Science.gov

Sample records for additive gene action

  1. Overexpression of the ped/pea-15 gene causes diabetes by impairing glucose-stimulated insulin secretion in addition to insulin action.

    PubMed

    Vigliotta, Giovanni; Miele, Claudia; Santopietro, Stefania; Portella, Giuseppe; Perfetti, Anna; Maitan, Maria Alessandra; Cassese, Angela; Oriente, Francesco; Trencia, Alessandra; Fiory, Francesca; Romano, Chiara; Tiveron, Cecilia; Tatangelo, Laura; Troncone, Giancarlo; Formisano, Pietro; Beguinot, Francesco

    2004-06-01

    Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. In the present work, we show that transgenic mice ubiquitously overexpressing ped/pea-15 exhibited mildly elevated random-fed blood glucose levels and decreased glucose tolerance. Treatment with a 60% fat diet led ped/pea-15 transgenic mice to develop diabetes. Consistent with insulin resistance in these mice, insulin administration reduced glucose levels by only 35% after 45 min, compared to 70% in control mice. In vivo, insulin-stimulated glucose uptake was decreased by almost 50% in fat and muscle tissues of the ped/pea-15 transgenic mice, accompanied by protein kinase Calpha activation and block of insulin induction of protein kinase Czeta. These changes persisted in isolated adipocytes from the transgenic mice and were rescued by the protein kinase C inhibitor bisindolylmaleimide. In addition to insulin resistance, ped/pea-15 transgenic mice showed a 70% reduction in insulin response to glucose loading. Stable overexpression of ped/pea-15 in the glucose-responsive MIN6 beta-cell line also caused protein kinase Calpha activation and a marked decline in glucose-stimulated insulin secretion. Antisense block of endogenous ped/pea-15 increased glucose sensitivity by 2.5-fold in these cells. Thus, in vivo, overexpression of ped/pea-15 may lead to diabetes by impairing insulin secretion in addition to insulin action.

  2. 45 CFR 33.16 - Additional administrative collection action.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Additional administrative collection action. 33.16 Section 33.16 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION SALARY OFFSET § 33.16 Additional administrative collection action. Nothing contained in this part is intended...

  3. 5 CFR 179.218 - Additional administrative collection action.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Additional administrative collection action. 179.218 Section 179.218 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS CLAIMS COLLECTION STANDARDS Salary Offset § 179.218 Additional administrative collection...

  4. Additive Routes to Action Learning: Layering Experience Shapes Engagement of the Action Observation Network

    PubMed Central

    Kirsch, Louise P.; Cross, Emily S.

    2015-01-01

    The way in which we perceive others in action is biased by one's prior experience with an observed action. For example, we can have auditory, visual, or motor experience with actions we observe others perform. How action experience via 1, 2, or all 3 of these modalities shapes action perception remains unclear. Here, we combine pre- and post-training functional magnetic resonance imaging measures with a dance training manipulation to address how building experience (from auditory to audiovisual to audiovisual plus motor) with a complex action shapes subsequent action perception. Results indicate that layering experience across these 3 modalities activates a number of sensorimotor cortical regions associated with the action observation network (AON) in such a way that the more modalities through which one experiences an action, the greater the response is within these AON regions during action perception. Moreover, a correlation between left premotor activity and participants' scores for reproducing an action suggests that the better an observer can perform an observed action, the stronger the neural response is. The findings suggest that the number of modalities through which an observer experiences an action impacts AON activity additively, and that premotor cortical activity might serve as an index of embodiment during action observation. PMID:26209850

  5. Additive Routes to Action Learning: Layering Experience Shapes Engagement of the Action Observation Network.

    PubMed

    Kirsch, Louise P; Cross, Emily S

    2015-12-01

    The way in which we perceive others in action is biased by one's prior experience with an observed action. For example, we can have auditory, visual, or motor experience with actions we observe others perform. How action experience via 1, 2, or all 3 of these modalities shapes action perception remains unclear. Here, we combine pre- and post-training functional magnetic resonance imaging measures with a dance training manipulation to address how building experience (from auditory to audiovisual to audiovisual plus motor) with a complex action shapes subsequent action perception. Results indicate that layering experience across these 3 modalities activates a number of sensorimotor cortical regions associated with the action observation network (AON) in such a way that the more modalities through which one experiences an action, the greater the response is within these AON regions during action perception. Moreover, a correlation between left premotor activity and participants' scores for reproducing an action suggests that the better an observer can perform an observed action, the stronger the neural response is. The findings suggest that the number of modalities through which an observer experiences an action impacts AON activity additively, and that premotor cortical activity might serve as an index of embodiment during action observation.

  6. 12 CFR 1238.8 - Additional implementing action.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 12 Banks and Banking 10 2014-01-01 2014-01-01 false Additional implementing action. 1238.8 Section 1238.8 Banks and Banking FEDERAL HOUSING FINANCE AGENCY ENTITY REGULATIONS STRESS TESTING OF REGULATED..., require any regulated entity not subject to this part to conduct stress testing hereunder; and from...

  7. Osmotic regulation of gene action.

    PubMed Central

    Douzou, P

    1994-01-01

    Most reactions involved in gene translation systems are ionic-dependent and may be explained in electrostatic terms. However, a number of observations of equilibria and rate processes making up the overall reactions clearly indicate that there is still an enormous gap between the rough picture of the mechanism of ionic regulation and the detailed behavior of reactions at the molecular level that hold the key to specific mechanisms. The present paper deals with possible osmotic contributions arising from the gel state of gene systems that are complementary to, and interdependent of, electrostatic contributions. This treatment, although still oversimplified, explains many previous observations by relating them to a general osmotic mechanism and suggests experimental approaches to studying the mechanisms of gene regulation in organelle-free and intact systems. PMID:8127862

  8. 41 CFR 60-2.17 - Additional required elements of affirmative action programs.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... elements of affirmative action programs. 60-2.17 Section 60-2.17 Public Contracts and Property Management... Action Programs § 60-2.17 Additional required elements of affirmative action programs. In addition to the elements required by § 60-2.10 through § 60-2.16, an acceptable affirmative action program must include...

  9. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  10. Replacing and Additive Horizontal Gene Transfer in Streptococcus

    PubMed Central

    Choi, Sang Chul; Rasmussen, Matthew D.; Hubisz, Melissa J.; Gronau, Ilan; Stanhope, Michael J.; Siepel, Adam

    2012-01-01

    The prominent role of Horizontal Gene Transfer (HGT) in the evolution of bacteria is now well documented, but few studies have differentiated between evolutionary events that predominantly cause genes in one lineage to be replaced by homologs from another lineage (“replacing HGT”) and events that result in the addition of substantial new genomic material (“additive HGT”). Here in, we make use of the distinct phylogenetic signatures of replacing and additive HGTs in a genome-wide study of the important human pathogen Streptococcus pyogenes (SPY) and its close relatives S. dysgalactiae subspecies equisimilis (SDE) and S. dysgalactiae subspecies dysgalactiae (SDD). Using recently developed statistical models and computational methods, we find evidence for abundant gene flow of both kinds within each of the SPY and SDE clades and of reduced levels of exchange between SPY and SDD. In addition, our analysis strongly supports a pronounced asymmetry in SPY–SDE gene flow, favoring the SPY-to-SDE direction. This finding is of particular interest in light of the recent increase in virulence of pathogenic SDE. We find much stronger evidence for SPY–SDE gene flow among replacing than among additive transfers, suggesting a primary influence from homologous recombination between co-occurring SPY and SDE cells in human hosts. Putative virulence genes are correlated with transfer events, but this correlation is found to be driven by additive, not replacing, HGTs. The genes affected by additive HGTs are enriched for functions having to do with transposition, recombination, and DNA integration, consistent with previous findings, whereas replacing HGTs seen to influence a more diverse set of genes. Additive transfers are also found to be associated with evidence of positive selection. These findings shed new light on the manner in which HGT has shaped pathogenic bacterial genomes. PMID:22617954

  11. Additional Actions Can Improve Naval Air Systems Command’s Use of Undefinitized Contractual Actions

    DTIC Science & Technology

    2011-06-08

    Naval Air Systems Command NTE Not-to-Exceed UCA Undefinitized Contractual Action U.S.C. United States Code INSPECTOR GENERAL DEPARTMENT...States Code . We reviewed 52 UCAs with a total not-to-exceed value of about $1.6 billion awarded by the Naval Air Systems Command (NAVAIR) from FY...2004 through FY 2009 to determine whether NAVAIR personnel complied with the restrictions of the United States Code and whether they appropriately

  12. 41 CFR 60-2.17 - Additional required elements of affirmative action programs.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 41 Public Contracts and Property Management 1 2014-07-01 2014-07-01 false Additional required elements of affirmative action programs. 60-2.17 Section 60-2.17 Public Contracts and Property Management... EMPLOYMENT OPPORTUNITY, DEPARTMENT OF LABOR 2-AFFIRMATIVE ACTION PROGRAMS Purpose and Contents of...

  13. 41 CFR 60-2.17 - Additional required elements of affirmative action programs.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 41 Public Contracts and Property Management 1 2012-07-01 2009-07-01 true Additional required elements of affirmative action programs. 60-2.17 Section 60-2.17 Public Contracts and Property Management... EMPLOYMENT OPPORTUNITY, DEPARTMENT OF LABOR 2-AFFIRMATIVE ACTION PROGRAMS Purpose and Contents of...

  14. From gene action to reactive genomes

    PubMed Central

    Keller, Evelyn Fox

    2014-01-01

    Poised at a critical turning point in the history of genetics, recent work (e.g. in genomics, epigenetics, genomic plasticity) obliges us to critically reexamine many of our most basic concepts. For example, I argue that genomic research supports a radical transformation in our understanding of the genome – a shift from an earlier conception of that entity as an effectively static collection of active genes to that of a dynamic and reactive system dedicated to the context specific regulation of protein-coding sequences. PMID:24882822

  15. Antidepressant actions of the exercise-regulated gene VGF.

    PubMed

    Hunsberger, Joshua G; Newton, Samuel S; Bennett, Alicia H; Duman, Catharine H; Russell, David S; Salton, Stephen R; Duman, Ronald S

    2007-12-01

    Exercise has many health benefits, including antidepressant actions in depressed human subjects, but the mechanisms underlying these effects have not been elucidated. We used a custom microarray to identify a previously undescribed profile of exercise-regulated genes in the mouse hippocampus, a brain region implicated in mood and antidepressant response. Pathway analysis of the regulated genes shows that exercise upregulates a neurotrophic factor signaling cascade that has been implicated in the actions of antidepressants. One of the most highly regulated target genes of exercise and of the growth factor pathway is the gene encoding the VGF nerve growth factor, a peptide precursor previously shown to influence synaptic plasticity and metabolism. We show that administration of a synthetic VGF-derived peptide produces a robust antidepressant response in mice and, conversely, that mutation of VGF in mice produces the opposite effects. The results suggest a new role for VGF and identify VGF signaling as a potential therapeutic target for antidepressant drug development.

  16. Additive Functions in Boolean Models of Gene Regulatory Network Modules

    PubMed Central

    Darabos, Christian; Di Cunto, Ferdinando; Tomassini, Marco; Moore, Jason H.; Provero, Paolo; Giacobini, Mario

    2011-01-01

    Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome's evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in Boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a Boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred Boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity

  17. Additive functions in boolean models of gene regulatory network modules.

    PubMed

    Darabos, Christian; Di Cunto, Ferdinando; Tomassini, Marco; Moore, Jason H; Provero, Paolo; Giacobini, Mario

    2011-01-01

    Gene-on-gene regulations are key components of every living organism. Dynamical abstract models of genetic regulatory networks help explain the genome's evolvability and robustness. These properties can be attributed to the structural topology of the graph formed by genes, as vertices, and regulatory interactions, as edges. Moreover, the actual gene interaction of each gene is believed to play a key role in the stability of the structure. With advances in biology, some effort was deployed to develop update functions in boolean models that include recent knowledge. We combine real-life gene interaction networks with novel update functions in a boolean model. We use two sub-networks of biological organisms, the yeast cell-cycle and the mouse embryonic stem cell, as topological support for our system. On these structures, we substitute the original random update functions by a novel threshold-based dynamic function in which the promoting and repressing effect of each interaction is considered. We use a third real-life regulatory network, along with its inferred boolean update functions to validate the proposed update function. Results of this validation hint to increased biological plausibility of the threshold-based function. To investigate the dynamical behavior of this new model, we visualized the phase transition between order and chaos into the critical regime using Derrida plots. We complement the qualitative nature of Derrida plots with an alternative measure, the criticality distance, that also allows to discriminate between regimes in a quantitative way. Simulation on both real-life genetic regulatory networks show that there exists a set of parameters that allows the systems to operate in the critical region. This new model includes experimentally derived biological information and recent discoveries, which makes it potentially useful to guide experimental research. The update function confers additional realism to the model, while reducing the complexity

  18. 21 CFR 58.215 - Alternative or additional actions to disqualification.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 1 2014-04-01 2014-04-01 false Alternative or additional actions to disqualification. 58.215 Section 58.215 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Disqualification of...

  19. 21 CFR 58.215 - Alternative or additional actions to disqualification.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 1 2011-04-01 2011-04-01 false Alternative or additional actions to disqualification. 58.215 Section 58.215 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Disqualification of...

  20. 21 CFR 58.215 - Alternative or additional actions to disqualification.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 1 2013-04-01 2013-04-01 false Alternative or additional actions to disqualification. 58.215 Section 58.215 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Disqualification of...

  1. 21 CFR 58.215 - Alternative or additional actions to disqualification.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 1 2012-04-01 2012-04-01 false Alternative or additional actions to disqualification. 58.215 Section 58.215 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Disqualification of...

  2. 21 CFR 58.215 - Alternative or additional actions to disqualification.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 1 2010-04-01 2010-04-01 false Alternative or additional actions to disqualification. 58.215 Section 58.215 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES Disqualification of...

  3. 42 CFR 460.48 - Additional actions by CMS or the State.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 42 Public Health 4 2012-10-01 2012-10-01 false Additional actions by CMS or the State. 460.48... CMS or the State. After consultation with the State administering agency, if CMS determines that the PACE organization is not in substantial compliance with requirements in this part, CMS or the...

  4. 42 CFR 460.48 - Additional actions by CMS or the State.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 4 2010-10-01 2010-10-01 false Additional actions by CMS or the State. 460.48... CMS or the State. After consultation with the State administering agency, if CMS determines that the PACE organization is not in substantial compliance with requirements in this part, CMS or the...

  5. 42 CFR 460.48 - Additional actions by CMS or the State.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 42 Public Health 4 2013-10-01 2013-10-01 false Additional actions by CMS or the State. 460.48... CMS or the State. After consultation with the State administering agency, if CMS determines that the PACE organization is not in substantial compliance with requirements in this part, CMS or the...

  6. 42 CFR 460.48 - Additional actions by CMS or the State.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 4 2014-10-01 2014-10-01 false Additional actions by CMS or the State. 460.48... CMS or the State. After consultation with the State administering agency, if CMS determines that the PACE organization is not in substantial compliance with requirements in this part, CMS or the...

  7. 42 CFR 460.48 - Additional actions by CMS or the State.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 4 2011-10-01 2011-10-01 false Additional actions by CMS or the State. 460.48... CMS or the State. After consultation with the State administering agency, if CMS determines that the PACE organization is not in substantial compliance with requirements in this part, CMS or the...

  8. Explanation of non-additive effects in mixtures of similar mode of action chemicals.

    PubMed

    Kamo, Masashi; Yokomizo, Hiroyuki

    2015-09-01

    Many models have been developed to predict the combined effect of drugs and chemicals. Most models are classified into two additive models: independent action (IA) and concentration addition (CA). It is generally considered if the modes of action of chemicals are similar then the combined effect obeys CA; however, many empirical studies report nonlinear effects deviating from the predictions by CA. Such deviations are termed synergism and antagonism. Synergism, which leads to a stronger toxicity, requires more careful management, and hence it is important to understand how and which combinations of chemicals lead to synergism. In this paper, three types of chemical reactions are mathematically modeled and the cause of the nonlinear effects among chemicals with similar modes of action was investigated. Our results show that combined effects obey CA only when the modes of action are exactly the same. Contrary to existing knowledge, combined effects are generally nonlinear even if the modes of action of the chemicals are similar. Our results further show that the nonlinear effects vanish out when the chemical concentrations are low, suggesting that the current management procedure of assuming CA is rarely inappropriate because environmental concentrations of chemicals are generally low.

