b elements in order for ERG gene expression induction to take place. Thus, the two UPC2-AR1b elements drive expression of all ERG genes necessary for maintaining normal antifungal susceptibility, as wild type cells lacking these elements have increased susceptibility to azole antifungal drugs. Therefore, targeting these specific sites for antifungal therapy represents a novel approach to treat systemic fungal infections. PMID:24163365

The effect of loading time on flexible pavement dynamic response: a finite element analysis

NASA Astrophysics Data System (ADS)

Yin, Hao; Solaimanian, Mansour; Kumar, Tanmay; Stoffels, Shelley

2007-12-01

Dynamic response of asphalt concrete (AC) pavements under moving load is a key component for accurate prediction of flexible pavement performance. The time and temperature dependency of AC materials calls for utilizing advanced material characterization and mechanistic theories, such as viscoelasticity and stress/strain analysis. In layered elastic analysis, as implemented in the new Mechanistic-Empirical Pavement Design Guide (MEPDG), the time dependency is accounted for by calculating the loading times at different AC layer depths. In this study, the time effect on pavement response was evaluated by means of the concept of “pseudo temperature.” With the pavement temperature measured from instrumented thermocouples, the time and temperature dependency of AC materials was integrated into one single factor, termed “effective temperature.” Via this effective temperature, pavement responses under a transient load were predicted through finite element analysis. In the finite element model, viscoelastic behavior of AC materials was characterized through relaxation moduli, while the layers with unbound granular material were assumed to be in an elastic mode. The analysis was conducted for two different AC mixtures in a simplified flexible pavement structure at two different seasons. Finite element analysis results reveal that the loading time has a more pronounced impact on pavement response in the summer for both asphalt types. The results indicate that for reasonable prediction of dynamic response in flexible pavements, the effect of the depth-dependent loading time on pavement temperature should be considered.

Meta-analysis of the effect of overexpression of dehydration-responsive element binding family genes on temperature stress tolerance and related responses

USDA-ARS?s Scientific Manuscript database

C-repeat/dehydration-responsive element binding proteins are transcription factors that play a critical role in plant response to temperature stress. Over-expression of CBF/DREB genes has been demonstrated to enhance temperature stress tolerance. A series of physiological and biochemical modificat...

42 CFR 431.810 - Basic elements of the Medicaid eligibility quality control (MEQC) program.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 4 2011-10-01 2011-10-01 false Basic elements of the Medicaid eligibility quality control (MEQC) program. 431.810 Section 431.810 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... elements of the Medicaid eligibility quality control (MEQC) program. (a) General requirements. The agency...

An internal regulatory element controls troponin I gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yutzey, K.E.; Kline, R.L.; Konieczmy, S.F.

1989-04-01

During skeletal myogenesis, approximately 20 contractile proteins and related gene products temporally accumulate as the cells fuse to form multinucleated muscle fibers. In most instances, the contractile protein genes are regulated transcriptionally, which suggests that a common molecular mechanism may coordinate the expression of this diverse and evolutionarily unrelated gene set. Recent studies have examined the muscle-specific cis-acting elements associated with numerous contractile protein genes. All of the identified regulatory elements are positioned in the 5'-flanking regions, usually within 1,500 base pairs of the transcription start site. Surprisingly, a DNA consensus sequence that is common to each contractile protein genemore » has not been identified. In contrast to the results of these earlier studies, the authors have found that the 5'-flanking region of the quail troponin I (TnI) gene is not sufficient to permit the normal myofiber transcriptional activation of the gene. Instead, the TnI gene utilizes a unique internal regulatory element that is responsible for the correct myofiber-specific expression pattern associated with the TnI gene. This is the first example in which a contractile protein gene has been shown to rely primarily on an internal regulatory element to elicit transcriptional activation during myogenesis. The diversity of regulatory elements associated with the contractile protein genes suggests that the temporal expression of the genes may involve individual cis-trans regulatory components specific for each gene.« less

An internal regulatory element controls troponin I gene expression.

PubMed Central

Yutzey, K E; Kline, R L; Konieczny, S F

1989-01-01

During skeletal myogenesis, approximately 20 contractile proteins and related gene products temporally accumulate as the cells fuse to form multinucleated muscle fibers. In most instances, the contractile protein genes are regulated transcriptionally, which suggests that a common molecular mechanism may coordinate the expression of this diverse and evolutionarily unrelated gene set. Recent studies have examined the muscle-specific cis-acting elements associated with numerous contractile protein genes. All of the identified regulatory elements are positioned in the 5'-flanking regions, usually within 1,500 base pairs of the transcription start site. Surprisingly, a DNA consensus sequence that is common to each contractile protein gene has not been identified. In contrast to the results of these earlier studies, we have found that the 5'-flanking region of the quail troponin I (TnI) gene is not sufficient to permit the normal myofiber transcriptional activation of the gene. Instead, the TnI gene utilizes a unique internal regulatory element that is responsible for the correct myofiber-specific expression pattern associated with the TnI gene. This is the first example in which a contractile protein gene has been shown to rely primarily on an internal regulatory element to elicit transcriptional activation during myogenesis. The diversity of regulatory elements associated with the contractile protein genes suggests that the temporal expression of the genes may involve individual cis-trans regulatory components specific for each gene. Images PMID:2725509

Non-specific protein modifications by a phytochemical induce heat shock response for self-defense.

PubMed

Ohnishi, Kohta; Ohkura, Shinya; Nakahata, Erina; Ishisaka, Akari; Kawai, Yoshichika; Terao, Junji; Mori, Taiki; Ishii, Takeshi; Nakayama, Tsutomu; Kioka, Noriyuki; Matsumoto, Shinya; Ikeda, Yasutaka; Akiyama, Minoru; Irie, Kazuhiro; Murakami, Akira

2013-01-01

Accumulated evidence shows that some phytochemicals provide beneficial effects for human health. Recently, a number of mechanistic studies have revealed that direct interactions between phytochemicals and functional proteins play significant roles in exhibiting their bioactivities. However, their binding selectivities to biological molecules are considered to be lower due to their small and simple structures. In this study, we found that zerumbone, a bioactive sesquiterpene, binds to numerous proteins with little selectivity. Similar to heat-denatured proteins, zerumbone-modified proteins were recognized by heat shock protein 90, a constitutive molecular chaperone, leading to heat shock factor 1-dependent heat shock protein induction in hepa1c1c7 mouse hepatoma cells. Furthermore, oral administration of this phytochemical up-regulated heat shock protein expressions in the livers of Sprague-Dawley rats. Interestingly, pretreatment with zerumbone conferred a thermoresistant phenotype to hepa1c1c7 cells as well as to the nematode Caenorhabditis elegans. It is also important to note that several phytochemicals with higher hydrophobicity or electrophilicity, including phenethyl isothiocyanate and curcumin, markedly induced heat shock proteins, whereas most of the tested nutrients did not. These results suggest that non-specific protein modifications by xenobiotic phytochemicals cause mild proteostress, thereby inducing heat shock response and leading to potentiation of protein quality control systems. We considered these bioactivities to be xenohormesis, an adaptation mechanism against xenobiotic chemical stresses. Heat shock response by phytochemicals may be a fundamental mechanism underlying their various bioactivities.

Non-Specific Protein Modifications by a Phytochemical Induce Heat Shock Response for Self-Defense

PubMed Central

Ohnishi, Kohta; Ohkura, Shinya; Nakahata, Erina; Ishisaka, Akari; Kawai, Yoshichika; Terao, Junji; Mori, Taiki; Ishii, Takeshi; Nakayama, Tsutomu; Kioka, Noriyuki; Matsumoto, Shinya; Ikeda, Yasutaka; Akiyama, Minoru; Irie, Kazuhiro; Murakami, Akira

2013-01-01

Accumulated evidence shows that some phytochemicals provide beneficial effects for human health. Recently, a number of mechanistic studies have revealed that direct interactions between phytochemicals and functional proteins play significant roles in exhibiting their bioactivities. However, their binding selectivities to biological molecules are considered to be lower due to their small and simple structures. In this study, we found that zerumbone, a bioactive sesquiterpene, binds to numerous proteins with little selectivity. Similar to heat-denatured proteins, zerumbone-modified proteins were recognized by heat shock protein 90, a constitutive molecular chaperone, leading to heat shock factor 1-dependent heat shock protein induction in hepa1c1c7 mouse hepatoma cells. Furthermore, oral administration of this phytochemical up-regulated heat shock protein expressions in the livers of Sprague-Dawley rats. Interestingly, pretreatment with zerumbone conferred a thermoresistant phenotype to hepa1c1c7 cells as well as to the nematode Caenorhabditis elegans. It is also important to note that several phytochemicals with higher hydrophobicity or electrophilicity, including phenethyl isothiocyanate and curcumin, markedly induced heat shock proteins, whereas most of the tested nutrients did not. These results suggest that non-specific protein modifications by xenobiotic phytochemicals cause mild proteostress, thereby inducing heat shock response and leading to potentiation of protein quality control systems. We considered these bioactivities to be xenohormesis, an adaptation mechanism against xenobiotic chemical stresses. Heat shock response by phytochemicals may be a fundamental mechanism underlying their various bioactivities. PMID:23536805

SPCC- Software Elements for Security Partition Communication Controller

NASA Astrophysics Data System (ADS)

Herpel, H. J.; Willig, G.; Montano, G.; Tverdyshev, S.; Eckstein, K.; Schoen, M.

2016-08-01

Future satellite missions like Earth Observation, Telecommunication or any other kind are likely to be exposed to various threats aiming at exploiting vulnerabilities of the involved systems and communications. Moreover, the growing complexity of systems coupled with more ambitious types of operational scenarios imply increased security vulnerabilities in the future. In the paper we will describe an architecture and software elements to ensure high level of security on-board a spacecraft. First the threats to the Security Partition Communication Controller (SPCC) will be addressed including the identification of specific vulnerabilities to the SPCC. Furthermore, appropriate security objectives and security requirements are identified to be counter the identified threats. The security evaluation of the SPCC will be done in accordance to the Common Criteria (CC). The Software Elements for SPCC has been implemented on flight representative hardware which consists of two major elements: the I/O board and the SPCC board. The SPCC board provides the interfaces with ground while the I/O board interfaces with typical spacecraft equipment busses. Both boards are physically interconnected by a high speed spacewire (SpW) link.

SCF(KMD) controls cytokinin signaling by regulating the degradation of type-B response regulators.

PubMed

Kim, Hyo Jung; Chiang, Yi-Hsuan; Kieber, Joseph J; Schaller, G Eric

2013-06-11

Cytokinins are plant hormones that play critical roles in growth and development. In Arabidopsis, the transcriptional response to cytokinin is regulated by action of type-B Arabidopsis response regulators (ARRs). Although central elements in the cytokinin signal transduction pathway have been identified, mechanisms controlling output remain to be elucidated. Here we demonstrate that a family of F-box proteins, called the kiss me deadly (KMD) family, targets type-B ARR proteins for degradation. KMD proteins form an S-phase kinase-associated PROTEIN1 (SKP1)/Cullin/F-box protein (SCF) E3 ubiquitin ligase complex and directly interact with type-B ARR proteins. Loss-of-function KMD mutants stabilize type-B ARRs and exhibit an enhanced cytokinin response. In contrast, plants with elevated KMD expression destabilize type-B ARR proteins leading to cytokinin insensitivity. Our results support a model in which an SCF(KMD) complex negatively regulates cytokinin responses by controlling levels of a key family of transcription factors.

Analysis of Resonance Response Performance of C-Band Antenna Using Parasitic Element

PubMed Central

Islam, M. T.; Misran, N.; Mandeep, J. S.

2014-01-01

Analysis of the resonance response improvement of a planar C-band (4–8 GHz) antenna is proposed using parasitic element method. This parasitic element based method is validated for change in the active and parasitic antenna elements. A novel dual-band antenna for C-band application covering 5.7 GHz and 7.6 GHz is designed and fabricated. The antenna is composed of circular parasitic element with unequal microstrip lines at both sides and a rectangular partial ground plane. A fractional bandwidth of 13.5% has been achieved from 5.5 GHz to 6.3 GHz (WLAN band) for the lower band. The upper band covers from 7.1 GHz to 8 GHz with a fractional bandwidth of 12%. A gain of 6.4 dBi is achieved at the lower frequency and 4 dBi is achieved at the upper frequency. The VSWR of the antenna is less than 2 at the resonance frequency. PMID:24895643

Analysis of resonance response performance of C-band antenna using parasitic element.

PubMed

Zaman, M R; Islam, M T; Misran, N; Mandeep, J S

2014-01-01

Analysis of the resonance response improvement of a planar C-band (4-8 GHz) antenna is proposed using parasitic element method. This parasitic element based method is validated for change in the active and parasitic antenna elements. A novel dual-band antenna for C-band application covering 5.7 GHz and 7.6 GHz is designed and fabricated. The antenna is composed of circular parasitic element with unequal microstrip lines at both sides and a rectangular partial ground plane. A fractional bandwidth of 13.5% has been achieved from 5.5 GHz to 6.3 GHz (WLAN band) for the lower band. The upper band covers from 7.1 GHz to 8 GHz with a fractional bandwidth of 12%. A gain of 6.4 dBi is achieved at the lower frequency and 4 dBi is achieved at the upper frequency. The VSWR of the antenna is less than 2 at the resonance frequency.

Development of a rapidly deployed Department of Energy emergency response element.

PubMed

Tighe, R J; Riland, C A; Hopkins, R C

2000-02-01

The Federal Radiological Emergency Response Plan (FRERP) directs the Department of Energy (DOE) to maintain a viable, timely, and fully documented response option capable of supporting the responsible Lead Federal Agency in the event of a radiological emergency impacting any state or United States territory (e.g., CONUS). In addition, the DOE maintains a response option to support radiological emergencies outside the continental United States (OCONUS). While the OCONUS mission is not governed by the FRERP, this response is operationally similar to that assigned to the DOE by the FRERP The DOE is prepared to alert, activate, and deploy radiological response teams to augment the Radiological Assistance Program and/or local responders. The Radiological Monitoring and Assessment Center (RMAC) is a phased response that integrates with the Federal Radiological Monitoring and Assessment Center (FRMAC) in CONUS environments and represents a stand-alone DOE response for OCONUS environments. The FRMAC/RMAC Phase I was formally "stood up" as an operational element in April 1999. The FRMAC/RMAC Phase II proposed "stand-up" date is midyear 2000.

Investigation of runoff generation from anthropogenic sources with dissolved xenobiotics

NASA Astrophysics Data System (ADS)

Krein, A.; Pailler, J.; Guignard, C.; Iffly, J.; Pfister, L.; Hoffmann, L.

2009-04-01

In the experimental Mess basin (35 km2, Luxembourg) dissolved xenobiotics in surface water are used to study the influences of anthropogenic sources like separated sewer systems on runoff generation. Emerging contaminants like pharmaceuticals are of growing interest because of their use in large quantities in human and veterinary medicine. The amounts reaching surface waters depend on rainfall patterns, hydraulic conditions, consumption, metabolism, degradation, and disposal. The behaviour of endocrine disruptors including pharmaceuticals in the aquatic environment is widely unknown. The twelve molecules analyzed belong to three families: the estrogens, the antibiotics (sulfonamides, tetracyclines), and the painkillers (ibuprofen, diclofenac). Xenobiotics can be used as potential environmental tracers for untreated sewerage. Our results show that the concentrations are highly variable during flood events. The highest concentrations are reached in the first flush period, mainly during the rising limb of the flood hydrographs. As a result of the kinematic wave effect the concentration peak occurs in some cases a few hours after the discharge maximum. In floodwater (eleven floods, 66 samples) the highest concentrations were measured for ibuprofen (g/l range), estrone, and diclofenac (all ng/l range). From the tetracycline group, essentially tetracycline itself is of relevance, while the sulfonamides are mainly represented by sulfamethoxazole (all in ng/l range). In the Mess River the pharmaceuticals fluxes during flood events proved to be influenced by hydrological conditions. Different pharmaceuticals showed their concentration peaks during different times of a flood event. An example is the estrone peak that - during summer flash floods - often occurred one to two hours prior to the largest concentrations of the painkillers. This suggests for more sources than the sole storm drainage through the spillway of the single sewage water treatment plant, different

Cytotype Control of Drosophila Melanogaster P Element Transposition: Genomic Position Determines Maternal Repression

PubMed Central

Misra, S.; Buratowski, R. M.; Ohkawa, T.; Rio, D. C.

1993-01-01

P element transposition in Drosophila is controlled by the cytotype regulatory state: in P cytotype, transposition is repressed, whereas in M cytotype, transposition can occur. P cytotype is determined by a combination of maternally inherited factors and chromosomal P elements in the zygote. Transformant strains containing single elements that encoded the 66-kD P element protein zygotically repressed transposition, but did not display the maternal repression characteristic of P cytotype. Upon mobilization to new genomic positions, some of these repressor elements showed significant maternal repression of transposition in genetic assays, involving a true maternal effect. Thus, the genomic position of repressor elements can determine the maternal vs. zygotic inheritance of P cytotype. Immunoblotting experiments indicate that this genomic position effect does not operate solely by controlling the expression level of the 66-kD repressor protein during oogenesis. Likewise, P element derivatives containing the hsp26 maternal regulator sequence expressed high levels of the 66-kD protein during oogenesis, but showed no detectable maternal repression. These data suggest that the location of a repressor element in the genome may determine maternal inheritance of P cytotype by a mechanism involving more than the overall level of expression of the 66-kD protein in the ovary. PMID:8293979

Response analysis of curved bridge with unseating failure control system under near-fault ground motions

NASA Astrophysics Data System (ADS)

Zuo, Ye; Sun, Guangjun; Li, Hongjing

2018-01-01

Under the action of near-fault ground motions, curved bridges are prone to pounding, local damage of bridge components and even unseating. A multi-scale fine finite element model of a typical three-span curved bridge is established by considering the elastic-plastic behavior of piers and pounding effect of adjacent girders. The nonlinear time-history method is used to study the seismic response of the curved bridge equipped with unseating failure control system under the action of near-fault ground motion. An in-depth analysis is carried to evaluate the control effect of the proposed unseating failure control system. The research results indicate that under the near-fault ground motion, the seismic response of the curved bridge is strong. The unseating failure control system perform effectively to reduce the pounding force of the adjacent girders and the probability of deck unseating.

Polymorphisms in xenobiotic metabolizing genes, intakes of heterocyclic amines and red meat, and postmenopausal breast cancer

PubMed Central

Lee, Hae-Jeung; Wu, Kana; Cox, David G.; Hunter, David; Hankinson, Susan E.; Willett, Walter C.; Sinha, Rashmi; Cho, Eunyoung

2013-01-01

Heterocyclic amines (HCAs) are mutagenic compounds generated when meats are cooked at high temperature and for long duration. The findings from previous studies on the relation between HCAs and breast cancer are inconsistent, possibly due to genetic variations in the enzymes metabolizing HCAs. To evaluate whether the associations of intakes of estimated HCAs, meat-derived mutagenicity (MDM), and red meat with risk of postmenopausal breast cancer were modified by N-acetyltransferase 2 (NAT2) acetylator genotype or cytochrome P450 1A2 -164 A/C (CYP1A2) polymorphism, we conducted a nested case-control study with 579 cases and 981 controls within a prospective cohort, the Nurses’ Health Study (NHS). HCAs and MDM intakes were derived using a cooking method questionnaire administered in 1996. NAT2 acetylator genotype, the CYP1A2 polymorphism, and intakes of HCAs, MDM, and red meat were not associated with risk of postmenopausal breast cancer. There was also no interaction between NAT2 acetylator genotype or CYP1A2 polymorphism and HCAs and MDM and red meat intake in relation to breast cancer. These results do not support the hypothesis that genetic polymorphisms of xenobiotic enzymes involved in the metabolism of HCAs may modify the associations between intakes of red meat or meat-related mutagens and breast cancer risk. PMID:24099317

Transformation of RDX and other energetic compounds by xenobiotic reductases XenA and XenB

PubMed Central

McClay, Kevin; Hawari, Jalal; Paquet, Louise; Malone, Thomas E.; Fox, Brian G.; Steffan, Robert J.

2017-01-01

The transformation of explosives, including hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), by xenobiotic reductases XenA and XenB (and the bacterial strains harboring these enzymes) under both aerobic and anaerobic conditions was assessed. Under anaerobic conditions, Pseudomonas fluorescens I-C (XenB) degraded RDX faster than Pseudomonas putida II-B (XenA), and transformation occurred when the cells were supplied with sources of both carbon (succinate) and nitrogen (NH4+), but not when only carbon was supplied. Transformation was always faster under anaerobic conditions compared to aerobic conditions, with both enzymes exhibiting a O2 concentration-dependent inhibition of RDX transformation. The primary degradation pathway for RDX was conversion to methylenedinitramine and then to formaldehyde, but a minor pathway that produced 4-nitro-2,4-diazabutanal (NDAB) also appeared to be active during transformation by whole cells of P. putida II-B and purified XenA. Both XenA and XenB also degraded the related nitramine explosives octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine and 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane. Purified XenB was found to have a broader substrate range than XenA, degrading more of the explosive compounds examined in this study. The results show that these two xenobiotic reductases (and their respective bacterial strains) have the capacity to transform RDX as well as a wide variety of explosive compounds, especially under low oxygen concentrations. PMID:19455327

Application of simple mathematical expressions to relate the half-lives of xenobiotics in rats to values in humans.

PubMed

Ward, Keith W; Erhardt, Paul; Bachmann, Kenneth

2005-01-01

Previous publications from GlaxoSmithKline and University of Toledo laboratories convey our independent attempts to predict the half-lives of xenobiotics in humans using data obtained from rats. The present investigation was conducted to compare the performance of our published models against a common dataset obtained by merging the two sets of rat versus human half-life (hHL) data previously used by each laboratory. After combining data, mathematical analyses were undertaken by deploying both of our previous models, namely the use of an empirical algorithm based on a best-fit model and the use of rat-to-human liver blood flow ratios as a half-life correction factor. Both qualitative and quantitative analyses were performed, as well as evaluation of the impact of molecular properties on predictability. The merged dataset was remarkably diverse with respect to physiochemical and pharmacokinetic (PK) properties. Application of both models revealed similar predictability, depending upon the measure of stipulated accuracy. Certain molecular features, particularly rotatable bond count and pK(a), appeared to influence the accuracy of prediction. This collaborative effort has resulted in an improved understanding and appreciation of the value of rats to serve as a surrogate for the prediction of xenobiotic half-lives in humans when clinical pharmacokinetic studies are not possible or practicable.

SPE-IMS-MS: An automated platform for sub-sixty second surveillance of endogenous metabolites and xenobiotics in biofluids

DOE PAGES

Zhang, Xing; Romm, Michelle; Zheng, Xueyun; ...

2016-12-29

Characterization of endogenous metabolites and xenobiotics is essential to deconvoluting the genetic and environmental causes of disease. However, surveillance of chemical exposure and disease-related changes in large cohorts requires an analytical platform that offers rapid measurement, high sensitivity, efficient separation, broad dynamic range, and application to an expansive chemical space. Here in this article, we present a novel platform for small molecule analyses that addresses these requirements by combining solid-phase extraction with ion mobility spectrometry and mass spectrometry (SPE-IMS-MS). This platform is capable of performing both targeted and global measurements of endogenous metabolites and xenobiotics in human biofluids with highmore » reproducibility (CV ≤ 3%), sensitivity (LODs in the pM range in biofluids) and throughput (10-s sample-to-sample duty cycle). We report application of this platform to the analysis of human urine from patients with and without type 1 diabetes, where we observed statistically significant variations in the concentration of disaccharides and previously unreported chemical isomers. Lastly, this SPE-IMS-MS platform overcomes many of the current challenges of large-scale metabolomic and exposomic analyses and offers a viable option for population and patient cohort screening in an effort to gain insights into disease processes and human environmental chemical exposure.« less

SPE-IMS-MS: An automated platform for sub-sixty second surveillance of endogenous metabolites and xenobiotics in biofluids.

PubMed

Zhang, Xing; Romm, Michelle; Zheng, Xueyun; Zink, Erika M; Kim, Young-Mo; Burnum-Johnson, Kristin E; Orton, Daniel J; Apffel, Alex; Ibrahim, Yehia M; Monroe, Matthew E; Moore, Ronald J; Smith, Jordan N; Ma, Jian; Renslow, Ryan S; Thomas, Dennis G; Blackwell, Anne E; Swinford, Glenn; Sausen, John; Kurulugama, Ruwan T; Eno, Nathan; Darland, Ed; Stafford, George; Fjeldsted, John; Metz, Thomas O; Teeguarden, Justin G; Smith, Richard D; Baker, Erin S

2016-12-01

Characterization of endogenous metabolites and xenobiotics is essential to deconvoluting the genetic and environmental causes of disease. However, surveillance of chemical exposure and disease-related changes in large cohorts requires an analytical platform that offers rapid measurement, high sensitivity, efficient separation, broad dynamic range, and application to an expansive chemical space. Here, we present a novel platform for small molecule analyses that addresses these requirements by combining solid-phase extraction with ion mobility spectrometry and mass spectrometry (SPE-IMS-MS). This platform is capable of performing both targeted and global measurements of endogenous metabolites and xenobiotics in human biofluids with high reproducibility (CV 6 3%), sensitivity (LODs in the pM range in biofluids) and throughput (10-s sample-to-sample duty cycle). We report application of this platform to the analysis of human urine from patients with and without type 1 diabetes, where we observed statistically significant variations in the concentration of disaccharides and previously unreported chemical isomers. This SPE-IMS-MS platform overcomes many of the current challenges of large-scale metabolomic and exposomic analyses and offers a viable option for population and patient cohort screening in an effort to gain insights into disease processes and human environmental chemical exposure.

SPE-IMS-MS: An automated platform for sub-sixty second surveillance of endogenous metabolites and xenobiotics in biofluids

PubMed Central

Zhang, Xing; Romm, Michelle; Zheng, Xueyun; Zink, Erika M.; Kim, Young-Mo; Burnum-Johnson, Kristin E.; Orton, Daniel J.; Apffel, Alex; Ibrahim, Yehia M.; Monroe, Matthew E.; Moore, Ronald J.; Smith, Jordan N.; Ma, Jian; Renslow, Ryan S.; Thomas, Dennis G.; Blackwell, Anne E.; Swinford, Glenn; Sausen, John; Kurulugama, Ruwan T.; Eno, Nathan; Darland, Ed; Stafford, George; Fjeldsted, John; Metz, Thomas O.; Teeguarden, Justin G.; Smith, Richard D.; Baker, Erin S.

2017-01-01

Characterization of endogenous metabolites and xenobiotics is essential to deconvoluting the genetic and environmental causes of disease. However, surveillance of chemical exposure and disease-related changes in large cohorts requires an analytical platform that offers rapid measurement, high sensitivity, efficient separation, broad dynamic range, and application to an expansive chemical space. Here, we present a novel platform for small molecule analyses that addresses these requirements by combining solid-phase extraction with ion mobility spectrometry and mass spectrometry (SPE-IMS-MS). This platform is capable of performing both targeted and global measurements of endogenous metabolites and xenobiotics in human biofluids with high reproducibility (CV 6 3%), sensitivity (LODs in the pM range in biofluids) and throughput (10-s sample-to-sample duty cycle). We report application of this platform to the analysis of human urine from patients with and without type 1 diabetes, where we observed statistically significant variations in the concentration of disaccharides and previously unreported chemical isomers. This SPE-IMS-MS platform overcomes many of the current challenges of large-scale metabolomic and exposomic analyses and offers a viable option for population and patient cohort screening in an effort to gain insights into disease processes and human environmental chemical exposure. PMID:29276770

Neisseria conserved protein DMP19 is a DNA mimic protein that prevents DNA binding to a hypothetical nitrogen-response transcription factor

PubMed Central

Wang, Hao-Ching; Ko, Tzu-Ping; Wu, Mao-Lun; Ku, Shan-Chi; Wu, Hsing-Ju; Wang, Andrew H.-J.