  9. Effect of Nitrogen Additives on Flame Retardant Action of Tributyl Phosphate: Phosphorus – Nitrogen Synergism

    SciTech Connect

    Gaan, Sabyasachi; Sun, Gang; Hutches, Katherine; Engelhard, Mark H.

    2008-01-01

    The effect of nitrogen additives like urea, guanidine carbonate and melamine formaldehyde on the flame retardant efficacy of tributyl phosphate (TBP) has been investigated. From the LOI tests on treated cotton it is clear that the nitrogen additives have synergistic action. Estimation of activation energy of decomposition of treated cotton indicated that nitrogen additives enhance the thermal stability during the burning process. SEM pictures of chars formed after LOI test showed the formation of protective polymeric coating on the surface. The surface of chars formed were evaluated using FTIR-ATR and XPS analysis which showed that the coating was composed of Phosphorus-Nitrogen-Oxygen containing species. Formation of this coating during the burning process could lead to the synergistic interaction of phosphorus and nitrogen. Based on the experimental data we have further proposed several reaction mechanisms which could contribute to synergistic action and formation of protective coating on the surface of char.

  10. Concentration Addition, Independent Action and Generalized Concentration Addition Models for Mixture Effect Prediction of Sex Hormone Synthesis In Vitro

    PubMed Central

    Hadrup, Niels; Taxvig, Camilla; Pedersen, Mikael; Nellemann, Christine; Hass, Ulla; Vinggaard, Anne Marie

    2013-01-01

    Humans are concomitantly exposed to numerous chemicals. An infinite number of combinations and doses thereof can be imagined. For toxicological risk assessment the mathematical prediction of mixture effects, using knowledge on single chemicals, is therefore desirable. We investigated pros and cons of the concentration addition (CA), independent action (IA) and generalized concentration addition (GCA) models. First we measured effects of single chemicals and mixtures thereof on steroid synthesis in H295R cells. Then single chemical data were applied to the models; predictions of mixture effects were calculated and compared to the experimental mixture data. Mixture 1 contained environmental chemicals adjusted in ratio according to human exposure levels. Mixture 2 was a potency adjusted mixture containing five pesticides. Prediction of testosterone effects coincided with the experimental Mixture 1 data. In contrast, antagonism was observed for effects of Mixture 2 on this hormone. The mixtures contained chemicals exerting only limited maximal effects. This hampered prediction by the CA and IA models, whereas the GCA model could be used to predict a full dose response curve. Regarding effects on progesterone and estradiol, some chemicals were having stimulatory effects whereas others had inhibitory effects. The three models were not applicable in this situation and no predictions could be performed. Finally, the expected contributions of single chemicals to the mixture effects were calculated. Prochloraz was the predominant but not sole driver of the mixtures, suggesting that one chemical alone was not responsible for the mixture effects. In conclusion, the GCA model seemed to be superior to the CA and IA models for the prediction of testosterone effects. A situation with chemicals exerting opposing effects, for which the models could not be applied, was identified. In addition, the data indicate that in non-potency adjusted mixtures the effects cannot always be

  11. Methods for detecting additional genes underlying Alzheimer disease

    SciTech Connect

    Locke, P.A.; Haines, J.L.; Ter-Minassian, M.

    1994-09-01

    Alzheimer`s disease (AD) is a complex inherited disorder with proven genetic heterogeneity. To date, genes on chromosome 21 (APP) and 14 (not yet identified) are associated with early-onset familial AD, while the APOE gene on chromosome 19 is associated with both late onset familial and sporadic AD and early onset sporadic AD. Although these genes likely account for the majority of AD, many familial cases cannot be traced to any of these genes. From a set of 127 late-onset multiplex families screened for APOE, 43 (34%) families have at least one affected individual with no APOE-4 allele, suggesting an alternative genetic etiology. Simulation studies indicated that additional loci could be identified through a genomic screen with a 10 cM sieve on a subset of 21 well documented, non-APOE-4 families. Given the uncertainties in the mode of inheritance, reliance on a single analytical method could result in a missed linkage. Therefore, we have developed a strategy of using multiple overlapping yet complementary methods to detect linkage. These include sib-pair analysis and affected-pedigree-member analysis, neither of which makes assumptions about mode of inheritance, and lod score analysis (using two predefined genetic models). In order for a marker to qualify for follow-up, it must fit at least two of three criteria. These are nominal P values of 0.05 or less for the non-parametric methods, and/or a lod score greater than 1.0. Adjacent markers each fulfilling a single criterion also warrant follow-up. To date, we have screened 61 markers on chromosomes 1, 2, 3, 18, 19, 21, and 22. One marker, D2S163, generated a lod score of 1.06 ({theta} = 0.15) and an APMT statistic of 3.68 (P < 0.001). This region is currently being investigated in more detail. Updated results of this region plus additional screening data will be presented.

  12. Defense Contractors: Additional Actions Needed to Facilitate the Use of DOD’s Inventory of Contracted Services

    DTIC Science & Technology

    2014-11-01

    DEFENSE CONTRACTORS Additional Actions Needed to Facilitate the Use of DOD’s Inventory of Contracted Services...COVERED 00-00-2014 to 00-00-2014 4. TITLE AND SUBTITLE Defense Contractors: Additional Actions Needed to Facilitate the Use of DOD’s Inventory of...CONTRACTORS Additional Actions Needed to Facilitate the Use of DOD’s Inventory of Contracted Services Why GAO Did This Study DOD is the government’s

  13. New frontiers in the therapy of primary immunodeficiency: From gene addition to gene editing.

    PubMed

    Kohn, Donald B; Kuo, Caroline Y

    2017-03-01

    The most severe primary immune deficiency diseases (PIDs) have been successfully treated with allogeneic hematopoietic stem cell transplantation for more than 4 decades. However, such transplantations have the best outcomes when there is a well-matched donor available because immune complications, such as graft-versus-host disease, are greater without a matched sibling donor. Gene therapy has been developed as a method to perform autologous transplantations of a patient's own stem cells that are genetically corrected. Through an iterative bench-to-bedside-and-back process, methods to efficiently add new copies of the relevant gene to hematopoietic stem cells have led to safe and effective treatments for several PIDs, including forms of severe combined immune deficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. New methods for gene editing might allow additional PIDs to be treated by gene therapy because they will allow the endogenous gene to be repaired and expressed under its native regulatory elements, which are essential for genes involved in cell processes of signaling, activation, and proliferation. Gene therapy is providing exciting new treatment options for patients with PIDs, and advances are sure to continue.

  14. Hairy and Groucho mediate the action of juvenile hormone receptor Methoprene-tolerant in gene repression

    PubMed Central

    Saha, Tusar T.; Shin, Sang Woon; Dou, Wei; Roy, Sourav; Zhao, Bo; Hou, Yuan; Wang, Xue-Li; Zou, Zhen; Girke, Thomas; Raikhel, Alexander S.

    2016-01-01

    The arthropod-specific juvenile hormone (JH) controls numerous essential functions. Its involvement in gene activation is known to be mediated by the transcription factor Methoprene-tolerant (Met), which turns on JH-controlled genes by directly binding to E-box–like motifs in their regulatory regions. However, it remains unclear how JH represses genes. We used the Aedes aegypti female mosquito, in which JH is necessary for reproductive maturation, to show that a repressor, Hairy, is required for the gene-repressive action of JH and Met. The RNA interference (RNAi) screen for Met and Hairy in the Aedes female fat body revealed a large cohort of Met- and Hairy-corepressed genes. Analysis of selected genes from this cohort demonstrated that they are repressed by JH, but RNAi of either Met or Hairy renders JH ineffective in repressing these genes in an in vitro fat-body culture assay. Moreover, this JH action was prevented by the addition of the translational inhibitor cycloheximide (CHX) to the culture, indicating the existence of an indirect regulatory hierarchy. The lack of Hairy protein in the CHX-treated tissue was verified using immunoblot analysis, and the upstream regions of Met/Hairy-corepressed genes were shown to contain common binding motifs that interact with Hairy. Groucho (gro) RNAi silencing phenocopied the effect of Hairy RNAi knockdown, indicating that it is involved in the JH/Met/Hairy hierarchy. Finally, the requirement of Hairy and Gro for gene repression was confirmed in a cell transfection assay. Thus, our study has established that Hairy and its cofactor Gro mediate the repressive function of JH and Met. PMID:26744312

  15. Two GATA transcription factors are downstream effectors of floral homeotic gene action in Arabidopsis.

    PubMed

    Mara, Chloe D; Irish, Vivian F

    2008-06-01

    Floral organogenesis is dependent on the combinatorial action of MADS-box transcription factors, which in turn control the expression of suites of genes required for growth, patterning, and differentiation. In Arabidopsis (Arabidopsis thaliana), the specification of petal and stamen identity depends on the action of two MADS-box gene products, APETALA3 (AP3) and PISTILLATA (PI). In a screen for genes whose expression was altered in response to the induction of AP3 activity, we identified GNC (GATA, nitrate-inducible, carbon-metabolism-involved) as being negatively regulated by AP3 and PI. The GNC gene encodes a member of the Arabidopsis GATA transcription factor family and has been implicated in the regulation of chlorophyll biosynthesis as well as carbon and nitrogen metabolism. In addition, we found that the GNC paralog, GNL (GNC-like), is also negatively regulated by AP3 and PI. Using chromatin immunoprecipitation, we showed that promoter sequences of both GNC and GNL are bound by PI protein, suggesting a direct regulatory interaction. Analyses of single and double gnc and gnl mutants indicated that the two genes share redundant roles in promoting chlorophyll biosynthesis, suggesting that in repressing GNC and GNL, AP3/PI have roles in negatively regulating this biosynthetic pathway in flowers. In addition, coexpression analyses of genes regulated by AP3, PI, GNC, and GNL indicate a complex regulatory interplay between these transcription factors in regulating a variety of light and nutrient responsive genes. Together, these results provide new insights into the transcriptional cascades controlling the specification of floral organ identities.

  16. Gene mutations and actionable genetic lesions in mantle cell lymphoma

    PubMed Central

    Ahmed, Makhdum; Zhang, Leo; Nomie, Krystle; Lam, Laura; Wang, Michael

    2016-01-01

    Mutations and epigenetic alterations are key events in transforming normal cells to cancer cells. Mantle cell lymphoma (MCL), a non-Hodgkin's lymphoma of the B-cell, is an aggressive malignancy with poor prognosis especially for those patients who are resistant to the frontline drugs. There is a great need to describe the molecular basis and mechanism of drug resistance in MCL to develop new strategies for treatment. We reviewed frequent somatic mutations and mutations involving the B-cell pathways in MCL and discussed clinical trials that attempted to disrupt these gene pathways and/or epigenetic events. Recurrent gene mutations were discussed in the light of prognostic and therapeutic opportunity and also the challenges of targeting these lesions. Mutations in the ATM, CCND1, TP53, MLL2, TRAF2 and NOTCH1 were most frequently encountered in mantle cell lymphoma. Translational models should be built that would assess mutations longitudinally to identify important compensatory, pro-survival and anti-apoptic pathways and actionable genetic targets. PMID:27449094

  17. A versatile element for gene addition in bacterial chromosomes

    PubMed Central

    Sibley, Marion H.; Raleigh, Elisabeth A.

    2012-01-01

    The increasing interest in genetic manipulation of bacterial host metabolic pathways for protein or small molecule production has led to a need to add new genes to a chromosome quickly and easily without leaving behind a selectable marker. The present report describes a vector and four-day procedure that enable site-specific chromosomal insertion of cloned genes in a context insulated from external transcription, usable once in a construction series. The use of rhamnose-inducible transcription from rhaBp allows regulation of the inserted genes independently of the commonly used IPTG and arabinose strategies. Using lacZ as a reporter, we first show that expression from the rhamnose promoter is tightly regulatable, exhibiting very low leakage of background expression compared with background, and moderate rhamnose-induced expression compared with IPTG-induced expression from lacp. Second, the expression of a DNA methyltransferase was used to show that rhamnose regulation yielded on-off expression of this enzyme, such that a resident high-copy plasmid was either fully sensitive or fully resistant to isoschizomer restriction enzyme cleavage. In both cases, growth medium manipulation allows intermediate levels of expression. The vehicle can also be adapted as an ORF-cloning vector. PMID:22123741

  18. Congruence of additive and non-additive effects on gene expression estimated from pedigree and SNP data.

    PubMed

    Powell, Joseph E; Henders, Anjali K; McRae, Allan F; Kim, Jinhee; Hemani, Gibran; Martin, Nicholas G; Dermitzakis, Emmanouil T; Gibson, Greg; Montgomery, Grant W; Visscher, Peter M

    2013-05-01

    There is increasing evidence that heritable variation in gene expression underlies genetic variation in susceptibility to disease. Therefore, a comprehensive understanding of the similarity between relatives for transcript variation is warranted--in particular, dissection of phenotypic variation into additive and non-additive genetic factors and shared environmental effects. We conducted a gene expression study in blood samples of 862 individuals from 312 nuclear families containing MZ or DZ twin pairs using both pedigree and genotype information. From a pedigree analysis we show that the vast majority of genetic variation across 17,994 probes is additive, although non-additive genetic variation is identified for 960 transcripts. For 180 of the 960 transcripts with non-additive genetic variation, we identify expression quantitative trait loci (eQTL) with dominance effects in a sample of 339 unrelated individuals and replicate 31% of these associations in an independent sample of 139 unrelated individuals. Over-dominance was detected and replicated for a trans association between rs12313805 and ETV6, located 4MB apart on chromosome 12. Surprisingly, only 17 probes exhibit significant levels of common environmental effects, suggesting that environmental and lifestyle factors common to a family do not affect expression variation for most transcripts, at least those measured in blood. Consistent with the genetic architecture of common diseases, gene expression is predominantly additive, but a minority of transcripts display non-additive effects.

  19. Veterans Affairs Health Care: Addition to GAO’s High Risk List and Actions Needed for Removal

    DTIC Science & Technology

    2015-04-29

    VETERANS AFFAIRS HEALTH CARE Addition to GAO’s High Risk List and Actions Needed for Removal Statement of Debra A...Draper Director, Health Care Testimony Before the Committee on Veterans’ Affairs, U.S. Senate For Release on Delivery Expected at 2:30 p.m. ET...to 00-00-2015 4. TITLE AND SUBTITLE Veterans Affairs Health Care: Addition to GAO’s High Risk List and Actions Needed for Removal 5a. CONTRACT

  20. Linking Genes to Cardiovascular Diseases: Gene Action and Gene-Environment Interactions.

    PubMed

    Pasipoularides, Ares

    2015-12-01

    A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the "post-genomic" era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how "modifier genes" influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many-practitioners and investigators-to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area.

  1. Correlating chemical sensitivity and basal gene expression reveals mechanism of action | Office of Cancer Genomics

    Cancer.gov

    Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown.

  2. Demonstration of transcriptional regulation of specific genes by phytochrome action

    PubMed Central

    Silverthorne, Jane; Tobin, Elaine M.

    1984-01-01

    We have developed an in vitro transcription system that uses nuclei isolated from Lemna gibba G-3. The in vitro transcripts include sequences homologous to hybridization probes for the small subunit of ribulose-1,5-bisphosphate carboxylase [3-phospho-D-glycerate carboxy-lyase (dimerizing), EC 4.1.1.39], the light-harvesting chlorophyll a/b-protein, and rRNA. Light-harvesting chlorophyll a/b-protein sequences are transcribed to a greater extent in nuclei isolated from plants grown in darkness with 2 min of red light every 8 hr than in nuclei isolated from dark-treated plants. Furthermore, the amount of these transcripts measured in plants given a single minute of red light after dark treatment is increased over the amount measured in dark-treated plants. The effect of red light is at least partially reversible by 10 min of far-red light given immediately after the red light pulse. Transcription of both rRNA and small subunit sequences is also stimulated by a single minute of red light as compared to dark-treated tissue. However, the relative magnitudes of the increases compared to the dark levels are smaller than the increase seen for the chlorophyll a/b-protein, possibly because of the higher level of transcription of these sequences in the dark. The effect of red light on the transcription of small subunit and rRNA sequences is also reversible by immediate treatment with 10 min of far-red light. Pulse chase studies of dark-treated nuclei for up to 110 min do not show substantial turnover of in vitro labeled small subunit and chlorophyll a/b-protein transcripts. We therefore conclude that phytochrome action has induced specific changes in transcription of these genes. Images PMID:16593420

  3. Under Settlement Bangor, Maine Takes Additional Action to Address Wastewater and Stormwater Discharges

    EPA Pesticide Factsheets

    Under the terms of a Consent Decree lodged today in federal court to address noncompliance with the CWA, the City of Bangor, ME, will take action to prevent sewer overflows & contaminated stormwater from entering the Penobscot River & Kenduskeag Stream.

  4. Additivity of Pyrethroid Actions on Sodium Influx in Cortical Neuronsin vitro

    EPA Science Inventory

    Background: Pyrethroid insecticides bind to voltage-gated sodium channels (VGSCs) and modify their gating kinetics, thereby disrupting neuronal function. While previous work has tested the additivity of pyrethroids in vivo, the additivity of these compounds at the major target si...

  5. Additional duplicated Hox genes in the earthworm: Perionyx excavatus Hox genes consist of eleven paralog groups.

    PubMed

    Cho, Sung-Jin; Vallès, Yvonne; Kim, Kyong Min; Ji, Seong Chul; Han, Seock Jung; Park, Soon Cheol

    2012-02-10

    Annelida is a lophotrochozoan phylum whose members have a high degree of diversity in body plan morphology, reproductive strategies and ecological niches among others. Of the two traditional classes pertaining to the phylum Annelida (Polychaete and Clitellata), the structure and function of the Hox genes has not been clearly defined within the Oligochaeta class. Using a PCR-based survey, we were able to identify five new Hox genes from the earthworm Perionyx excavatus: a Hox3 gene (Pex-Hox3b), two Dfd genes (Pex-Lox6 and Pex-Lox18), and two posterior genes (Pex-post1 and -post2a). Our result suggests that the eleven earthworm Hox genes contain at least four paralog groups (PG) that have duplicated. We found the clitellates-diagnostic signature residues and annelid signature motif. Also, we show by semi-quantitative RT-PCR that duplicated Hox gene orthologs are differentially expressed in six different anterior-posterior body regions. These results provide essential data for comparative evolution of the Hox cluster within the Annelida.

  6. Additivity of Pyrethroid Actions on Sodium Influx in Cortical Neurons in Cerebrocortical Neurons in Primary Culture

    EPA Science Inventory

    BACKGROUND: Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Although previous work has tested the additivity of pyrethroids in vivo, this has not been assessed directly at the primary molecular ...

  7. Gene actions of QTLs affecting several agronomic traits resolved in a recombinant inbred rice population and two testcross populations.

    PubMed

    Mei, H W; Luo, L J; Ying, C S; Wang, Y P; Yu, X Q; Guo, L B; Paterson, A H; Li, Z K

    2003-06-01

    To understand the types of gene action controlling seven quantitative traits in rice, QTL mapping was performed to dissect the main effect (M-QTLs) and digenic epistatic (E-QTLs) QTLs responsible for the trait performance of 254 recombinant inbred lines (RILs) of "Lemont/Teqing", and two testcross (TC) F(1) populations derived from these RILs. The correlation analyses reveal a general pattern, i.e. trait heritability in the RILs was negatively correlated to trait heterosis in the TC hybrids. A large number of M-QTLs and E-QTLs affecting seven traits, including heading date (HD), plant height (PH), flag leaf length (FLL), flag leaf width (FLW), panicle length (PL), spikelet number per panicle (SN) and spikelet fertility (SF), were identified and could be classified into two predominant groups, additive QTLs detected primarily in the RILs, and overdominant QTLs identified exclusively in the TC populations. There is little overlap between QTLs identified in the RILs and in the TC populations. This result implied that additive gene action is largely independent from non-additive gene action in the genetic control of quantitative traits of rice. The detected E-QTLs collectively explained a much greater portion of the total phenotypic variation than the M-QTLs, supporting prior findings that epistasis has played an important role in the genetic control of quantitative traits in rice. The implications of these results to the development of inbred and hybrid cultivars were discussed.

  8. Additive action of honey and starch against Candida albicans and Aspergillus niger.

    PubMed

    Boukraâ, Laid; Bouchegrane, Sarah

    2007-12-31

    A comparative method of adding honey to culture media with and without starch was used to evaluate the action of starch on the antifungal activity of honey. The minimum inhibitory concentration (MIC) expressed in % (v/v) for two varieties of honey without starch against Candida albicans was 42% and 46%, respectively. For Aspergillus niger the MIC without starch was 51% and 59%, respectively. When starch was incubated with honey and then added to media the MIC for C. albicans was 28% and 38%, respectively, with a starch concentration of 3.6% whereas the MIC for A. niger was 40% and 45%, with a starch concentration of 5.6% and 5.1% respectively. This study suggests that the amylase present in honey increases the osmotic effect in the media by increasing the amount of sugars and consequently increasing the antifungal activity.

  9. An analysis of the mode of gene action affecting pupa weight in Tribolium castaneum.

    PubMed

    Goodwill, R

    1975-02-01

    Triple-testcross experiments (Kearsey and Jinks 1968) were employed to investigate the mode of gene action affecting pupa weight in Tribolium castaneum. Their experimental design involves two inbred lines, the F1 progeny and a segregating population derived from the cross of the inbred lines. In the present experiments, four segregating populations were used. These populations included the F2 generation, a select line (SEL) and two relaxed select lines (RSI and RSII). In addition, all possible reciprocal crosses were made among the RSI, RSII, and SEL populations. It was observed that: (1) additive, dominant and epistatic gene effects all made significant contributions to the pupa weight of the progeny from all four segregating populations: (2) there was no evidence of either accumulation of epistasis as a result of selection in the SEL population or decline in epistasis as a result of removing selection pressure from the RSI and RSII populations; and (3) significant negative heterosis and maternal effects contributed to the pupa weight of the crossbred progeny of the RSI, RSII and SEL populations.

  10. Unmanned Aircraft Systems: Additional Actions Needed to Improve Management and Integration of DOD Efforts to Support Warfighter Needs

    DTIC Science & Technology

    2008-11-01

    Services, House of Representatives UNMANNED AIRCRAFT SYSTEMS Additional Actions Needed to Improve Management and Integration of DOD Efforts to...Armed Services, House of Representatives The Department of Defense’s (DOD) use of unmanned aircraft systems (UAS) continues to increase. In 2000...unmanned aircraft systems This is a work of the U.S. government and is not subject to copyright protection in the United States. It may be reproduced

  11. Defense Business Transformation: DOD Has Taken Some Steps to Address Weaknesses, but Additional Actions Are Needed

    DTIC Science & Technology

    2015-02-01

    responsible for DOD’s business transformation efforts. What GAO Recommends GAO recommends that the CMO and DCMO document and communicate priorities for...concurred with GAO’s recommendations. What GAO Found Department of Defense (DOD) senior leadership—specifically the Chief Management Officer ( CMO ) and...not implemented leading performance management practices for federal agencies to help ensure additional progress. For example, DOD’s CMO and DCMO

  12. Inverse gene-for-gene interactions contribute additively to tan spot susceptibility in wheat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Tan spot of wheat, caused by Pyrenophora tritici-repentis, is an important disease in almost all wheat-growing areas of the world. The disease system is known to involve at least three fungal-produced necrotrophic effectors (NEs) that interact with corresponding host sensitivity (S) genes in an inv...

  13. Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons

    PubMed Central

    Lee, Philip R.; Cohen, Jonathan E.; Iacobas, Dumitru A.; Iacobas, Sanda; Fields, R. Douglas

    2017-01-01

    Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life. PMID:28256583

  14. Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons.

    PubMed

    Lee, Philip R; Cohen, Jonathan E; Iacobas, Dumitru A; Iacobas, Sanda; Fields, R Douglas

    2017-03-03

    Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life.

  15. Cardiovascular pleiotropic actions of DPP-4 inhibitors: a step at the cutting edge in understanding their additional therapeutic potentials.

    PubMed

    Balakumar, Pitchai; Dhanaraj, Sokkalingam A

    2013-09-01

    Dipeptidyl peptidase 4 (DPP-4) is a serine protease enzyme expressed widely in many tissues, including the cardiovascular system. The incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released from the small intestine into the vasculature during a meal, and these incretins have a potential to release insulin from pancreatic beta cells of islets of Langerhans, affording a glucose-lowering action. However, both incretins are hurriedly degraded by the DPP-4. Inhibitors of DPP-4, therefore, enhance the bioavailability of GLP-1 and GIP, and thus have been approved for better glycemic management in patients afflicted with type 2 diabetes mellitus (T2DM). Five different DPP-4 inhibitors, often called as 'gliptins', namely sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin have been approved hitherto for clinical use. These drugs are used along with diet and exercise to lower blood sugar in diabetic subjects. T2DM is intricately related with an increased risk of cardiovascular disease. Growing body of evidence suggests that gliptins, in addition to their persuasive anti-diabetic action, have a beneficial pleiotropic action on the heart and vessels. In view of the fact of cardiovascular disease susceptibility of patients afflicted with T2DM, gliptins might offer additional therapeutic benefits in treating diabetic cardiovascular complications. Exploring further the cardiovascular pleiotropic potentials of gliptins might open a panorama in impeccably employing these agents for the dual management of T2DM and T2DM-associated perilous cardiovascular complications. This review will shed lights on the newly identified beneficial pleiotropic actions of gliptins on the cardiovascular system.

  16. Cross-Family Transcription Factor Interactions: An Additional Layer of Gene Regulation.

    PubMed

    Bemer, Marian; van Dijk, Aalt D J; Immink, Richard G H; Angenent, Gerco C

    2017-01-01

    Specific and dynamic gene expression strongly depends on transcription factor (TF) activity and most plant TFs function in a combinatorial fashion. They can bind to DNA and control the expression of the corresponding gene in an additive fashion or cooperate by physical interactions, forming larger protein complexes. The importance of protein-protein interactions between members of a particular plant TF family has long been recognised; however, a significant number of interfamily TF interactions has recently been reported. The biological implications and the molecular mechanisms involved in cross-family interactions have now started to be elucidated and the examples illustrate potential roles in the bridging of biological processes. Hence, cross-family TF interactions expand the molecular toolbox for plants with additional mechanisms to control and fine-tune robust gene expression patterns and to adapt to their continuously changing environment.

  17. Orsomucoid: A new variant and additional duplicated ORM1 gene in Qatari population

    SciTech Connect

    Sebetan, I.M.; Alali, K.A.; Alzaman, A.

    1994-09-01

    A new genetically determined ORM2 variant and additional duplicated ORM1 gene were observed in Qatari population using isoelectric focusing in ultra thin layer polyacrylamide gels. The studied population samples indicate occurence of six ORM1 alleles and three ORM2 ones. A simple reliable method for separation of orsomucoid variations with comparison of different reported methods will be presented.

  18. Antagonistic control of a dual-input mammalian gene switch by food additives

    PubMed Central

    Xie, Mingqi; Ye, Haifeng; Hamri, Ghislaine Charpin-El; Fussenegger, Martin

    2014-01-01

    Synthetic biology has significantly advanced the design of mammalian trigger-inducible transgene-control devices that are able to programme complex cellular behaviour. Fruit-based benzoate derivatives licensed as food additives, such as flavours (e.g. vanillate) and preservatives (e.g. benzoate), are a particularly attractive class of trigger compounds for orthogonal mammalian transgene control devices because of their innocuousness, physiological compatibility and simple oral administration. Capitalizing on the genetic componentry of the soil bacterium Comamonas testosteroni, which has evolved to catabolize a variety of aromatic compounds, we have designed different mammalian gene expression systems that could be induced and repressed by the food additives benzoate and vanillate. When implanting designer cells engineered for gene switch-driven expression of the human placental secreted alkaline phosphatase (SEAP) into mice, blood SEAP levels of treated animals directly correlated with a benzoate-enriched drinking programme. Additionally, the benzoate-/vanillate-responsive device was compatible with other transgene control systems and could be assembled into higher-order control networks providing expression dynamics reminiscent of a lap-timing stopwatch. Designer gene switches using licensed food additives as trigger compounds to achieve antagonistic dual-input expression profiles and provide novel control topologies and regulation dynamics may advance future gene- and cell-based therapies. PMID:25030908

  19. Antagonistic control of a dual-input mammalian gene switch by food additives.

    PubMed

    Xie, Mingqi; Ye, Haifeng; Hamri, Ghislaine Charpin-El; Fussenegger, Martin

    2014-08-01

    Synthetic biology has significantly advanced the design of mammalian trigger-inducible transgene-control devices that are able to programme complex cellular behaviour. Fruit-based benzoate derivatives licensed as food additives, such as flavours (e.g. vanillate) and preservatives (e.g. benzoate), are a particularly attractive class of trigger compounds for orthogonal mammalian transgene control devices because of their innocuousness, physiological compatibility and simple oral administration. Capitalizing on the genetic componentry of the soil bacterium Comamonas testosteroni, which has evolved to catabolize a variety of aromatic compounds, we have designed different mammalian gene expression systems that could be induced and repressed by the food additives benzoate and vanillate. When implanting designer cells engineered for gene switch-driven expression of the human placental secreted alkaline phosphatase (SEAP) into mice, blood SEAP levels of treated animals directly correlated with a benzoate-enriched drinking programme. Additionally, the benzoate-/vanillate-responsive device was compatible with other transgene control systems and could be assembled into higher-order control networks providing expression dynamics reminiscent of a lap-timing stopwatch. Designer gene switches using licensed food additives as trigger compounds to achieve antagonistic dual-input expression profiles and provide novel control topologies and regulation dynamics may advance future gene- and cell-based therapies.

  20. Genome-wide transcript analysis of maize hybrids: allelic additive gene expression and yield heterosis.

    PubMed

    Guo, Mei; Rupe, Mary A; Yang, Xiaofeng; Crasta, Oswald; Zinselmeier, Christopher; Smith, Oscar S; Bowen, Ben

    2006-09-01

    Heterosis, or hybrid vigor, has been widely exploited in plant breeding for many decades, but the molecular mechanisms underlying the phenomenon remain unknown. In this study, we applied genome-wide transcript profiling to gain a global picture of the ways in which a large proportion of genes are expressed in the immature ear tissues of a series of 16 maize hybrids that vary in their degree of heterosis. Key observations include: (1) the proportion of allelic additively expressed genes is positively associated with hybrid yield and heterosis; (2) the proportion of genes that exhibit a bias towards the expression level of the paternal parent is negatively correlated with hybrid yield and heterosis; and (3) there is no correlation between the over- or under-expression of specific genes in maize hybrids with either yield or heterosis. The relationship of the expression patterns with hybrid performance is substantiated by analysis of a genetically improved modern hybrid (Pioneer hybrid 3394) versus a less improved older hybrid (Pioneer hybrid 3306) grown at different levels of plant density stress. The proportion of allelic additively expressed genes is positively associated with the modern high yielding hybrid, heterosis and high yielding environments, whereas the converse is true for the paternally biased gene expression. The dynamic changes of gene expression in hybrids responding to genotype and environment may result from differential regulation of the two parental alleles. Our findings suggest that differential allele regulation may play an important role in hybrid yield or heterosis, and provide a new insight to the molecular understanding of the underlying mechanisms of heterosis.