2012-01-01

DNA mimic proteins occupy the DNA binding sites of DNA-binding proteins, and prevent these sites from being accessed by DNA. We show here that the Neisseria conserved hypothetical protein DMP19 acts as a DNA mimic. The crystal structure of DMP19 shows a dsDNA-like negative charge distribution on the surface, suggesting that this protein should be added to the short list of known DNA mimic proteins. The crystal structure of another related protein, NHTF (Neisseria hypothetical transcription factor), provides evidence that it is a member of the xenobiotic-response element (XRE) family of transcriptional factors. NHTF binds to a palindromic DNA sequence containing a 5′-TGTNAN11TNACA-3′ recognition box that controls the expression of an NHTF-related operon in which the conserved nitrogen-response protein [i.e. (Protein-PII) uridylyltransferase] is encoded. The complementary surface charges between DMP19 and NHTF suggest specific charge–charge interaction. In a DNA-binding assay, we found that DMP19 can prevent NHTF from binding to its DNA-binding sites. Finally, we used an in situ gene regulation assay to provide evidence that NHTF is a repressor of its down-stream genes and that DMP19 can neutralize this effect. We therefore conclude that the interaction of DMP19 and NHTF provides a novel gene regulation mechanism in Neisseria spps. PMID:22373915

Screening and monitoring microbial xenobiotics' biodegradation by rapid, inexpensive and easy to perform microplate UV-absorbance measurements.

PubMed

Herzog, Bastian; Lemmer, Hilde; Horn, Harald; Müller, Elisabeth

2014-02-22

Evaluation of xenobiotics biodegradation potential, shown here for benzotriazoles (corrosion inhibitors) and sulfamethoxazole (sulfonamide antibiotic) by microbial communities and/or pure cultures normally requires time intensive and money consuming LC/GC methods that are, in case of laboratory setups, not always needed. The usage of high concentrations to apply a high selective pressure on the microbial communities/pure cultures in laboratory setups, a simple UV-absorbance measurement (UV-AM) was developed and validated for screening a large number of setups, requiring almost no preparation and significantly less time and money compared to LC/GC methods. This rapid and easy to use method was evaluated by comparing its measured values to LC-UV and GC-MS/MS results. Furthermore, its application for monitoring and screening unknown activated sludge communities (ASC) and mixed pure cultures has been tested and approved to detect biodegradation of benzotriazole (BTri), 4- and 5-tolyltriazole (4-TTri, 5-TTri) as well as SMX. In laboratory setups, xenobiotics concentrations above 1.0 mg L(-1) without any enrichment or preparation could be detected after optimization of the method. As UV-AM does not require much preparatory work and can be conducted in 96 or even 384 well plate formats, the number of possible parallel setups and screening efficiency was significantly increased while analytic and laboratory costs were reduced to a minimum.

Confirmation of high-throughput screening data and novel mechanistic insights into VDR-xenobiotic interactions by orthogonal assays.

PubMed

Mahapatra, Debabrata; Franzosa, Jill A; Roell, Kyle; Kuenemann, Melaine Agnes; Houck, Keith A; Reif, David M; Fourches, Denis; Kullman, Seth W

2018-06-11

High throughput screening (HTS) programs have demonstrated that the Vitamin D receptor (VDR) is activated and/or antagonized by a wide range of structurally diverse chemicals. In this study, we examined the Tox21 qHTS data set generated against VDR for reproducibility and concordance and elucidated functional insights into VDR-xenobiotic interactions. Twenty-one potential VDR agonists and 19 VDR antagonists were identified from a subset of >400 compounds with putative VDR activity and examined for VDR functionality utilizing select orthogonal assays. Transient transactivation assay (TT) using a human VDR plasmid and Cyp24 luciferase reporter construct revealed 20/21 active VDR agonists and 18/19 active VDR antagonists. Mammalian-2-hybrid assay (M2H) was then used to evaluate VDR interactions with co-activators and co-regulators. With the exception of a select few compounds, VDR agonists exhibited significant recruitment of co-regulators and co-activators whereas antagonists exhibited considerable attenuation of recruitment by VDR. A unique set of compounds exhibiting synergistic activity in antagonist mode and no activity in agonist mode was identified. Cheminformatics modeling of VDR-ligand interactions were conducted and revealed selective ligand VDR interaction. Overall, data emphasizes the molecular complexity of ligand-mediated interactions with VDR and suggest that VDR transactivation may be a target site of action for diverse xenobiotics.

Characterization of an estrogen-responsive element implicated in regulation of the rainbow trout estrogen receptor gene.

PubMed

Le Dréan, Y; Lazennec, G; Kern, L; Saligaut, D; Pakdel, F; Valotaire, Y

1995-08-01

We previously reported that the expression of the rainbow trout estrogen receptor (rtER) gene is markedly increased by estradiol (E2). In this paper, we have used transient transfection assays with reporter plasmids expressing chloramphenicol acetyl transferase (CAT), linked to 5' flanking regions of the rtER gene promoter, to identify cis-elements responsible for E2 inducibility. Deletion analysis localized an estrogen-responsive element (ERE), at position +242, with one mutation on the first base compared with the consensus sequence. This element confers estrogen responsiveness to CAT reporter linked to both the herpes simplex virus thymidine kinase promoter and the homologous rtER promoter. Moreover, using a 0.2 kb fragment of the rtER promoter encompassing the ERE and the rtER DNA binding domain obtained from a bacterial expression system, DNase I footprinting experiments demonstrated a specific protection covering 20 bp (+240/+260) containing the ERE sequence. Based on these studies, we believe that this ERE sequence, identified in the rtER gene promoter, may be a major cis-acting element involved in the regulation of the gene by estrogen.

Transcriptome response of the foundation plant Spartina alterniflora to the Deepwater Horizon oil spill.

PubMed

Alvarez, Mariano; Ferreira de Carvalho, Julie; Salmon, Armel; Ainouche, Malika L; Cavé-Radet, Armand; El Amrani, Abdelhak; Foster, Tammy E; Moyer, Sydney; Richards, Christina L

2018-06-04

Despite the severe impacts of the Deepwater Horizon oil spill, the foundation plant species Spartina alterniflora proved resilient to heavy oiling, providing an opportunity to identify mechanisms of response to the anthropogenic stress of crude oil exposure. We assessed plants from oil-affected and unaffected populations using a custom DNA microarray to identify genomewide transcription patterns and gene expression networks that respond to crude oil exposure. In addition, we used T-DNA insertion lines of the model grass Brachypodium distachyon to assess the contribution of four novel candidate genes to crude oil response. Responses in S. alterniflora to hydrocarbon exposure across the transcriptome as well as xenobiotic specific response pathways had little overlap with those previously identified in the model plant Arabidopsis thaliana. Among T-DNA insertion lines of B. distachyon, we found additional support for two candidate genes, one (ATTPS21) involved in volatile production, and the other (SUVH5) involved in epigenetic regulation of gene expression, that may be important in the response to crude oil. The architecture of crude oil response in S. alterniflora is unique from that of the model species A. thaliana, suggesting that xenobiotic response may be highly variable across plant species. In addition, further investigations of regulatory networks may benefit from more information about epigenetic response pathways. © 2018 John Wiley & Sons Ltd.

Metabolic response against sulfur-containing heterocyclic compounds by the lignin-degrading basidiomycete Coriolus versicolor.

PubMed

Ichinose, H; Nakamizo, M; Wariishi, H; Tanaka, H

2002-03-01

The fungal conversions of sulfur-containing heterocyclic compounds were investigated using the lignin-degrading basidiomycete Coriolus versicolor. The fungus metabolized a series of sulfur compounds--25 structurally related thiophene derivatives--via several different pathways. Under primary metabolic conditions, C. versicolor utilized thiophenes, such as 2-hydroxymethyl-, 2-formyl-, and 2-carboxyl-thiophenes, as a nutrient sulfur source for growth; thus, the fungus degraded these compounds more effectively in a non-sulfur-containing medium than in conventional medium. The product analysis revealed that several redox reactions, decarboxylation reactions, and C-S cleavage reactions were involved in the fungal conversion of non-aromatic thiophenes. On the other hand, benzothiophene (BT) and dibenzothiophene (DBT) skeletons were converted to water-soluble products. All the products and metabolic intermediates were more hydrophilic than the starting substrates. These metabolic actions seemed to be a chemical stress response against exogenously added xenobiotics. These metabolic reactions were optimized under ligninolytic conditions, also suggesting the occurrence of a fungal xenobiotic response. Furthermore, the fungus converted a series of BTs and DBTs via several different pathways, which seemed to be controlled by the chemical structure of the substrates. DBT, 4-methylDBT, 4, 6-dimethylDBT, 2-methylBT, and 7-methylBT were immediately oxidized to their S-oxides. BTs and DBTs with the hydroxymethyl substituent were converted to their xylosides without S-oxidation. Those with carboxyl and formyl substituents were reduced to form a hydroxymethyl group, then xylosidated. These observations strongly suggested the involvement of a fungal substrate-recognition and metabolic response mechanism in the metabolism of sulfur-containing heterocyclic compounds by C. versicolor.

The Role of Xenobiotic-Metabolizing Enzymes in Anthelmintic Deactivation and Resistance in Helminths.

PubMed

Matoušková, Petra; Vokřál, Ivan; Lamka, Jiří; Skálová, Lenka

2016-06-01

Xenobiotic-metabolizing enzymes (XMEs) modulate the biological activity and behavior of many drugs, including anthelmintics. The effects of anthelmintics can often be abolished by XMEs when the drugs are metabolized to an inefficient compound. XMEs therefore play a significant role in anthelmintic efficacy. Moreover, differences in XMEs between helminths are reflected by differences in anthelmintic metabolism between target species. Taking advantage of the newly sequenced genomes of many helminth species, progress in this field has been remarkable. The present review collects up to date information regarding the most important XMEs (phase I and phase II biotransformation enzymes; efflux transporters) in helminths. The participation of these XMEs in anthelmintic metabolism and their possible roles in drug resistance are evaluated. Copyright © 2016 Elsevier Ltd. All rights reserved.

Implementation of structural response sensitivity calculations in a large-scale finite-element analysis system

NASA Technical Reports Server (NTRS)

Giles, G. L.; Rogers, J. L., Jr.

1982-01-01

The methodology used to implement structural sensitivity calculations into a major, general-purpose finite-element analysis system (SPAR) is described. This implementation includes a generalized method for specifying element cross-sectional dimensions as design variables that can be used in analytically calculating derivatives of output quantities from static stress, vibration, and buckling analyses for both membrane and bending elements. Limited sample results for static displacements and stresses are presented to indicate the advantages of analytically calculating response derivatives compared to finite difference methods. Continuing developments to implement these procedures into an enhanced version of SPAR are also discussed.

CARDIAC AND THERMOREGULATORY RESPONSES TO INHALED POLLUTANTS IN HEALTHY AND COMPROMISED RODENTS: MODULATION VIA INTERACTION WITH ENVIRONMENTAL FACTORS

EPA Science Inventory

ABSTRACT
Rodents often demonstrate a profound depression in physiological function following acute exposure to toxic xenobiotic agents. This effect, termed the hypothermic response, is primarily characterized by significant decreases in core temperature and heart rate, and is...

Effect of storage temperature on cultured epidermal cell sheets stored in xenobiotic-free medium.

PubMed

Jackson, Catherine; Aabel, Peder; Eidet, Jon R; Messelt, Edward B; Lyberg, Torstein; von Unge, Magnus; Utheim, Tor P

2014-01-01

Cultured epidermal cell sheets (CECS) are used in regenerative medicine in patients with burns, and have potential to treat limbal stem cell deficiency (LSCD), as demonstrated in animal models. Despite widespread use, short-term storage options for CECS are limited. Advantages of storage include: flexibility in scheduling surgery, reserve sheets for repeat operations, more opportunity for quality control, and improved transportation to allow wider distribution. Studies on storage of CECS have thus far focused on cryopreservation, whereas refrigeration is a convenient method commonly used for whole skin graft storage in burns clinics. It has been shown that preservation of viable cells using these methods is variable. This study evaluated the effect of different temperatures spanning 4°C to 37°C, on the cell viability, morphology, proliferation and metabolic status of CECS stored over a two week period in a xenobiotic-free system. Compared to non-stored control, best cell viability was obtained at 24°C (95.2±9.9%); reduced cell viability, at approximately 60%, was demonstrated at several of the temperatures (12°C, 28°C, 32°C and 37°C). Metabolic activity was significantly higher between 24°C and 37°C, where glucose, lactate, lactate/glucose ratios, and oxygen tension indicated increased activation of the glycolytic pathway under aerobic conditions. Preservation of morphology as shown by phase contrast and scanning electron micrographs was best at 12°C and 16°C. PCNA immunocytochemistry indicated that only 12°C and 20°C allowed maintenance of proliferative function at a similar level to non-stored control. In conclusion, results indicate that 12°C and 24°C merit further investigation as the prospective optimum temperature for short-term storage of cultured epidermal cell sheets.

33 CFR Appendix D to Part 154 - Training Elements for Oil Spill Response Plans

Code of Federal Regulations, 2010 CFR

2010-07-01

... Response Plans D Appendix D to Part 154 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) POLLUTION FACILITIES TRANSFERRING OIL OR HAZARDOUS MATERIAL IN BULK Pt. 154, App. D Appendix D to Part 154—Training Elements for Oil Spill Response Plans 1. General 1.1The portion of the plan...

TECHNICAL NOTE: Direct finite-element analysis of the frequency response of a Y-Z lithium niobate SAW filter

NASA Astrophysics Data System (ADS)

Xu, Guanshui

2000-12-01

A direct finite-element model is developed for the full-scale analysis of the electromechanical phenomena involved in surface acoustic wave (SAW) devices. The equations of wave propagation in piezoelectric materials are discretized using the Galerkin method, in which an implicit algorithm of the Newmark family with unconditional stability is implemented. The Rayleigh damping coefficients are included in the elements near the boundary to reduce the influence of the reflection of waves. The performance of the model is demonstrated by the analysis of the frequency response of a Y-Z lithium niobate filter with two uniform ports, with emphasis on the influence of the number of electrodes. The frequency response of the filter is obtained through the Fourier transform of the impulse response, which is solved directly from the finite-element simulation. It shows that the finite-element results are in good agreement with the characteristic frequency response of the filter predicted by the simple phase-matching argument. The ability of the method to evaluate the influence of the bulk waves at the high-frequency end of the filter passband and the influence of the number of electrodes on insertion loss is noteworthy. We conclude that the direct finite-element analysis of SAW devices can be used as an effective tool for the design of high-performance SAW devices. Some practical computational challenges of finite-element modeling of SAW devices are discussed.

Finite element predictions of active buckling control of stiffened panels

NASA Astrophysics Data System (ADS)

Thompson, Danniella M.; Griffin, O. H., Jr.

1993-04-01

Materials systems and structures that can respond 'intelligently' to their environment are currently being proposed and investigated. A series of finite element analyses was performed to investigate the potential for active buckling control of two different stiffened panels by embedded shape memory alloy (SMA) rods. Changes in the predicted buckling load increased with the magnitude of the actuation level for a given structural concept. Increasing the number of actuators for a given concept yielded greater predicted increases in buckling load. Considerable control authority was generated with a small number of actuators, with greater authority demonstrated for those structural concepts where the activated SMA rods could develop greater forces and moments on the structure. Relatively simple and inexpensive analyses were performed with standard finite elements to determine such information, indicating the viability of these types of models for design purposes.

A finite element based method for solution of optimal control problems

NASA Technical Reports Server (NTRS)

Bless, Robert R.; Hodges, Dewey H.; Calise, Anthony J.

1989-01-01

A temporal finite element based on a mixed form of the Hamiltonian weak principle is presented for optimal control problems. The mixed form of this principle contains both states and costates as primary variables that are expanded in terms of elemental values and simple shape functions. Unlike other variational approaches to optimal control problems, however, time derivatives of the states and costates do not appear in the governing variational equation. Instead, the only quantities whose time derivatives appear therein are virtual states and virtual costates. Also noteworthy among characteristics of the finite element formulation is the fact that in the algebraic equations which contain costates, they appear linearly. Thus, the remaining equations can be solved iteratively without initial guesses for the costates; this reduces the size of the problem by about a factor of two. Numerical results are presented herein for an elementary trajectory optimization problem which show very good agreement with the exact solution along with excellent computational efficiency and self-starting capability. The goal is to evaluate the feasibility of this approach for real-time guidance applications. To this end, a simplified two-stage, four-state model for an advanced launch vehicle application is presented which is suitable for finite element solution.

Time-course comparison of xenobiotic activators of CAR and PPAR{alpha} in mouse liver

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ross, Pamela K.; Woods, Courtney G.; ExxonMobil Biomedical Sciences, Annandale, NJ

Constitutive androstane receptor (CAR) and peroxisome proliferator activated receptor (PPAR){alpha} are transcription factors known to be primary mediators of liver effects, including carcinogenesis, by phenobarbital-like compounds and peroxisome proliferators, respectively, in rodents. Many similarities exist in the phenotypes elicited by these two classes of agents in rodent liver, and we hypothesized that the initial transcriptional responses to the xenobiotic activators of CAR and PPAR{alpha} will exhibit distinct patterns, but at later time-points these biological pathways will converge. In order to capture the global transcriptional changes that result from activation of these nuclear receptors over a time-course in the mouse liver,more » microarray technology was used. First, differences in basal expression of liver genes between C57Bl/6J wild-type and Car-null mice were examined and 14 significantly differentially expressed genes were identified. Next, mice were treated with phenobarbital (100 mg/kg by gavage for 24 h, or 0.085% w/w diet for 7 or 28 days), and liver gene expression changes with regards to both time and treatment were identified. While several pathways related to cellular proliferation and metabolism were affected by phenobarbital in wild-type mice, no significant changes in gene expression were found over time in the Car-nulls. Next, we determined commonalities and differences in the temporal response to phenobarbital and WY-14,643, a prototypical activator of PPAR {alpha}. Gene expression signatures from livers of wild-type mice C57Bl6/J mice treated with PB or WY-14,643 were compared. Similar pathways were affected by both compounds; however, considerable time-related differences were present. This study establishes common gene expression fingerprints of exposure to activators of CAR and PPAR{alpha} in rodent liver and demonstrates that despite similar phenotypic changes, molecular pathways differ between classes of chemical carcinogens.« less

Characterisation of human tubular cell monolayers as a model of proximal tubular xenobiotic handling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Colin D.A.; Sayer, Rachel; Windass, Amy S.

2008-12-15

The aim of this study was to determine whether primary human tubular cell monolayers could provide a powerful tool with which to investigate the renal proximal tubular handling of xenobiotics. Human proximal and distal tubule/collecting duct cells were grown as monolayers on permeable filter supports. After 10 days in culture, proximal tubule cells remained differentiated and expressed a wide palette of transporters at the mRNA level including NaPi-IIa, SGLT1, SGLT2, OCT2, OCTN2, OAT1, OAT3, OAT4, MDR1, MRP2 and BCRP. At the protein level, the expression of a subset of transporters including NaPi-IIa, OAT1 and OAT3 was demonstrated using immunohistochemistry. Analysismore » of the expression of the ATP binding cassette efflux pumps MDR1, MRP2 and BCRP confirmed their apical membrane localisation. At the functional level, tubule cell monolayers retain the necessary machinery to mediate the net secretion of the prototypic substrates; PAH and creatinine. PAH secretion across the monolayer consisted of the uptake of PAH across the basolateral membrane by OAT1 and OAT3 and the apical exit of PAH by a probenecid and MK571-sensitive route consistent with actions of MRP2 or MRP4. Creatinine secretion was by OCT2-mediated uptake at the basolateral membrane and via MDR1 at the apical membrane. Functional expression of MDR1 and BCRP at the apical membrane was also demonstrated using a Hoechst 33342 dye. Similarly, measurement of calcein efflux demonstrated the functional expression of MRP2 at the apical membrane of cell monolayers. In conclusion, human tubular cell monolayers provide a powerful tool to investigate renal xenobiotic handling.« less

Optimization of a cAMP response element signal pathway reporter system.

PubMed

Shan, Qiang; Storm, Daniel R

2010-08-15

A sensitive cAMP response element (CRE) reporter system is essential for studying the cAMP/protein kinase A/cAMP response element binding protein signal pathway. Here we have tested a few CRE promoters and found one with high sensitivity to external stimuli. Using this optimal CRE promoter and the enhanced green fluorescent protein as the reporter, we have established a CRE reporter cell line. This cell line can be used to study the signal pathway by fluorescent microscope, fluorescence-activated cell analysis and luciferase assay. This cell line's sensitivity to forskolin, using the technique of fluorescence-activated cell sorting, was increased to approximately seven times that of its parental HEK 293 cell line, which is currently the most commonly used cell line in the field for the signal pathway study. Therefore, this newly created cell line is potentially useful for studying the signal pathway's modulators, which generally have weaker effect than its mediators. Our research has also established a general procedure for optimizing transcription-based reporter cell lines, which might be useful in performing the same task when studying many other transcription-based signal pathways. (c) 2010 Elsevier B.V. All rights reserved.

Structural insights into xenobiotic and inhibitor binding to human aldehyde oxidase.

PubMed

Coelho, Catarina; Foti, Alessandro; Hartmann, Tobias; Santos-Silva, Teresa; Leimkühler, Silke; Romão, Maria João

2015-10-01

Aldehyde oxidase (AOX) is a xanthine oxidase (XO)-related enzyme with emerging importance due to its role in the metabolism of drugs and xenobiotics. We report the first crystal structures of human AOX1, substrate free (2.6-Å resolution) and in complex with the substrate phthalazine and the inhibitor thioridazine (2.7-Å resolution). Analysis of the protein active site combined with steady-state kinetic studies highlight the unique features, including binding and substrate orientation at the active site, that characterize human AOX1 as an important drug-metabolizing enzyme. Structural analysis of the complex with the noncompetitive inhibitor thioridazine revealed a new, unexpected and fully occupied inhibitor-binding site that is structurally conserved among mammalian AOXs and XO. The new structural insights into the catalytic and inhibition mechanisms of human AOX that we now report will be of great value for the rational analysis of clinical drug interactions involving inhibition of AOX1 and for the prediction and design of AOX-stable putative drugs.

Reciprocal Loss of CArG-Boxes and Auxin Response Elements Drives Expression Divergence of MPF2-Like MADS-Box Genes Controlling Calyx Inflation

PubMed Central

Khan, Muhammad Ramzan; Hu, Jinyong; Ali, Ghulam Muhammad

2012-01-01

Expression divergence is thought to be a hallmark of functional diversification between homologs post duplication. Modification in regulatory elements has been invoked to explain expression divergence after duplication for several MADS-box genes, however, verification of reciprocal loss of cis-regulatory elements is lacking in plants. Here, we report that the evolution of MPF2-like genes has entailed degenerative mutations in a core promoter CArG-box and an auxin response factor (ARF) binding element in the large 1st intron in the coding region. Previously, MPF2-like genes were duplicated into MPF2-like-A and -B through genome duplication in Withania and Tubocapsicum (Withaninae). The calyx of Withania grows exorbitantly after pollination unlike Tubocapsicum, where it degenerates. Besides inflated calyx syndrome formation, MPF2-like transcription factors are implicated in functions both during the vegetative and reproductive development as well as in phase transition. MPF2-like-A of Withania (WSA206) is strongly expressed in sepals, while MPF2-like-B (WSB206) is not. Interestingly, their combined expression patterns seem to replicate the pattern of their closely related hypothetical progenitors from Vassobia and Physalis. Using phylogenetic shadowing, site-directed mutagenesis and motif swapping, we could show that the loss of a conserved CArG-box in MPF2-like-B of Withania is responsible for impeding its expression in sepals. Conversely, loss of an ARE in MPF2-like-A relaxed the constraint on expression in sepals. Thus, the ARE is an active suppressor of MPF2-like gene expression in sepals, which in contrast is activated via the CArG-box. The observed expression divergence in MPF2-like genes due to reciprocal loss of cis-regulatory elements has added to genetic and phenotypic variations in the Withaninae and enhanced the potential of natural selection for the adaptive evolution of ICS. Moreover, these results provide insight into the interplay of floral

Draft Genome Sequence of Paenibacillus sp. Strain DMB20, Isolated from Alang Ship-Breaking Yard, Which Harbors Genes for Xenobiotic Degradation

PubMed Central

Shah, Binal; Jain, Kunal; Patel, Namrata; Pandit, Ramesh; Patel, Anand; Joshi, Chaitanya G.

2015-01-01

Paenibacillus sp. strain DMB20, in cometabolism with other Proteobacteria and Firmicutes, exhibits azoreduction of textile dyes. Here, we report the draft genome sequence of this bacterium, consisting of 6,647,181 bp with 7,668 coding sequences (CDSs). The data presented highlight multiple sets of functional genes associated with xenobiotic compound degradation. PMID:26067950

Serum trace element differences between Schizophrenia patients and controls in the Han Chinese population.

PubMed

Cai, Lei; Chen, Tianlu; Yang, Jinglei; Zhou, Kejun; Yan, Xiaomei; Chen, Wenzhong; Sun, Liya; Li, Linlin; Qin, Shengying; Wang, Peng; Yang, Ping; Cui, Donghong; Burmeister, Margit; He, Lin; Jia, Wei; Wan, Chunling

2015-10-12

Little is known about the trace element profile differences between Schizophrenia patients and healthy controls; previous studies about the association of certain elements with Schizophrenia have obtained conflicting results. To identify these differences in the Han Chinese population, inductively coupled plasma-mass spectrometry was used to quantify the levels of 35 elements in the sera of 111 Schizophrenia patients and 110 healthy participants, which consisted of a training (61/61 for cases/controls included) and a test group including remaining participants. An orthogonal projection to latent structures model was constructed from the training group (R(2)Y = 0.465, Q(2)cum = 0.343) had a sensitivity of 76.0% and a specificity of 71.4% in the test group. Single element analysis indicated that the concentrations of cesium, zinc, and selenium were significantly reduced in patients with Schizophrenia in both the training and test groups. The meta-analysis including 522 cases and 360 controls supported that Zinc was significantly associated with Schizophrenia (standardized mean difference [SMD], -0.81; 95% confidence intervals [CI], -1.46 to -0.16, P = 0.01) in the random-effect model. Information theory analysis indicated that Zinc could play roles independently in Schizophrenia. These results suggest clear element profile differences between patients with Schizophrenia and healthy controls, and reduced Zn level is confirmed in the Schizophrenia patients.

Finite element based model predictive control for active vibration suppression of a one-link flexible manipulator.

PubMed

Dubay, Rickey; Hassan, Marwan; Li, Chunying; Charest, Meaghan

2014-09-01

This paper presents a unique approach for active vibration control of a one-link flexible manipulator. The method combines a finite element model of the manipulator and an advanced model predictive controller to suppress vibration at its tip. This hybrid methodology improves significantly over the standard application of a predictive controller for vibration control. The finite element model used in place of standard modelling in the control algorithm provides a more accurate prediction of dynamic behavior, resulting in enhanced control. Closed loop control experiments were performed using the flexible manipulator, instrumented with strain gauges and piezoelectric actuators. In all instances, experimental and simulation results demonstrate that the finite element based predictive controller provides improved active vibration suppression in comparison with using a standard predictive control strategy. Copyright © 2014 ISA. Published by Elsevier Ltd. All rights reserved.