  1. Genetic evidence for an additional function of phage T4 gene 32 protein: interaction with ligase.

    PubMed

    Mosig, G; Breschkin, A M

    1975-04-01

    Gene 32 of bacteriophage T4 is essential for DNA replication, recombination, and repair. In an attempt to clarify the role of the corresponding gene product, we have looked for mutations that specifically inactivate one but not all of its functions and for compensating suppressor mutations in other genes. Here we describe a gene 32 ts mutant that does not produce progeny, but in contrast to an am mutant investigated by others, is capable of some primary and secondary DNA replication and of forming "joint" recombinational intermediates after infection of Escherichia coli B at the restrictive temperature. However, parental and progeny DNA strands are not ligated to covalently linked "recombinant" molecules, and single strands of vegetative DNA do not exceed unit length. Progeny production as well as capacity for covalent linkage in this gene 32 ts mutant are partially restored by additional rII mutations. Suppression by rII depends on functioning host ligase [EC 6.5.1.2; poly(deoxyribonucleotide):poly(deoxyribonucleotide) ligase (AMP-forming, NMN-forming)]. This gene 32 ts mutation (unlike some others) in turn suppresses the characteristic plaque morphology of rII mutants. We conclude that gene 32 protein, in addition to its role in DNA replication and in the formation of "joint" recombinational intermediates, interacts with T4 ligase [EC 6.5.1.1; poly(deoxyribonucleotide):poly(deoxyribonucleotide) ligase (AMP-forming)] when recombining DNA strands are covalently linked. The protein of the mutant that we describe here is mainly defective in this interaction, thus inactivating T4 ligase in recombination. Suppressing rII mutations facilitate substitution of host ligase. There is suggestive evidence that these interactions occur at the membrane.

  2. Identification of the biosynthetic gene cluster and an additional gene for resistance to the antituberculosis drug capreomycin.

    PubMed

    Felnagle, Elizabeth A; Rondon, Michelle R; Berti, Andrew D; Crosby, Heidi A; Thomas, Michael G

    2007-07-01

    Capreomycin (CMN) belongs to the tuberactinomycin family of nonribosomal peptide antibiotics that are essential components of the drug arsenal for the treatment of multidrug-resistant tuberculosis. Members of this antibiotic family target the ribosomes of sensitive bacteria and disrupt the function of both subunits of the ribosome. Resistance to these antibiotics in Mycobacterium species arises due to mutations in the genes coding for the 16S or 23S rRNA but can also arise due to mutations in a gene coding for an rRNA-modifying enzyme, TlyA. While Mycobacterium species develop resistance due to alterations in the drug target, it has been proposed that the CMN-producing bacterium, Saccharothrix mutabilis subsp. capreolus, uses CMN modification as a mechanism for resistance rather than ribosome modification. To better understand CMN biosynthesis and resistance in S. mutabilis subsp. capreolus, we focused on the identification of the CMN biosynthetic gene cluster in this bacterium. Here, we describe the cloning and sequence analysis of the CMN biosynthetic gene cluster from S. mutabilis subsp. capreolus ATCC 23892. We provide evidence for the heterologous production of CMN in the genetically tractable bacterium Streptomyces lividans 1326. Finally, we present data supporting the existence of an additional CMN resistance gene. Initial work suggests that this resistance gene codes for an rRNA-modifying enzyme that results in the formation of CMN-resistant ribosomes that are also resistant to the aminoglycoside antibiotic kanamycin. Thus, S. mutabilis subsp. capreolus may also use ribosome modification as a mechanism for CMN resistance.

  3. Linking Genes to Cardiovascular Diseases: Gene Action and Gene–Environment Interactions

    PubMed Central

    2016-01-01

    A unique myocardial characteristic is its ability to grow/remodel in order to adapt; this is determined partly by genes and partly by the environment and the milieu intérieur. In the “post-genomic” era, a need is emerging to elucidate the physiologic functions of myocardial genes, as well as potential adaptive and maladaptive modulations induced by environmental/epigenetic factors. Genome sequencing and analysis advances have become exponential lately, with escalation of our knowledge concerning sometimes controversial genetic underpinnings of cardiovascular diseases. Current technologies can identify candidate genes variously involved in diverse normal/abnormal morphomechanical phenotypes, and offer insights into multiple genetic factors implicated in complex cardiovascular syndromes. The expression profiles of thousands of genes are regularly ascertained under diverse conditions. Global analyses of gene expression levels are useful for cataloging genes and correlated phenotypes, and for elucidating the role of genes in maladies. Comparative expression of gene networks coupled to complex disorders can contribute insights as to how “modifier genes” influence the expressed phenotypes. Increasingly, a more comprehensive and detailed systematic understanding of genetic abnormalities underlying, for example, various genetic cardiomyopathies is emerging. Implementing genomic findings in cardiology practice may well lead directly to better diagnosing and therapeutics. There is currently evolving a strong appreciation for the value of studying gene anomalies, and doing so in a non-disjointed, cohesive manner. However, it is challenging for many—practitioners and investigators—to comprehend, interpret, and utilize the clinically increasingly accessible and affordable cardiovascular genomics studies. This survey addresses the need for fundamental understanding in this vital area. PMID:26545598

  4. THE mPER2 CLOCK GENE MODULATES COCAINE ACTIONS IN THE MOUSE CIRCADIAN SYSTEM

    PubMed Central

    Brager, Allison J.; Stowie, Adam C.; Prosser, Rebecca A.; Glass, J. David

    2014-01-01

    Cocaine is a potent disruptor of photic and non-photic pathways for circadian entrainment of the master circadian clock of the suprachiasmatic nucleus (SCN). These actions of cocaine likely involve its modulation of molecular (clock gene) components for SCN clock timekeeping. At present, however, the physiological basis of such an interaction is unclear. To address this question, we compared photic and non-photic phase-resetting responses between wild-type (WT) and Per2 mutant mice expressing nonfunctional PER2 protein to systemic and intra-SCN cocaine administrations. In the systemic trials, cocaine was administered i.p. (20 mg/kg) either at midday or prior to a light pulse in the early night to assess its non-photic and photic behavioral phase-resetting actions, respectively. In the intra-SCN trial, cocaine was administered by reverse microdialysis at midday to determine if the SCN is a direct target for its non-photic phase-resetting action. Non-photic phase-advancing responses to i.p. cocaine at midday were significantly (~3.5-fold) greater in Per2 mutants than WTs. However, the phase-advancing action of intra-SCN cocaine perfusion at midday did not differ between genotypes. In the light pulse trial, Per2 mutants exhibited larger photic phase-delays than did WTs, and the attenuating action of cocaine on this response was proportionately larger than in WTs. These data indicate that the Per2 clock gene is a potent modulator of cocaine’s actions in the circadian system. With regard to non-photic phase-resetting, the SCN is confirmed as a direct target of cocaine action; however, Per2 modulation of this effect likely occurs outside of the SCN. PMID:23333842

  5. All possible modes of gene action are observed in a global comparison of gene expression in a maize F1 hybrid and its inbred parents

    PubMed Central

    Swanson-Wagner, Ruth A.; Jia, Yi; DeCook, Rhonda; Borsuk, Lisa A.; Nettleton, Dan; Schnable, Patrick S.

    2006-01-01

    Heterosis is the phenomenon whereby the progeny of particular inbred lines have enhanced agronomic performance relative to both parents. Although several hypotheses have been proposed to explain this fundamental biological phenomenon, the responsible molecular mechanisms have not been determined. The maize inbred lines B73 and Mo17 produce a heterotic F1 hybrid. Global patterns of gene expression were compared in seedlings of these three genotypes by using a microarray that contains 13,999 cDNAs. Using an estimated 15% false discovery rate as a cutoff, 1,367 ESTs (9.8%) were identified as being significantly differentially expressed among genotypes. All possible modes of gene action were observed, including additivity, high- and low-parent dominance, underdominance, and overdominance. The largest proportion of the ESTs (78%; 1,062 of 1,367) exhibited expression patterns that are not statistically distinguishable from additivity. Even so, 22% of the differentially regulated ESTs exhibited nonadditive modes of gene expression. Classified on the basis of significant pairwise comparisons of genotype means, 181 of these 305 nonadditive ESTs exhibited high-parent dominance and 23 exhibited low-parent dominance. In addition, 44 ESTs exhibited underdominance or overdominance. These findings are consistent with the hypothesis that multiple molecular mechanisms, including overdominance, contribute to heterosis. PMID:16641103

  6. Fine Mapping of Two Additive Effect Genes for Awn Development in Rice (Oryza sativa L.)

    PubMed Central

    Li, Jinjie; Yao, Guoxin; Pan, Huiqiao; Hu, Guanglong; Chen, Chao; Zhang, Hongliang; Li, Zichao

    2016-01-01

    Awns, important domestication and agronomic traits in rice (Oryza sativa L.), are conferred by polygenes and the environment. Near isogenic line (NIL) pairs BM33 and BM38 were constructed from crosses between awnless japonica cv Nipponbare as recurrent parent, and lines SLG or Funingxiaohongmang (awned japonica accessions), respectively, as donors. In order to study the genetic and molecular mechanism of awning, two unknown, independent genes with additive effects were identified in a cross between the NILs. To map and clone the two genes, a BC4F4 population of 8,103 individuals and a BC4F6 population of 11,206 individuals were constructed. Awn3-1 was fine mapped to a 101.13 kb genomic region between Indel marker In316 and SNP marker S9-1 on chromosome 3. Nine predicted genes in the interval were annotated in the Rice Annotation Project Database (RAP-DB), and Os03g0418600 was identified as the most likely candidate for Awn3-1 through sequence comparisons and RT-PCR assays. Awn4-2 was fine mapped to a 62.4 kb genomic region flanked by simple sequence repeat (SSR) marker M1126 and Indel maker In73 on chromosome 4L. This region contained the previously reported gene An-1 that regulates awn development. Thus, An-1 may be the candidate gene of Awn4-2. These results will facilitate cloning of the awn genes and thereby provide an understanding of the molecular basis of awn development. PMID:27494628

  7. Targeted gene addition into a specified location in the human genome using designed zinc finger nucleases

    PubMed Central

    Moehle, Erica A.; Rock, Jeremy M.; Lee, Ya-Li; Jouvenot, Yann; DeKelver, Russell C.; Gregory, Philip D.; Urnov, Fyodor D.; Holmes, Michael C.

    2007-01-01

    Efficient incorporation of novel DNA sequences into a specific site in the genome of living human cells remains a challenge despite its potential utility to genetic medicine, biotechnology, and basic research. We find that a precisely placed double-strand break induced by engineered zinc finger nucleases (ZFNs) can stimulate integration of long DNA stretches into a predetermined genomic location, resulting in high-efficiency site-specific gene addition. Using an extrachromosomal DNA donor carrying a 12-bp tag, a 900-bp ORF, or a 1.5-kb promoter-transcription unit flanked by locus-specific homology arms, we find targeted integration frequencies of 15%, 6%, and 5%, respectively, within 72 h of treatment, and with no selection for the desired event. Importantly, we find that the integration event occurs in a homology-directed manner and leads to the accurate reconstruction of the donor-specified genotype at the endogenous chromosomal locus, and hence presumably results from synthesis-dependent strand annealing repair of the break using the donor DNA as a template. This site-specific gene addition occurs with no measurable increase in the rate of random integration. Remarkably, we also find that ZFNs can drive the addition of an 8-kb sequence carrying three distinct promoter-transcription units into an endogenous locus at a frequency of 6%, also in the absence of any selection. These data reveal the surprising versatility of the specialized polymerase machinery involved in double-strand break repair, illuminate a powerful approach to mammalian cell engineering, and open the possibility of ZFN-driven gene addition therapy for human genetic disease. PMID:17360608

  8. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing.

    PubMed

    Herrmann, Martin J; Huter, Theresa; Müller, Frauke; Mühlberger, Andreas; Pauli, Paul; Reif, Andreas; Renner, Tobias; Canli, Turhan; Fallgatter, Andreas J; Lesch, Klaus-Peter

    2007-05-01

    Prior studies reported that functional variants of both the serotonin transporter (5-HTT) and tryptophan hydroxylase-2 genes (TPH2), 2 key regulators of the serotonergic signaling pathway, modulate amygdala activation during emotional processing. We addressed the question whether these 2 gene variants modulate each other, using an emotional picture-processing task. Specifically, we measured event-related potentials (ERPs) during a passive emotional picture perception task, focusing on ERPs for the early posterior negativity (EPN) around 240 ms and for the slow wave starting at 315 ms. We found evidence for increased neural activity at 240 ms in individuals who carried 1 or 2 copies of the low-expression short variant of the 5-HTT. Carriers of T variant of the TPH2 also showed a tendency toward increased neural activity at 240 ms. Moreover, we observed an additive effect of both genotypes for EPN, with highest neural activity to emotional stimuli in individuals carrying combination of both short variant of 5-HTT and T variant of TPH2. Our results indicate that both the 5-HTT and the TPH2 genotypes modulate the sensory encoding of affective stimuli during early steps of visual processing and reveal additive effects of 2 genes in the serotonergic control of emotion regulation.

  9. An additional Meyerozyma guilliermondii IMH3 gene confers mycophenolic acid resistance in fungal CTG clade species.

    PubMed

    Defosse, Tatiana A; Mélin, Céline; Clastre, Marc; Besseau, Sébastien; Lanoue, Arnaud; Glévarec, Gaëlle; Oudin, Audrey; Dugé de Bernonville, Thomas; Vandeputte, Patrick; Linder, Tomas; Bouchara, Jean-Philippe; Courdavault, Vincent; Giglioli-Guivarc'h, Nathalie; Papon, Nicolas

    2016-09-01

    The fungal CTG clade comprises a number of well-known yeasts that impact human health or with high biotechnological potential. To further extend the set of molecular tools dedicated to these microorganisms, the initial focus of this study was to develop a mycophenolic acid (MPA) resistance cassette. Surprisingly, while we were carrying out preliminary susceptibility testing experiments in a set of yeast species, Meyerozyma guilliermondii, although not being a MPA producer, was found to be primarily resistant toward this drug, whereas a series of nine related species were susceptible to MPA. Using comparative and functional genomic approaches, we demonstrated that all MPA-susceptible CTG clade species display a single gene, referred to as IMH3.1, encoding the MPA target inosine monophosphate dehydrogenase (IMPDH) and that MPA resistance relies on the presence in the M. guilliermondii genome of an additional IMPDH-encoding gene (IMH3.2). The M. guilliermondii IMH3.2 gene displays marked differences compared to IMH3.1 including the lack of intron, a roughly 160-fold higher transcription level and a serine residue at position 251. Placed under the control of the M. guilliermondii actin 1 gene promoter, IMH3.2 was successfully used to transform Lodderomyces elongisporus, Clavispora lusitaniae, Scheffersomyces stipitis and Candida parapsilosis.

  10. LASS6, an additional member of the longevity assurance gene family.

    PubMed

    Weinmann, Arndt; Galle, Peter R; Teufel, Andreas

    2005-11-01

    Longevity assurance genes (LAGs) represent a subgroup of the homeobox gene family. Five mammalian homologs have been reported, and the corresponding proteins have previously been investigated with respect to their key role in ceramide synthesis. However, members of the LAG family have been shown to be involved in cell growth regulation and cancer differentiation. In an effort to characterize additional members of the LAG family, we have screened the latest releases of genomic databases and report on the bioinformatic characterization of yet another member, LAG1 longevity assurance homolog 6 (LASS6). Like other LAG family members, the LASS6 protein contained a homeodomain and LAG1 domain. In phylogenetic analyses, it displayed highest homology to LASS5. The corresponding gene was localized to human chromosome 2q24.3, spanning a rather large genomic region of 318 kb. Orthologous sequences in mouse and zebrafish suggested a conservation of LASS6 in vertebrates as the protein and corresponding genomic sequences were highly conserved. LASS6 expression was analyzed in silico, and the gene was shown to be broadly expressed in a wide range of tissues. Furthermore, available microarray data suggested a role in cancer differentiation and early embryonic development.

  11. Phorbol ester and A23187 have additive but mechanistically separate effects on vasopressin action in rabbit collecting tubule.

    PubMed Central

    Ando, Y; Jacobson, H R; Breyer, M D

    1988-01-01

    AVP on CCT at 37 degrees C. (b) When stimulated simultaneously these two intracellular mediators are additive in their antagonism of AVP action. These results suggest that stimulated PIP2 breakdown may be an important modulator of water transport in CCT. (c) Different mechanisms underlie PKC and Ca-mediated suppression of the AVP-induced water transport. The inhibition of AVP action by increased [Ca++]i is primarily pre-cAMP, and involves a cyclooxygenase metabolite(s) of arachidonic acid, while the inhibition by PKC is post-cAMP, and independent of cyclooxygenase products of arachidonic acid. Images PMID:3130397

  12. Extracellular complementation and the identification of additional genes involved in aerial mycelium formation in Streptomyces coelicolor.

    PubMed

    Nodwell, J R; Yang, M; Kuo, D; Losick, R

    1999-02-01

    Morphogenesis in the bacterium Streptomyces coelicolor involves the formation of a lawn of hair-like aerial hyphae on the colony surface that stands up in the air and differentiates into chains of spores. bld mutants are defective in the formation of this aerial mycelium and grow as smooth, hairless colonies. When certain pairs of bld mutants are grown close to one another on rich sporulation medium, they exhibit extracellular complementation such that one mutant restores aerial mycelium formation to the other. The extracellular complementation relationships of most of the previously isolated bld mutants placed them in a hierarchy of extracellular complementation groups. We have screened for further bld mutants with precautions intended to maximize the discovery of additional genes. Most of the 50 newly isolated mutant strains occupy one of three of the previously described positions in the hierarchy, behaving like bldK, bldC, or bldD mutants. We show that the mutations in some of the strains that behave like bldK are bldK alleles but that others fall in a cluster at a position on the chromosome distinct from that of any known bld gene. We name this locus bldL. By introducing cloned genes into the strains that exhibit bldC or bldD-like extracellular complementation phenotypes, we show that most of these strains are likely to contain mutations in genes other than bldC or bldD. These results indicate that the genetic control of aerial mycelium formation is more complex than previously recognized and support the idea that a high proportion of bld genes are directly or indirectly involved in the production of substances that are exchanged between cells during morphological differentiation.

  13. Extracellular complementation and the identification of additional genes involved in aerial mycelium formation in Streptomyces coelicolor.

    PubMed Central

    Nodwell, J R; Yang, M; Kuo, D; Losick, R

    1999-01-01

    Morphogenesis in the bacterium Streptomyces coelicolor involves the formation of a lawn of hair-like aerial hyphae on the colony surface that stands up in the air and differentiates into chains of spores. bld mutants are defective in the formation of this aerial mycelium and grow as smooth, hairless colonies. When certain pairs of bld mutants are grown close to one another on rich sporulation medium, they exhibit extracellular complementation such that one mutant restores aerial mycelium formation to the other. The extracellular complementation relationships of most of the previously isolated bld mutants placed them in a hierarchy of extracellular complementation groups. We have screened for further bld mutants with precautions intended to maximize the discovery of additional genes. Most of the 50 newly isolated mutant strains occupy one of three of the previously described positions in the hierarchy, behaving like bldK, bldC, or bldD mutants. We show that the mutations in some of the strains that behave like bldK are bldK alleles but that others fall in a cluster at a position on the chromosome distinct from that of any known bld gene. We name this locus bldL. By introducing cloned genes into the strains that exhibit bldC or bldD-like extracellular complementation phenotypes, we show that most of these strains are likely to contain mutations in genes other than bldC or bldD. These results indicate that the genetic control of aerial mycelium formation is more complex than previously recognized and support the idea that a high proportion of bld genes are directly or indirectly involved in the production of substances that are exchanged between cells during morphological differentiation. PMID:9927452

  14. Illuminating drug action by network integration of disease genes: a case study of myocardial infarction.

    PubMed

    Wang, Rui-Sheng; Loscalzo, Joseph

    2016-04-26

    Drug discovery has produced many successful therapeutic agents; however, most of these drugs were developed without a deep understanding of the system-wide mechanisms of action responsible for their indications. Gene-disease associations produced by molecular and genetic studies of complex diseases provide great opportunities for a system-level understanding of drug activity. In this study, we focused on acute myocardial infarction (MI) and conducted an integrative network analysis to illuminate drug actions. We integrated MI drugs, MI drug interactors, drug targets, and MI disease genes into the human interactome and showed that MI drug targets are significantly proximate to MI disease proteins. We then constructed a bipartite network of MI-related drug targets and MI disease proteins and derived 12 drug-target-disease (DTD) modules. We assessed the biological relevance of these modules and demonstrated the benefits of incorporating disease genes. The results indicate that DTD modules provide insights into the mechanisms of action of MI drugs and the cardiovascular (side) effects of non-MI drugs.

  15. Older paternal age and fresh gene mutation: data on additional disorders.

    PubMed

    Jones, K L; Smith, D W; Harvey, M A; Hall, B D; Quan, L

    1975-01-01

    Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.

  16. A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine

    PubMed Central

    Lee, Kuen-Haur; Lo, Hsiang-Ling; Tang, Wan-Chun; Hsiao, Heidi Hao-yun; Yang, Pei-Ming

    2014-01-01

    Berberine (BBR), a traditional Chinese herbal medicine, was shown to display anticancer activity. In this study, we attempted to provide a global view of the molecular pathways associated with its anticancer effect through a gene expression-based chemical approach. BBR-induced differentially expressed genes obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were analyzed using the Connectivity Map (CMAP) database to compare similarities of gene expression profiles between BBR and CMAP compounds. Candidate compounds were further analyzed using the Search Tool for Interactions of Chemicals (STITCH) database to explore chemical-protein interactions. Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways. Further analyses demonstrated that BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK). However, BBR did not alter mTOR or HDAC activities. Interestingly, BBR induced the acetylation of α-tubulin, a substrate of HDAC6. In addition, the combination of BBR and SAHA, a pan-HDAC inhibitor, synergistically inhibited cell proliferation and induced cell cycle arrest. Our results provide novel insights into the mechanisms of action of BBR in cancer therapy. PMID:25227736

  17. A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine.

    PubMed

    Lee, Kuen-Haur; Lo, Hsiang-Ling; Tang, Wan-Chun; Hsiao, Heidi Hao-yun; Yang, Pei-Ming

    2014-09-17

    Berberine (BBR), a traditional Chinese herbal medicine, was shown to display anticancer activity. In this study, we attempted to provide a global view of the molecular pathways associated with its anticancer effect through a gene expression-based chemical approach. BBR-induced differentially expressed genes obtained from the Gene Expression Omnibus (GEO) at the National Center for Biotechnology Information (NCBI) were analyzed using the Connectivity Map (CMAP) database to compare similarities of gene expression profiles between BBR and CMAP compounds. Candidate compounds were further analyzed using the Search Tool for Interactions of Chemicals (STITCH) database to explore chemical-protein interactions. Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways. Further analyses demonstrated that BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK). However, BBR did not alter mTOR or HDAC activities. Interestingly, BBR induced the acetylation of α-tubulin, a substrate of HDAC6. In addition, the combination of BBR and SAHA, a pan-HDAC inhibitor, synergistically inhibited cell proliferation and induced cell cycle arrest. Our results provide novel insights into the mechanisms of action of BBR in cancer therapy.

  18. Differential DNA sequence recognition is a determinant of specificity in homeotic gene action.

    PubMed Central

    Ekker, S C; von Kessler, D P; Beachy, P A

    1992-01-01

    The homeotic genes of Drosophila encode transcriptional regulatory proteins that specify distinct segment identities. Previous studies have implicated the homeodomain as a major determinant of biological specificity within these proteins, but have not established the physical basis of this specificity. We show here that the homeodomains encoded by the Ultrabithorax and Deformed homeotic genes bind optimally to distinct DNA sequences and have mapped the determinants responsible for differential recognition. We further show that relative transactivation by these two proteins in a simple in vivo system can differ by nearly two orders of magnitude. Such differences in DNA sequence recognition and target activation provide a biochemical basis for at least part of the biological specificity of homeotic gene action. Images PMID:1356765

  19. Circadian Rhythms in Gene Expression: Relationship to Physiology, Disease, Drug Disposition and Drug Action

    PubMed Central

    Sukumaran, Siddharth; Almon, Richard R.; DuBois, Debra C.; Jusko, William J.

    2010-01-01

    Circadian rhythms (24 h cycles) are observed in virtually all aspects of mammalian function from expression of genes to complex physiological processes. The master clock is present in the suprachiasmatic nucleus (SCN) in the anterior part of the hypothalamus and controls peripheral clocks present in other parts of the body. Components of this core clock mechanism regulate the circadian rhythms in genome-wide mRNA expression, which in turn regulate various biological processes. Disruption of circadian rhythms can be either the cause or the effect of various disorders including metabolic syndrome, inflammatory diseases and cancer. Furthermore, circadian rhythms in gene expression regulate both the action and disposition of various drugs and affect therapeutic efficacy and toxicity based on dosing time. Understanding the regulation of circadian rhythms in gene expression plays an important role in both optimizing the dosing time for existing drugs and in development of new therapeutics targeting the molecular clock. PMID:20542067

  20. Arrays in rays: terminal addition in echinoderms and its correlation with gene expression.

    PubMed

    Mooi, Rich; David, Bruno; Wray, Gregory A

    2005-01-01

    The echinoderms are deuterostomes that superimpose radial symmetry upon bilateral larval morphology. Consequently, they are not the first animals that come to mind when the concepts of segmentation and terminal addition are being discussed. However, it has long been recognized that echinoderms have serial elements along their radii formed in accordance with the ocular plate rule (OPR). The OPR is a special case of terminal growth, forming elements of the ambulacra that define the rays in echinoderms. New elements are added at the terminus of the ray, which may or may not be marked by a calcified element called the terminal plate (the "ocular" of sea urchins). The OPR operates in every echinoderm, from the occasionally bizarre fossils of the Cambrian to the most familiar extant taxa. Using the OPR and other criteria of recognition, echinoderm body wall can be divided into two main regions: extraxial components are associated with the somatocoels, axial components (formed in accordance with the OPR) with the hydrocoel. We compare patterns of development in axial regions of echinoderms with those found in the anterior-posterior axes of the earliest echinoderms as well as other invertebrates. Although axial and extraxial skeletons appear to be composed of the same biomineral matrix, the genes involved in patterning these two skeletal components are likely distinct. During development of the axial skeleton, for instance, the genes engrailed and orthodenticle are expressed in spatial and temporal patterns consistent with the OPR. Other genes such as distal-less seem to demarcate early ontogenetic boundaries between the axial rudiment and the extraxial larval body. There is a complex and pervasive reorganization of gene expression domains to produce the highly divergent morphologies seen in the Echinodermata. We integrate morphological and genetic information, particularly with respect to the origins of radial symmetry in the rudiment, and the concomitant development of

  1. Liver lipid molecules induce PEPCK-C gene transcription and attenuate insulin action

    SciTech Connect

    Chen Guoxun

    2007-09-28

    Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) plays key roles in gluconeogenesis, glyceroneogenesis, and cataplerosis. Experiments were designed to examine the effects of endogenous lipid molecules from rat livers on the expression of PEPCK-C gene in primary rat hepatocytes. The lipid extracts prepared from livers of Zucker fatty, lean, and Wistar rats induced the expression levels of PEPCK-C transcripts. Insulin-mediated reduction of PEPCK-C gene expression was attenuated by the same treatment. The lipid extracts induced the relative luciferase activity of reporter gene constructs that contain a 2.2-kb 5' promoter fragment of PEPCK-C gene, but not the construct that contains only the 3' untranslated region (UTR) of its mRNA. The estimated half life of PEPCK-C transcripts in the presence of the lipid extract is the same as that in the absence of it. My results demonstrate for the first time that endogenous lipid molecules induce PEPCK-C gene transcription and attenuate insulin action in liver.

  2. Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes.

    PubMed

    de Jong, Simone; van Eijk, Kristel R; Zeegers, Dave W L H; Strengman, Eric; Janson, Esther; Veldink, Jan H; van den Berg, Leonard H; Cahn, Wiepke; Kahn, René S; Boks, Marco P M; Ophoff, Roel A

    2012-09-01

    There is genetic evidence that schizophrenia is a polygenic disorder with a large number of loci of small effect on disease susceptibility. Genome-wide association studies (GWASs) of schizophrenia have had limited success, with the best finding at the MHC locus at chromosome 6p. A recent effort of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs (eQTLs) and differential gene expression in whole blood of schizophrenia patients and controls. We examined the 6192 single-nucleotide polymorphisms (SNPs) with significance threshold at P<0.001. eQTLs were calculated for these SNPs in a sample of healthy controls (n=437). The transcripts significantly regulated by the top SNPs from the GWAS meta-analysis were subsequently tested for differential expression in an independent set of schizophrenia cases and controls (n=202). After correction for multiple testing, the eQTL analysis yielded 40 significant cis-acting effects of the SNPs. Seven of these transcripts show differential expression between cases and controls. Of these, the effect of three genes (RNF5, TRIM26 and HLA-DRB3) coincided with the direction expected from meta-analysis findings and were all located within the MHC region. Our results identify new genes of interest and highlight again the involvement of the MHC region in schizophrenia susceptibility.

  3. Four Additional Cases of Diphyllobothrium nihonkaiense Infection Confirmed by Analysis of COX1 Gene in Korea

    PubMed Central

    Park, Sang Hyun; Jeon, Hyeong Kyu; Kim, Jin Bong

    2015-01-01

    Most of the diphyllobothriid tapeworms isolated from human samples in the Republic of Korea (= Korea) have been identified as Diphyllobothrium nihonkaiense by genetic analysis. This paper reports confirmation of D. nihonkaiense infections in 4 additional human samples obtained between 1995 and 2014, which were analyzed at the Department of Parasitology, Hallym University College of Medicine, Korea. Analysis of the mitochondrial cytochrome c oxidase 1 (cox1) gene revealed a 98.5-99.5% similarity with a reference D. nihonkaiense sequence in GenBank. The present report adds 4 cases of D. nihonkaiense infections to the literature, indicating that the dominant diphyllobothriid tapeworm species in Korea is D. nihonkaiense but not D. latum. PMID:25748716

  4. Sparse Additive Ordinary Differential Equations for Dynamic Gene Regulatory Network Modeling.

    PubMed

    Wu, Hulin; Lu, Tao; Xue, Hongqi; Liang, Hua

    2014-04-02

    The gene regulation network (GRN) is a high-dimensional complex system, which can be represented by various mathematical or statistical models. The ordinary differential equation (ODE) model is one of the popular dynamic GRN models. High-dimensional linear ODE models have been proposed to identify GRNs, but with a limitation of the linear regulation effect assumption. In this article, we propose a sparse additive ODE (SA-ODE) model, coupled with ODE estimation methods and adaptive group LASSO techniques, to model dynamic GRNs that could flexibly deal with nonlinear regulation effects. The asymptotic properties of the proposed method are established and simulation studies are performed to validate the proposed approach. An application example for identifying the nonlinear dynamic GRN of T-cell activation is used to illustrate the usefulness of the proposed method.