ESTROGENIC RESPONSES TO XENOBIOTICS IN CHANNEL CATFISH (ICTALURUS PUNCTATUS) (R823450)

EPA Science Inventory

Abstract

Several environmentally relevant contaminants are characterized as xenoestrogens by virtue of their ability to induce responses similar to 17-estradiol (E2). T...

Optimal frequency-response sensitivity of compressible flow over roughness elements

NASA Astrophysics Data System (ADS)

Fosas de Pando, Miguel; Schmid, Peter J.

2017-04-01

Compressible flow over a flat plate with two localised and well-separated roughness elements is analysed by global frequency-response analysis. This analysis reveals a sustained feedback loop consisting of a convectively unstable shear-layer instability, triggered at the upstream roughness, and an upstream-propagating acoustic wave, originating at the downstream roughness and regenerating the shear-layer instability at the upstream protrusion. A typical multi-peaked frequency response is recovered from the numerical simulations. In addition, the optimal forcing and response clearly extract the components of this feedback loop and isolate flow regions of pronounced sensitivity and amplification. An efficient parametric-sensitivity framework is introduced and applied to the reference case which shows that first-order increases in Reynolds number and roughness height act destabilising on the flow, while changes in Mach number or roughness separation cause corresponding shifts in the peak frequencies. This information is gained with negligible effort beyond the reference case and can easily be applied to more complex flows.

Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination

PubMed Central

Pedotti, Rosetta; DeVoss, Jason J.; Youssef, Sawsan; Mitchell, Dennis; Wedemeyer, Jochen; Madanat, Rami; Garren, Hideki; Fontoura, Paulo; Tsai, Mindy; Galli, Stephen J.; Sobel, Raymond A.; Steinman, Lawrence

2003-01-01

Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc ɛ receptor 1 (FcɛRI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig FcγRIII or both FcγRIII and FcɛRI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and “allergic” responses. PMID:12576552

Demand Response Advanced Controls Framework and Assessment of Enabling Technology Costs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Potter, Jennifer; Cappers, Peter

The Demand Response Advanced Controls Framework and Assessment of Enabling Technology Costs research describe a variety of DR opportunities and the various bulk power system services they can provide. The bulk power system services are mapped to a generalized taxonomy of DR “service types”, which allows us to discuss DR opportunities and bulk power system services in fewer yet broader categories that share similar technological requirements which mainly drive DR enablement costs. The research presents a framework for the costs to automate DR and provides descriptions of the various elements that drive enablement costs. The report introduces the various DRmore » enabling technologies and end-uses, identifies the various services that each can provide to the grid and provides the cost assessment for each enabling technology. In addition to a report, this research includes a Demand Response Advanced Controls Database and User Manual. They are intended to provide users with the data that underlies this research and instructions for how to use that database more effectively and efficiently.« less

Revisiting the Relationship between Transposable Elements and the Eukaryotic Stress Response.

PubMed

Horváth, Vivien; Merenciano, Miriam; González, Josefa

2017-11-01

A relationship between transposable elements (TEs) and the eukaryotic stress response was suggested in the first publications describing TEs. Since then, it has often been assumed that TEs are activated by stress, and that this activation is often beneficial for the organism. In recent years, the availability of new high-throughput experimental techniques has allowed further interrogation of the relationship between TEs and stress. By reviewing the recent literature, we conclude that although there is evidence for a beneficial effect of TE activation under stress conditions, the relationship between TEs and the eukaryotic stress response is quite complex. Copyright © 2017 Elsevier Ltd. All rights reserved.

Detection and Characterization of Conjugative Degradative Plasmids in Xenobiotic-Degrading Sphingomonas Strains

PubMed Central

Basta, Tamara; Keck, Andreas; Klein, Joachim; Stolz, Andreas

2004-01-01

A systematic survey for the presence of plasmids in 17 different xenobiotic-degrading Sphingomonas strains was performed. In almost all analyzed strains, two to five plasmids with sizes of about 50 to 500 kb were detected by using pulsed-field gel electrophoresis. A comparison of plasmid preparations untreated or treated with S1 nuclease suggested that, in general, Sphingomonas plasmids are circular. Hybridization experiments with labeled gene probes suggested that large plasmids are involved in the degradation of dibenzo-p-dioxin, dibenzofuran, and naphthalenesulfonates in S. wittichii RW1, Sphingomonas sp. HH69, and S. xenophaga BN6, respectively. The plasmids which are responsible for the degradation of naphthalene, biphenyl, and toluene by S. aromaticivorans F199 (pNL1) and of naphthalenesulfonates by S. xenophaga BN6 (pBN6) were site-specifically labeled with a kanamycin resistance cassette. The conjugative transfer of these labeled plasmids was attempted with various bacterial strains as putative recipient strains. Thus, a conjugative transfer of plasmid pBN6 from S. xenophaga BN6 to a cured mutant of strain BN6 and to Sphingomonas sp. SS3 was observed. The conjugation experiments with plasmid pNL1 suggested a broader host range of this plasmid, because it was transferred without any obvious structural changes to S. yanoikuyae B1, Sphingomonas sp. SS3, and S. herbicidovorans. In contrast, major plasmid rearrangements were observed in the transconjugants after the transfer of plasmid pNL1 to Sphingomonas sp. HH69 and of pBN6 to Sphingomonas sp. SS3. No indications for the transfer of a Sphingomonas plasmid to bacteria outside of the Sphingomonadaceae were obtained. PMID:15175300

Elevated levels of antibodies against xenobiotics in a subgroup of healthy subjects

PubMed Central

Vojdani, Aristo; Kharrazian, Datis; Mukherjee, Partha Sarathi

2015-01-01

In spite of numerous research efforts, the exact etiology of autoimmune diseases remains largely unknown. Genetics and environmental factors, including xenobiotics, are believed to be involved in the induction of autoimmune disease. Some environmental chemicals, acting as haptens, can bind to a high-molecular-weight carrier protein such as human serum albumin (HSA), causing the immune system to misidentify self-tissue as an invader and launch an immune response against it, leading to autoimmunity. This study aimed to examine the percentage of blood samples from healthy donors in which chemical agents mounted immune challenges and produced antibodies against HSA-bound chemicals. The levels of specific antibodies against 12 different chemicals bound to HSA were measured by ELISA in serum from 400 blood donors. We found that 10% (IgG) and 17% (IgM) of tested individuals showed significant antibody elevation against aflatoxin-HSA adduct. The percentage of elevation against the other 11 chemicals ranged from 8% to 22% (IgG) and 13% to 18% (IgM). Performance of serial dilution and inhibition of the chemical–antibody reaction by specific antigens but not by non-specific antigens were indicative of the specificity of these antibodies. Although we lack information about chemical exposure in the tested individuals, detection of antibodies against various protein adducts may indicate chronic exposure to these chemical haptens in about 20% of the tested individuals. Currently the pathological significance of these antibodies in human blood is still unclear, and this protein adduct formation could be one of the mechanisms by which environmental chemicals induce autoimmune reactivity in a significant percentage of the population. PMID:25042713

An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells.

PubMed

Gonsky, R; Deem, R L; Bream, J H; Young, H A; Targan, S R

2006-07-01

This study examines mucosa-specific regulatory pathways involved in modulation of interferon-gamma (IFN-gamma) in lamina propria T cells. Previous studies identified mucosa-specific CD2 cis-elements within the -204 to -108 bp IFNG promoter. Within this region, a single-site nucleotide polymorphism, -179G/T, imparts tumor necrosis factor-alpha stimulation of IFNG in peripheral blood lymphocytes, and is linked with accelerated AIDS progression. We discovered a putative estrogen response element (ERE) introduced by the -179T, which displays selective activation in peripheral blood mononuclear cells (PBMC) vs lamina propria mononuclear cells (LPMC). Transfection of PBMC with constructs containing the -179G or -179T site revealed CD2-mediated enhancement of the -179T compared to -179G allele, although, in LPMC, a similar level of expression was detected. Electrophoretic mobility shift assay (EMSA) analysis demonstrated CD2-mediated nucleoprotein binding to the -179T but not the -179G in PBMC. In LPMC, binding is constitutive to both -179G and -179T regions. Sequence and EMSA analysis suggests that the -179T allele creates an ERE-like binding site capable of binding recombinant estrogen receptor. Estrogen response element transactivation is enhanced by CD2 signaling, but inhibited by estrogen in PBMC but not in LPMC, although expression of estrogen receptor was similar. This is the first report to describe a potential molecular mechanism responsible for selectively controlling IFN-gamma production in LPMC.

Identification of Regulatory Elements That Control PPARγ Expression in Adipocyte Progenitors

PubMed Central

Chou, Wen-Ling; Galmozzi, Andrea; Partida, David; Kwan, Kevin; Yeung, Hui; Su, Andrew I.; Saez, Enrique

2013-01-01

Adipose tissue renewal and obesity-driven expansion of fat cell number are dependent on proliferation and differentiation of adipose progenitors that reside in the vasculature that develops in coordination with adipose depots. The transcriptional events that regulate commitment of progenitors to the adipose lineage are poorly understood. Because expression of the nuclear receptor PPARγ defines the adipose lineage, isolation of elements that control PPARγ expression in adipose precursors may lead to discovery of transcriptional regulators of early adipocyte determination. Here, we describe the identification and validation in transgenic mice of 5 highly conserved non-coding sequences from the PPARγ locus that can drive expression of a reporter gene in a manner that recapitulates the tissue-specific pattern of PPARγ expression. Surprisingly, these 5 elements appear to control PPARγ expression in adipocyte precursors that are associated with the vasculature of adipose depots, but not in mature adipocytes. Characterization of these five PPARγ regulatory sequences may enable isolation of the transcription factors that bind these cis elements and provide insight into the molecular regulation of adipose tissue expansion in normal and pathological states. PMID:24009687

Controls on foliar nutrient and aluminium concentrations in a tropical tree flora: phylogeny, soil chemistry and interactions among elements.

PubMed

Metali, Faizah; Abu Salim, Kamariah; Tennakoon, Kushan; Burslem, David F R P

2015-01-01

Foliar elemental concentrations are predictors of life-history variation and contribute to spatial patterns in biogeochemical cycling. We examined the contributions of habitat association, local soil environment, and elemental interactions to variation in foliar elemental concentrations in tropical trees using methods that account for phylogeny. We sampled top-soils and leaves of 58 tropical trees in heath forest (HF) on nutrient-poor sand and mixed dipterocarp forest (MDF) on nutrient-rich clay soils. A phylogenetic generalized least squares method was used to determine how foliar nutrient and aluminium (Al) concentrations varied in response to habitat distribution, soil chemistry and other elemental concentrations. Foliar nitrogen (N) and Al concentrations were greater for specialists of MDF than for specialists of HF, while foliar calcium (Ca) concentrations showed the opposite trend. Foliar magnesium (Mg) concentrations were lower for generalists than for MDF specialists. Foliar element concentrations were correlated with fine-scale variation in soil chemistry in phylogenetically controlled analyses across species, but there was limited within-species plasticity in foliar elemental concentrations. Among Al accumulators, foliar Al concentration was positively associated with foliar Ca and Mg concentrations, and negatively associated with foliar phosphorus (P) concentrations. The Al-accumulation trait and relationships between foliar elemental and Al concentrations may contribute to species habitat partitioning and ecosystem-level differences in biogeochemical cycles. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

Small RNAs, big impact: small RNA pathways in transposon control and their effect on the host stress response.

PubMed

Wheeler, Bayly S

2013-12-01

Transposons are mobile genetic elements that are a major constituent of most genomes. Organisms regulate transposable element expression, transposition, and insertion site preference, mitigating the genome instability caused by uncontrolled transposition. A recent burst of research has demonstrated the critical role of small non-coding RNAs in regulating transposition in fungi, plants, and animals. While mechanistically distinct, these pathways work through a conserved paradigm. The presence of a transposon is communicated by the presence of its RNA or by its integration into specific genomic loci. These signals are then translated into small non-coding RNAs that guide epigenetic modifications and gene silencing back to the transposon. In addition to being regulated by the host, transposable elements are themselves capable of influencing host gene expression. Transposon expression is responsive to environmental signals, and many transposons are activated by various cellular stresses. TEs can confer local gene regulation by acting as enhancers and can also confer global gene regulation through their non-coding RNAs. Thus, transposable elements can act as stress-responsive regulators that control host gene expression in cis and trans.

Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics

PubMed Central

2012-01-01

Introduction In order to assess the significance of drug levels measured in intensive care medicine, clinical and forensic toxicology, as well as for therapeutic drug monitoring, it is essential that a comprehensive collection of data is readily available. Therefore, it makes sense to offer a carefully referenced compilation of therapeutic and toxic plasma concentration ranges, as well as half-lives, of a large number of drugs and other xenobiotics for quick and comprehensive information. Methods Data have been abstracted from original papers and text books, as well as from previous compilations, and have been completed with data collected in our own forensic and clinical toxicology laboratory. The data presented in the table and corresponding annotations have been developed over the past 20 years and longer. A previous compilation has been completely revised and updated. In addition, more than 170 substances, especially drugs that have been introduced to the market since 2003 as well as illegal drugs, which became known to cause intoxications, were added. All data were carefully referenced and more than 200 new references were included. Moreover, the annotations providing details were completely revised and more than 100 annotations were added. Results For nearly 1,000 drugs and other xenobiotics, therapeutic ("normal") and, if data were available, toxic and comatose-fatal blood-plasma concentrations and elimination half-lives were compiled in a table. Conclusions In case of intoxications, the concentration of the ingested substances and/or metabolites in blood plasma better predicts the clinical severity of the case when compared to the assumed amount and time of ingestion. Comparing and contrasting the clinical case against the data provided, including the half-life, may support the decision for or against further intensive care. In addition, the data provided are useful for the therapeutic monitoring of pharmacotherapies, to facilitate the diagnostic assessment

Decreased detoxification genes and genome size make the human body louse an efficient model to study xenobiotic metabolism

PubMed Central

Lee, Si Hyeock; Kang, Jae Soon; Min, Jee Sun; Yoon, Kyong Sup; Strycharz, Joseph P.; Johnson, Reed; Mittapalli, Omprakash; Margam, Venu M.; Sun, Weilin; Li, Hong-Mei; Xie, Jun; Wu, Jing; Kirkness, Ewen F.; Berenbaum, May R.; Pittendrigh, Barry R.; Clark, J. Marshall

2010-01-01

The human body louse, Pediculus humanus humanus, has one of the smallest insect genomes, containing ~10,775 annotated genes (Kirkness et al. 2010). Annotation of detoxification [cytochrome P450 monooxygenase (P450), glutathione-S-transferase (GST), esterase (Est), and ATP-binding cassette transporter (ABC transporter)] genes revealed that they are dramatically reduced in P. h. humanus compared to other insects except for Apis mellifera. There are 37 P450, 13 GST and 17 Est genes present in P. h. humanus, approximately half of that found in Drosophila melanogaster and Anopheles gambiae. The number of putatively functional ABC transporter genes in P. h. humanus and A. mellifera are the same (36) but both have fewer than An. gambiae (44) or D. melanogaster (65). The reduction of detoxification genes in P. h. humanus may be due to their simple life history, where they do not encounter a wide variety of xenobiotics. Neuronal component genes are highly conserved across different insect species as expected due to their critical function. Although reduced in number, P. h. humanus still retains at least a minimum repertoire of genes known to confer metabolic or toxicokinetic resistance to xenobiotics (e.g., Cyp3 clade P450s, Delta GSTs, B clade Ests and B/C subfamily ABC transporters), suggestive of its high potential for resistance development. PMID:20561088

Decreased detoxification genes and genome size make the human body louse an efficient model to study xenobiotic metabolism.

PubMed

Lee, S H; Kang, J S; Min, J S; Yoon, K S; Strycharz, J P; Johnson, R; Mittapalli, O; Margam, V M; Sun, W; Li, H-M; Xie, J; Wu, J; Kirkness, E F; Berenbaum, M R; Pittendrigh, B R; Clark, J M

2010-10-01

The human body louse, Pediculus humanus humanus, has one of the smallest insect genomes, containing ∼10 775 annotated genes. Annotation of detoxification [cytochrome P450 monooxygenase (P450), glutathione-S-transferase (GST), esterase (Est) and ATP-binding cassette transporter (ABC transporter)] genes revealed that they are dramatically reduced in P. h. humanus compared to other insects except for Apis mellifera. There are 37 P450, 13 GST and 17 Est genes present in P. h. humanus, approximately half the number found in Drosophila melanogaster and Anopheles gambiae. The number of putatively functional ABC transporter genes in P. h. humanus and Ap. mellifera are the same (36) but both have fewer than An. gambiae (44) or Dr. melanogaster (65). The reduction of detoxification genes in P. h. humanus may be a result of this louse's simple life history, in which it does not encounter a wide variety of xenobiotics. Neuronal component genes are highly conserved across different insect species as expected because of their critical function. Although reduced in number, P. h. humanus still retains at least a minimum repertoire of genes known to confer metabolic or toxicokinetic resistance to xenobiotics (eg Cyp3 clade P450s, Delta GSTs, B clade Ests and B/C subfamily ABC transporters), suggestive of its high potential for resistance development. © 2010 The Authors. Insect Molecular Biology © 2010 The Royal Entomological Society.

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

PubMed Central

Sestak, Karol; Conroy, Lauren; Aye, Pyone P.; Mehra, Smriti; Doxiadis, Gaby G.; Kaushal, Deepak

2011-01-01

Background A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). Methodology Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. Principal Findings When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. Conclusions/Significance A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research. PMID:21533263

Implementation of structural response sensitivity calculations in a large-scale finite-element analysis system

NASA Technical Reports Server (NTRS)

Giles, G. L.; Rogers, J. L., Jr.

1982-01-01

The implementation includes a generalized method for specifying element cross-sectional dimensions as design variables that can be used in analytically calculating derivatives of output quantities from static stress, vibration, and buckling analyses for both membrane and bending elements. Limited sample results for static displacements and stresses are presented to indicate the advantages of analytically calclating response derivatives compared to finite difference methods. Continuing developments to implement these procedures into an enhanced version of the system are also discussed.

Prevalence of xenobiotic substances in first-trimester blood samples from Danish pregnant women: a cross-sectional study.

PubMed

Aagaard, Sissel Kramer; Larsen, Agnete; Andreasen, Mette Findal; Lesnikova, Iana; Telving, Rasmus; Vestergaard, Anna Louise; Tørring, Niels; Uldbjerg, Niels; Bor, Pinar

2018-03-03

The aim of this study was to investigate the prevalence of xenobiotic substances, such as caffeine, nicotine and illicit drugs (eg, cannabis and cocaine), in blood samples from first-trimester Danish pregnant women unaware of the screening. A cross - sectional study examined 436 anonymised residual blood samples obtained during 2014 as part of the nationwide prenatal first-trimester screening programme. The samples were analysed by ultra performance liquid chromatography with high-resolution time-of-flight mass spectrometry. An antenatal clinic in a Danish city with 62 000 inhabitants, where >95% of pregnant women joined the screening programme. The prevalence and patterns of caffeine, nicotine, medication and illicit drug intake during the first trimester of pregnancy. The prevalence of prescription and over-the-counter drug detection was 17.9%, including acetaminophen (8.9%) and antidepressants (3.0%), of which citalopram (0.9%) was the most frequent. The prevalence of illegal drugs, indicators of smoking (nicotine/cotinine) and caffeine was 0.9%, 9.9%, and 76.4%, respectively. Only 17.4% of women had no substance identified in their sample. This study emphasises the need for further translational studies investigating lifestyle habits during pregnancy, as well as the underlying molecular mechanisms through which xenobiotic substances may affect placental function and fetal development. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Draft Genome Sequence of Paenibacillus sp. Strain DMB20, Isolated from Alang Ship-Breaking Yard, Which Harbors Genes for Xenobiotic Degradation.

PubMed

Shah, Binal; Jain, Kunal; Patel, Namrata; Pandit, Ramesh; Patel, Anand; Joshi, Chaitanya G; Madamwar, Datta

2015-06-11

Paenibacillus sp. strain DMB20, in cometabolism with other Proteobacteria and Firmicutes, exhibits azoreduction of textile dyes. Here, we report the draft genome sequence of this bacterium, consisting of 6,647,181 bp with 7,668 coding sequences (CDSs). The data presented highlight multiple sets of functional genes associated with xenobiotic compound degradation. Copyright © 2015 Shah et al.

Rapid birth-and-death evolution of the xenobiotic metabolizing NAT gene family in vertebrates with evidence of adaptive selection

PubMed Central

2013-01-01

Background The arylamine N-acetyltransferases (NATs) are a unique family of enzymes widely distributed in nature that play a crucial role in the detoxification of aromatic amine xenobiotics. Considering the temporal changes in the levels and toxicity of environmentally available chemicals, the metabolic function of NATs is likely to be under adaptive evolution to broaden or change substrate specificity over time, making NATs a promising subject for evolutionary analyses. In this study, we trace the molecular evolutionary history of the NAT gene family during the last ~450 million years of vertebrate evolution and define the likely role of gene duplication, gene conversion and positive selection in the evolutionary dynamics of this family. Results A phylogenetic analysis of 77 NAT sequences from 38 vertebrate species retrieved from public genomic databases shows that NATs are phylogenetically unstable genes, characterized by frequent gene duplications and losses even among closely related species, and that concerted evolution only played a minor role in the patterns of sequence divergence. Local signals of positive selection are detected in several lineages, probably reflecting response to changes in xenobiotic exposure. We then put a special emphasis on the study of the last ~85 million years of primate NAT evolution by determining the NAT homologous sequences in 13 additional primate species. Our phylogenetic analysis supports the view that the three human NAT genes emerged from a first duplication event in the common ancestor of Simiiformes, yielding NAT1 and an ancestral NAT gene which in turn, duplicated in the common ancestor of Catarrhini, giving rise to NAT2 and the NATP pseudogene. Our analysis suggests a main role of purifying selection in NAT1 protein evolution, whereas NAT2 was predicted to mostly evolve under positive selection to change its amino acid sequence over time. These findings are consistent with a differential role of the two human isoenzymes

Responses of Noccaea caerulescens and Lupinus albus in trace elements-contaminated soils.

PubMed

Martínez-Alcalá, Isabel; Hernández, Luis E; Esteban, Elvira; Walker, David J; Bernal, M Pilar

2013-05-01

Plants exposed to trace elements can suffer from oxidative stress, which is characterised by the accumulation of reactive oxygen species, alteration in the cellular antioxidant defence system and ultimately lipid peroxidation. We assessed the most-appropriate stress indexes to describe the response of two plant species, with different strategies for coping with trace elements (TEs), to particular contaminants. Noccaea caerulescens, a hyperaccumulator, and Lupinus albus, an excluder, were grown in three soils of differing pH: an acidic soil, a neutral soil (both contaminated mainly by Cu, Zn and As) and a control soil. Then, plant stress indicators were measured. As expected, N. caerulescens accumulated higher levels of Zn and Cd in shoots than L. albus, this effect being stronger in the acid soil, reflecting greater TE solubility in this soil. However, the shoot concentrations of Mn were higher in L. albus than in N. caerulescens, while the As concentration was similar in the two species. In L. albus, the phenolic content and lipid peroxidation were related with the Cu concentration, whereas the Zn and Cd concentrations in N. caerulescens were more closely related to glutathione content and lipid peroxidation. Interestingly, phytochelatins were only found in L. albus grown in polluted soils. Hence, the two species differed with respect to the TEs which provoked stress and the biochemical indicators of the stress, there being a close relationship between the accumulation of TEs and their associated stress indicators in the different plant organs. Crown Copyright © 2013. Published by Elsevier Masson SAS. All rights reserved.

Atrazine-xenobiotic nuclear receptor interactions induce cardiac inflammation and endoplasmic reticulum stress in quail (Coturnix coturnix coturnix).

PubMed

Li, Xue-Nan; Zuo, Yu-Zhu; Qin, Lei; Liu, Wei; Li, Yan-Hua; Li, Jin-Long

2018-05-09

Atrazine (ATR) is one of the most extensively used herbicide that eventually leaches into groundwater and surface water from agricultural areas. Exposure to ATR does harm to the health of human and animals, especially the heart. However, ATR exposure caused cardiotoxicity in bird remains unclear. To evaluate ATR-exerted potential cardiotoxicity in heart, quail were exposed with 0, 50, 250, and 500 mg/kg BW/day ATR by gavage treatment for 45 days. Cardiac histopathological alternation was observed in ATR-induced quail. ATR exposure increased the Cytochrome P450s and Cytochrome b5 contents, Cytochrome P450 (CYP) enzyme system (APND, ERND, AH, and NCR) activities and the expression of CYP isoforms (CYP1B1, CYP2C18, CYP2D6, CYP3A4, CYP3A7, and CYP4B1) in quail heart. The expression of nuclear xenobiotic receptors (NXRs) was also influenced in the heart by ATR exposure. ATR exposure significantly caused the up-regulation of pro-inflammatory cytokines (TNF-α, IL-6, NF-κB, and IL-8), down-regulation of anti-inflammatory cytokines (IL-10) expression levels and increased NO content and iNOS activity. The present research provides new insights into the mechanism that ATR-induced cardiotoxicity through up-regulating the expression levels of GRP78 and XBP-1s, triggering ER stress, activating the expression of IRE1α/TRAF2/NF-κB signaling pathway related factors (IRE1α, TRAF2, IKK, and NF-κB) and inducing an inflammatory response in quail hearts. In conclusion, ATR exposure could induce cardiac inflammatory injury via activating NXRs responses, disrupting CYP homeostasis and CYP isoforms transcription, altering NO metabolism and triggering ER stress and inflammatory response by activating IRE1α/TRAF2/NF-κB signaling pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

An adaptive human response mechanism controlling the V/STOL aircraft. Appendix 3: The adaptive control model of a pilot in V/STOL aircraft control loops. M.S. Thesis. Final Report

NASA Technical Reports Server (NTRS)

Kucuk, Senol

1988-01-01

Importance of the role of human operator in control systems has led to the particular area of manual control theory. Human describing functions were developed to model human behavior for manual control studies to take advantage of the successful and safe human operations. A single variable approach is presented that can be extended for multi-variable tasks where a low order human response model is used together with its rules, to adapt the model on-line, being capable of responding to the changes in the controlled element dynamics. Basic control theory concepts are used to combine the model, constrained with the physical observations, particularly, for the case of aircraft control. Pilot experience is represented as the initial model parameters. An adaptive root-locus method is presented as the adaptation law of the model where the closed loop bandwidth of the system is to be preserved in a stable manner with the adjustments of the pilot handling qualities which relate the latter to the closed loop bandwidth and damping of the closed loop pilot aircraft combination. A Kalman filter parameter estimator is presented as the controlled element identifier of the adaptive model where any discrepancies of the open loop dynamics from the presented one, are sensed to be compensated.

Dehydration responsive element binding transcription factors and their applications for the engineering of stress tolerance.