  5. Sparse Additive Ordinary Differential Equations for Dynamic Gene Regulatory Network Modeling

    PubMed Central

    Wu, Hulin; Lu, Tao; Xue, Hongqi; Liang, Hua

    2014-01-01

    Summary The gene regulation network (GRN) is a high-dimensional complex system, which can be represented by various mathematical or statistical models. The ordinary differential equation (ODE) model is one of the popular dynamic GRN models. High-dimensional linear ODE models have been proposed to identify GRNs, but with a limitation of the linear regulation effect assumption. In this article, we propose a sparse additive ODE (SA-ODE) model, coupled with ODE estimation methods and adaptive group LASSO techniques, to model dynamic GRNs that could flexibly deal with nonlinear regulation effects. The asymptotic properties of the proposed method are established and simulation studies are performed to validate the proposed approach. An application example for identifying the nonlinear dynamic GRN of T-cell activation is used to illustrate the usefulness of the proposed method. PMID:25061254

  6. Additive insulinogenic action of Opuntia ficus-indica cladode and fruit skin extract and leucine after exercise in healthy males

    PubMed Central

    2013-01-01

    Background Oral intake of a specific extract of Opuntia ficus-indica cladode and fruit skin (OpunDia™) (OFI) has been shown to increase serum insulin concentration while reducing blood glucose level for a given amount of glucose ingestion after an endurance exercise bout in healthy young volunteers. However, it is unknown whether OFI-induced insulin stimulation after exercise is of the same magnitude than the stimulation by other insulinogenic agents like leucine as well as whether OFI can interact with those agents. Therefore, the aims of the present study were: 1) to compare the degree of insulin stimulation by OFI with the effect of leucine administration; 2) to determine whether OFI and leucine have an additive action on insulin stimulation post-exercise. Methods Eleven subjects participated in a randomized double-blind cross-over study involving four experimental sessions. In each session the subjects successively underwent a 2-h oral glucose tolerance test (OGTT) after a 30-min cycling bout at ~70% VO2max. At t0 and t60 during the OGTT, subjects ingested 75 g glucose and capsules containing either 1) a placebo; 2) 1000 mg OFI; 3) 3 g leucine; 4) 1000 mg OFI + 3 g leucine. Blood samples were collected before and at 30-min intervals during the OGTT for determination of blood glucose and serum insulin. Results Whereas no effect of leucine was measured, OFI reduced blood glucose at t90 by ~7% and the area under the glucose curve by ~15% and increased serum insulin concentration at t90 by ~35% compared to placebo (P<0.05). From t60 to the end of the OGTT, serum insulin concentration was higher in OFI+leucine than in placebo which resulted in a higher area under the insulin curve (+40%, P<0.05). Conclusion Carbohydrate-induced insulin stimulation post-exercise can be further increased by the combination of OFI with leucine. OFI and leucine could be interesting ingredients to include together in recovery drinks to resynthesize muscle glycogen faster post

  7. Additional Evidence of the Trypanocidal Action of (−)-Elatol on Amastigote Forms through the Involvement of Reactive Oxygen Species

    PubMed Central

    Desoti, Vânia Cristina; Lazarin-Bidóia, Danielle; Sudatti, Daniela Bueno; Pereira, Renato Crespo; Ueda-Nakamura, Tania; Nakamura, Celso Vataru; de Oliveira Silva, Sueli

    2014-01-01

    Chagas’ disease, a vector-transmitted infectious disease, is caused by the protozoa parasite Trypanosoma cruzi. Drugs that are currently available for the treatment of this disease are unsatisfactory, making the search for new chemotherapeutic agents a priority. We recently described the trypanocidal action of (−)-elatol, extracted from the macroalga Laurencia dendroidea. However, nothing has been described about the mechanism of action of this compound on amastigotes that are involved in the chronic phase of Chagas’ disease. The goal of the present study was to evaluate the effect of (−)-elatol on the formation of superoxide anions (O2•−), DNA fragmentation, and autophagy in amastigotes of T. cruzi to elucidate the possible mechanism of the trypanocidal action of (−)-elatol. Treatment of the amastigotes with (−)-elatol increased the formation of O2•− at all concentrations of (−)-elatol assayed compared with untreated parasites. Increased fluorescence was observed in parasites treated with (−)-elatol, indicating DNA fragmentation and the formation of autophagic compartments. The results suggest that the trypanocidal action of (−)-elatol might involve the induction of the autophagic and apoptotic death pathways triggered by an imbalance of the parasite’s redox metabolism. PMID:25257785

  8. Correlating chemical sensitivity and basal gene expression reveals mechanism of action

    PubMed Central

    Rees, Matthew G.; Seashore-Ludlow, Brinton; Cheah, Jaime H.; Adams, Drew J.; Price, Edmund V.; Gill, Shubhroz; Javaid, Sarah; Coletti, Matthew E.; Jones, Victor L.; Bodycombe, Nicole E.; Soule, Christian K.; Alexander, Benjamin; Li, Ava; Montgomery, Philip; Kotz, Joanne D.; Hon, C. Suk-Yee; Munoz, Benito; Liefeld, Ted; Dančík, Vlado; Haber, Daniel A.; Clish, Clary B.; Bittker, Joshua A.; Palmer, Michelle; Wagner, Bridget K.; Clemons, Paul A.; Shamji, Alykhan F.; Schreiber, Stuart L.

    2015-01-01

    Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ~19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters, and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal. PMID:26656090

  9. Correlating chemical sensitivity and basal gene expression reveals mechanism of action.

    PubMed

    Rees, Matthew G; Seashore-Ludlow, Brinton; Cheah, Jaime H; Adams, Drew J; Price, Edmund V; Gill, Shubhroz; Javaid, Sarah; Coletti, Matthew E; Jones, Victor L; Bodycombe, Nicole E; Soule, Christian K; Alexander, Benjamin; Li, Ava; Montgomery, Philip; Kotz, Joanne D; Hon, C Suk-Yee; Munoz, Benito; Liefeld, Ted; Dančík, Vlado; Haber, Daniel A; Clish, Clary B; Bittker, Joshua A; Palmer, Michelle; Wagner, Bridget K; Clemons, Paul A; Shamji, Alykhan F; Schreiber, Stuart L

    2016-02-01

    Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ∼19,000 basal transcript levels across 823 different human cancer cell lines and identified selective outlier transcripts. This process yielded many novel mechanistic insights, including the identification of activation mechanisms, cellular transporters and direct protein targets. We found that ML239, originally identified in a phenotypic screen for selective cytotoxicity in breast cancer stem-like cells, most likely acts through activation of fatty acid desaturase 2 (FADS2). These data and analytical tools are available to the research community through the Cancer Therapeutics Response Portal.

  10. Chemopreventive agents alters global gene expression pattern: predicting their mode of action and targets.

    PubMed

    Narayanan, Bhagavathi A

    2006-12-01

    Chemoprevention has the potential to be a major component of colon, breast, prostate and lung cancer control. Epidemiological, experimental, and clinical studies provide evidence that antioxidants, anti-inflammatory agents, n-3 polyunsaturated fatty acids and several other phytochemicals possess unique modes of action against cancer growth. However, the mode of action of several of these agents at the gene transcription level is not completely understood. Completion of the human genome sequence and the advent of DNA microarrays using cDNAs enhanced the detection and identification of hundreds of differentially expressed genes in response to anticancer drugs or chemopreventive agents. In this review, we are presenting an extensive analysis of the key findings from studies using potential chemopreventive agents on global gene expression patterns, which lead to the identification of cancer drug targets. The summary of the study reports discussed in this review explains the extent of gene alterations mediated by more than 20 compounds including antioxidants, fatty acids, NSAIDs, phytochemicals, retinoids, selenium, vitamins, aromatase inhibitor, lovastatin, oltipraz, salvicine, and zinc. The findings from these studies further reveal the utility of DNA microarray in characterizing and quantifying the differentially expressed genes that are possibly reprogrammed by the above agents against colon, breast, prostate, lung, liver, pancreatic and other cancer types. Phenolic antioxidant resveratrol found in berries and grapes inhibits the formation of prostate tumors by acting on the regulatory genes such as p53 while activating a cascade of genes involved in cell cycle and apoptosis including p300, Apaf-1, cdk inhibitor p21, p57 (KIP2), p53 induced Pig 7, Pig 8, Pig 10, cyclin D, DNA fragmentation factor 45. The group of genes significantly altered by selenium includes cyclin D1, cdk5, cdk4, cdk2, cdc25A and GADD 153. Vitamine D shows impact on p21(Waf1/Cip1) p27 cyclin B

  11. Toxicological safety assessment of genetically modified Bacillus thuringiensis with additional N-acyl homoserine lactonase gene.

    PubMed

    Peng, Donghai; Zhou, Chenfei; Chen, Shouwen; Ruan, Lifang; Yu, Ziniu; Sun, Ming

    2008-01-01

    The aim of the present study is to evaluate the toxicology safety to mammals of a genetically modified (GM) Bacillus thuringiensis with an additional N-acyl homoserine lactones gene (aiiA), which possesses insecticidal activity together with restraint of bacterial pathogenicity and is intended for use as a multifunctional biopesticide. Safety assessments included an acute oral toxicity test and 28-d animal feeding study in Wistar rats, primary eye and dermal irritation in Zealand White rabbits, and delayed contact hypersensitivity in guinea pigs. Tests were conducted using spray-dried powder preparation. This GM product showed toxicity neither in oral acute toxicity test nor in 28-d animal feeding test at a dose of 5,000 mg/kg body weight. During the animal feeding test, there were no significant differences in growth, food and water consumption, hematology, blood biochemical indices, organ weights, and histopathology finding between rats in controls and tested groups. Tested animals in primary eye and dermal irritation and delayed contact hypersensitivity test were also devoid of any toxicity compared to controls. All the above results demonstrated that the GM based multifunctional B. thuringiensis has low toxicity and low eye and dermal irritation and would not cause hypersensitivity to laboratory mammals and therefore could be regarded as safe for use as a pesticide.

  12. Mechanism of Action of 2-Aminobenzamide HDAC Inhibitors in Reversing Gene Silencing in Friedreich's Ataxia.

    PubMed

    Soragni, Elisabetta; Chou, C James; Rusche, James R; Gottesfeld, Joel M

    2015-01-01

    The genetic defect in Friedreich's ataxia (FRDA) is the hyperexpansion of a GAA•TTC triplet in the first intron of the FXN gene, encoding the essential mitochondrial protein frataxin. Histone post-translational modifications near the expanded repeats are consistent with heterochromatin formation and consequent FXN gene silencing. Using a newly developed human neuronal cell model, derived from patient-induced pluripotent stem cells, we find that 2-aminobenzamide histone deacetylase (HDAC) inhibitors increase FXN mRNA levels and frataxin protein in FRDA neuronal cells. However, only compounds targeting the class I HDACs 1 and 3 are active in increasing FXN mRNA in these cells. Structural analogs of the active HDAC inhibitors that selectively target either HDAC1 or HDAC3 do not show similar increases in FXN mRNA levels. To understand the mechanism of action of these compounds, we probed the kinetic properties of the active and inactive inhibitors, and found that only compounds that target HDACs 1 and 3 exhibited a slow-on/slow-off mechanism of action for the HDAC enzymes. HDAC1- and HDAC3-selective compounds did not show this activity. Using siRNA methods in the FRDA neuronal cells, we show increases in FXN mRNA upon silencing of either HDACs 1 or 3, suggesting the possibility that inhibition of each of these class I HDACs is necessary for activation of FXN mRNA synthesis, as there appears to be redundancy in the silencing mechanism caused by the GAA•TTC repeats. Moreover, inhibitors must have a long residence time on their target enzymes for this activity. By interrogating microarray data from neuronal cells treated with inhibitors of different specificity, we selected two genes encoding histone macroH2A (H2AFY2) and Polycomb group ring finger 2 (PCGF2) that were specifically down-regulated by the inhibitors targeting HDACs1 and 3 versus the more selective inhibitors for further investigation. Both genes are involved in transcriptional repression and we speculate

  13. Localization of eight additional genes in the human major histocompatibility complex, including the gene encoding the casein kinase II {beta} subunit (CSNK2B)

    SciTech Connect

    Albertella, M.R.; Jones, H.; Thomson, W.

    1996-09-01

    A wide range of autoimmune and other diseases are known to be associated with the major histocompatibility complex. Many of these diseases are linked to the genes encoding the polymorphic histocompatibility complex. Many of these diseases are linked to the genes encoding the polymorphic histocompatibility antigens in the class I and class II regions, but some appear to be more strongly associated with genes in the central 1100-kb class III region, making it important to characterize this region fully for the presence of novel genes. An {approximately}220-kb segment of DNA in the class III region separating the Hsp70 (HSPA1L) and BAT1 (D6S8IE) genes, which was previously known to contain 14 genes. Genomic DNA fragments spanning the gaps between the known genes were used as probes to isolate cDNAs corresponding to five new genes within this region. Evidence from Northern blot analysis and exon trapping experiments that suggested the presence of at least two more new genes was also obtained. Partial cDNA and complete exonic genomic sequencing of one of the new genes has identified it as the casein kinase II{beta} subunit (CSNK2B). Two of the other novel genes lie within a region syntenic to that implicated in susceptibility to experimental allergic orchitis in the mouse, an autoimmune disease of the testis, and represent additional candidates for the Orch-1 locus associated with this disease. In addition, characterization of the 13-kb intergenic gap separating the RD (D6545) and G11 (D6S60E) genes has revealed the presence of a gene encoding a 1246-amino-acid polypeptide that shows significant sequence similarity to the yeast anti-viral Ski2p gene product. 49 refs., 8 figs.

  14. Gene actions for yield and its attributes and their implications in the inheritance pattern over three generations in opium poppy (Papaver somniferum L.).

    PubMed

    Mishra, Brij K; Mishra, R; Jena, S N; Shukla, Sudhir

    2016-09-01

    The gene actions for yield and its attributes and their inheritance pattern based on five parameter model have been explored in four single crosses (NBIHT-5 × NBIHT-6, NBIHT-5 × NBMHT-1, NBMHT-1 × NBIHT-6 and NBMHT-2 × NBMHT-1) obtained using thebaine rich pure lines of opium poppy (Papaver somniferum L.) for three consecutive generations. All the traits showed nonallelic mode of interaction, however, dominance effect (h) was more pronounced for all the traits except thebaine and papaverine. The dominance × dominance (l) effects were predominant over additive × additive (i) for all traits in all the four crosses except for papaverine. The seed and opium yield, and its contributing traits inherited quantitatively. The fixable gene effects (d) and (i) were lower in magnitude than nonfixable (h) and (l) gene effects. The estimates of heterosis were also higher in comparison to the respective parents which suggested preponderance of dominance gene action for controlling most of the traits. The phenotypic coefficient of variation was marginally higher than those of genotypic coefficient of variation for all the traits. The traits thebaine, narcotine, morphine and opium yield had high heritability coupled with high genetic advance. The leaf number, branches per plant and stem diameter showed positive correlation with opium and seed yields. The selection of plants having large number of leaves, branches and capsules with bigger size would be advantageous to enhance the yield potential.

  15. RNA-seq validation of RNAi identifies additional gene connectivity in Tribolium castaneum (Coleoptera: Tenebrionidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    RNA interference (RNAi) is a functional genomics tool to validate phenotypes by delivering targeted, gene-specific, and complementary dsRNA into a host via injection, feeding, or other means in order to reduce gene expression. RNAi in the red flour beetle, Tribolium castaneum, has been successful du...

  16. Cardiovascular actions of DOPA mediated by the gene product of ocular albinism 1.

    PubMed

    Goshima, Yoshio; Nakamura, Fumio; Masukawa, Daiki; Chen, Sandy; Koga, Motokazu

    2014-01-01

    l-3,4-Dihydroxyphenylalanine (DOPA) is the metabolic precursor of dopamine, and the single most effective agent in the treatment of Parkinson's disease. One problem with DOPA therapy for Parkinson's disease is its cardiovascular side effects including hypotension and syncope, the underlying mechanisms of which are largely unknown. We proposed that DOPA is a neurotransmitter in the central nervous system, but specific receptors for DOPA had not been identified. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPA-binding activity. It was unknown, however, whether or not OA1 is responsible for the actions of DOPA itself. Immunohistochemical examination revealed that OA1 was expressed in the nucleus tractus solitarii (NTS). OA1-positive cells adjacent to tyrosine hydroxylase-positive cell bodies and nerve fibers were detected in the depressor sites of the NTS. OA1 knockdown using oa1-specific shRNA-adenovirus vectors in the NTS reduced the expression levels of OA1 in the NTS. The prior injection of the shRNA against OA1 suppressed the depressor and bradycardic responses to DOPA but not to glutamate in the NTS of anesthetized rats. Thus OA-1 is a functional receptor of DOPA in the NTS, which warrants reexamination of the mechanisms for the therapeutic and untoward actions of DOPA.

  17. Non-additive gene regulation in a citrus allotetraploid somatic hybrid between C. reticulata Blanco and C. limon (L.) Burm.

    PubMed

    Bassene, J B; Froelicher, Y; Dubois, C; Ferrer, R M; Navarro, L; Ollitrault, P; Ancillo, G

    2010-09-01

    Polyploid plants often produce new phenotypes, exceeding the range of variability existing in the diploid gene pool. Several hundred citrus allotetraploid hybrids have been created by somatic hybridization. These genotypes are interesting models to study the immediate effects of allopolyploidization on the regulation of gene expression. Here, we report genome-wide gene expression analysis in fruit pulp of a Citrus interspecific somatic allotetraploid between C. reticulata cv 'Willowleaf mandarin'+C. limon cv 'Eureka lemon', using a Citrus 20K cDNA microarray. Around 4% transcriptome divergence was observed between the two parental species, and 212 and 160 genes were more highly expressed in C. reticulata and C. limon, respectively. Differential expression of certain genes was confirmed by quantitative real-time RT-PCR. A global downregulation of the allotetraploid hybrid transcriptome was observed, as compared with a theoretical mid parent, for the genes displaying interspecific expression divergence between C. reticulata and C. limon. The genes underexpressed in mandarin, as compared with lemon, were also systematically repressed in the allotetraploid. When genes were overexpressed in C. reticulata compared with C. limon, the distribution of allotetraploid gene expression was far more balanced. Cluster analysis on the basis of gene expression clearly indicated the hybrid was much closer to C. reticulata than to C. limon. These results suggest there is a global dominance of the mandarin transcriptome, in consistence with our previous studies on aromatic compounds and proteomics. Interspecific differentiation of gene expression and non-additive gene regulation involved various biological pathways and different cellular components.

  18. Random transposon mutagenesis of the Saccharopolyspora erythraea genome reveals additional genes influencing erythromycin biosynthesis

    PubMed Central

    Fedashchin, Andrij; Cernota, William H.; Gonzalez, Melissa C.; Leach, Benjamin I.; Kwan, Noelle; Wesley, Roy K.; Weber, J. Mark

    2015-01-01

    A single cycle of strain improvement was performed in Saccharopolyspora erythraea mutB and 15 genotypes influencing erythromycin production were found. Genotypes generated by transposon mutagenesis appeared in the screen at a frequency of ∼3%. Mutations affecting central metabolism and regulatory genes were found, as well as hydrolases, peptidases, glycosyl transferases and unknown genes. Only one mutant retained high erythromycin production when scaled-up from micro-agar plug fermentations to shake flasks. This mutant had a knockout of the cwh1 gene (SACE_1598), encoding a cell-wall-associated hydrolase. The cwh1 knockout produced visible growth and morphological defects on solid medium. This study demonstrated that random transposon mutagenesis uncovers strain improvement-related genes potentially useful for strain engineering. PMID:26468041

  19. Communication as a predictor of willingness to donate one's organs: an addition to the Theory of Reasoned Action.

    PubMed

    Jeffres, Leo W; Carroll, Jeanine A; Rubenking, Bridget E; Amschlinger, Joe

    2008-12-01

    Fishbein and Ajzen's theory of reasoned action has been used by many researchers, particularly in regard to health communication, to predict behavioral intentions and behavior. According to that theory, one's intention is the best predictor that one will engage in a behavior, and attitudes and social norms predict behavioral intentions. Other researchers have added different variables to the postulates of attitudes and social norms that Fishbein and Ajzen maintain are the best predictors of behavioral intention. Here we draw on data from a 2006 telephone survey (N = 420) gauging the awareness of an organ donation campaign in Northeast Ohio to examine the impact of communication on people's intentions. The current study supports the hypothesis that those who communicate with others are more likely to express a greater willingness to become an organ donor, but it expands the range of communication contexts. With demographics and attitudes toward organ donation controlled for, this study shows that communication with others about organ donation increases the willingness of individuals to have favorable attitudes about being an organ donor.

  20. Action dynamics in multitasking: the impact of additional task factors on the execution of the prioritized motor movement

    PubMed Central

    Scherbaum, Stefan; Gottschalk, Caroline; Dshemuchadse, Maja; Fischer, Rico

    2015-01-01

    In multitasking, the execution of a prioritized task is in danger of crosstalk by the secondary task. Task shielding allows minimizing this crosstalk. However, the locus and temporal dynamics of crosstalk effects and further sources of influence on the execution of the prioritized task are to-date only vaguely understood. Here we combined a dual-task paradigm with an action dynamics approach and studied how and according to which temporal characteristics crosstalk, previously experienced interference and previously executed responses influenced participants' mouse movements in the prioritized task's execution. Investigating continuous mouse movements of the prioritized task, our results indicate a continuous crosstalk from secondary task processing until the endpoint of the movement was reached, although the secondary task could only be executed after finishing execution of the prioritized task. The motor movement in the prioritized task was further modulated by previously experienced interference between the prioritized and the secondary task. Furthermore, response biases from previous responses of the prioritized and the secondary task in movements indicate different sources of such biases. The bias by previous responses to the prioritized task follows a sustained temporal pattern typical for a contextual reactivation, while the bias by previous responses to the secondary task follows a decaying temporal pattern indicating residual activation of previously activated spatial codes. PMID:26217267

  1. Human Capital: Additional Actions Needed to Enhance DOD’s Efforts to Address Mental Health Care Stigma

    DTIC Science & Technology

    2016-04-01

    stress disorder or traumatic brain injury. Additionally, the Defense Suicide Prevention Office reports through the Executive Director of the Office of...Efforts to Address Mental Health Care Stigma Why GAO Did This Study A 2010 DOD task force on suicide prevention concluded that stigma—the negative...Representatives A 2010 Department of Defense (DOD) Task Force on the Prevention of Suicide by Members of the Armed Forces concluded that

  2. Identification of a sugar beet BvM14-MADS box gene through differential gene expression analysis of monosomic addition line M14.

    PubMed

    Ma, Chunquan; Wang, Yuguang; Wang, Yuting; Wang, Lifa; Chen, Sixue; Li, Haiying

    2011-11-01

    Monosomic addition line M14 carrying an additional chromosome 9 from Beta corolliflora Zosimovic ex Buttler was obtained through hybridization between the wild species B. corolliflora and a cultivated species Beta vulgaris L. var Saccharifera Alef. The M14 line showed diplosporic reproduction and stress tolerance. To identify differentially expressed genes in M14, a subtractive cDNA library was prepared by suppression subtractive hybridization (SSH) between M14 (2n=18+1) and B. vulgaris (2n=18). A total of 190 unique sequences were identified in the library and their putative functions were analyzed using Gene Ontology (GO). One of the genes, designated as BvM14-MADS box, encodes a MADS box transcription factor. It was cloned from M14 and over-expressed in transgenic tobacco plants. Interestingly, this gene was located on chromosome 2 of B. vulgaris, not on the additional chromosome 9. Overexpression of BvM14-MADS box led to significant phenotypic changes in tobacco. The differential expression of BvM14-MADS box gene in M14 may be caused by the interaction between the additional chromosome 9 from B. corolliflora and the B. vulgaris chromosomes in M14.

  3. Non-additive genome-wide association scan reveals a new gene associated with habitual coffee consumption

    PubMed Central

    Pirastu, Nicola; Kooyman, Maarten; Robino, Antonietta; van der Spek, Ashley; Navarini, Luciano; Amin, Najaf; Karssen, Lennart C.; Van Duijn, Cornelia M; Gasparini, Paolo

    2016-01-01

    Coffee is one of the most consumed beverages world-wide and one of the primary sources of caffeine intake. Given its important health and economic impact, the underlying genetics of its consumption has been widely studied. Despite these efforts, much has still to be uncovered. In particular, the use of non-additive genetic models may uncover new information about the genetic variants driving coffee consumption. We have conducted a genome-wide association study in two Italian populations using additive, recessive and dominant models for analysis. This has uncovered a significant association in the PDSS2 gene under the recessive model that has been replicated in an independent cohort from the Netherlands (ERF). The identified gene has been shown to negatively regulate the expression of the caffeine metabolism genes and can thus be linked to coffee consumption. Further bioinformatics analysis of eQTL and histone marks from Roadmap data has evidenced a possible role of the identified SNPs in regulating PDSS2 gene expression through enhancers present in its intron. Our results highlight a novel gene which regulates coffee consumption by regulating the expression of the genes linked to caffeine metabolism. Further studies will be needed to clarify the biological mechanism which links PDSS2 and coffee consumption. PMID:27561104

  4. Characterization of the Soluble NSF Attachment Protein gene family identifies two members involved in additive resistance to a plant pathogen

    PubMed Central

    Lakhssassi, Naoufal; Liu, Shiming; Bekal, Sadia; Zhou, Zhou; Colantonio, Vincent; Lambert, Kris; Barakat, Abdelali; Meksem, Khalid

    2017-01-01

    Proteins with Tetratricopeptide-repeat (TPR) domains are encoded by large gene families and distributed in all plant lineages. In this study, the Soluble NSF-Attachment Protein (SNAP) subfamily of TPR containing proteins is characterized. In soybean, five members constitute the SNAP gene family: GmSNAP18, GmSNAP11, GmSNAP14, GmSNAP02, and GmSNAP09. Recently, GmSNAP18 has been reported to mediate resistance to soybean cyst nematode (SCN). Using a population of recombinant inbred lines from resistant and susceptible parents, the divergence of the SNAP gene family is analysed over time. Phylogenetic analysis of SNAP genes from 22 diverse plant species showed that SNAPs were distributed in six monophyletic clades corresponding to the major plant lineages. Conservation of the four TPR motifs in all species, including ancestral lineages, supports the hypothesis that SNAPs were duplicated and derived from a common ancestor and unique gene still present in chlorophytic algae. Syntenic analysis of regions harbouring GmSNAP genes in soybean reveals that this family expanded from segmental and tandem duplications following a tetraploidization event. qRT-PCR analysis of GmSNAPs indicates a co-regulation following SCN infection. Finally, genetic analysis demonstrates that GmSNAP11 contributes to an additive resistance to SCN. Thus, GmSNAP11 is identified as a novel minor gene conferring resistance to SCN. PMID:28338077

  5. GENE EXPRESSION PROFILING IN TESTIS AND LIVER OF MICE TO IDENTIFY MODES OF ACTION OF CONAZOLE TOXICITIES

    EPA Science Inventory

    Gene Expression Profiling in Testis and Liver of Mice to Identify MODES OF ACTION OF Conazole TOXICITies

    Amber K. Goetz1, Wenjun Bao2, Judith E. Schmid2, Carmen Wood2, Hongzu Ren2, Deborah S. Best2, Rachel N. Murrell1, John C. Rockett2, Michael G. Narotsky2, Douglas C. Wol...

  6. Detection of additional genes of the patulin biosynthetic pathway in Penicillium griseofulvum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genes in the patulin biosynthetic pathway are likely to be arranged in a cluster as has been found for biosynthetic pathways of other mycotoxins. The mycotoxin patulin, common in apples and apple juice, is most often associated with Penicillium expansum. However, of 15 fungal species capable of sy...

  7. Integrated fuzzy concentration addition-independent action (IFCA-IA) model outperforms two-stage prediction (TSP) for predicting mixture toxicity.

    PubMed

    Wang, Zhuang; Chen, Jingwen; Huang, Liping; Wang, Ying; Cai, Xiyun; Qiao, Xianliang; Dong, Yuying

    2009-02-01

    Mixture toxicities were determined for 12 industrial organic chemicals bearing four different modes of toxic action (MOAs) to Vibrio fischeri, to compare the predictability of the integrated fuzzy concentration addition-independent action (IFCA-IA) model and the two-stage prediction (TSP) model. Three mixtures were designed: The first and second mixtures were based on the ratios of each component at the 1% and 50% effect concentrations (EC(1) and EC(50)), respectively; and the third mixture contained an equimolar ratio of individual components. For the EC(1), EC(50) and equimolar ratio, prediction errors from the IFCA-IA model at the 50% experimental mixture effects were 0.3%, 6% and 0.6%, respectively; while for the TSP model, the corresponding errors were 2.8%, 19% and 24%, respectively. Thus, the IFCA-IA model performed better than the TSP model. The IFCA-IA model calculated two weight coefficients from the molecular structural descriptors, which weigh the relation between concentration addition (CA) and independent action (IA) through the fuzzy membership functions. Thus, MOAs are not pre-requisites for mixture toxicity prediction by the IFCA-IA approach, implying the practicability of this method in toxicity assessment of mixtures.

  8. Chromosomal Localization of Genes Conferring Desirable Agronomic Traits from Wheat-Agropyron cristatum Disomic Addition Line 5113.

    PubMed

    Li, Qingfeng; Lu, Yuqing; Pan, Cuili; Yao, Miaomiao; Zhang, Jinpeng; Yang, Xinming; Liu, Weihua; Li, Xiuquan; Xi, Yajun; Li, Lihui

    2016-01-01

    Creation of wheat-alien disomic addition lines and localization of desirable genes on alien chromosomes are important for utilization of these genes in genetic improvement of common wheat. In this study, wheat-Agropyron cristatum derivative line 5113 was characterized by genomic in situ hybridization (GISH) and specific-locus amplified fragment sequencing (SLAF-seq), and was demonstrated to be a novel wheat-A. cristatum disomic 6P addition line. Compared with its parent Fukuhokomugi (Fukuho), 5113 displayed multiple elite agronomic traits, including higher uppermost internode/plant height ratio, larger flag leaf, longer spike length, elevated grain number per spike and spikelet number per spike, more kernel number in the middle spikelet, more fertile tiller number per plant, and enhanced resistance to powdery mildew and leaf rust. Genes conferring these elite traits were localized on the A. cristatum 6P chromosome by using SLAF-seq markers and biparental populations (F1, BC1F1 and BC1F2 populations) produced from the crosses between Fukuho and 5113. Taken together, chromosomal localization of these desirable genes will facilitate transferring of high-yield and high-resistance genes from A. cristatum into common wheat, and serve as the foundation for the utilization of 5113 in wheat breeding.

  9. Chromosomal Localization of Genes Conferring Desirable Agronomic Traits from Wheat-Agropyron cristatum Disomic Addition Line 5113

    PubMed Central

    Pan, Cuili; Yao, Miaomiao; Zhang, Jinpeng; Yang, Xinming; Liu, Weihua; Li, Xiuquan; Xi, Yajun; Li, Lihui

    2016-01-01

    Creation of wheat-alien disomic addition lines and localization of desirable genes on alien chromosomes are important for utilization of these genes in genetic improvement of common wheat. In this study, wheat-Agropyron cristatum derivative line 5113 was characterized by genomic in situ hybridization (GISH) and specific-locus amplified fragment sequencing (SLAF-seq), and was demonstrated to be a novel wheat-A. cristatum disomic 6P addition line. Compared with its parent Fukuhokomugi (Fukuho), 5113 displayed multiple elite agronomic traits, including higher uppermost internode/plant height ratio, larger flag leaf, longer spike length, elevated grain number per spike and spikelet number per spike, more kernel number in the middle spikelet, more fertile tiller number per plant, and enhanced resistance to powdery mildew and leaf rust. Genes conferring these elite traits were localized on the A. cristatum 6P chromosome by using SLAF-seq markers and biparental populations (F1, BC1F1 and BC1F2 populations) produced from the crosses between Fukuho and 5113. Taken together, chromosomal localization of these desirable genes will facilitate transferring of high-yield and high-resistance genes from A. cristatum into common wheat, and serve as the foundation for the utilization of 5113 in wheat breeding. PMID:27824906

  10. Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells.