PubMed

Agarwal, Pradeep K; Gupta, Kapil; Lopato, Sergiy; Agarwal, Parinita

2017-04-01

Dehydration responsive element binding (DREB) factors or CRT element binding factors (CBFs) are members of the AP2/ERF family, which comprises a large number of stress-responsive regulatory genes. This review traverses almost two decades of research, from the discovery of DREB/CBF factors to their optimization for application in plant biotechnology. In this review, we describe (i) the discovery, classification, structure, and evolution of DREB genes and proteins; (ii) induction of DREB genes by abiotic stresses and involvement of their products in stress responses; (iii) protein structure and DNA binding selectivity of different groups of DREB proteins; (iv) post-transcriptional and post-translational mechanisms of DREB transcription factor (TF) regulation; and (v) physical and/or functional interaction of DREB TFs with other proteins during plant stress responses. We also discuss existing issues in applications of DREB TFs for engineering of enhanced stress tolerance and improved performance under stress of transgenic crop plants. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner*

PubMed Central

Gauthier, Karine; Billon, Cyrielle; Bissler, Marie; Beylot, Michel; Lobaccaro, Jean-Marc; Vanacker, Jean-Marc; Samarut, Jacques

2010-01-01

Thyroid hormone (TR) and liver X (LXR) receptors are transcription factors involved in lipogenesis. Both receptors recognize the same consensus DNA-response element in vitro. It was previously shown that their signaling pathways interact in the control of cholesterol elimination in the liver. In the present study, carbohydrate-response element-binding protein (ChREBP), a major transcription factor controlling the activation of glucose-induced lipogenesis in liver, is characterized as a direct target of thyroid hormones (TH) in liver and white adipose tissue (WAT), the two main lipogenic tissues in mice. Using genetic and molecular approaches, ChREBP is shown to be specifically regulated by TRβ but not by TRα in vivo, even in WAT where both TR isoforms are expressed. However, this isotype specificity is not found in vitro. This TRβ specific regulation correlates with the loss of TH-induced lipogenesis in TRβ−/− mice. Fasting/refeeding experiments show that TRβ is not required for the activation of ChREBP expression particularly marked in WAT following refeeding. However, TH can stimulate ChREBP expression in WAT even under fasting conditions, suggesting completely independent pathways. Because ChREBP has been described as an LXR target, the interaction of LXR and TRβ in ChREBP regulation was assayed both in vitro and in vivo. Each receptor recognizes a different response element on the ChREBP promoter, located only 8 bp apart. There is a cross-talk between LXR and TRβ signaling on the ChREBP promoter in liver but not in WAT where LXR does not regulate ChREBP expression. The molecular basis for this cross-talk has been determined in in vitro systems. PMID:20615868

A Liver-Centric Multiscale Modeling Framework for Xenobiotics.

PubMed

Sluka, James P; Fu, Xiao; Swat, Maciej; Belmonte, Julio M; Cosmanescu, Alin; Clendenon, Sherry G; Wambaugh, John F; Glazier, James A

2016-01-01

We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics.

A Liver-Centric Multiscale Modeling Framework for Xenobiotics

PubMed Central

Swat, Maciej; Cosmanescu, Alin; Clendenon, Sherry G.; Wambaugh, John F.; Glazier, James A.

2016-01-01

We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics. PMID:27636091

Xenobiotic metabolizing gene variants, pesticide use, and risk of prostate cancer

PubMed Central

Koutros, Stella; Andreotti, Gabriella; Berndt, Sonja I.; Barry, Kathryn Hughes; Lubin, Jay H.; Hoppin, Jane A.; Kamel, Freya; Sandler, Dale P.; Burdette, Laurie A.; Yuenger, Jeffrey; Yeager, Meredith; Alavanja, Michael C.R.; Beane Freeman, Laura E.

2011-01-01

Background To explore associations with prostate cancer and farming, it is important to investigate the relationship between pesticide use and single nucleotide polymorphisms (SNPs) in xenobiotic metabolic enzyme (XME) genes. Objectives We evaluated pesticide-SNP interactions between 45 pesticides and 1,913 XME SNPs with respect to prostate cancer among 776 cases and 1,444 controls in the Agricultural Health Study. Methods We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. Results A positive monotonic interaction was observed between petroleum oil/petroleum distillate use and rs1883633 in the oxidative stress gene glutamate-cysteine ligase (GCLC) (p-interaction=1.0×10−4); men carrying at least one variant allele (minor allele) experienced an increased prostate cancer risk (OR=3.7, 95% CI: 1.9–7.3). Among men carrying the variant allele for thioredoxin reductase 2 (TXNRD2) rs4485648, microsomal epoxide hyrdolase 1 (EPHX1) rs17309872, or myeloperoxidase (MPO) rs11079344, increased prostate cancer risk was observed with high compared to no petroleum oil/petroleum distillate (OR=1.9, 95% CI: 1.1–3.2, p-interaction=0.01), (OR=2.1, 95% CI: 1.1–4.0, p-interaction=0.01), or terbufos (OR=3.0, 95% CI: 1.5–6.0 p-interaction=2.0×10−3) use, respectively. No interactions were deemed noteworthy at the false discovery rate = 0.20 level; the number of observed interactions in XMEs was comparable to the number expected by chance alone. Conclusions We observed several pesticide-SNP interactions in oxidative stress and phase I/phase II enzyme genes and risk of prostate cancer. Additional work is needed to explain the joint contribution of genetic variation in XMEs, pesticide use, and prostate cancer risk. PMID:21716162

Trace elements in children suffering from sickle cell anemia: A case-control study.

PubMed

Sungu, Joseph K; Mukuku, Olivier; Mutombo, Augustin Mulangu; Mawaw, Paul; Aloni, Michel N; Luboya, Oscar N

2018-01-01

Information on serum albumin and trace elements among children suffering from Sickle Cell Anemia (SCA) was poorly documented in Africa. The aim of this study was to describe and to compare different values of trace elements with published reports from other parts of the world. We carried out a case-control study. Seventy-six steady state children suffering from SCA (Hb-SS). One hundred and fifty-two children were recruited with 76 (cases, Hb-SS) and 76 (control, Hb-AA) to compare the data. The mean age was 10.0 years (SD=5.4) in SCA children and 9.2 years (SD=4.7) in the control group. The mean level of zinc and magnesium were slightly lower in the Hb-SS group than in the Hb-AA group (P<.001). The first literature about trace elements in SCA is briefly reported in Central Africa. In our midst, zinc, magnesium, and selenium deficiencies underline the need for their systematic among all children with SCA to identify patients with these deficiencies and provide early management. © 2017 Wiley Periodicals, Inc.

COMMENTS ON "EFFECT OF PRENATAL EXPOSURE OF DELTAMETHRIN ON THE ONTOGENY OF XENOBIOTIC METABOLIZING CYTOCHROME P450S IN THE BRAIN AND LIVER OF OFFSPRINGS.

EPA Science Inventory

Comments on: Effect of prenatal exposure of deltamethrin on the ontogeny of xenobiotic metabolizing cytochrome P450s in the brain and liver of offsprings [Johri et al. Toxicol Appl Pharmacol. 214:279-289, 2006]

Johri and colleagues recently reported that maternal exposur...

Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts.

PubMed

Ding, Xinxin; Kaminsky, Laurence S

2003-01-01

Cytochrome P450 (CYP) enzymes in extrahepatic tissues often play a dominant role in target tissue metabolic activation of xenobiotic compounds. They may also determine drug efficacy and influence the tissue burden of foreign chemicals or bioavailability of therapeutic agents. This review focuses on xenobiotic-metabolizing CYPs of the human respiratory and gastrointestinal tracts, including the lung, trachea, nasal respiratory and olfactory mucosa, esophagus, stomach, small intestine, and colon. Many CYPs are expressed in one or more of these organs, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2F1, CYP2J2, CYP2S1, CYP3A4, CYP3A5, and CYP4B1. Of particular interest are the preferential expression of certain CYPs in the respiratory tract and the regional differences in CYP expression profile in different parts of the gastrointestinal tract. Current research activities on the characterization of CYP expression, function, and regulation in these tissues, as well as future research needs, are discussed.

Binding of TFIIIC to sine elements controls the relocation of activity-dependent neuronal genes to transcription factories.

PubMed

Crepaldi, Luca; Policarpi, Cristina; Coatti, Alessandro; Sherlock, William T; Jongbloets, Bart C; Down, Thomas A; Riccio, Antonella

2013-01-01

In neurons, the timely and accurate expression of genes in response to synaptic activity relies on the interplay between epigenetic modifications of histones, recruitment of regulatory proteins to chromatin and changes to nuclear structure. To identify genes and regulatory elements responsive to synaptic activation in vivo, we performed a genome-wide ChIPseq analysis of acetylated histone H3 using somatosensory cortex of mice exposed to novel enriched environmental (NEE) conditions. We discovered that Short Interspersed Elements (SINEs) located distal to promoters of activity-dependent genes became acetylated following exposure to NEE and were bound by the general transcription factor TFIIIC. Importantly, under depolarizing conditions, inducible genes relocated to transcription factories (TFs), and this event was controlled by TFIIIC. Silencing of the TFIIIC subunit Gtf3c5 in non-stimulated neurons induced uncontrolled relocation to TFs and transcription of activity-dependent genes. Remarkably, in cortical neurons, silencing of Gtf3c5 mimicked the effects of chronic depolarization, inducing a dramatic increase of both dendritic length and branching. These findings reveal a novel and essential regulatory function of both SINEs and TFIIIC in mediating gene relocation and transcription. They also suggest that TFIIIC may regulate the rearrangement of nuclear architecture, allowing the coordinated expression of activity-dependent neuronal genes.

Binding of TFIIIC to SINE Elements Controls the Relocation of Activity-Dependent Neuronal Genes to Transcription Factories

PubMed Central

Crepaldi, Luca; Policarpi, Cristina; Coatti, Alessandro; Sherlock, William T.; Jongbloets, Bart C.; Down, Thomas A.; Riccio, Antonella

2013-01-01

In neurons, the timely and accurate expression of genes in response to synaptic activity relies on the interplay between epigenetic modifications of histones, recruitment of regulatory proteins to chromatin and changes to nuclear structure. To identify genes and regulatory elements responsive to synaptic activation in vivo, we performed a genome-wide ChIPseq analysis of acetylated histone H3 using somatosensory cortex of mice exposed to novel enriched environmental (NEE) conditions. We discovered that Short Interspersed Elements (SINEs) located distal to promoters of activity-dependent genes became acetylated following exposure to NEE and were bound by the general transcription factor TFIIIC. Importantly, under depolarizing conditions, inducible genes relocated to transcription factories (TFs), and this event was controlled by TFIIIC. Silencing of the TFIIIC subunit Gtf3c5 in non-stimulated neurons induced uncontrolled relocation to TFs and transcription of activity-dependent genes. Remarkably, in cortical neurons, silencing of Gtf3c5 mimicked the effects of chronic depolarization, inducing a dramatic increase of both dendritic length and branching. These findings reveal a novel and essential regulatory function of both SINEs and TFIIIC in mediating gene relocation and transcription. They also suggest that TFIIIC may regulate the rearrangement of nuclear architecture, allowing the coordinated expression of activity-dependent neuronal genes. PMID:23966877

Cytochrome P450 Monooxygenases for Fatty Acids and Xenobiotics in Marine Macroalgae1

PubMed Central

Pflugmacher, Stephan; Sandermann, Heinrich

1998-01-01

The metabolism of xenobiotics has mainly been investigated in higher plant species. We studied them in various marine macroalgae of the phyla Chlorophyta, Chromophyta, and Rhodophyta. Microsomes contained high oxidative activities for known cytochrome (Cyt) P450 substrates (fatty acids, cinnamic acid, 3- and 4-chlorobiphenyl, 2,3-dichlorobiphenyl, and isoproturon; up to 54 pkat/mg protein). The presence of Cyt P450 (approximately 50 pmol/mg protein) in microsomes of the three algal families was demonstrated by CO-difference absorption spectra. Intact algal tissue converted 3-chlorobiphenyl to the same monohydroxy-metabolite formed in vitro. This conversion was 5-fold stimulated upon addition of phenobarbital, and was abolished by the known P450 inhibitor, 1-aminobenzotriazole. It is concluded that marine macroalgae contain active species of Cyt P450 and could act as a metabolic sink for marine pollutants. PMID:9576781

Combination of microautoradiography and fluorescence in situ hybridization for identification of microorganisms degrading xenobiotic contaminants.

PubMed

Yang, Yanru; Zarda, Annatina; Zeyer, Josef

2003-12-01

One of the central topics in environmental bioremediation research is to identify microorganisms that are capable of degrading the contaminants of interest. Here we report application of combined microautoradiography (MAR) and fluorescence in situ hybridization (FISH). The method has previously been used in a number of systems; however, here we demonstrate its feasibility in studying the degradation of xenobiotic compounds. With a model system (coculture of Pseudomonas putida B2 and Sphingomonas stygia incubated with [14C] o-nitrophenol), combination of MAR and FISH was shown to be able to successfully identify the microorganisms degrading o-nitrophenol. Compared with the conventional techniques, MAR-FISH allows fast and accurate identification of the microorganisms involved in environmental contaminant degradation.

Performance of a Single Liquid Column Damper for the Control of Dynamic Responses of a Tension Leg Platform

NASA Astrophysics Data System (ADS)

Jaksic, V.; Wright, C.; Chanayil, Afeef; Faruque Ali, Shaikh; Murphy, Jimmy; Pakrashi, Vikram

2015-07-01

Tuned liquid column dampers have been proved to be successful in mitigating the dynamic responses of civil infrastructure. There have been some recent applications of this concept on wind turbines and this passive control system can help to mitigate responses of offshore floating platforms and wave devices. The control of dynamic responses of these devices is important for reducing loads on structural elements and facilitating operations and maintenance (O&M) activities. This paper outlines the use of a tuned single liquid column damper for the control of a tension leg platform supported wind turbine. Theoretical studies were carried out and a scaled model was tested in a wave basin to assess the performance of the damper. The tests on the model presented in this paper correspond to a platform with a very low natural frequency for surge, sway and yaw motions. For practical purposes, it was not possible to tune the liquid damper exactly to this frequency. The consequent approach taken and the efficiency of such approach are presented in this paper. Responses to waves of a single frequency are investigated along with responses obtained from wave spectra characterising typical sea states. The extent of control is quantified using peak and root mean squared dynamic responses respectively. The tests present some guidelines and challenges for testing scaled devices in relation to including response control mechanisms. Additionally, the results provide a basis for dictating future research on tuned liquid column damper based control on floating platforms.

Dynamic and thermal response finite element models of multi-body space structural configurations

NASA Technical Reports Server (NTRS)

Edighoffer, Harold H.

1987-01-01

Presented is structural dynamics modeling of two multibody space structural configurations. The first configuration is a generic space station model of a cylindrical habitation module, two solar array panels, radiator panel, and central connecting tube. The second is a 15-m hoop-column antenna. Discussed is the special joint elimination sequence used for these large finite element models, so that eigenvalues could be extracted. The generic space station model aided test configuration design and analysis/test data correlation. The model consisted of six finite element models, one of each substructure and one of all substructures as a system. Static analysis and tests at the substructure level fine-tuned the finite element models. The 15-m hoop-column antenna is a truss column and structural ring interconnected with tension stabilizing cables. To the cables, pretensioned mesh membrane elements were attached to form four parabolic shaped antennae, one per quadrant. Imposing thermal preloads in the cables and mesh elements produced pretension in the finite element model. Thermal preload variation in the 96 control cables was adjusted to maintain antenna shape within the required tolerance and to give pointing accuracy.

In Silico Prediction of Cytochrome P450-Mediated Biotransformations of Xenobiotics: A Case Study of Epoxidation.

PubMed

Zhang, Jing; Ji, Li; Liu, Weiping

2015-08-17

Predicting the biotransformation of xenobiotics is important in toxicology; however, as more compounds are synthesized than can be investigated experimentally, powerful computational methods are urgently needed to prescreen potentially useful candidates. Cytochrome P450 enzymes (P450s) are the major enzymes involved in xenobiotic metabolism, and many substances are bioactivated by P450s to form active compounds. An example is the conversion of olefinic substrates to epoxides, which are intermediates in the metabolic activation of many known or suspected carcinogens. We have calculated the activation energies for epoxidation by the active species of P450 enzymes (an iron-oxo porphyrin cation radical oxidant, compound I) for a diverse set of 36 olefinic substrates with state-of-the-art density functional theory (DFT) methods. Activation energies can be estimated by the computationally less demanding method of calculating the ionization potentials of the substrates, which provides a useful and simple predictive model based on the reaction mechanism; however, the preclassification of these diverse substrates into weakly polar and strongly polar groups is a prerequisite for the construction of specific predictive models with good predictability for P450 epoxidation. This approach has been supported by both internal and external validations. Furthermore, the relation between the activation energies for the regioselective epoxidation and hydroxylation reactions of P450s and experimental data has been investigated. The results show that the computational method used in this work, single-point energy calculations with the B3LYP functional including zero-point energy and solvation and dispersion corrections based on B3LYP-optimized geometries, performs well in reproducing the experimental trends of the epoxidation and hydroxylation reactions.

The Nrf2-antioxidant response element pathway: a target for regulating energy metabolism

USDA-ARS?s Scientific Manuscript database

The nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that responds to oxidative stress by binding to the antioxidant response element (ARE) in the promoter of genes coding for antioxidant enzymes like NAD(P)H:quinone oxidoreductase 1 (NQO1) and proteins for glutathione synthesis. ...

Investigation of control law reconfigurations to accommodate a control element failure on a commercial airplane

NASA Technical Reports Server (NTRS)

Ostroff, A. J.; Hueschen, R. M.

1984-01-01

The ability of a pilot to reconfigure the control surfaces on an airplane after a failure, allowing the airplane to recover to a safe condition, becomes more difficult with increasing airplane complexity. Techniques are needed to stabilize and control the airplane immediately after a failure, allowing the pilot more time to make longer range decisions. This paper presents a baseline design of a discrete multivariable control law using four controls for the longitudinal channel of a B-737. Non-reconfigured and reconfigured control laws are then evaluated, both analytically and by means of a digital airplane simulation, for three individual control element failures (stabilizer, elevator, spoilers). The simulation results are used to evaluate the effectiveness of the control reconfiguration on tracking ability during the approach and landing phase of flight with severe windshear and turbulence disturbing the airplane dynamics.

Hypoxia-induced endothelial NO synthase gene transcriptional activation is mediated through the tax-responsive element in endothelial cells.

PubMed

Min, Jiho; Jin, Yoon-Mi; Moon, Je-Sung; Sung, Min-Sun; Jo, Sangmee Ahn; Jo, Inho

2006-06-01

Although hypoxia is known to induce upregulation of endothelial NO synthase (eNOS) gene expression, the underlying mechanism is largely unclear. In this study, we show that hypoxia increases eNOS gene expression through the binding of phosphorylated cAMP-responsive element binding (CREB) protein (pCREB) to the eNOS gene promoter. Hypoxia (1% O2) increased both eNOS expression and NO production, peaking at 24 hours, in bovine aortic endothelial cells, and these increases were accompanied by increases in pCREB. Treatment with the protein kinase A inhibitor H-89 or transfection with dominant-negative inhibitor of CREB reversed the hypoxia-induced increases in eNOS expression and NO production, with concomitant inhibition of the phosphorylation of CREB induced by hypoxia, suggesting an involvement of protein kinase A/pCREB-mediated pathway. To map the regulatory elements of the eNOS gene responsible for pCREB binding under hypoxia, we constructed an eNOS gene promoter (-1600 to +22 nucleotides) fused with a luciferase reporter gene [pGL2-eNOS(-1600)]. Hypoxia (for 24-hour incubation) increased the promoter activity by 2.36+/-0.18-fold in the bovine aortic endothelial cells transfected with pGL2-eNOS(-1600). However, progressive 5'-deletion from -1600 to -873 completely attenuated the hypoxia-induced increase in promoter activity. Electrophoretic mobility shift, anti-pCREB antibody supershift, and site-specific mutation analyses showed that pCREB is bound to the Tax-responsive element (TRE) site, a cAMP-responsive element-like site, located at -924 to -921 of the eNOS promoter. Our data demonstrate that the interaction between pCREB and the Tax-responsive element site within the eNOS promoter may represent a novel mechanism for the mediation of hypoxia-stimulated eNOS gene expression.

Identification of an estrogen response element in the 3'-flanking region of the murine c-fos protooncogene.

PubMed

Hyder, S M; Stancel, G M; Nawaz, Z; McDonnell, D P; Loose-Mitchell, D S

1992-09-05

We have used transient transfection assays with reporter plasmids expressing chloramphenicol acetyltransferase, linked to regions of mouse c-fos, to identify a specific estrogen response element (ERE) in this protooncogene. This element is located in the untranslated 3'-flanking region of the c-fos gene, 5 kilobases (kb) downstream from the c-fos promoter and 1.5 kb downstream of the poly(A) signal. This element confers estrogen responsiveness to chloramphenicol acetyltransferase reporters linked to both the herpes simplex virus thymidine kinase promoter and the homologous c-fos promoter. Deletion analysis localized the response element to a 200-base pair fragment which contains the element GGTCACCACAGCC that resembles the consensus ERE sequence GGTCACAGTGACC originally identified in Xenopus vitellogenin A2 gene. A synthetic 36-base pair oligodeoxynucleotide containing this c-fos sequence conferred estrogen inducibility to the thymidine kinase promoter. The corresponding sequence also induced reporter activity when present in the c-fos gene fragment 3 kb from the thymidine kinase promoter. Gel-shift experiments demonstrated that synthetic oligonucleotides containing either the consensus ERE or the c-fos element bind human estrogen receptor obtained from a yeast expression system. However, the mobility of the shifted band is faster for the fos-ERE-complex than the consensus ERE complex suggesting that the three-dimensional structure of the protein-DNA complexes is different or that other factors are differentially involved in the two reactions. When the 5'-GGTCA sequence present in the c-fos ERE is mutated to 5'-TTTCA, transcriptional activation and receptor binding activities are both lost. Mutation of the CAGCC-3' element corresponding to the second half-site of the c-fos sequence also led to the loss of receptor binding activity, suggesting that both half-sites of this element are involved in this function. The estrogen induction mediated by either the c-fos or

Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

PubMed Central

Prakash, Chandra; Zuniga, Baltazar; Song, Chung Seog; Jiang, Shoulei; Cropper, Jodie; Park, Sulgi; Chatterjee, Bandana

2016-01-01

Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs), and transport proteins coordinate drug influx (phase 0) and drug/drug-metabolite efflux (phase III). Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs), i.e. PXR (pregnane X receptor) and CAR (constitutive androstane receptor), and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR), due to transactivation of xenobiotic-response elements (XREs) present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification) facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP) and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs) on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome) of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug’s impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse models and

SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins.

PubMed

Koch, C A; Anderson, D; Moran, M F; Ellis, C; Pawson, T

1991-05-03

Src homology (SH) regions 2 and 3 are noncatalytic domains that are conserved among a series of cytoplasmic signaling proteins regulated by receptor protein-tyrosine kinases, including phospholipase C-gamma, Ras GTPase (guanosine triphosphatase)-activating protein, and Src-like tyrosine kinases. The SH2 domains of these signaling proteins bind tyrosine phosphorylated polypeptides, implicated in normal signaling and cellular transformation. Tyrosine phosphorylation acts as a switch to induce the binding of SH2 domains, thereby mediating the formation of heteromeric protein complexes at or near the plasma membrane. The formation of these complexes is likely to control the activation of signal transduction pathways by tyrosine kinases. The SH3 domain is a distinct motif that, together with SH2, may modulate interactions with the cytoskeleton and membrane. Some signaling and transforming proteins contain SH2 and SH3 domains unattached to any known catalytic element. These noncatalytic proteins may serve as adaptors to link tyrosine kinases to specific target proteins. These observations suggest that SH2 and SH3 domains participate in the control of intracellular responses to growth factor stimulation.

Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response.

PubMed

Haze, K; Okada, T; Yoshida, H; Yanagi, H; Yura, T; Negishi, M; Mori, K

2001-04-01

Eukaryotic cells control the levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element consisting of 19 nt (CCAATN(9)CCACG), the CCACG part of which is considered to provide specificity. We recently identified the basic leucine zipper (bZIP) protein ATF6 as a mammalian UPR-specific transcription factor; ATF6 is activated by ER stress-induced proteolysis and binds directly to CCACG. Here we report that eukaryotic cells express another bZIP protein closely related to ATF6 in both structure and function. This protein encoded by the G13 (cAMP response element binding protein-related protein) gene is constitutively synthesized as a type II transmembrane glycoprotein anchored in the ER membrane and processed into a soluble form upon ER stress as occurs with ATF6. The proteolytic processing of ATF6 and the G13 gene product is accompanied by their relocation from the ER to the nucleus; their basic regions seem to function as a nuclear localization signal. Overexpression of the soluble form of the G13 product constitutively activates the UPR, whereas overexpression of a mutant lacking the activation domain exhibits a strong dominant-negative effect. Furthermore, the soluble forms of ATF6 and the G13 gene product are unable to bind to several point mutants of the cis-acting ER stress response element in vitro that hardly respond to ER stress in vivo. We thus concluded that the two related bZIP proteins are crucial transcriptional regulators of the mammalian UPR, and propose calling the ATF6 gene product ATF6alpha and the G13 gene product ATF6beta.

Joint Forward Operating Base Elements of Command and Control

NASA Astrophysics Data System (ADS)

Summers, William C.

2002-01-01

Since the 1986 Goldwater-Nichols Act directed the Chairman of the Joint Chiefs of Staff to develop doctrine for the joint employment of the armed forces, tactics, techniques, and procedures have evolved at different rates depending on the competency. Whereas the command of joint air forces is well prescribed within the structure of the air operations center and its associated leadership, command of air assets at a joint forward operating base lacks guidance. Today, the United States prosecutes an air war over Afghanistan from bases in Uzbekistan, Pakistan, and Afghanistan. Elements of the United States Army, Air Force, and Marines combine at these geographically minute locations, each bringing a certain complement of support and command and control. Evidence from operations during the 1999 air war for Kosovo at Tirana Rinas Airport in Albania suggests that when these service elements meet at the airfield for the first time, there are problems associated with local procedure. At best, time is wasted creating local joint systems to overcome the difficulties. At worst, safety and mission accomplishment are jeopardized. This thesis will address the need to develop doctrine and a jointly integrated organization to support the command and control function at a forward operating base.

Effect of Storage Temperature on the Phenotype of Cultured Epidermal Cells Stored in Xenobiotic-Free Medium.

PubMed

Jackson, Catherine; Eidet, Jon R; Reppe, Sjur; Aass, Hans Christian D; Tønseth, Kim A; Roald, Borghild; Lyberg, Torstein; Utheim, Tor P

2016-06-01

Cultured epidermal cell sheets (CECS) are used in the treatment of large area burns to the body and have potential to treat limbal stem cell deficiency (LSCD) as shown in animal studies. Despite widespread use, storage options for CECS are limited. Short-term storage allows flexibility in scheduling surgery, quality control and improved transportation to clinics worldwide. Recent evidence points to the phenotype of cultured epithelial cells as a critical predictor of post-operative success following transplantation of CECS in burns and in transplantation of cultured epithelial cells in patients with LSCD. This study, therefore assessed the effect of a range of temperatures, spanning 4-37 °C, on the phenotype of CECS stored over a 2-week period in a xenobiotic-free system. Progenitor cell (p63, ΔNp63α and ABCG2) and differentiation (C/EBPδ and CK10) associated marker expression was assessed using immunocytochemistry. Immunohistochemistry staining of normal skin for the markers p63, ABCG2 and C/EBPδ was also carried out. Assessment of progenitor cell side population (SP) was performed using JC1 dye by flow cytometry. P63 expression remained relatively constant throughout the temperature range but was significantly lower compared to control between 20 and 28 °C (p < 0.05). High C/EBPδ together with low p63 suggested more differentiation beginning at 20 °C and above. Lower CK10 and C/EBPδ expression most similar to control was seen at 12 °C. The percentage of ABCG2 positive cells was most similar to control between 8 and 24 °C. Between 4 and 24 °C, the SP fluctuated, but was not significantly different compared to control. Results were supported by staining patterns indicating differentiation status associated with markers in normal skin sections. Lower storage temperatures, and in particular 12 °C, merit further investigation as optimal storage temperature for maintenance of undifferentiated phenotype in CECS.

Influence of bacterial N-acyl-homoserine lactones on growth parameters, pigments, antioxidative capacities and the xenobiotic phase II detoxification enzymes in barley and yam bean.

PubMed

Götz-Rösch, Christine; Sieper, Tina; Fekete, Agnes; Schmitt-Kopplin, Philippe; Hartmann, Anton; Schröder, Peter

2015-01-01

Bacteria are able to communicate with each other and sense their environment in a population density dependent mechanism known as quorum sensing (QS). N-acyl-homoserine lactones (AHLs) are the QS signaling compounds of Gram-negative bacteria which are frequent colonizers of rhizospheres. While cross-kingdom signaling and AHL-dependent gene expression in plants has been confirmed, the responses of enzyme activities in the eukaryotic host upon AHLs are unknown. Since AHL are thought to be used as so-called plant boosters or strengthening agents, which might change their resistance toward radiation and/or xenobiotic stress, we have examined the plants' pigment status and their antioxidative and detoxifying capacities upon AHL treatment. Because the yield of a crop plant should not be negatively influenced, we have also checked for growth and root parameters. We investigated the influence of three different AHLs, namely N-hexanoyl- (C6-HSL), N-octanoyl- (C8-HSL), and N-decanoyl- homoserine lactone (C10-HSL) on two agricultural crop plants. The AHL-effects on Hordeum vulgare (L.) as an example of a monocotyledonous crop and on the tropical leguminous crop plant Pachyrhizus erosus (L.) were compared. While plant growth and pigment contents in both plants showed only small responses to the applied AHLs, AHL treatment triggered tissue- and compound-specific changes in the activity of important detoxification enzymes. The activity of dehydroascorbate reductase in barley shoots after C10-HSL treatment for instance increased up to 384% of control plant levels, whereas superoxide dismutase activity in barley roots was decreased down to 23% of control levels upon C6-HSL treatment. Other detoxification enzymes reacted similarly within this range, with interesting clusters of positive or negative answers toward AHL treatment. In general the changes on the enzyme level were more severe in barley than in yam bean which might be due to the different abilities of the plants to

Influence of bacterial N-acyl-homoserine lactones on growth parameters, pigments, antioxidative capacities and the xenobiotic phase II detoxification enzymes in barley and yam bean

PubMed Central

Götz-Rösch, Christine; Sieper, Tina; Fekete, Agnes; Schmitt-Kopplin, Philippe; Hartmann, Anton; Schröder, Peter

2015-01-01

Bacteria are able to communicate with each other and sense their environment in a population density dependent mechanism known as quorum sensing (QS). N-acyl-homoserine lactones (AHLs) are the QS signaling compounds of Gram-negative bacteria which are frequent colonizers of rhizospheres. While cross-kingdom signaling and AHL-dependent gene expression in plants has been confirmed, the responses of enzyme activities in the eukaryotic host upon AHLs are unknown. Since AHL are thought to be used as so-called plant boosters or strengthening agents, which might change their resistance toward radiation and/or xenobiotic stress, we have examined the plants’ pigment status and their antioxidative and detoxifying capacities upon AHL treatment. Because the yield of a crop plant should not be negatively influenced, we have also checked for growth and root parameters. We investigated the influence of three different AHLs, namely N-hexanoyl- (C6-HSL), N-octanoyl- (C8-HSL), and N-decanoyl- homoserine lactone (C10-HSL) on two agricultural crop plants. The AHL-effects on Hordeum vulgare (L.) as an example of a monocotyledonous crop and on the tropical leguminous crop plant Pachyrhizus erosus (L.) were compared. While plant growth and pigment contents in both plants showed only small responses to the applied AHLs, AHL treatment triggered tissue- and compound-specific changes in the activity of important detoxification enzymes. The activity of dehydroascorbate reductase in barley shoots after C10-HSL treatment for instance increased up to 384% of control plant levels, whereas superoxide dismutase activity in barley roots was decreased down to 23% of control levels upon C6-HSL treatment. Other detoxification enzymes reacted similarly within this range, with interesting clusters of positive or negative answers toward AHL treatment. In general the changes on the enzyme level were more severe in barley than in yam bean which might be due to the different abilities of the plants to

Altered carbohydrate, lipid, and xenobiotic metabolism by liver from rats flown on Cosmos 1887

NASA Technical Reports Server (NTRS)

Merrill, A. H. Jr; Hoel, M.; Wang, E.; Mullins, R. E.; Hargrove, J. L.; Jones, D. P.; Popova, I. A.; Merrill AH, J. r. (Principal Investigator)

1990-01-01

To determine the possible biochemical effects of prolonged weightlessness on liver function, samples of liver from rats that had flown aboard Cosmos 1887 were analyzed for protein, glycogen, and lipids as well as the activities of a number of key enzymes involved in metabolism of these compounds and xenobiotics. Among the parameters measured, the major differences were elevations in the glycogen content and hydroxymethylglutaryl-CoA (HMG-CoA) reductase activities for the rats flown on Cosmos 1887 and decreases in the amount of microsomal cytochrome P-450 and the activities of aniline hydroxylase and ethylmorphine N-demethylase, cytochrome P-450-dependent enzymes. These results support the earlier finding of differences in these parameters and suggest that altered hepatic function could be important during spaceflight and/or the postflight recovery period.

Four-terminal circuit element with photonic core

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sampayan, Stephen

A four-terminal circuit element is described that includes a photonic core inside of the circuit element that uses a wide bandgap semiconductor material that exhibits photoconductivity and allows current flow through the material in response to the light that is incident on the wide bandgap material. The four-terminal circuit element can be configured based on various hardware structures using a single piece or multiple pieces or layers of a wide bandgap semiconductor material to achieve various designed electrical properties such as high switching voltages by using the photoconductive feature beyond the breakdown voltages of semiconductor devices or circuits operated basedmore » on electrical bias or control designs. The photonic core aspect of the four-terminal circuit element provides unique features that enable versatile circuit applications to either replace the semiconductor transistor-based circuit elements or semiconductor diode-based circuit elements.« less

Endothelial responses of magnesium and other alloying elements in magnesium-based stent materials

PubMed Central

Zhao, Nan; Zhu, Donghui

2016-01-01

Biodegradable tailored magnesium (Mg) alloys are some of the most promising scaffolds for cardiovascular stents. During the course of degradation after implantation, all the alloying elements in the scaffold will be released to the surrounding vascular tissues. However, fundamental questions regarding the toxicity of alloying elements towards vascular cells, the maximum amount of each element that could be used in alloy design, or how each of the alloying elements affects vascular cellular activity and gene expression, are still not fully answered. This work systematically addressed these questions by revealing how application of different alloying elements commonly used in Mg stent materials influences several indices of human endothelial cell health, i.e., viability, proliferations, cytoskeletal reorganizations, migration, and the gene expression profile. The overall cell viability and proliferation showed a decreasing trend with increasing concentrations of the ions, and the half maximal effective concentrations (EC50) for each element were determined. When applied at a low concentration of around 10 mM, Mg had no adverse effects but improved cell proliferation and migration instead. Mg ions also altered endothelial gene expression significantly in a dose dependent manner. Most of the changed genes are related to angiogenesis and the cell adhesion signaling pathways. Findings from this work provide useful information on maximum safe doses of these ions for endothelial cells, endothelial responses towards these metal ions, and some guidance for future Mg stent design. PMID:25363018

Underwater hydraulic shock shovel control system

NASA Astrophysics Data System (ADS)

Liu, He-Ping; Luo, A.-Ni; Xiao, Hai-Yan

2008-06-01

The control system determines the effectiveness of an underwater hydraulic shock shovel. This paper begins by analyzing the working principles of these shovels and explains the importance of their control systems. A new type of control system’s mathematical model was built and analyzed according to those principles. Since the initial control system’s response time could not fulfill the design requirements, a PID controller was added to the control system. System response time was still slower than required, so a neural network was added to nonlinearly regulate the proportional element, integral element and derivative element coefficients of the PID controller. After these improvements to the control system, system parameters fulfilled the design requirements. The working performance of electrically-controlled parts such as the rapidly moving high speed switch valve is largely determined by the control system. Normal control methods generally can’t satisfy a shovel’s requirements, so advanced and normal control methods were combined to improve the control system, bringing good results.

The Specificity of Innate Immune Responses Is Enforced by Repression of Interferon Response Elements by NF-κB p50

PubMed Central

Cheng, Christine S.; Feldman, Kristyn E.; Lee, James; Verma, Shilpi; Huang, De-Bin; Huynh, Kim; Chang, Mikyoung; Ponomarenko, Julia V.; Sun, Shao-Cong; Benedict, Chris A.; Ghosh, Gourisankar; Hoffmann, Alexander

2011-01-01

The specific binding of transcription factors to cognate sequence elements is thought to be critical for the generation of specific gene expression programs. Members of the nuclear factor κB (NF-κB) and interferon (IFN) regulatory factor (IRF) transcription factor families bind to the κB site and the IFN response element (IRE), respectively, of target genes, and they are activated in macrophages after exposure to pathogens. However, how these factors produce pathogen-specific inflammatory and immune responses remains poorly understood. Combining top-down and bottom-up systems biology approaches, we have identified the NF-κB p50 homodimer as a regulator of IRF responses. Unbiased genome-wide expression and biochemical and structural analyses revealed that the p50 homodimer repressed a subset of IFN-inducible genes through a previously uncharacterized subclass of guanine-rich IRE (G-IRE) sequences. Mathematical modeling predicted that the p50 homodimer might enforce the stimulus specificity of composite promoters. Indeed, the production of the antiviral regulator IFN-β was rendered stimulus-specific by the binding of the p50 homodimer to the G-IRE–containing IFNβ enhancer to suppress cytotoxic IFN signaling. Specifically, a deficiency in p50 resulted in the inappropriate production of IFN-β in response to bacterial DNA sensed by Toll-like receptor 9. This role for the NF-κB p50 homodimer in enforcing the specificity of the cellular response to pathogens by binding to a subset of IRE sequences alters our understanding of how the NF-κB and IRF signaling systems cooperate to regulate antimicrobial immunity. PMID:21343618

Measuring the photodetector frequency response for ultrasonic applications by a heterodyne system with difference- frequency servo control.

PubMed

Koch, Christian

2010-05-01

A technique for the calibration of photodiodes in ultrasonic measurement systems using standard and cost-effective optical and electronic components is presented. A heterodyne system was realized using two commercially available distributed feedback lasers, and the required frequency stability and resolution were ensured by a difference-frequency servo control scheme. The frequency-sensitive element generating the error signal for the servo loop comprised a delay-line discriminator constructed from electronic elements. Measurements were carried out at up to 450 MHz, and the uncertainties of about 5% (k = 2) can be further reduced by improved radio frequency power measurement without losing the feature of using only simple elements. The technique initially dedicated to the determination of the frequency response of photodetectors applied in ultrasonic applications can be transferred to other application fields of optical measurements.

Dietary lipids differentially modulate the initiation of experimental breast carcinogenesis through their influence on hepatic xenobiotic metabolism and DNA damage in the mammary gland.

PubMed

Manzanares, Miguel Ángel; de Miguel, Cristina; Ruiz de Villa, M Carme; Santella, Regina M; Escrich, Eduard; Solanas, Montserrat

2017-05-01

Breast cancer is the most common malignancy among women worldwide. In addition to reproductive factors, environmental factors such as nutrition and xenobiotic exposure have a role in the etiology of this malignancy. A stimulating and a potentially protective effect on experimental breast cancer has been previously described for high corn oil and high extra-virgin olive oil diets, respectively. This work investigates the effect of these lipids on the metabolism of 7,12-dimethylbenz(a)anthracene (DMBA), a polycyclic aromatic hydrocarbon that can initiate carcinogenesis and its consequences in an experimental rat breast cancer model. The PUFA n-6-enriched diet increased expression of Phase I enzymes prior to DMBA administration and raised the activity of CYP1s in the hours immediately after induction, while reducing the activity of Phase II enzymes, mainly NQO1. The levels of reactive metabolites measured in plasma by GC-MS and DMBA-DNA adducts in the mammary gland of the animals fed the high corn oil diet were also higher than in the other groups. On the other hand, the high extra-virgin olive oil diet and the control low-fat diet exhibited better coordinated Phase I and Phase II activity, with a lower production of reactive metabolites and less DNA damage in the mammary gland. The concordance between these effects and the different efficacy of the carcinogenesis process due to the dietary treatment suggest that lipids may differently modify mammary gland susceptibility or resistance to cancer initiation over the exposure to environmental carcinogens. Dietary lipids influence the initiation of DMBA-induced mammary cancer through the modulation of liver xenobiotic metabolism, formation of reactive metabolites and subsequent DNA damage in the target tissue. Copyright © 2017 Elsevier Inc. All rights reserved.

Human-simulated intelligent control of train braking response of bridge with MRB

NASA Astrophysics Data System (ADS)

Li, Rui; Zhou, Hongli; Wu, Yueyuan; Wang, Xiaojie

2016-04-01

The urgent train braking could bring structural response menace to the bridge under passive control. Based on the analysis of breaking dynamics of a train-bridge vibration system, a magnetorheological elastomeric bearing (MRB) whose mechanical parameters are adjustable is designed, tested and modeled. A finite element method (FEM) is carried out to model and optimize a full scale vibration isolation system for railway bridge based on MRB. According to the model above, we also consider the effect of different braking stop positions on the vibration isolation system and classify the bridge longitudinal vibration characteristics into several cases. Because the train-bridge vibration isolation system has multiple vibration states and strongly coupling with nonlinear characteristics, a human-simulated intelligent control (HSIC) algorithm for isolating the bridge vibration under the impact of train braking is proposed, in which the peak shear force of pier top, the displacement of beam and the acceleration of beam are chosen as control goals. The simulation of longitudinal vibration control system under the condition of train braking is achieved by MATLAB. The results indicate that different braking stop positions significantly affect the vibration isolation system and the structural response is the most drastic when the train stops at the third cross-span. With the proposed HSIC smart isolation system, the displacement of bridge beam and peak shear force of pier top is reduced by 53.8% and 34.4%, respectively. Moreover, the acceleration of bridge beam is effectively controlled within limited range.

Verification of Advective Bar Elements Implemented in the Aria Thermal Response Code.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mills, Brantley

2016-01-01

A verification effort was undertaken to evaluate the implementation of the new advective bar capability in the Aria thermal response code. Several approaches to the verification process were taken : a mesh refinement study to demonstrate solution convergence in the fluid and the solid, visually examining the mapping of the advective bar element nodes to the surrounding surfaces, and a comparison of solutions produced using the advective bars for simple geometries with solutions from commercial CFD software . The mesh refinement study has shown solution convergence for simple pipe flow in both temperature and velocity . Guidelines were provided tomore » achieve appropriate meshes between the advective bar elements and the surrounding volume. Simulations of pipe flow using advective bars elements in Aria have been compared to simulations using the commercial CFD software ANSYS Fluent (r) and provided comparable solutions in temperature and velocity supporting proper implementation of the new capability. Verification of Advective Bar Elements iv Acknowledgements A special thanks goes to Dean Dobranich for his guidance and expertise through all stages of this effort . His advice and feedback was instrumental to its completion. Thanks also goes to Sam Subia and Tolu Okusanya for helping to plan many of the verification activities performed in this document. Thank you to Sam, Justin Lamb and Victor Brunini for their assistance in resolving issues encountered with running the advective bar element model. Finally, thanks goes to Dean, Sam, and Adam Hetzler for reviewing the document and providing very valuable comments.« less

IMS Infrasound Monitoring Test Site at Trafelberg, Austria: Preliminary Results from In-Situ Response Measurements of Infrasound Elements

DTIC Science & Technology

2010-09-01

IMS INFRASOUND MONITORING TEST SITE AT TRAFELBERG, AUSTRIA: PRELIMINARY RESULTS FROM IN-SITU RESPONSE MEASUREMENTS OF INFRASOUND ELEMENTS Thomas...The International Monitoring System (IMS) of the Comprehensive Nuclear Test-Ban Treaty Organization (CTBTO) has a unique infrasound test site...all four infrasound elements at I99 were made from 0.008 Hz to several Hz. For all four elements, from 0.01 to 0.1 Hz, the measured magnitude and

Active Robust Control of Elastic Blade Element Containing Magnetorheological Fluid

NASA Astrophysics Data System (ADS)

Sivrioglu, Selim; Cakmak Bolat, Fevzi

2018-03-01

This research study proposes a new active control structure to suppress vibrations of a small-scale wind turbine blade filled with magnetorheological (MR) fluid and actuated by an electromagnet. The aluminum blade structure is manufactured using the airfoil with SH3055 code number which is designed for use on small wind turbines. An interaction model between MR fluid and the electromagnetic actuator is derived. A norm based multi-objective H2/H∞ controller is designed using the model of the elastic blade element. The H2/H∞ controller is experimentally realized under the impact and steady state aerodynamic load conditions. The results of experiments show that the MR fluid is effective for suppressing vibrations of the blade structure.

42 CFR 431.810 - Basic elements of the Medicaid eligibility quality control (MEQC) program.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Basic elements of the Medicaid eligibility quality control (MEQC) program. 431.810 Section 431.810 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES... GENERAL ADMINISTRATION Quality Control Medicaid Eligibility Quality Control (meqc) Program § 431.810 Basic...

Carcinogen-induced mdr overexpression is associated with xenobiotic resistance in rat preneoplastic liver nodules and hepatocellular carcinomas.

PubMed

Fairchild, C R; Ivy, S P; Rushmore, T; Lee, G; Koo, P; Goldsmith, M E; Myers, C E; Farber, E; Cowan, K H

1987-11-01

We have previously reported the isolation of a human breast cancer cell line resistant to doxorubicin (adriamycin; AdrR MCF-7 cells) that has also developed the phenotype of multidrug resistance (MDR). MDR in this cell line is associated with increased expression of mdr (P glycoprotein) gene sequences. The development of MDR in AdrR MCF-7 cells is also associated with changes in the expression of several phase I and phase II drug-detoxifying enzymes. These changes are remarkably similar to those associated with development of xenobiotic resistance in rat hyperplastic liver nodules, a well-studied model system of chemical carcinogenesis. Using an mdr-encoded cDNA sequence isolated from AdrR MCF-7 cells, we have examined the expression of mdr sequences in rat livers under a variety of experimental conditions. The expression of mdr increased 3-fold in regenerating liver. It was also elevated (3- to 12-fold) in several different samples of rat hyperplastic nodules and in four of five hepatomas that developed in this system. This suggests that overexpression of mdr, a gene previously associated with resistance to antineoplastic agents, may also be involved in the development of resistance to xenobiotics in rat hyperplastic nodules. In addition, although the acute administration of 2-acetylaminofluorene induced an 8-fold increase in hepatic mdr-encoded RNA, performance of a partial hepatectomy either before or after administration of 2-acetylaminofluorene resulted in a greater than 80-fold increase in mdr gene expression over that in normal untreated livers. This represents an important in vivo model system in which to study the acute regulation of this drug resistance gene.

Social Responsibility as a Management Control System

DTIC Science & Technology

2004-06-01

the model from corporate America onto the Naval Postgraduate School to examine where socially responsible management control systems operate to control...examples. Finally, we overlay the model from corporate America onto the Naval Postgraduate School to examine where socially responsible management...34 CSRwire: The Corporate Social Responsibility Newswire Service. htt://www.csrwire.com/page.cgi/intro.html.. 16 March 2004. Core Values, http

The transcriptional regulatory network in the drought response and its crosstalk in abiotic stress responses including drought, cold, and heat.

PubMed

Nakashima, Kazuo; Yamaguchi-Shinozaki, Kazuko; Shinozaki, Kazuo

2014-01-01

Drought negatively impacts plant growth and the productivity of crops around the world. Understanding the molecular mechanisms in the drought response is important for improvement of drought tolerance using molecular techniques. In plants, abscisic acid (ABA) is accumulated under osmotic stress conditions caused by drought, and has a key role in stress responses and tolerance. Comprehensive molecular analyses have shown that ABA regulates the expression of many genes under osmotic stress conditions, and the ABA-responsive element (ABRE) is the major cis-element for ABA-responsive gene expression. Transcription factors (TFs) are master regulators of gene expression. ABRE-binding protein and ABRE-binding factor TFs control gene expression in an ABA-dependent manner. SNF1-related protein kinases 2, group A 2C-type protein phosphatases, and ABA receptors were shown to control the ABA signaling pathway. ABA-independent signaling pathways such as dehydration-responsive element-binding protein TFs and NAC TFs are also involved in stress responses including drought, heat, and cold. Recent studies have suggested that there are interactions between the major ABA signaling pathway and other signaling factors in stress responses. The important roles of these TFs in crosstalk among abiotic stress responses will be discussed. Control of ABA or stress signaling factor expression can improve tolerance to environmental stresses. Recent studies using crops have shown that stress-specific overexpression of TFs improves drought tolerance and grain yield compared with controls in the field.

[The status of soil contamination in areas of northern and northwestern Bohemia affected by pollution].

PubMed

Podlesáková, E; Nĕmecek, J; Vácha, R

1999-10-20

A regional study of soil contamination in North and Northwest immission-impacted Bohemian regions present the results of the assessment of soil loads of agricultural soils by hazardous trace elements and organic xenobiotic substances. The evaluation is based on the exceeding of background values of contaminants (upper limit of their variability). Two forms of soil loads by trace elements are differentiated, the anthropogenic and geogenic one. They occur simultaneously on the territory under study. Geogenic "loads" prevail (basalts, metallogenic zones). Anthropogenic contamination by both hazardous elements and organic xenobiotic substances occurs only in some parts of these severely immission-impacted regions.

Subtask 4.8 - Fate and Control of Mercury and Trace Elements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pavlish, John; Lentz, Nicholas; Martin, Christopher

2011-12-31

The Center for Air Toxic Metals® (CATM®) Program at the Energy & Environmental Research Center (EERC) continues to focus on vital basic and applied research related to the fate, behavior, measurement, and control of trace metals, especially mercury, and the impact that these trace metals have on human health and the environment. For years, the CATM Program has maintained an international perspective, performing research and providing results that apply to both domestic and international audiences, with reports distributed in the United States and abroad. In addition to trace metals, CATM’s research focuses on other related emissions and issues that impactmore » trace metal releases to the environment, such as SO x, NO x, CO 2, ash, and wastewater streams. Of paramount interest and focus has been performing research that continues to enable the power and industrial sectors to operate in an environmentally responsible manner to meet regulatory standards. The research funded by the U.S. Department of Energy’s (DOE’s) National Energy Technology Laboratory (NETL) through CATM has allowed significant strides to be made to gain a better understanding of trace metals and other emissions, improve sampling and measurement techniques, fill data gaps, address emerging technical issues, and develop/test control technologies that allow industry to cost-effectively meet regulatory standards. The DOE NETL–CATM research specifically focused on the fate and control of mercury and trace elements in power systems that use CO 2 control technologies, such as oxycombustion and gasification systems, which are expected to be among those technologies that will be used to address climate change issues. In addition, research addressed data gaps for systems that use conventional and multipollutant control technologies, such as electrostatic precipitators, selective catalytic reduction units, flue gas desulfurization systems, and flue gas-conditioning methods, to understand mercury

Switching sliding mode force tracking control of piezoelectric-hydraulic pump-based friction element actuation systems for automotive transmissions

NASA Astrophysics Data System (ADS)

Kim, Gi-Woo; Wang, K. W.

2009-08-01

In this study, a nonlinear sliding-mode controller is designed for force tracking of a piezoelectric-hydraulic pump (PHP)-based actuation system, which is developed to replace the current electro-hydraulic actuation systems for automatic transmission (AT) friction elements, such as band brakes or clutches. By utilizing the PHP, one can eliminate the various hydraulic components (oil pump, regulating valve and control valve) in current ATs and achieve a simpler configuration with more efficient operation. With the derived governing equation of motion of the PHP-based actuation system integrated with the friction element (band brake), a switching control law is synthesized based on the sliding-mode theory. To evaluate the effectiveness of the proposed control law, its force tracking performance for the engagement of a friction element during an AT 1\\to 2 up-shift is examined experimentally. It is shown that one can successfully track the desired force trajectory for AT shift control with small tracking error. This study demonstrates the potential of the PHP as a new controllable actuation system for AT friction elements.

Functional analysis of the Arabidopsis PLDZ2 promoter reveals an evolutionarily conserved low-Pi-responsive transcriptional enhancer element

PubMed Central

Oropeza-Aburto, Araceli; Cruz-Ramírez, Alfredo; Acevedo-Hernández, Gustavo J.; Pérez-Torres, Claudia-Anahí; Caballero-Pérez, Juan; Herrera-Estrella, Luis

2012-01-01

Plants have evolved a plethora of responses to cope with phosphate (Pi) deficiency, including the transcriptional activation of a large set of genes. Among Pi-responsive genes, the expression of the Arabidopsis phospholipase DZ2 (PLDZ2) is activated to participate in the degradation of phospholipids in roots in order to release Pi to support other cellular activities. A deletion analysis was performed to identify the regions determining the strength, tissue-specific expression, and Pi responsiveness of this regulatory region. This study also reports the identification and characterization of a transcriptional enhancer element that is present in the PLDZ2 promoter and able to confer Pi responsiveness to a minimal, inactive 35S promoter. This enhancer also shares the cytokinin and sucrose responsive properties observed for the intact PLDZ2 promoter. The EZ2 element contains two P1BS motifs, each of which is the DNA binding site of transcription factor PHR1. Mutation analysis showed that the P1BS motifs present in EZ2 are necessary but not sufficient for the enhancer function, revealing the importance of adjacent sequences. The structural organization of EZ2 is conserved in the orthologous genes of at least eight families of rosids, suggesting that architectural features such as the distance between the two P1BS motifs are also important for the regulatory properties of this enhancer element. PMID:22210906

Controls on Fe(II)-Activated Trace Element Release from Goethite and Hematite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Frierdich, Andrew J.; Catalano, Jeffrey G.

2012-03-26

Electron transfer and atom exchange (ETAE) between aqueous Fe(II) and Fe(III) oxides induces surface growth and dissolution that affects trace element fate and transport. We have recently demonstrated Ni(II) cycling through goethite and hematite (adsorbed Ni incorporates into the mineral structure and preincorporated Ni releases to solution) during Fe(II)-Fe(III) ETAE. However, the chemical parameters affecting net trace element release remain unknown. Here, we examine the chemical controls on Ni(II) and Zn(II) release from Ni- and Zn-substituted goethite and hematite during reaction with Fe(II). Release follows a rate law consistent with surface reaction limited mineral dissolution and suggests that release occursmore » near sites of Fe(III) reductive dissolution during Fe(II)-Fe(III) ETAE. Metal substituent type affects reactivity; Zn release is more pronounced from hematite than goethite, whereas the opposite trend occurs for Ni. Buildup of Ni or Zn in solution inhibits further release but this resumes upon fluid exchange, suggesting that sustained release is possible under flow conditions. Mineral and aqueous Fe(II) concentrations as well as pH strongly affect sorbed Fe(II) concentrations, which directly control the reaction rates and final metal concentrations. Our results demonstrate that structurally incorporated trace elements are mobilized from iron oxides into fluids without abiotic or microbial net iron reduction. Such release may affect micronutrient availability, contaminant transport, and the distribution of redox-inactive trace elements in natural and engineered systems.« less

Elements for successful sensor-based process control {Integrated Metrology}

NASA Astrophysics Data System (ADS)

Butler, Stephanie Watts

1998-11-01

Current productivity needs have stimulated development of alternative metrology, control, and equipment maintenance methods. Specifically, sensor applications provide the opportunity to increase productivity, tighten control, reduce scrap, and improve maintenance schedules and procedures. Past experience indicates a complete integrated solution must be provided for sensor-based control to be used successfully in production. In this paper, Integrated Metrology is proposed as the term for an integrated solution that will result in a successful application of sensors for process control. This paper defines and explores the perceived four elements of successful sensor applications: business needs, integration, components, and form. Based upon analysis of existing successful commercially available controllers, the necessary business factors have been determined to be strong, measurable industry-wide business needs whose solution is profitable and feasible. This paper examines why the key aspect of integration is the decision making process. A detailed discussion is provided of the components of most importance to sensor based control: decision-making methods, the 3R's of sensors, and connectivity. A metric for one of the R's (resolution) is proposed to allow focus on this important aspect of measurement. A form for these integrated components which synergistically partitions various aspects of control at the equipment and MES levels to efficiently achieve desired benefits is recommended.

Training Manual for Elements of Interface Definition and Control

NASA Technical Reports Server (NTRS)

Lalli, Vincent R. (Editor); Kastner, Robert E. (Editor); Hartt, Henry N. (Editor)

1997-01-01

The primary thrust of this manual is to ensure that the format and information needed to control interfaces between equipment are clear and understandable. The emphasis is on controlling the engineering design of the interface and not on the functional performance requirements of the system or the internal workings of the interfacing equipment. Interface control should take place, with rare exception, at the interfacing elements and no further. There are two essential sections of the manual. Chapter 2, Principles of Interface Control, discusses how interfaces are defined. It describes different types of interfaces to be considered and recommends a format for the documentation necessary for adequate interface control. Chapter 3, The Process: Through the Design Phases, provides tailored guidance for interface definition and control. This manual can be used to improve planned or existing interface control processes during system design and development. It can also be used to refresh and update the corporate knowledge base. The information presented herein will reduce the amount of paper and data required in interface definition and control processes by as much as 50 percent and will shorten the time required to prepare an interface control document. It also highlights the essential technical parameters that ensure that flight subsystems will indeed fit together and function as intended after assembly and checkout.

The muscle spindle as a feedback element in muscle control

NASA Technical Reports Server (NTRS)

Andrews, L. T.; Iannone, A. M.; Ewing, D. J.

1973-01-01

The muscle spindle, the feedback element in the myotatic (stretch) reflex, is a major contributor to muscular control. Therefore, an accurate description of behavior of the muscle spindle during active contraction of the muscle, as well as during passive stretch, is essential to the understanding of muscle control. Animal experiments were performed in order to obtain the data necessary to model the muscle spindle. Spectral density functions were used to identify a linear approximation of the two types of nerve endings from the spindle. A model reference adaptive control system was used on a hybrid computer to optimize the anatomically defined lumped parameter estimate of the spindle. The derived nonlinear model accurately predicts the behavior of the muscle spindle both during active discharge and during its silent period. This model is used to determine the mechanism employed to control muscle movement.

Cis-regulatory element based targeted gene finding: genome-wide identification of abscisic acid- and abiotic stress-responsive genes in Arabidopsis thaliana.

PubMed

Zhang, Weixiong; Ruan, Jianhua; Ho, Tuan-Hua David; You, Youngsook; Yu, Taotao; Quatrano, Ralph S

2005-07-15

A fundamental problem of computational genomics is identifying the genes that respond to certain endogenous cues and environmental stimuli. This problem can be referred to as targeted gene finding. Since gene regulation is mainly determined by the binding of transcription factors and cis-regulatory DNA sequences, most existing gene annotation methods, which exploit the conservation of open reading frames, are not effective in finding target genes. A viable approach to targeted gene finding is to exploit the cis-regulatory elements that are known to be responsible for the transcription of target genes. Given such cis-elements, putative target genes whose promoters contain the elements can be identified. As a case study, we apply the above approach to predict the genes in model plant Arabidopsis thaliana which are inducible by a phytohormone, abscisic acid (ABA), and abiotic stress, such as drought, cold and salinity. We first construct and analyze two ABA specific cis-elements, ABA-responsive element (ABRE) and its coupling element (CE), in A.thaliana, based on their conservation in rice and other cereal plants. We then use the ABRE-CE module to identify putative ABA-responsive genes in A.thaliana. Based on RT-PCR verification and the results from literature, this method has an accuracy rate of 67.5% for the top 40 predictions. The cis-element based targeted gene finding approach is expected to be widely applicable since a large number of cis-elements in many species are available.

14 CFR 91.1011 - Operational control responsibilities and delegation.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 14 Aeronautics and Space 2 2010-01-01 2010-01-01 false Operational control responsibilities and... Ownership Operations Operational Control § 91.1011 Operational control responsibilities and delegation. (a) Each owner in operational control of a program flight is ultimately responsible for safe operations and...

EFFECT OF PREGNANE XENOBIOTIC RECEPTOR ACTIVATION ON INFLAMMATORY BOWEL DISEASE TREATED WITH RIFAXIMIN.

PubMed

Wan, Y C; Li, T; Han, Y-D; Zhang, H-Y; Lin, H; Zhang, B

2015-01-01

The causes and pathogenesis of Inflammatory Bowel Disease (IBD) are still not clearly understood. This study aims to prove the important role of rifaximin played in inflammatory reaction caused by abnormity of the intestinal mucosal immune system. Intestinal microflora can greatly promote and maintain the inflammatory reaction of IBD, therefore, antibiotics can be used to treat IBD. Rifaximin is a medicine usually used for local intestinal infection. Many clinical and basic studies have shown that both a single application of rifaximin and the joint application with other medicines could achieve a good efficacy. This paper studied the activation of Pregnane Xenobiotic Receptor (PXR) in treating IBD with rifaximin and analyzed its efficacy in IBD when PXR was involved in the transport of medicine and metabolism. The results prove that rifaximin can not only serve as an anti-microbial drug, but can activate PXR and actually weaken the reaction of IBD. Thus it is safe to say that rifaximin has great potential in treating IBD.

Phosphorylation of Isoflavones by Bacillus subtilis BCRC 80517 May Represent Xenobiotic Metabolism.

PubMed

Hsu, Chen; Wu, Bo-Yuan; Chang, Yu-Chuan; Chang, Chi-Fon; Chiou, Tai-Ying; Su, Nan-Wei

2018-01-10

The soy isoflavones daidzein (DAI) and genistein (GEN) have beneficial effects on human health. However, their oral bioavailability is hampered by their low aqueous solubility. Our previous study revealed two water-soluble phosphorylated conjugates of isoflavones, daidzein 7-O-phosphate and genistein 7-O-phosphate, generated via biotransformation by Bacillus subtilis BCRC80517 cultivated with isoflavones. In this study, two novel derivatives of isoflavones, daidzein 4'-O-phosphate and genistein 4'-O-phosphate, were identified by HPLC-ESI-MS/MS and 1 H, 13 C, and 31 P NMR, and their biotransformation roadmaps were proposed. Primarily, isoflavone glucosides were deglycosylated and then phosphorylated predominantly into 7-O-phosphate conjugates with traces of 4'-O-phosphate conjugates. Inevitably, trace quantities of glucosides were converted into 6″-O-succinyl glucosides. GEN was more efficiently phosphorylated than DAI. Nevertheless, the presence of GEN prolonged the time until the exponential phase of cell growth, whereas the other isoflavones showed little effect on cell growth. Our findings provide new insights into the novel microbial phosphorylation of isoflavones involved in xenobiotic metabolism.

Finite element modelling of Plantar Fascia response during running on different surface types

NASA Astrophysics Data System (ADS)

Razak, A. H. A.; Basaruddin, K. S.; Salleh, A. F.; Rusli, W. M. R.; Hashim, M. S. M.; Daud, R.

2017-10-01

Plantar fascia is a ligament found in human foot structure located beneath the skin of human foot that functioning to stabilize longitudinal arch of human foot during standing and normal gait. To perform direct experiment on plantar fascia seems very difficult since the structure located underneath the soft tissue. The aim of this study is to develop a finite element (FE) model of foot with plantar fascia and investigate the effect of the surface hardness on biomechanical response of plantar fascia during running. The plantar fascia model was developed using Solidworks 2015 according to the bone structure of foot model that was obtained from Turbosquid database. Boundary conditions were set out based on the data obtained from experiment of ground reaction force response during running on different surface hardness. The finite element analysis was performed using Ansys 14. The results found that the peak of stress and strain distribution were occur on the insertion of plantar fascia to bone especially on calcaneal area. Plantar fascia became stiffer with increment of Young’s modulus value and was able to resist more loads. Strain of plantar fascia was decreased when Young’s modulus increased with the same amount of loading.

Abnormal expression and functional characteristics of cyclic adenosine monophosphate response element binding protein in postmortem brain of suicide subjects.

PubMed

Dwivedi, Yogesh; Rao, Jagadeesh Sridhara; Rizavi, Hooriyah S; Kotowski, Jacek; Conley, Robert R; Roberts, Rosalinda C; Tamminga, Carol A; Pandey, Ghanshyam N

2003-03-01

Cyclic adenosine monophosphate response element binding protein (CREB) is a transcription factor that, on phosphorylation by protein kinases, is activated, and in response, regulates the transcription of many neuronally expressed genes. In view of the recent observations that catalytic properties and/or expression of many kinases that mediate their physiological responses through the activation of CREB are altered in the postmortem brain of subjects who commit suicide (hereafter referred to as suicide subjects), we examined the status of CREB in suicidal behavior. These studies were performed in Brodmann area (BA) 9 and hippocampus obtained from 26 suicide subjects and 20 nonpsychiatric healthy control subjects. Messenger RNA levels of CREB and neuron-specific enolase were determined in total RNA by means of quantitative reverse transcriptase-polymerase chain reaction. Protein levels and the functional characteristics of CREB were determined in nuclear fractions by means of Western blot and cyclic adenosine monophosphate response element (CRE)-DNA binding activity, respectively. In the same nuclear fraction, we determined the catalytic activity of cyclic adenosine monophosphate-stimulated protein kinase A by means of enzymatic assay. We observed a significant reduction in messenger RNA and protein levels of CREB, CRE-DNA binding activity, and basal and cyclic adenosine monophosphate-stimulated protein kinase A activity in BA 9 and hippocampus of suicide subjects, without any change in messenger RNA levels of neuron-specific enolase in BA 9. Except for protein kinase A activity, changes in CREB expression and CRE-DNA binding activity were present in all suicide subjects, irrespective of diagnosis. These changes were unrelated to postmortem intervals, age, sex, or antidepressant treatment. Given the significance of CREB in mediating various physiological functions through gene transcription, our results of decreased expression and functional characteristics of CREB

Lentiviral vectors containing mouse Csf1r control elements direct macrophage-restricted expression in multiple species of birds and mammals

PubMed Central

Pridans, Clare; Lillico, Simon; Whitelaw, Bruce; Hume, David A

2014-01-01

The development of macrophages requires signaling through the lineage-restricted receptor Csf1r. Macrophage-restricted expression of transgenic reporters based upon Csf1r requires the highly conserved Fms-intronic regulatory element (FIRE). We have created a lentiviral construct containing mouse FIRE and promoter. The lentivirus is capable of directing macrophage-restricted reporter gene expression in mouse, rat, human, pig, cow, sheep, and even chicken. Rat bone marrow cells transduced with the lentivirus were capable of differentiating into macrophages expressing the reporter gene in vitro. Macrophage-restricted expression may be desirable for immunization or immune response modulation, and for gene therapy for lysosomal storage diseases and some immunodeficiencies. The small size of the Csf1r transcription control elements will allow the insertion of large “cargo” for applications in gene therapy and vaccine delivery. PMID:26015955

Finite element approximation of an optimal control problem for the von Karman equations

NASA Technical Reports Server (NTRS)

Hou, L. Steven; Turner, James C.

1994-01-01

This paper is concerned with optimal control problems for the von Karman equations with distributed controls. We first show that optimal solutions exist. We then show that Lagrange multipliers may be used to enforce the constraints and derive an optimality system from which optimal states and controls may be deduced. Finally we define finite element approximations of solutions for the optimality system and derive error estimates for the approximations.

Development of biomarkers of exposure to xenobiotics in the honey bee Apis mellifera: application to the systemic insecticide thiamethoxam.

PubMed

Badiou-Bénéteau, Alexandra; Carvalho, Stephan M; Brunet, Jean-Luc; Carvalho, Geraldo A; Buleté, Audrey; Giroud, Barbara; Belzunces, Luc P

2012-08-01

This study describes the development of acetylcholinesterase (AChE), carboxylesterases (CaE1, CaE2, CaE3), glutathion-S-transferase (GST), alkaline phosphatase (ALP) and catalase (CAT) as enzyme biomarkers of exposure to xenobiotics such as thiamethoxam in the honey bee Apis mellifera. Extraction efficiency, stability under freezing and biological variability were studied. The extraction procedure achieved good recovery rates in one extraction step and ranged from 65 percent (AChE) to 97.3 percent (GST). Most of the enzymes were stable at -20°C, except ALP that displayed a slight but progressive decrease in its activity. Modifications of enzyme activities were considered after exposure to thiamethoxam at the lethal dose 50 percent (LD(50), 51.16 ng bee(-1)) and two sublethal doses, LD(50)/10 (5.12 ng bee(-1)) and LD(50)/20 (2.56 ng bee(-1)). The biomarker responses revealed that, even at the lowest dose used, exposure to thiamethoxam elicited sublethal effects and modified the activity of CaEs, GST, CAT and ALP. Different patterns of biomarker responses were observed: no response for AChE, an increase for GST and CAT, and differential effects for CaEs isoforms with a decrease in CaE1 and CaE3 and an increase in CaE2. ALP and CaE3 displayed contrasting variations but only at 2.56 ng bee(-1). We consider that this profile of biomarker variation could represent a useful fingerprint to characterise exposure to thiamethoxam in the honey bee A. mellifera. This battery of honey bee biomarkers might be a promising option to biomonitor the health of aerial and terrestrial ecosystems and to generate valuable information on the modes of action of pesticides. Copyright © 2012 Elsevier Inc. All rights reserved.

Novel Yeast-based Strategy Unveils Antagonist Binding Regions on the Nuclear Xenobiotic Receptor PXR*

PubMed Central

Li, Hao; Redinbo, Matthew R.; Venkatesh, Madhukumar; Ekins, Sean; Chaudhry, Anik; Bloch, Nicolin; Negassa, Abdissa; Mukherjee, Paromita; Kalpana, Ganjam; Mani, Sridhar

2013-01-01

The pregnane X receptor (PXR) is a master regulator of xenobiotic metabolism, and its activity is critical toward understanding the pathophysiology of several diseases, including inflammation, cancer, and steatosis. Previous studies have demonstrated that ketoconazole binds to ligand-activated PXR and antagonizes receptor control of gene expression. Structure-function as well as computational docking analysis suggested a putative binding region containing critical charge clamp residues Gln-272, and Phe-264 on the AF-2 surface of PXR. To define the antagonist binding surface(s) of PXR, we developed a novel assay to identify key amino acid residues on PXR based on a yeast two-hybrid screen that examined mutant forms of PXR. This screen identified multiple “gain-of-function” mutants that were “resistant” to the PXR antagonist effects of ketoconazole. We then compared our screen results identifying key PXR residues to those predicted by computational methods. Of 15 potential or putative binding residues based on docking, we identified three residues in the yeast screen that were then systematically verified to functionally interact with ketoconazole using mammalian assays. Among the residues confirmed by our study was Ser-208, which is on the opposite side of the protein from the AF-2 region critical for receptor regulation. The identification of new locations for antagonist binding on the surface or buried in PXR indicates novel aspects to the mechanism of receptor antagonism. These results significantly expand our understanding of antagonist binding sites on the surface of PXR and suggest new avenues to regulate this receptor for clinical applications. PMID:23525103

Directional control-response relationships for mining equipment.

PubMed

Burgess-Limerick, R; Krupenia, V; Wallis, G; Pratim-Bannerjee, A; Steiner, L

2010-06-01

A variety of directional control-response relationships are currently found in mining equipment. Two experiments were conducted in a virtual environment to determine optimal direction control-response relationships in a wide variety of circumstances. Direction errors were measured as a function of control orientation (horizontal or vertical), location (left, front, right) and directional control-response relationships. The results confirm that the principles of consistent direction and visual field compatibility are applicable to the majority of situations. An exception is that fewer direction errors were observed when an upward movement of a horizontal lever or movement of a vertical lever away from the participants caused extension (lengthening) of the controlled device, regardless of whether the direction of movement of the control is consistent with the direction in which the extension occurs. Further, both the control of slew by horizontally oriented controls and the control of device movements in a frontal plane by the perpendicular movements of vertical levers were associated with relatively high rates of directional errors, regardless of the directional control-response relationship, and these situations should be avoided. STATEMENT OF RELEVANCE: The results are particularly applicable to the design of mining equipment such as drilling and bolting machines, and have been incorporated into MDG35.1 Guideline for bolting & drilling plant in mines (Industry & Investment NSW, 2010). The results are also relevant to the design of any equipment where vertical or horizontal levers are used to control the movement of equipment appendages, e.g. cranes mounted to mobile equipment and the like.

21 CFR 211.22 - Responsibilities of quality control unit.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Responsibilities of quality control unit. 211.22... Personnel § 211.22 Responsibilities of quality control unit. (a) There shall be a quality control unit that... have been fully investigated. The quality control unit shall be responsible for approving or rejecting...

21 CFR 211.22 - Responsibilities of quality control unit.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Responsibilities of quality control unit. 211.22... Personnel § 211.22 Responsibilities of quality control unit. (a) There shall be a quality control unit that... have been fully investigated. The quality control unit shall be responsible for approving or rejecting...

Simultaneous shifts in elemental stoichiometry and fatty acids of Emiliania huxleyi in response to environmental changes

NASA Astrophysics Data System (ADS)

Bi, Rong; Ismar, Stefanie M. H.; Sommer, Ulrich; Zhao, Meixun

2018-02-01

Climate-driven changes in environmental conditions have significant and complex effects on marine ecosystems. Variability in phytoplankton elements and biochemicals can be important for global ocean biogeochemistry and ecological functions, while there is currently limited understanding on how elements and biochemicals respond to the changing environments in key coccolithophore species such as Emiliania huxleyi. We investigated responses of elemental stoichiometry and fatty acids (FAs) in a strain of E. huxleyi under three temperatures (12, 18 and 24 °C), three N : P supply ratios (molar ratios 10:1, 24:1 and 63:1) and two pCO2 levels (560 and 2400 µatm). Overall, C : N : P stoichiometry showed the most pronounced response to N : P supply ratios, with high ratios of particulate organic carbon vs. particulate organic nitrogen (POC : PON) and low ratios of PON vs. particulate organic phosphorus (PON : POP) in low-N media, and high POC : POP and PON : POP in low-P media. The ratio of particulate inorganic carbon vs. POC (PIC : POC) and polyunsaturated fatty acid proportions strongly responded to temperature and pCO2, both being lower under high pCO2 and higher with warming. We observed synergistic interactions between warming and nutrient deficiency (and high pCO2) on elemental cellular contents and docosahexaenoic acid (DHA) proportion in most cases, indicating the enhanced effect of warming under nutrient deficiency (and high pCO2). Our results suggest differential sensitivity of elements and FAs to the changes in temperature, nutrient availability and pCO2 in E. huxleyi, which is to some extent unique compared to non-calcifying algal classes. Thus, simultaneous changes of elements and FAs should be considered when predicting future roles of E. huxleyi in the biotic-mediated connection between biogeochemical cycles, ecological functions and climate change.

Helicopter pilots' views of air traffic controller responsibilities: a mismatch.

PubMed

Martin, Daniel; Nixon, Jim

2018-02-21

Controllers and pilots must work together to ensure safe and efficient helicopter flight within the London control zone. Subjective ratings of pilot perception of controller responsibility for five key flight tasks were obtained from thirty helicopter pilots. Three types of airspace were investigated. Results indicate that there is variation in pilot understanding of controller responsibility compared to the formal regulations that define controller responsibility. Significant differences in the perception of controller responsibility were found for the task of aircraft separation in class D airspace and along helicopter routes. Analysis of the patterns of response suggests that task type rather than the airspace type may be the key factor. Results are framed using the concept of a shared mental model. This research demonstrates that pilots flying in complex London airspace have an expectation of controller responsibility for certain flight tasks, in certain airspace types that is not supported by aviation regulation. Practitioner Summary: The responsibility for tasks during flight varies according to the flight rules used and airspace type. Helicopter pilots may attribute responsibility to controllers for tasks when controllers have no responsibility as defined by regulation. This variation between pilot perceptions of controller responsibility could affect safety within the London control zone.

Geological occurrence response to trace elemental migration in coal liquefaction based on SPSS: take no. 11 coalbed in Antaibao mine for example

NASA Astrophysics Data System (ADS)

Xia, Xiaohong; Qin, Yong; Yang, Weifeng

2013-03-01

Coal liquefaction is an adoptable method to transfer the solid fossil energy into liquid oil in large scale, but the dirty material in which will migrate to different step of liquefaction. The migration rule of some trace elements is response to the react activity of macerals in coal and the geological occurrence of the element nature of itself. In this paper, from the SPSS data correlation analysis and hierarchical clustering dendrogram about the trace elements with macerals respond to coal liquefaction yield, it shows the trace elements in No.11 Antaibao coal seam originated from some of lithophile and sulphophle elements. Correlation coefficient between liquefaction yield of three organic macerals and migration of the elements in liquefaction residue indicated that the lithophile are easy to transfer to residue, while sulphophle are apt to in the liquid products. The activated macerals are response to sulphophle trace elements. The conclusion is useful to the coal blending and environmental effects on coal direct liquefaction.

Contributions of individual domains to function of the HIV-1 Rev response element.

PubMed

O'Carroll, Ina P; Thappeta, Yashna; Fan, Lixin; Ramirez-Valdez, Edric A; Smith, Sean; Wang, Yun-Xing; Rein, Alan

2017-08-16

The HIV-1 Rev response element (RRE) is a 351-base element in unspliced and partially spliced viral RNA; binding of the RRE by the viral Rev protein induces nuclear export of RRE-containing RNAs, as required for virus replication. It contains one long, imperfect double helix (domain I), one branched domain (domain II) containing a high-affinity Rev-binding site, and two or three additional domains. We previously reported that the RRE assumes an "A" shape in solution and suggested that the location of the Rev binding sites in domains I and II, opposite each other on the two legs of the A, is optimal for Rev binding and explains Rev's specificity for RRE-containing RNAs. Using SAXS and a quantitative functional assay, we have now analyzed a panel of RRE mutants. All the results support the essential role of the A shape for RRE function. Moreover, they suggest that the distal portion of domain I and the three crowning domains all contribute to the maintenance of the A shape. Domains I and II are necessary and sufficient for substantial RRE function, provided they are joined by a flexible linker that allows the two domains to face each other. IMPORTANCE Retroviral replication requires that some of the viral RNAs transcribed in the cell nucleus be exported to the cytoplasm without being spliced. To achieve this, HIV-1 encodes a protein, Rev, which binds to a complex, highly structured element within viral RNA, the Rev Response Element (RRE), and escorts RRE-containing RNAs from the nucleus. We previously reported that the RRE is "A"-shaped and suggested that this architecture, with the 2 legs opposite one another, can explain the specificity of Rev for the RRE. We have analyzed the functional contributions of individual RRE domains, and now report that several domains contribute, with some redundancy, to maintenance of the overall RRE shape. The data strongly support the hypothesis that the opposed placement of the 2 legs is essential for RRE function. Copyright © 2017

Contributions of Individual Domains to Function of the HIV-1 Rev Response Element

PubMed Central

O'Carroll, Ina P.; Thappeta, Yashna; Fan, Lixin; Ramirez-Valdez, Edric A.; Smith, Sean; Wang, Yun-Xing

2017-01-01

ABSTRACT The HIV-1 Rev response element (RRE) is a 351-base element in unspliced and partially spliced viral RNA; binding of the RRE by the viral Rev protein induces nuclear export of RRE-containing RNAs, as required for virus replication. It contains one long, imperfect double helix (domain I), one branched domain (domain II) containing a high-affinity Rev-binding site, and two or three additional domains. We previously reported that the RRE assumes an “A” shape in solution and suggested that the location of the Rev binding sites in domains I and II, opposite each other on the two legs of the A, is optimal for Rev binding and explains Rev's specificity for RRE-containing RNAs. Using small-angle X-ray scattering (SAXS) and a quantitative functional assay, we have now analyzed a panel of RRE mutants. All the results support the essential role of the A shape for RRE function. Moreover, they suggest that the distal portion of domain I and the three crowning domains all contribute to the maintenance of the A shape. Domains I and II are necessary and sufficient for substantial RRE function, provided they are joined by a flexible linker that allows the two domains to face each other. IMPORTANCE Retroviral replication requires that some of the viral RNAs transcribed in the cell nucleus be exported to the cytoplasm without being spliced. To achieve this, HIV-1 encodes a protein, Rev, which binds to a complex, highly structured element within viral RNA, the Rev response element (RRE), and escorts RRE-containing RNAs from the nucleus. We previously reported that the RRE is “A” shaped and suggested that this architecture, with the 2 legs opposite one another, can explain the specificity of Rev for the RRE. We have analyzed the functional contributions of individual RRE domains and now report that several domains contribute, with some redundancy, to maintenance of the overall RRE shape. The data strongly support the hypothesis that the opposed placement of the 2 legs

Optimal control penalty finite elements - Applications to integrodifferential equations

NASA Astrophysics Data System (ADS)

Chung, T. J.

The application of the optimal-control/penalty finite-element method to the solution of integrodifferential equations in radiative-heat-transfer problems (Chung et al.; Chung and Kim, 1982) is discussed and illustrated. The nonself-adjointness of the convective terms in the governing equations is treated by utilizing optimal-control cost functions and employing penalty functions to constrain auxiliary equations which permit the reduction of second-order derivatives to first order. The OCPFE method is applied to combined-mode heat transfer by conduction, convection, and radiation, both without and with scattering and viscous dissipation; the results are presented graphically and compared to those obtained by other methods. The OCPFE method is shown to give good results in cases where standard Galerkin FE fail, and to facilitate the investigation of scattering and dissipation effects.

Purification and characterization of akr1b10 from human liver: role in carbonyl reduction of xenobiotics.

PubMed

Martin, Hans-Jörg; Breyer-Pfaff, Ursula; Wsol, Vladimir; Venz, Simone; Block, Simone; Maser, Edmund

2006-03-01

Members of the aldo-keto reductase (AKR) superfamily have a broad substrate specificity in catalyzing the reduction of carbonyl group-containing xenobiotics. In the present investigation, a member of the aldose reductase subfamily, AKR1B10, was purified from human liver cytosol. This is the first time AKR1B10 has been purified in its native form. AKR1B10 showed a molecular mass of 35 kDa upon gel filtration and SDS-polyacrylamide gel electrophoresis. Kinetic parameters for the NADPH-dependent reduction of the antiemetic 5-HT3 receptor antagonist dolasetron, the antitumor drugs daunorubicin and oracin, and the carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) to the corresponding alcohols have been determined by HPLC. Km values ranged between 0.06 mM for dolasetron and 1.1 mM for daunorubicin. Enzymatic efficiencies calculated as kcat/Km were more than 100 mM-1 min-1 for dolasetron and 1.3, 0.43, and 0.47 mM-1 min-1 for daunorubicin, oracin, and NNK, respectively. Thus, AKR1B10 is one of the most significant reductases in the activation of dolasetron. In addition to its reducing activity, AKR1B10 catalyzed the NADP+-dependent oxidation of the secondary alcohol (S)-1-indanol to 1-indanone with high enzymatic efficiency (kcat/Km=112 mM-1 min-1). The gene encoding AKR1B10 was cloned from a human liver cDNA library and the recombinant enzyme was purified. Kinetic studies revealed lower activity of the recombinant compared with the native form. Immunoblot studies indicated large interindividual variations in the expression of AKR1B10 in human liver. Since carbonyl reduction of xenobiotics often leads to their inactivation, AKR1B10 may play a role in the occurrence of chemoresistance of tumors toward carbonyl group-bearing cytostatic drugs.

Associations Between Selected Xenobiotics and Antinuclear Antibodies in the National Health and Nutrition Examination Survey, 1999-2004.

PubMed

Dinse, Gregg E; Jusko, Todd A; Whitt, Irene Z; Co, Caroll A; Parks, Christine G; Satoh, Minoru; Chan, Edward K L; Rose, Kathryn M; Walker, Nigel J; Birnbaum, Linda S; Zeldin, Darryl C; Weinberg, Clarice R; Miller, Frederick W

2016-04-01

Potential associations between background environmental chemical exposures and autoimmunity are understudied. Our exploratory study investigated exposure to individual environmental chemicals and selected mixtures in relation to the presence of antinuclear antibodies (ANA), a widely used biomarker of autoimmunity, in a representative sample of the U.S. This cross-sectional analysis used data on 4,340 participants from the National Health and Nutrition Examination Survey (1999-2004), of whom 14% were ANA positive, to explore associations between ANA and concentrations of dioxins, dibenzofurans, polychlorinated biphenyls, organochlorines, organophosphates, phenols, metals, and other environmental exposures and metabolites measured in participants' serum, whole blood, or urine. For dioxin-like compounds with toxic equivalency factors, we developed and applied a new statistical approach to study selected mixtures. Lognormal models and censored-data methods produced estimates of chemical associations with ANA in males, nulliparous females, and parous females; these estimates were adjusted for confounders and accommodated concentrations below detectable levels. Several associations between chemical concentration and ANA positivity were observed, but only the association in males exposed to triclosan remained statistically significant after correcting for multiple comparisons (mean concentration ratio = 2.8; 95% CI: 1.8, 4.5; p < 0.00001). These data suggest that background levels of most xenobiotic exposures typical in the U.S. population are not strongly associated with ANA. Future studies should ideally reduce exposure misclassification by including prospective measurement of the chemicals of concern and should track changes in ANA and other autoantibodies over time. Dinse GE, Jusko TA, Whitt IZ, Co CA, Parks CG, Satoh M, Chan EKL, Rose KM, Walker NJ, Birnbaum LS, Zeldin DC, Weinberg CR, Miller FW. 2016. Associations between selected xenobiotics and antinuclear

Regulation of cyclic adenosine monophosphate response element binding protein on renin expression in kidney via complex cyclic adenosine monophosphate response element-binding-protein-binding protein/P300 recruitment.

PubMed

Li, Pei; Zhang, Jing; Zhu, Yuanfang; Liu, Ming; Xuan, Jin

2015-11-01

Renin synthesis and release is the rate-limiting step in the renin-angiotensin system, because cyclic adenosine monophosphate (cAMP) has been identified as dominant pathway for renin gene expression, and cAMP response element-binding protein (CREB) is found in the human and mouse renin promoter. This study aimed to evaluate the role of CREB in expression of the renin gene. We created conditional deletion of CREB in mice with low-sodium diet, specifically in renin cells of the kidney. To assess the effect of CREB on renin expression, immunostaining of renin was used in samples from wild-type mice and mice with gene knock-down of CREB. Cyclic AMP response element-binding-protein-binding protein (CBP) and p300 were measured in cultured renin cells of the mice, and RNA detection was done with real-time polymerase chain reaction. With low-sodium diet, renin was expressed along the whole wall of the afferent glomerular arterioles in wild-type mice, while there was no increase or even decrease in renin expression in CREB-specific deletion mice; RNA level of renin in cultured cells decreased by 50% with single knock-down of CREB, CBP, or p300, and decreased 70% with triple knock-down of CREB, CBP, and p300. This study found that CREB was important for renin synthesis and the role of CREB can be achieved through the recruitment of co-activators CBP and p300.

Mode of action from dose-response microarray data: case study using 10 environmental chemicals

EPA Science Inventory

Ligand-activated nuclear receptors regulate many biological processes through complex interactions with biological macromolecules. Certain xenobiotics alter nuclear receptor signaling through direct or indirect interactions. Defining the mode of action of such xenobiotics is di...

The in vivo plantar soft tissue mechanical property under the metatarsal head: implications of tissues׳ joint-angle dependent response in foot finite element modeling.

PubMed

Chen, Wen-Ming; Lee, Sung-Jae; Lee, Peter Vee Sin

2014-12-01

Material properties of the plantar soft tissue have not been well quantified in vivo (i.e., from life subjects) nor for areas other than the heel pad. This study explored an in vivo investigation of the plantar soft tissue material behavior under the metatarsal head (MTH). We used a novel device collecting indentation data at controlled metatarsophalangeal joint angles. Combined with inverse analysis, tissues׳ joint-angle dependent material properties were identified. The results showed that the soft tissue under MTH exhibited joint-angle dependent material responses, and the computed parameters using the Ogden material model were 51.3% and 30.9% larger in the dorsiflexed than in the neutral positions, respectively. Using derived parameters in subject-specific foot finite element models revealed only those models that used tissues׳ joint-dependent responses could reproduce the known plantar pressure pattern under the MTH. It is suggested that, to further improve specificity of the personalized foot finite element models, quantitative mechanical properties of the tissue inclusive of the effects of metatarsophalangeal joint dorsiflexion are needed. Copyright © 2014 Elsevier Ltd. All rights reserved.

Creating diversified response profiles from a single quenchometric sensor element by using phase-resolved luminescence.

PubMed

Tehan, Elizabeth C; Bukowski, Rachel M; Chodavarapu, Vamsy P; Titus, Albert H; Cartwright, Alexander N; Bright, Frank V

2015-01-05

We report a new strategy for generating a continuum of response profiles from a single luminescence-based sensor element by using phase-resolved detection. This strategy yields reliable responses that depend in a predictable manner on changes in the luminescent reporter lifetime in the presence of the target analyte, the excitation modulation frequency, and the detector (lock-in amplifier) phase angle. In the traditional steady-state mode, the sensor that we evaluate exhibits a linear, positive going response to changes in the target analyte concentration. Under phase-resolved conditions the analyte-dependent response profiles: (i) can become highly non-linear; (ii) yield negative going responses; (iii) can be biphasic; and (iv) can exhibit super sensitivity (e.g., sensitivities up to 300 fold greater in comparison to steady-state conditions).

In silico platform for xenobiotics ADME-T pharmacological properties modeling and prediction. Part II: The body in a Hilbertian space.

PubMed

Jacob, Alexandre; Pratuangdejkul, Jaturong; Buffet, Sébastien; Launay, Jean-Marie; Manivet, Philippe

2009-04-01

We have broken old surviving dogmas and concepts used in computational chemistry and created an efficient in silico ADME-T pharmacological properties modeling and prediction toolbox for any xenobiotic. With the help of an innovative and pragmatic approach combining various in silico techniques, like molecular modeling, quantum chemistry and in-house developed algorithms, the interactions between drugs and those enzymes, transporters and receptors involved in their biotransformation can be studied. ADME-T pharmacological parameters can then be predicted after in vitro and in vivo validations of in silico models.

"Checkerboard" assessments of periodontal microbiota and serum antibody responses: a case-control study.

PubMed

Papapanou, P N; Neiderud, A M; Papadimitriou, A; Sandros, J; Dahlén, G

2000-06-01

only one was positive (V. parvula). Both bacterial levels and antibody responses declined in ages over 55 years. A logistic regression employing selected elements of bacterial colonization and antibody responses as independent variables resulted in 81.1% correct diagnosis, with sensitivity of 83.1%, specificity of 77.8%, positive predictability of 86%, and negative predictability of 73.7%. Smoking did not reach statistical significance in this model. A combined microbial colonization/antibody response profile can effectively discriminate between periodontitis patients and periodontally intact controls.

Characterization of a hypoxia-response element in the Epo locus of the pufferfish, Takifugu rubripes.

PubMed

Kulkarni, Rashmi P; Tohari, Sumanty; Ho, Adrian; Brenner, Sydney; Venkatesh, Byrappa

2010-06-01

Animals respond to hypoxia by increasing synthesis of the glycoprotein hormone erythropoietin (Epo) which in turn stimulates the production of red blood cells. The gene encoding Epo has been recently cloned in teleost fishes such as the pufferfish Takifugu rubripes (fugu) and zebrafish (Danio rerio). It has been shown that the transcription levels of Epo in teleost fishes increase in response to anemia or hypoxia in a manner similar to its human ortholog. However, the cis-regulatory element(s) mediating the hypoxia response of Epo gene in fishes has not been identified. In the present study, using the human hepatoma cell line (Hep3B), we have identified and characterized a hypoxia response element (HRE) in the fugu Epo locus. The sequence of the fugu HRE (ACGTGCTG) is identical to that of the HRE in the human EPO locus. However, unlike the HRE in the mammalian Epo locus, which is located in the 3' region of the gene, the fugu HRE is located in the 5' flanking region and on the opposite strand of DNA. This HRE is conserved in other teleosts such as Tetraodon and zebrafish in a similar location. A 365-bp fragment containing the fugu HRE was able to drive GFP expression in the liver of transgenic zebrafish. However, we could not ascertain if the expression of transgene is induced by hypoxia in vivo due to the low and variable levels of GFP expression in transgenic zebrafish. Our investigations also revealed that the Epo locus has experienced extensive rearrangements during vertebrate evolution. Copyright © 2010 Elsevier B.V. All rights reserved.

Voltage control of nanoscale magnetoelastic elements: theory and experiments (Presentation Recording)

NASA Astrophysics Data System (ADS)

Carman, Gregory P.

2015-09-01

Electromagnetic devices rely on electrical currents to generate magnetic fields. While extremely useful this approach has limitations in the small-scale. To overcome the scaling problem, researchers have tried to use electric fields to manipulate a magnetic material's intrinsic magnetization (i.e. multiferroic). The strain mediated class of multiferroics offers up to 70% of energy transduction using available piezoelectric and magnetoelastic materials. While strain mediated multiferroic is promising, few studies exist on modeling/testing of nanoscale magnetic structures. This talk presents motivation, analytical models, and experimental data on electrical control of nanoscale single magnetic domain structures. This research is conducted in a NSF Engineering Research Center entitled Translational Applications for Nanoscale Multiferroics TANMS. The models combine micromagnetics (Landau-Lifshitz-Gilbert) with elastodynamics using the electrostatic approximation producing eight fully coupled nonlinear partial differential equations. Qualitative and quantitative verification is achieved with direct comparison to experimental data. The modeling effort guides fabrication and testing on three elements, i.e. nanoscale rings (onion states), ellipses (single domain reorientation), and superparamagnetic elements. Experimental results demonstrate electrical and deterministic control of the magnetic states in the 5-500 nm structures as measured with Photoemission Electron Microscopy PEEM, Magnetic Force Microscopy MFM, or Lorentz Transmission Electron Microscopy TEM. These data strongly suggests efficient control of nanoscale magnetic spin states is possible with voltage.

Dynamic Response of a Planetary Gear System Using a Finite Element/Contact Mechanics Model

NASA Technical Reports Server (NTRS)

Parker, Robert G.; Agashe, Vinayak; Vijayakar, Sandeep M.

2000-01-01

The dynamic response of a helicopter planetary gear system is examined over a wide range of operating speeds and torques. The analysis tool is a unique, semianalytical finite element formulation that admits precise representation of the tooth geometry and contact forces that are crucial in gear dynamics. Importantly, no a priori specification of static transmission error excitation or mesh frequency variation is required; the dynamic contact forces are evaluated internally at each time step. The calculated response shows classical resonances when a harmonic of mesh frequency coincides with a natural frequency. However, peculiar behavior occurs where resonances expected to be excited at a given speed are absent. This absence of particular modes is explained by analytical relationships that depend on the planetary configuration and mesh frequency harmonic. The torque sensitivity of the dynamic response is examined and compared to static analyses. Rotation mode response is shown to be more sensitive to input torque than translational mode response.

Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder☆

PubMed Central

Wang, Hongyan; Zhang, Yingquan; Qiao, Mingqi

2013-01-01

The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression. PMID:25206732

Pilot-model analysis and simulation study of effect of control task desired control response

NASA Technical Reports Server (NTRS)

Adams, J. J.; Gera, J.; Jaudon, J. B.

1978-01-01

A pilot model analysis was performed that relates pilot control compensation, pilot aircraft system response, and aircraft response characteristics for longitudinal control. The results show that a higher aircraft short period frequency is required to achieve superior pilot aircraft system response in an altitude control task than is required in an attitude control task. These results were confirmed by a simulation study of target tracking. It was concluded that the pilot model analysis provides a theoretical basis for determining the effect of control task on pilot opinions.

Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity[S

PubMed Central

Bindesbøll, Christian; Fan, Qiong; Nørgaard, Rikke C.; MacPherson, Laura; Ruan, Hai-Bin; Wu, Jing; Pedersen, Thomas Å.; Steffensen, Knut R.; Yang, Xiaoyong; Matthews, Jason; Mandrup, Susanne; Nebb, Hilde I.; Grønning-Wang, Line M.

2015-01-01

Liver X receptor (LXR)α and LXRβ play key roles in hepatic de novo lipogenesis through their regulation of lipogenic genes, including sterol regulatory element-binding protein (SREBP)-1c and carbohydrate responsive element-binding protein (ChREBP). LXRs activate lipogenic gene transcription in response to feeding, which is believed to be mediated by insulin. We have previously shown that LXRs are targets for glucose-hexosamine-derived O-linked β-N-acetylglucosamine (O-GlcNAc) modification enhancing their ability to regulate SREBP-1c promoter activity in vitro. To elucidate insulin-independent effects of feeding on LXR-mediated lipogenic gene expression in vivo, we subjected control and streptozotocin-treated LXRα/β+/+ and LXRα/β−/− mice to a fasting-refeeding regime. We show that under hyperglycemic and hypoinsulinemic conditions, LXRs maintain their ability to upregulate the expression of glycolytic and lipogenic enzymes, including glucokinase (GK), SREBP-1c, ChREBPα, and the newly identified shorter isoform ChREBPβ. Furthermore, glucose-dependent increases in LXR/retinoid X receptor-regulated luciferase activity driven by the ChREBPα promoter was mediated, at least in part, by O-GlcNAc transferase (OGT) signaling in Huh7 cells. Moreover, we show that LXR and OGT interact and colocalize in the nucleus and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling and ChREBPα promoter binding activity in vivo. In summary, our study provides evidence that LXRs act as nutrient and glucose metabolic sensors upstream of ChREBP by modulating GK expression, nuclear O-GlcNAc signaling, and ChREBP expression and activity. PMID:25724563

Effects of Caste on the Expression of Genes Associated with Septic Injury and Xenobiotic Exposure in the Formosan Subterranean Termite

PubMed Central

2014-01-01

As social insects, termites live in densely populated colonies with specialized castes under conditions conducive to microbial growth and transmission. Furthermore, termites are exposed to xenobiotics in soil and their lignocellulose diet. Therefore, termites are valuable models for studying gene expression involved in response to septic injury, immunity and detoxification in relation to caste membership. In this study, workers and soldiers of the Formosan subterranean termite, Coptotermes formosanus, were challenged by bacterial injection or by no-choice feeding with a sublethal concentration (0.5%) of phenobarbital. Constitutive and induced expression of six putative immune response genes (two encoding for lectin-like proteins, one for a ficolin-precursor, one for the Down syndrome cell adhesion molecule, one for a chitin binding protein, and one for the gram-negative binding protein 2) and four putative detoxification genes (two encoding for cytochrome P450s, one for glutathione S-transferase, and one for the multi antimicrobial extrusion protein), were measured via quantitative real time polymerase chain reaction and compared within and among 1) colonies, 2) treatment types and 3) castes via ANOVA. Eight genes were inducible by septic injury, feeding with phenobarbital or both. Colony origin had no effect on inducibility or differential gene expression. However, treatment type showed significant effects on the expression of the eight inducible genes. Caste effects on expression levels were significant in five of the eight inducible genes with constitutive and induced expression of most target genes being higher in workers than in soldiers. PMID:25141339

Xenobiotic metabolizing enzyme activities in cells used for testing skin sensitization in vitro.

PubMed

Fabian, E; Vogel, D; Blatz, V; Ramirez, T; Kolle, S; Eltze, T; van Ravenzwaay, B; Oesch, F; Landsiedel, R

2013-09-01

For ethical and regulatory reasons, in vitro tests for scoring potential toxicities of cosmetics are essential. A test strategy for investigating potential skin sensitization using two human keratinocytic and two human dendritic cell lines has been developed (Mehling et al. Arch Toxicol 86:1273–1295, 2012). Since prohaptens may be metabolically activated in the skin, information on xenobiotic metabolizing enzyme (XME) activities in these cell lines is of high interest. In this study, XME activity assays, monitoring metabolite or cofactor, showed the following: all three passages of keratinocytic (KeratinoSens® and LuSens) and dendritic (U937 und THP-1) cells displayed N-acetyltransferase 1 (NAT1) activities (about 6–60 nmol/min/mg S9-protein for acetylation of para-aminobenzoic acid). This is relevant since reactive species of many cosmetics are metabolically controlled by cutaneous NAT1. Esterase activities of about 1–4 nmol fluorescein diacetate/min/mg S9-protein were observed in all passages of investigated keratinocytic and about 1 nmol fluorescein diacetate/min/mg S9-protein in dendritic cell lines. This is also of practical relevance since many esters and amides are detoxified and others activated by cutaneous esterases. In both keratinocytic cell lines, activities of aldehyde dehydrogenase (ALDH) were observed (5–17 nmol product/min/mg cytosolic protein). ALDH is relevant for the detoxication of reactive aldehydes. Activities of several other XME were below detection, namely the investigated cytochrome P450-dependent alkylresorufin O-dealkylases 7-ethylresorufin O-deethylase, 7-benzylresorufin O-debenzylase and 7-pentylresorufin O-depentylase (while NADPH cytochrome c reductase activities were much above the limit of quantification), the flavin-containing monooxygenase, the alcohol dehydrogenase as well as the UDP glucuronosyl transferase activities.

Organochlorine pesticide, endosulfan induced cellular and organismal response in Drosophila melanogaster.

PubMed

Sharma, Anurag; Mishra, M; Shukla, A K; Kumar, R; Abdin, M Z; Chowdhuri, D Kar

2012-06-30

The effect of endosulfan (0.02-2.0μgmL(-1)) to Drosophila melanogaster (Oregon R(+)) at the cellular and organismal levels was examined. Third instar larvae of D. melanogaster and the strains transgenic for hsp70, hsp83 and hsp26 were exposed to endosulfan through food for 12-48h to examine the heat shock proteins (hsps), reactive oxygen species (ROS) generation, anti-oxidant stress markers and xenobiotic metabolism enzymes. We observed a concentration- and time-dependent significant induction of only small hsps (hsp23>hsp22) in the exposed organism in concurrence with a significant induction of ROS generation, oxidative stress and xenobiotic metabolism markers. Sub-organismal response was to be propagated towards organismal response, i.e., delay in the emergence of flies and decreased locomotor behaviour. Organisms with diminished locomotion also exhibited significantly lowered acetylcholinesterase activity. A significant positive correlation observed among ROS generation and different cellular endpoints (small hsps, oxidative stress markers, cytochrome P450 activities) in the exposed organism indicate a modulatory role of ROS in endosulfan-mediated cellular toxicity. The study thus suggests that the adverse effects of endosulfan in exposed Drosophila are manifested both at cellular and organismal levels and recommends Drosophila as an alternative animal model for screening the risk caused by environmental chemicals. Copyright © 2012 Elsevier B.V. All rights reserved.

Characterization of xenobiotic metabolizing enzymes of a reconstructed human epidermal model from adult hair follicles.

PubMed

Bacqueville, Daniel; Jacques, Carine; Duprat, Laure; Jamin, Emilien L; Guiraud, Beatrice; Perdu, Elisabeth; Bessou-Touya, Sandrine; Zalko, Daniel; Duplan, Hélène

2017-08-15

In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and β-naphthoflavone (βNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients. Copyright © 2017 Elsevier Inc. All rights reserved.

Three-Dimensional Finite Element Ablative Thermal Response and Thermostructural Design of Thermal Protection Systems

NASA Technical Reports Server (NTRS)

Dec, John A.; Braun, Robert D.

2011-01-01

A finite element ablation and thermal response program is presented for simulation of three-dimensional transient thermostructural analysis. The three-dimensional governing differential equations and finite element formulation are summarized. A novel probabilistic design methodology for thermal protection systems is presented. The design methodology is an eight step process beginning with a parameter sensitivity study and is followed by a deterministic analysis whereby an optimum design can determined. The design process concludes with a Monte Carlo simulation where the probabilities of exceeding design specifications are estimated. The design methodology is demonstrated by applying the methodology to the carbon phenolic compression pads of the Crew Exploration Vehicle. The maximum allowed values of bondline temperature and tensile stress are used as the design specifications in this study.

False responses of Renilla luciferase reporter control to nuclear receptor TR4.

PubMed

Zhang, Dongyun; Atlasi, Sam S; Patel, Krishna K; Zhuang, Zihao; Heaney, Anthony P

2017-06-01

Renilla luciferase reporter is a widely used internal control in dual luciferase reporter assay system, where its transcription is driven by a constitutively active promoter. However, the authenticity of the Renilla luciferase response in some experimental settings has recently been questioned. Testicular receptor 4 (TR4, also known as NR2C2) belongs to the subfamily 2 of nuclear receptors. TR4 binds to a direct repeat regulatory element in the promoter of a variety of target genes and plays a key role in tumorigenesis, lipoprotein regulation, and central nervous system development. In our experimental system using murine pituitary corticotroph tumor AtT20 cells to investigate TR4 actions on POMC transcription, we found that overexpression of TR4 resulted in reduced Renilla luciferase expression whereas knockdown TR4 increased Renilla luciferase expression. The TR4 inhibitory effect was mediated by the TR4 DNA-binding domain and behaved similarly to the GR and its agonist, Dexamethasone. We further demonstrated that the chimeric intron, commonly present in various Renilla plasmid backbones such as pRL-Null, pRL-SV40, and pRL-TK, was responsible for TR4's inhibitory effect. The results suggest that an intron-free Renilla luciferase reporter may provide a satisfactory internal control for TR4 at certain dose range. Our findings advocate caution on the use of Renilla luciferase as an internal control in TR4-directed studies to avoid misleading data interpretation.

Profiling Environmental Chemicals in the Antioxidant Response Element Pathway using Quantitative High Throughput Screening (qHTS)

EPA Science Inventory

The antioxidant response element (ARE) signaling pathway plays an important role in the amelioration of oxidative stress, which can contribute to a number of diseases, including cancer. We screened 1408 NTP-provided substances in 1536-well qHTS format at concentrations ranging fr...

A temperature control design for a tapered element oscillating microbalance sensing surface

NASA Technical Reports Server (NTRS)

1982-01-01

A design study is presented which shows that a tapered element oscillating microbalance can be adapted for temperature control under space application by mating with multistage thermoelectric coolers in such a way that an integral structure evolves. The control of the temperature of the sensing surface can be achieved in a number of ways. An indirect method which uses a measurement of the absorbed power is recommended. The design goals can be met if a relaxation of the power requirement can be considered.

The yeast genome may harbor hypoxia response elements (HRE).

PubMed

Ferreira, Túlio César; Hertzberg, Libi; Gassmann, Max; Campos, Elida Geralda

2007-01-01

The hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor activated when cells are submitted to hypoxia. The heterodimer is composed of two subunits, HIF-1alpha and the constitutively expressed HIF-1beta. During normoxia, HIF-1alpha is degraded by the 26S proteasome, but hypoxia causes HIF-1alpha to be stabilized, enter the nucleus and bind to HIF-1beta, thus forming the active complex. The complex then binds to the regulatory sequences of various genes involved in physiological and pathological processes. The specific regulatory sequence recognized by HIF-1 is the hypoxia response element (HRE) that has the consensus sequence 5'BRCGTGVBBB3'. Although the basic transcriptional regulation machinery is conserved between yeast and mammals, Saccharomyces cerevisiae does not express HIF-1 subunits. However, we hypothesized that baker's yeast has a protein analogous to HIF-1 which participates in the response to changes in oxygen levels by binding to HRE sequences. In this study we screened the yeast genome for HREs using probabilistic motif search tools. We described 24 yeast genes containing motifs with high probability of being HREs (p-value<0.1) and classified them according to biological function. Our results show that S. cerevisiae may harbor HREs and indicate that a transcription factor analogous to HIF-1 may exist in this organism.

Acetaminophen induces xenobiotic-metabolizing enzymes in rat: Impact of a uranium chronic exposure.

PubMed

Rouas, Caroline; Souidi, Maâmar; Grandcolas, Line; Grison, Stephane; Baudelin, Cedric; Gourmelon, Patrick; Pallardy, Marc; Gueguen, Yann

2009-11-01

The extensive use of uranium in civilian and military applications increases the risk of human chronic exposure. Uranium is a slightly radioactive heavy metal with a predominantly chemical toxicity, especially in kidney but also in liver. Few studies have previously shown some effects of uranium on xenobiotic-metabolizing enzymes (XME) that might disturb drug pharmacokinetic. The aim of this study was to determine whether a chronic (9 months) non-nephrotoxic low dose exposure to depleted uranium (DU, 1mg/rat/day) could modify the liver XME, using a single non-hepatotoxic acetaminophen (APAP) treatment (50mg/kg). Most of XME analysed were induced by APAP treatment at the gene expression level but at the protein level only CYP3A2 was significantly increased 3h after APAP treatment in DU-exposed rats whereas it remained at a basal level in unexposed rats. In conclusion, these results showed that a chronic non-nephrotoxic DU exposure specially modify CYP3A2 after a single therapeutic APAP treatment. Copyright © 2009 Elsevier B.V. All rights reserved.

Conflict control in task conflict and response conflict.

PubMed

Braverman, Ami; Meiran, Nachshon

2015-03-01

Studies have suggested that conflict control can modulate conflict effects in response to differing levels of conflict context. The current study probed, in two experiments of proportion congruence, the relevance of both task conflict (between a currently relevant task and irrelevant task alternatives) and response conflict (between a currently relevant response and irrelevant response alternatives) to conflict control. In Experiment 1, proportion congruence between blocks was manipulated and in Experiment 2, proportion congruence was manipulated between items. The response conflict effect was smaller when proportion of incongruence was high, regardless if task conflict or response conflict proportions were manipulated. These findings suggest that both task conflict and response conflict are monitored but that only response conflict is being influenced by this monitoring process. Theoretical implications are discussed.

Using Large-Scale Roughness Elements to Control Sand and Dust Flux at the Keeler Dunes, Keeler, CA

NASA Astrophysics Data System (ADS)

Gillies, John; McCarley-Holder, Grace

2014-05-01

Controlling dust emission from areas that subsequently degrade air quality and threaten human and animal health and reduce the quality of life for people residing in proximity to such sources is necessary, but also challenging. Recent research has indicated that arrays of large roughness elements (height >0.3 m) can be used effectively to modulate sand transport and the associated dust emissions. Prediction of the rate of sand flux reduction as a function of downwind distance upon entering an array of roughness elements, and the equilibrium flux reduction in the interior of the array is possible using the known geometric properties of the roughness elements, their number, and published relationships. Air quality in the town of Keeler, CA (36 deg 29' 17.92" N, 117 deg 52' 24.62" W) is degraded by levels of particulate matter <10 µm aerodynamic diameter (PM10) during periods of elevated wind speeds due to sand transport and dust emissions in the nearby Keeler Dunes. A demonstration project was designed to evaluate the effectiveness of an array of roughness elements composed of solid elements and managed vegetation to meet sand and dust flux reduction criteria. This project has two major goals: 1) to demonstrate that solid roughness elements placed on areas of the Keeler Dunes immediately arrest sand movement to specified levels (target of 85% reduction), and 2) to assess whether native plant species, planted in the sheltered area of the solid roughness elements can effectively thrive and subsequently replace the solid roughness to achieve the desired sand flux reduction control efficiency. This poster describes the results related mostly to objective one, as considerable time has to pass before sufficient data will be obtained to evaluate the success of the planted and managed vegetation to achieve a control level provided by the solid element roughness array.

Element uptake and physiological responses of Lactuca sativa upon co-exposures to tourmaline and dissolved humic acids.

PubMed

Jia, Weili; Wang, Cuiping; Ma, Chuanxin; Wang, Jicheng; Sun, Hongwen

2018-06-01

Element migration and physiological response in Lactuca sativa upon co-exposure to tourmaline (T) and dissolved humic acids (DHAs) were investigated. Different fractions of DHA 1 and DHA 4 and three different doses of T were introduced into Hoagland's solution. The results indicated that T enhanced the contents of elements such as N and C, Si and Al in the roots and shoots. The correlation between TF values of Si and Al (R 2  = 0.7387) was higher than that of Si and Mn (R 2  = 0.4961) without the presence of DHAs. However, both DHA 1 and DHA 4 increased the correlation between Si and Mn, but decreased the one between Si and Al. CAT activities in T treatments were positively correlated to the contents of N and Al in the shoots, whose R 2 was 0.9994 and 0.9897, respectively. In the co-exposure of DHAs and tourmaline, DHA 4 exhibited more impacts on element uptake, CAT activities, as well as ABA contents in comparison with the presence of DHA 1 , regardless of the T exposure doses. These results suggested that DHAs have effects on mineral element behaviors and physiological response in Lactuca sativa upon exposure to tourmaline for the first time, which had great use in guiding soil remediation.

Molecular cloning and preliminary function study of iron responsive element binding protein 1 gene from cypermethrin-resistant Culex pipiens pallens

PubMed Central

2011-01-01

Background Insecticide resistance jeopardizes the control of mosquito populations and mosquito-borne disease control, which creates a major public health concern. Two-dimensional electrophoresis identified one protein segment with high sequence homology to part of Aedes aegypti iron-responsive element binding protein (IRE-BP). Method RT-PCR and RACE (rapid amplification of cDNA end) were used to clone a cDNA encoding full length IRE-BP 1. Real-time quantitative RT-PCR was used to evaluate the transcriptional level changes in the Cr-IRE strain Aedes aegypti compared to the susceptible strain of Cx. pipiens pallens. The expression profile of the gene was established in the mosquito life cycle. Methyl tritiated thymidine (3H-TdR) was used to observe the cypermethrin resistance changes in C6/36 cells containing the stably transfected IRE-BP 1 gene of Cx. pipiens pallens. Results The complete sequence of iron responsive element binding protein 1 (IRE-BP 1) has been cloned from the cypermethrin-resistant strain of Culex pipiens pallens (Cr-IRE strain). Quantitative RT-PCR analysis indicated that the IRE-BP 1 transcription level was 6.7 times higher in the Cr-IRE strain than in the susceptible strain of 4th instar larvae. The IRE-BP 1 expression was also found to be consistently higher throughout the life cycle of the Cr-IRE strain. A protein of predicted size 109.4 kDa has been detected by Western blotting in IRE-BP 1-transfected mosquito C6/36 cells. These IRE-BP 1-transfected cells also showed enhanced cypermethrin resistance compared to null-transfected or plasmid vector-transfected cells as determined by 3H-TdR incorporation. Conclusion IRE-BP 1 is expressed at higher levels in the Cr-IRE strain, and may confer some insecticide resistance in Cx. pipiens pallens. PMID:22075242

Plant growth, nutrients and potentially toxic elements in leaves of yerba mate clones in response to phosphorus in acid soils.

PubMed

Barbosa, Julierme Z; Motta, Antonio C V; Consalter, Rangel; Poggere, Giovana C; Santin, Delmar; Wendling, Ivar

2018-01-01

Native to subtropical region of South America, yerba mate is responsive to P under some conditions, but the degree of influence of genetic and soil on the growth and composition of the leaf is unknown. The aim of study was to evaluate plant growth, nutrients and potentially toxic elements in leaves of yerba mate clones in response to P application in acid soils. In greenhouse condition, two yerba mate clone seedlings were grown (210 days) in pots, each clone in a completely randomized design in factorial scheme (with and without P; four acid soils). The elemental composition of leaves and the growth of plants were determined. Phosphorus promoted plant growth, but this was not accompanied by increased P in leaf tissue in all conditions tested. The P effect on the elemental composition varied: decrease/null (N, K, Mg, Mn, Cu, Ni, B, Mo, Al, Cd); increase/null (C/N, C, Ca, Fe, V); increase/decrease/null (Zn, Ba, Pb) and; null (Cr). The soils affect the elemental composition of the leaves, especially Mn, with accumulation greater than 1000 mg kg-1. The Ba, Pb, Al and Zn in the leaves varied among clones. Yerba mate response to P was affected by edaphic and plant factors.

Integration of growth factor signals at the c-fos serum response element.

PubMed

Price, M A; Hill, C; Treisman, R

1996-04-29

A transcription factor ternary complex composed of serum response factor (SRF) and a second factor, ternary complex factor (TCF), mediates the response of the c-fos Serum Response Element to growth factors and mitogens. In NIH3T3 fibroblasts, TCF binding is required for transcriptional activation by the SRE in response to activation of the Ras-Raf-ERK pathway. We compared the properties of three members of the TCF family, Elk-1, SAP-1 and SAP-2 (ERP/NET). Although all the proteins contain sequences required for ternary complex formation with SRF, only Elk-1 and SAP-1 appear to interact with the c-fos SRE efficiently in vivo. Each TCF contains a C-terminal activation domain capable of transcriptional activation in response to activation of the Ras-Raf-ERK pathway, and this is dependent on the integrity of S/T-P motifs conserved between all the TCF family members. In contrast, activation of the SRE by whole serum and the mitogenic phospholipid LPA requires SRF binding alone. Constitutively activated members of the Rho subfamily of Ras-like GTPases are also capable of inducing activation of the SRE in the absence of TCF; unlike activated Ras itself, these proteins do not activate the TCFs in NIH3T3 cells. At the SRE, SRF- and TCF-linked signalling pathways act synergistically to potentiate transcription.

Serum trace elements in obese Egyptian children: a case–control study

PubMed Central

2014-01-01

Background To date, only a few studies on child obesity concerned Trace Elements (TE). TE is involved in the pathogenesis of obesity and obesity related diseases. We tried to assess trace elements status [zinc (Zn), copper (Cu), selenium (Se), iron (Fe), and chromium (Cr)] in obese Egyptian children and their relationships with serum leptin and metabolic risk factors of obesity. Methods This was a case–control study performed with 80 obese children (BMI ≥ 95thcentile for age and gender) and 80 healthy non-obese children with comparable age and gender as the control group. For all subjects, serum Zn, Cu, Se, Fe, ferritin and Cr as well as biochemical parameters including lipid profile, serum glucose and homeostasis model assessment of insulin resistance (HOMA-IR) were assessed. Levels of serum leptin were measured by (enzyme-linked immunosorbent assay [ELISA] method), and serum insulin was measured by an electrochemiluminesce immunoassay. Results Compared to the control group, serum Zn, Se, and Fe levels were significantly lower (all P < 0.01) and serum Cu level was significantly higher (P < 0.01) in the obese children. Meanwhile, no significant differences were observed in serum ferritin or Cr levels (P > 0.05). A significant negative correlation was found between serum leptin and zinc levels in the obese children (r = −0.746; P < 0.01). Further, serum Zn showed significant negative correlations with total cholesterol TC levels (P < 0.05) and were positively correlated with high density lipoprotein- cholesterol HDL-C levels (P < 0.01) in the obese children. In addition, serum Se levels showed significant positive correlations with HOMA-IR values in the obese children (P < 0.01). Conclusion The obese children may be at a greater risk of developing imbalance (mainly deficiency) of trace elements which may be playing an important role in the pathogenesis of obesity and related metabolic risk factors. PMID:24555483

42 CFR 431.830 - Basic elements of the Medicaid quality control (MQC) claims processing assessment system.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Basic elements of the Medicaid quality control (MQC... & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL ASSISTANCE PROGRAMS STATE ORGANIZATION AND GENERAL ADMINISTRATION Quality Control Medicaid Quality Control (mqc) Claims Processing...

Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements.

PubMed

Keller, H; Givel, F; Perroud, M; Wahli, W

1995-07-01

Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are nuclear hormone receptors that are activated by fatty acids and 9-cis-retinoic acid, respectively. PPARs and RXRs form heterodimers that activate transcription by binding to PPAR response elements (PPREs) in the promoter of target genes. The PPREs described thus far consist of a direct tandem repeat of the AGGTCA core element with one intervening nucleotide. We show here that the vitellogenin A2 estrogen response element (ERE) can also function as a PPRE and is bound by a PPAR/RXR heterodimer. Although this heterodimer can bind to several other ERE-related palindromic response elements containing AGGTCA half-sites, only the ERE is able to confer transactivation of test reporter plasmids, when the ERE is placed either close to or at a distance from the transcription initiation site. Examination of natural ERE-containing promoters, including the pS2, very-low-density apolipoprotein II and vitellogenin A2 genes, revealed considerable differences in the binding of PPAR/RXR heterodimers to these EREs. In their natural promoter context, these EREs did not allow transcriptional activation by PPARs/RXRs. Analysis of this lack of stimulation of the vitellogenin A2 promoter demonstrated that PPARs/RXRs bind to the ERE but cannot transactivate due to a nonpermissive promoter structure. As a consequence, PPARs/RXRs inhibit transactivation by the estrogen receptor through competition for ERE binding. This is the first example of signaling cross-talk between PPAR/RXR and estrogen receptor.

Rare earth elements in human and animal health: State of art and research priorities.

PubMed

Pagano, Giovanni; Aliberti, Francesco; Guida, Marco; Oral, Rahime; Siciliano, Antonietta; Trifuoggi, Marco; Tommasi, Franca

2015-10-01

A number of applications have been developed using rare earth elements (REE), implying several human exposures and raising unsolved questions as to REE-associated health effects. A MedLine survey was retrieved from early reports (1980s) up to June 2015, focused on human and animal exposures to REE. Literature from animal models was selected focusing on REE-associated health effects. Some REE occupational exposures, in jobs such as glass polishers, photoengravers and movie projectionists showed a few case reports on health effects affecting the respiratory system. No case-control or cohort studies of occupational REE exposures were retrieved. Environmental exposures have been biomonitored in populations residing in REE mining areas, showing REE accumulation. The case for a iatrogenic REE exposure was raised by the use of gadolinium-based contrast agents for nuclear magnetic resonance. Animal toxicity studies have shown REE toxicity, affecting a number of endpoints in liver, lungs and blood. On the other hand, the use of REE as feed additives in livestock is referred as a safe and promising device in zootechnical activities, possibly suggesting a hormetic effect both known for REE and for other xenobiotics. Thus, investigations on long-term exposures and observations are warranted. The state of art provides a limited definition of the health effects in occupationally or environmentally REE-exposed human populations. Research priorities should be addressed to case-control or cohort studies of REE-exposed humans and to life-long animal experiments. Copyright © 2015 Elsevier Inc. All rights reserved.

Dynamic Responses and Vibration Control of the Transmission Tower-Line System: A State-of-the-Art Review

PubMed Central

Chen, Bo; Guo, Wei-hua; Li, Peng-yun; Xie, Wen-ping

2014-01-01

This paper presented an overview on the dynamic analysis and control of the transmission tower-line system in the past forty years. The challenges and future developing trends in the dynamic analysis and mitigation of the transmission tower-line system under dynamic excitations are also put forward. It also reviews the analytical models and approaches of the transmission tower, transmission lines, and transmission tower-line systems, respectively, which contain the theoretical model, finite element (FE) model and the equivalent model; shows the advances in wind responses of the transmission tower-line system, which contains the dynamic effects under common wind loading, tornado, downburst, and typhoon; and discusses the dynamic responses under earthquake and ice loads, respectively. The vibration control of the transmission tower-line system is also reviewed, which includes the magnetorheological dampers, friction dampers, tuned mass dampers, and pounding tuned mass dampers. PMID:25105161

Controlled burn and immediate mobilization of potentially toxic elements in soil, from a legacy mine site in Central Victoria, Australia.

PubMed

Abraham, Joji; Dowling, Kim; Florentine, Singarayer

2018-03-01

Conducting controlled burns in fire prone areas is an efficient and economic method for forest management, and provides relief from the incidence of high severity wild fires and the consequent damage to human property and ecosystems. However, similar to wild fires, controlled burns also affect many of the physical and biogeochemical properties of the forest soil and may facilitate remobilization of potentially toxic elements (PTEs) sequestered in vegetation and soil organic matter. The objective of the current study is to investigate the mobilization of PTEs, in Central Victorian forest soils in Australia after a controlled burn. Surface soil samples were collected two days before and after the controlled burn to determine the concentration of PTEs and to examine the physicochemical properties. Results show that As, Cd, Mn, Ni and Zn concentrations increased 1.1, 1.6, 1.7, 1.1 and 1.9 times respectively in the post-burn environment, whereas the concentrations of Hg, Cr and Pb decreased to 0.7, 0.9 and 0.9 times respectively, highlighting considerable PTE mobility during and after a controlled burn. Whilst these results do not identify very strong correlations between physicochemical properties of soil and PTEs in the pre- and post-burn environments, PTEs themselves demonstrated very strong and significant correlations. The mobilization of As, Hg and other toxic elements raise potential health concerns as the number of controlled burns are projected to increase in response to climate change. Due to this increased level of PTE release and remobilization, the use of any kinds of controlled burn must be carefully considered before being used as a forest management strategy in mining-affected landscapes which include areas with high PTE concentrations. Copyright © 2017 Elsevier B.V. All rights reserved.

Progesterone Response Element Variation in the OXTR Promoter Region and Paternal Care in New World Monkeys.

PubMed

Vargas-Pinilla, Pedro; Babb, Paul; Nunes, Leandro; Paré, Pâmela; Rosa, Gabrielle; Felkl, Aline; Longo, Dânae; Salzano, Francisco M; Paixão-Côrtes, Vanessa R; Gonçalves, Gislene Lopes; Bortolini, Maria Cátira

2017-01-01

Paternal care is a complex social behavior common in primate species with socially monogamous mating systems and twin births. Evolutionary causes and consequences of such behavior are not well understood, nor are their neuroendocrine and genetic bases. However, the neuropeptide oxytocin (OXT) and its receptor (OXTR) are associated with parental care in mammalian lineages. Here we investigated the interspecific variation in the number of progesterone response elements (PREs) in the OXTR promoter region of 32 primate species, correlating genetic data with behavior, social systems, and ecological/life-history parameters, while controlling for phylogeny. We verified that PREs are only present in New World monkeys and that PRE number is significantly correlated with the presence of paternal care in this branch. We suggest that PRE number could be an essential part of the genetic repertoire that allowed the emergence of taxon-specific complex social behaviors, such as paternal care in marmosets and tamarins.

Identification of transcripts involved in digestion, detoxification and immune response from transcriptome of Empoasca vitis (Hemiptera: Cicadellidae) nymphs.

PubMed

Shao, En-Si; Lin, Gui-Fang; Liu, Sijun; Ma, Xiao-Li; Chen, Ming-Feng; Lin, Li; Wu, Song-Qing; Sha, Li; Liu, Zhao-Xia; Hu, Xiao-Hua; Guan, Xiong; Zhang, Ling-Ling

2017-01-01

Tea production has been significantly impacted by the false-eye leafhopper, Empoasca vitis (Göthe), around Asia. To identify the key genes which are responsible for nutrition absorption, xenobiotic metabolism and immune response, the transcriptome of either alimentary tracts or bodies minus alimentary tract of E. vitis was sequenced and analyzed. Over 31 million reads were obtained from Illumina sequencing. De novo sequence assembly resulted in 52,182 unigenes with a mean size of 848nt. The assembled unigenes were then annotated using various databases. Transcripts of at least 566 digestion-, 224 detoxification-, and 288 immune-related putative genes in E. vitis were identified. In addition, relative expression of highly abundant transcripts was verified through quantitative real-time PCR. Results from this investigation provide genomic information about E. vitis, which will be helpful in further study of E. vitis biology and in the development of novel strategies to control this devastating pest. Copyright © 2016 Elsevier Inc. All rights reserved.

High User Control in Game Design Elements Increases Compliance and In-game Performance in a Memory Training Game.

PubMed

Nagle, Aniket; Riener, Robert; Wolf, Peter

2015-01-01

Computer games are increasingly being used for training cognitive functions like working memory and attention among the growing population of older adults. While cognitive training games often include elements like difficulty adaptation, rewards, and visual themes to make the games more enjoyable and effective, the effect of different degrees of afforded user control in manipulating these elements has not been systematically studied. To address this issue, two distinct implementations of the three aforementioned game elements were tested among healthy older adults (N = 21, 69.9 ± 6.4 years old) playing a game-like version of the n-back task on a tablet at home for 3 weeks. Two modes were considered, differentiated by the afforded degree of user control of the three elements: user control of difficulty vs. automatic difficulty adaptation, difficulty-dependent rewards vs. automatic feedback messages, and user choice of visual theme vs. no choice. The two modes ("USER-CONTROL" and "AUTO") were compared for frequency of play, duration of play, and in-game performance. Participants were free to play the game whenever and for however long they wished. Participants in USER-CONTROL exhibited significantly higher frequency of playing, total play duration, and in-game performance than participants in AUTO. The results of the present study demonstrate the efficacy of providing user control in the three game elements, while validating a home-based study design in which participants were not bound by any training regimen, and could play the game whenever they wished. The results have implications for designing cognitive training games that elicit higher compliance and better in-game performance, with an emphasis on home-based training.

Rare earth elements in human and animal health: State of art and research priorities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pagano, Giovanni, E-mail: gbpagano@tin.it; Aliberti, Francesco; Guida, Marco

Background: A number of applications have been developed using rare earth elements (REE), implying several human exposures and raising unsolved questions as to REE-associated health effects. Methods: A MedLine survey was retrieved from early reports (1980s) up to June 2015, focused on human and animal exposures to REE. Literature from animal models was selected focusing on REE-associated health effects. Results: Some REE occupational exposures, in jobs such as glass polishers, photoengravers and movie projectionists showed a few case reports on health effects affecting the respiratory system. No case-control or cohort studies of occupational REE exposures were retrieved. Environmental exposures havemore » been biomonitored in populations residing in REE mining areas, showing REE accumulation. The case for a iatrogenic REE exposure was raised by the use of gadolinium-based contrast agents for nuclear magnetic resonance. Animal toxicity studies have shown REE toxicity, affecting a number of endpoints in liver, lungs and blood. On the other hand, the use of REE as feed additives in livestock is referred as a safe and promising device in zootechnical activities, possibly suggesting a hormetic effect both known for REE and for other xenobiotics. Thus, investigations on long-term exposures and observations are warranted. Conclusion: The state of art provides a limited definition of the health effects in occupationally or environmentally REE-exposed human populations. Research priorities should be addressed to case-control or cohort studies of REE-exposed humans and to life-long animal experiments. - Highlights: • An extensive number of activities have been developed utilizing rare earth elements (REE). • The literature of REE-associated health effects in humans, and on animal studies is reviewed. • The main literature gaps are discussed, in epidemiological and in animal studies. • Prospects studies are suggested, aimed at evaluating long-term effects of REE

Two-Dimensional Finite Element Ablative Thermal Response Analysis of an Arcjet Stagnation Test

NASA Technical Reports Server (NTRS)

Dec, John A.; Laub, Bernard; Braun, Robert D.

2011-01-01

The finite element ablation and thermal response (FEAtR, hence forth called FEAR) design and analysis program simulates the one, two, or three-dimensional ablation, internal heat conduction, thermal decomposition, and pyrolysis gas flow of thermal protection system materials. As part of a code validation study, two-dimensional axisymmetric results from FEAR are compared to thermal response data obtained from an arc-jet stagnation test in this paper. The results from FEAR are also compared to the two-dimensional axisymmetric computations from the two-dimensional implicit thermal response and ablation program under the same arcjet conditions. The ablating material being used in this arcjet test is phenolic impregnated carbon ablator with an LI-2200 insulator as backup material. The test is performed at the NASA, Ames Research Center Interaction Heating Facility. Spatially distributed computational fluid dynamics solutions for the flow field around the test article are used for the surface boundary conditions.

Tuning a fuzzy controller using quadratic response surfaces

NASA Technical Reports Server (NTRS)

Schott, Brian; Whalen, Thomas

1992-01-01

Response surface methodology, an alternative method to traditional tuning of a fuzzy controller, is described. An example based on a simulated inverted pendulum 'plant' shows that with (only) 15 trial runs, the controller can be calibrated using a quadratic form to approximate the response surface.

A hybrid symbolic/finite-element algorithm for solving nonlinear optimal control problems

NASA Technical Reports Server (NTRS)

Bless, Robert R.; Hodges, Dewey H.

1991-01-01

The general code described is capable of solving difficult nonlinear optimal control problems by using finite elements and a symbolic manipulator. Quick and accurate solutions are obtained with a minimum for user interaction. Since no user programming is required for most problems, there are tremendous savings to be gained in terms of time and money.

A versatile transfection assay system to evaluate the biological effects of diverse industrial chemicals.

PubMed

Koizumi, Shinji; Ohno, Shotaro; Otsuka, Fuminori

2012-01-01

Gene expression processes are now recognized as important targets of the toxic effects exerted by industrial chemicals. The transient transfection assay is a powerful tool to evaluate such effects. Thus, we developed a versatile assay system by constructing a basic reporter plasmid in which the regulatory DNA sequence to be studied can easily be substituted. To verify the performance of this system, reporter plasmids carrying any of the three distinct regulatory sequences, estrogen responsive element (ERE), glucocorticoid responsive element (GRE) and xenobiotic responsive element (XRE) were constructed. After transfection of human cells, these plasmids successfully expressed the relevant reporter genes in response to specific inducers, β-estradiol, dexamethasone and 3-methylcholanthrene, respectively. Several industrial chemicals were assayed using these reporter plasmids, and the ability of p-dimethylaminoazobenzene to elevate GRE- and XRE-mediated transcription was detected. α-Naphthylamine and o-tolidine were also observed to increase the XRE-mediated response. The transfection assay system established here will be useful to evaluate the effects of a wide variety of industrial chemicals.

Comparison of the SYNERGY with the PROMUS (XIENCE V) and bare metal and polymer-only Element control stents in porcine coronary arteries.

PubMed

Wilson, Gregory J; Huibregtse, Barbara A; Pennington, Douglas E; Dawkins, Keith D

2012-06-20

This study evaluated vascular compatibility of the novel platinum chromium alloy Element stent platform delivering abluminal everolimus from a poly-lactide-co-glycolide bioabsorbable polymer (SYNERGY stent), currently undergoing clinical trial, compared with the PROMUS (XIENCE V) and bare metal and polymer-only Element stents. Stents (n=161) were implanted one per coronary artery in 72 swine at a stent-to-artery ratio of 1.1:1. Similar numbers of each device group were explanted at each of 30, 90, 180, and 360 days (except no PROMUS (XIENCE V) stent at 360 days) for pathological analysis. There was no stent thrombosis, myocardial infarction, or strut fractures in any group. Vascular response was similar between the SYNERGY and PROMUS (XIENCE V) stents, with no thrombi and complete endothelialisation on both scanning electron microscopy and histology at 30, 90 and 180 days. There were no significant differences for the morphologic parameters of luminal thrombus, endothelial cell coverage, strut tissue coverage, inflammation, internal elastic lamina (IEL) disruption, external elastic lamina (EEL) disruption and medial smooth muscle cell loss across device groups or between time points, but there was mild but greater (p<0.0001) para-strut fibrin at 30 days for both drug-eluting stents (DES) compared with the bare and polymer-only controls; this difference completely dissipated by 90 days. Inflammation was predominantly minimal to mild for all device types. No morphometric parameters, including intimal thickness, stent profile-based area stenosis, and EEL area were significantly different when comparing the SYNERGY stent with the bare metal Element and polymer-only Element control stents at 90, 180 and 360 days. In this non-injured porcine coronary artery model, the bioabsorbable polymer SYNERGY stent demonstrated vascular compatibility equivalent to the PROMUS (XIENCE V) stent and to the bare metal and polymer-only Element stents.

Effects of rare earth elements and REE-binding proteins on physiological responses in plants.

PubMed

Liu, Dongwu; Wang, Xue; Chen, Zhiwei

2012-02-01

Rare earth elements (REEs), which include 17 elements in the periodic table, share chemical properties related to a similar external electronic configuration. REEs enriched fertilizers have been used in China since the 1980s. REEs could enter the cell and cell organelles, influence plant growth, and mainly be bound with the biological macromolecules. REE-binding proteins have been found in some plants. In addition, the chlorophyll activities and photosynthetic rate can be regulated by REEs. REEs could promote the protective function of cell membrane and enhance the plant resistance capability to stress produced by environmental factors, and affect the plant physiological mechanism by regulating the Ca²⁺ level in the plant cells. The focus of present review is to describe how REEs and REE-binding proteins participate in the physiological responses in plants.

Does aphid salivation affect phloem sieve element occlusion in vivo?

PubMed

Medina-Ortega, Karla J; Walker, G P

2013-12-01

To protect against loss of photo-assimilate-rich phloem sap, plants have evolved several mechanisms to plug phloem sieve tubes in response to damage. In many Fabaceae, each sieve element contains a discrete proteinaceous body called a forisome, which, in response to damage, rapidly transforms from a condensed configuration that does not impede the flow of sap to a dispersed configuration that plugs the sieve element. Aphids and other specialized phloem sap feeders can ingest phloem sap from a single sieve element for hours or days, and to do this, they must be able to suppress or reverse phloem plugging. A recent study provided in vitro evidence that aphid saliva can reverse forisome plugs. The present study tested this hypothesis in vivo by inducing forisome plugs which triggered aphids to switch behaviour from phloem sap ingestion to salivation into the sieve element. After salivating into the sieve element for various periods of time, the aphids were instantaneously cryofixed (freeze fixed) in situ on their leaf. The state of the forisome was then determined in the penetrated sieve element and in nearby non-penetrated sieve elements which served as controls for sieve elements not subjected to direct aphid salivation. Forisomes were almost always in close contact with the stylet tips and thus came into direct contact with the saliva. Nonetheless, forisome plugs in the penetrated sieve element did not revert back to a non-plugging state any faster than those in neighbouring sieve elements that were not subjected to direct aphid salivation.

Does aphid salivation affect phloem sieve element occlusion in vivo?

PubMed Central