    PubMed

    Heneweer, Marjoke; Muusse, Martine; van den Berg, Martin; Sanderson, J Thomas

    2005-10-15

    In order to protect consumers from ultraviolet (UV) radiation and enhance light stability of the product, three to eight UV filters are usually added to consumer sunscreen products. High lipophilicity of the UV filters has been shown to cause bioaccumulation in fish and humans, leading to environmental levels of UV filters that are similar to those of PCBs and DDT. In this paper, estrogen-regulated pS2 gene transcription in the human mammary tumor cell line MCF-7 was used as a measure of estrogenicity of four individual UV filters. Since humans are exposed to more than one UV filter at a time, an equipotent binary mixture of 2-hydroxy-4-methoxy-benzophenone (BP-3) and its metabolite 2,4-dihydroxy benzophenone (BP-1), as well as an equipotent multi-component mixture of BP-1, BP-3, octyl methoxy cinnamate (OMC) and 3-(4-methylbenzylidene) camphor (4-MBC), were also evaluated for their ability to induce pS2 gene transcription in order to examine additivity. An estrogen receptor-mediated mechanism of action was expected for all UV filters. Therefore, our null-hypothesis was that combined estrogenic responses, measured as increased pS2 gene transcription in MCF-7 cells after exposure to mixtures of UV filters, are additive, according to a concentration-addition model. Not all UV filters produced a full concentration-response curve within the concentration range tested (100 nM-1 microM). Therefore, instead of using EC50 values for comparison, the concentration at which each compound caused a 50% increase of basal pS2 gene transcription was defined as the C50 value for that compound and used to calculate relative potencies. For comparison, the EC50 value of a compound is the concentration at which the compound elicits an effect that is 50% of its maximal effect. Individual UV filters increased pS2 gene transcription concentration-dependently with C50 values of 0.12 microM, 0.5 microM, 1.9 microM, and 1.0 microM for BP-1, BP-3, 4-MBC and OMC, respectively. Estradiol (E2

  11. Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells

    SciTech Connect

    Heneweer, Marjoke . E-mail: M.Heneweer@iras.uu.nl; Muusse, Martine; Berg, Martin van den; Sanderson, J. Thomas

    2005-10-15

    In order to protect consumers from ultraviolet (UV) radiation and enhance light stability of the product, three to eight UV filters are usually added to consumer sunscreen products. High lipophilicity of the UV filters has been shown to cause bioaccumulation in fish and humans, leading to environmental levels of UV filters that are similar to those of PCBs and DDT. In this paper, estrogen-regulated pS2 gene transcription in the human mammary tumor cell line MCF-7 was used as a measure of estrogenicity of four individual UV filters. Since humans are exposed to more than one UV filter at a time, an equipotent binary mixture of 2-hydroxy-4-methoxy-benzophenone (BP-3) and its metabolite 2,4-dihydroxy benzophenone (BP-1), as well as an equipotent multi-component mixture of BP-1, BP-3, octyl methoxy cinnamate (OMC) and 3-(4-methylbenzylidene) camphor (4-MBC), were also evaluated for their ability to induce pS2 gene transcription in order to examine additivity. An estrogen receptor-mediated mechanism of action was expected for all UV filters. Therefore, our null-hypothesis was that combined estrogenic responses, measured as increased pS2 gene transcription in MCF-7 cells after exposure to mixtures of UV filters, are additive, according to a concentration-addition model. Not all UV filters produced a full concentration-response curve within the concentration range tested (100 nM-1 {mu}M). Therefore, instead of using EC{sub 50} values for comparison, the concentration at which each compound caused a 50% increase of basal pS2 gene transcription was defined as the C50 value for that compound and used to calculate relative potencies. For comparison, the EC{sub 50} value of a compound is the concentration at which the compound elicits an effect that is 50% of its maximal effect. Individual UV filters increased pS2 gene transcription concentration-dependently with C50 values of 0.12 {mu}M, 0.5 {mu}M, 1.9 {mu}M, and 1.0 {mu}M for BP-1, BP-3, 4-MBC and OMC, respectively. Estradiol

  12. Supplementing High-Density SNP Microarrays for Additional Coverage of Disease-Related Genes: Addiction as a Paradigm

    PubMed Central

    Saccone, Scott F.; Bierut, Laura J.; Chesler, Elissa J.; Kalivas, Peter W.; Lerman, Caryn; Saccone, Nancy L.; Uhl, George R.; Li, Chuan-Yun; Philip, Vivek M.; Edenberg, Howard J.; Sherry, Stephen T.; Feolo, Michael; Moyzis, Robert K.; Rutter, Joni L.

    2009-01-01

    Commercial SNP microarrays now provide comprehensive and affordable coverage of the human genome. However, some diseases have biologically relevant genomic regions that may require additional coverage. Addiction, for example, is thought to be influenced by complex interactions among many relevant genes and pathways. We have assembled a list of 486 biologically relevant genes nominated by a panel of experts on addiction. We then added 424 genes that showed evidence of association with addiction phenotypes through mouse QTL mappings and gene co-expression analysis. We demonstrate that there are a substantial number of SNPs in these genes that are not well represented by commercial SNP platforms. We address this problem by introducing a publicly available SNP database for addiction. The database is annotated using numeric prioritization scores indicating the extent of biological relevance. The scores incorporate a number of factors such as SNP/gene functional properties (including synonymy and promoter regions), data from mouse systems genetics and measures of human/mouse evolutionary conservation. We then used HapMap genotyping data to determine if a SNP is tagged by a commercial microarray through linkage disequilibrium. This combination of biological prioritization scores and LD tagging annotation will enable addiction researchers to supplement commercial SNP microarrays to ensure comprehensive coverage of biologically relevant regions. PMID:19381300

  13. Supplementing High-Density SNP Microarrays for Additional Coverage of Disease-Related Genes: Addiction as a Paradigm

    SciTech Connect

    SacconePhD, Scott F; Chesler, Elissa J; Bierut, Laura J; Kalivas, Peter J; Lerman, Caryn; Saccone, Nancy L; Uhl, George R; Li, Chuan-Yun; Philip, Vivek M; Edenberg, Howard; Sherry, Steven; Feolo, Michael; Moyzis, Robert K; Rutter, Joni L

    2009-01-01

    Commercial SNP microarrays now provide comprehensive and affordable coverage of the human genome. However, some diseases have biologically relevant genomic regions that may require additional coverage. Addiction, for example, is thought to be influenced by complex interactions among many relevant genes and pathways. We have assembled a list of 486 biologically relevant genes nominated by a panel of experts on addiction. We then added 424 genes that showed evidence of association with addiction phenotypes through mouse QTL mappings and gene co-expression analysis. We demonstrate that there are a substantial number of SNPs in these genes that are not well represented by commercial SNP platforms. We address this problem by introducing a publicly available SNP database for addiction. The database is annotated using numeric prioritization scores indicating the extent of biological relevance. The scores incorporate a number of factors such as SNP/gene functional properties (including synonymy and promoter regions), data from mouse systems genetics and measures of human/mouse evolutionary conservation. We then used HapMap genotyping data to determine if a SNP is tagged by a commercial microarray through linkage disequilibrium. This combination of biological prioritization scores and LD tagging annotation will enable addiction researchers to supplement commercial SNP microarrays to ensure comprehensive coverage of biologically relevant regions.

  14. Genetic variation at the TPH2 gene influences impulsivity in addition to eating disorders.

    PubMed

    Slof-Op't Landt, Margarita C T; Bartels, Meike; Middeldorp, Christel M; van Beijsterveldt, Catherina E M; Slagboom, P Eline; Boomsma, Dorret I; van Furth, Eric F; Meulenbelt, Ingrid

    2013-01-01

    Genes are involved in eating disorders (EDs) and self-induced vomiting (SV), a key symptom of different types of EDs. Perfectionism and impulsivity are potential risk factors for EDs. TPH2 (tryptophan hydroxylase 2) SNP rs1473473 was previously associated with anorexia nervosa and EDs characterized by SV. Could perfectionism or impulsivity be underlying the association between rs1473473 and EDs? Genetic association between TPH2 SNP rs1473473 and perfectionism or impulsivity was first evaluated in a random control group (N = 512). The associations obtained in this control group were subsequently tested in a group of patients with an ED (N = 267). The minor allele of rs1473473 (OR = 1.49) was more frequent in impulsive controls, but also in impulsive patients with an ED (OR = 1.83). The largest effect was found in the patients with an ED characterized by SV (OR = 2.51, p = 0.02). Genetic variation at the TPH2 gene appeared to affect impulsivity which, in turn, might predispose to the SV phenotype.

  15. Gene expression suggests conserved aspects of Hox gene regulation in arthropods and provides additional support for monophyletic Myriapoda.

    PubMed

    Janssen, Ralf; Budd, Graham E

    2010-07-05

    Antisense transcripts of Ultrabithorax (aUbx) in the millipede Glomeris and the centipede Lithobius are expressed in patterns complementary to that of the Ubx sense transcripts. A similar complementary expression pattern has been described for non-coding RNAs (ncRNAs) of the bithoraxoid (bxd) locus in Drosophila, in which the transcription of bxd ncRNAs represses Ubx via transcriptional interference. We discuss our findings in the context of possibly conserved mechanisms of Ubx regulation in myriapods and the fly.Bicistronic transcription of Ubx and Antennapedia (Antp) has been reported previously for a myriapod and a number of crustaceans. In this paper, we show that Ubx/Antp bicistronic transcripts also occur in Glomeris and an onychophoran, suggesting further conserved mechanisms of Hox gene regulation in arthropods.Myriapod monophyly is supported by the expression of aUbx in all investigated myriapods, whereas in other arthropod classes, including the Onychophora, aUbx is not expressed. Of the two splice variants of Ubx/Antp only one could be isolated from myriapods, representing a possible further synapomorphy of the Myriapoda.

  16. Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome.

    PubMed

    Hodes, M E; Woodward, K; Spinner, N B; Emanuel, B S; Enrico-Simon, A; Kamholz, J; Stambolian, D; Zackai, E H; Pratt, V M; Thomas, I T; Crandall, K; Dlouhy, S R; Malcolm, S

    2000-07-01

    The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.

  17. Identification of an additional gene required for eukaryotic nonsense mRNA turnover.

    PubMed Central

    Lee, B S; Culbertson, M R

    1995-01-01

    Loss of function of any one of three UPF genes prevents the accelerated decay of nonsense mRNAs in Saccharomyces cerevisiae. We report the identification and DNA sequence of UPF3, which is present in one nonessential copy on chromosome VII. Upf3 contains three putative nuclear localization signal sequences, suggesting that it may be located in a different compartment than the cytoplasmic Upf1 protein. Epitope-tagged Upf3 (FLAG-Upf3) does not cofractionate with polyribosomes or 80S ribosomal particles. Double disruptions of UPF1 and UPF3 affect nonsense mRNA decay in a manner indistinguishable from single disruptions. These results suggest that the Upf proteins perform related functions in a common pathway. Images Fig. 1 Fig. 3 PMID:7479783

  18. Computational investigations on polymerase actions in gene transcription and replication: Combining physical modeling and atomistic simulations

    NASA Astrophysics Data System (ADS)

    Jin, Yu

    2016-01-01

    Polymerases are protein enzymes that move along nucleic acid chains and catalyze template-based polymerization reactions during gene transcription and replication. The polymerases also substantially improve transcription or replication fidelity through the non-equilibrium enzymatic cycles. We briefly review computational efforts that have been made toward understanding mechano-chemical coupling and fidelity control mechanisms of the polymerase elongation. The polymerases are regarded as molecular information motors during the elongation process. It requires a full spectrum of computational approaches from multiple time and length scales to understand the full polymerase functional cycle. We stay away from quantum mechanics based approaches to the polymerase catalysis due to abundant former surveys, while addressing statistical physics modeling approaches along with all-atom molecular dynamics simulation studies. We organize this review around our own modeling and simulation practices on a single subunit T7 RNA polymerase, and summarize commensurate studies on structurally similar DNA polymerases as well. For multi-subunit RNA polymerases that have been actively studied in recent years, we leave systematical reviews of the simulation achievements to latest computational chemistry surveys, while covering only representative studies published very recently, including our own work modeling structure-based elongation kinetic of yeast RNA polymerase II. In the end, we briefly go through physical modeling on elongation pauses and backtracking activities of the multi-subunit RNAPs. We emphasize on the fluctuation and control mechanisms of the polymerase actions, highlight the non-equilibrium nature of the operation system, and try to build some perspectives toward understanding the polymerase impacts from the single molecule level to a genome-wide scale. Project supported by the National Natural Science Foundation (Grant No. 11275022).

  19. Infection of Mice by Salmonella enterica Serovar Enteritidis Involves Additional Genes That Are Absent in the Genome of Serovar Typhimurium

    PubMed Central

    Silva, Cecilia A.; Blondel, Carlos J.; Quezada, Carolina P.; Porwollik, Steffen; Andrews-Polymenis, Helene L.; Toro, Cecilia S.; Zaldívar, Mercedes; Contreras, Inés

    2012-01-01

    Salmonella enterica serovar Enteritidis causes a systemic, typhoid-like infection in newly hatched poultry and mice. In the present study, a library of 54,000 transposon mutants of S. Enteritidis phage type 4 (PT4) strain P125109 was screened for mutants deficient in the in vivo colonization of the BALB/c mouse model using a microarray-based negative-selection screening. Mutants in genes known to contribute to systemic infection (e.g., Salmonella pathogenicity island 2 [SPI-2], aro, rfa, rfb, phoP, and phoQ) and enteric infection (e.g., SPI-1 and SPI-5) in this and other Salmonella serovars displayed colonization defects in our assay. In addition, a strong attenuation was observed for mutants in genes and genomic islands that are not present in S. Typhimurium or in most other Salmonella serovars. These genes include a type I restriction/modification system (SEN4290 to SEN4292), the peg fimbrial operon (SEN2144A to SEN2145B), a putative pathogenicity island (SEN1970 to SEN1999), and a type VI secretion system remnant SEN1001, encoding a hypothetical protein containing a lysin motif (LysM) domain associated with peptidoglycan binding. Proliferation defects for mutants in these individual genes and in exemplar genes for each of these clusters were confirmed in competitive infections with wild-type S. Enteritidis. A ΔSEN1001 mutant was defective for survival within RAW264.7 murine macrophages in vitro. Complementation assays directly linked the SEN1001 gene to phenotypes observed in vivo and in vitro. The genes identified here may perform novel virulence functions not characterized in previous Salmonella models. PMID:22083712

  20. Neurotrophin gene expression in rat brain under the action of Semax, an analogue of ACTH 4-10.

    PubMed

    Agapova, T Y; Agniullin, Y V; Shadrina, M I; Shram, S I; Slominsky, P A; Lymborska, S A; Myasoedov, N F

    2007-05-01

    The heptapeptide Semax, an analogue of the N-terminal adrenocorticotropic hormone fragment (4-10) (ACTH(4-10)), has been shown to exert a number of neuroprotective effects. There are some investigations that connected these effects with the increase of neurotrophin gene expression under the peptide drug application in neuron cell cultures [M.I. Shadrina, O.V. Dolotov, I.A. Grivennikov, P.A. Slominsky, L.A. Andreeva, L.S. Inozemtseva, S.A. Limborska, N.F. Myasoedov, Rapid induction of neurotrophin mRNAs in rat glial cell cultures by Semax, an adrenocorticotropic hormone analogue, Neurosci. Lett. 308 (2001) (2) 115-118]. In this work, we examined the action of Semax on rapid changes of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) gene expression in vivo. Male Wistar rats were treated for 1h with Semax (50 microg/kg, single intranasal application) and neurotrophin gene expression in rat brain was analyzed by real-time polymerase chain reaction (PCR). It was revealed that an intranasal application of Semax increased the expression of both neurotrophin genes in rat hippocampus. Bdnf gene expression also increased in the brainstem and cerebellum. Ngf gene expression decreased in rat frontal cortex. Thus, Semax induces rapid, gene- and region-specific changes in neurotrophin gene expression in normal rat brain.

  1. Gene expression profiles of erythroid precursors characterise several mechanisms of the action of hydroxycarbamide in sickle cell anaemia.

    PubMed

    Costa, Flávia Chagas; da Cunha, Anderson Ferreira; Fattori, André; de Sousa Peres, Tarcísio; Costa, Gustavo Gilson Lacerda; Machado, Tiago Ferraz; de Albuquerque, Dulcinéia Martins; Gambero, Sheley; Lanaro, Carolina; Saad, Sara T Olala; Costa, Fernando Ferreira

    2007-01-01

    Hydroxycarbamide (HC) (or hydroxyurea) has been reported to increase fetal haemoglobin levels and improve clinical symptoms in sickle cell anaemia (SCA) patients. However, the complete pathway by which HC acts remains unclear. To study the mechanisms involved in the action of HC, global gene expression profiles were obtained from the bone marrow cells of a SCA patient before and after HC treatment using serial analysis of gene expression. In the comparison of both profiles, 147 differentially expressed transcripts were identified. The functional classification of these transcripts revealed a group of gene categories associated with transcriptional and translational regulation, e.g. EGR-1, CENTB1, ARHGAP4 and RIN3, suggesting a possible role for these pathways in the improvement of clinical symptoms of SCA patients. The genes involved in these mechanisms may represent potential tools for the identification of new targets for SCA therapy.

  2. Change in gene abundance in the nitrogen biogeochemical cycle with temperature and nitrogen addition in Antarctic soils.

    PubMed

    Jung, Jaejoon; Yeom, Jinki; Kim, Jisun; Han, Jiwon; Lim, Hyoun Soo; Park, Hyun; Hyun, Seunghun; Park, Woojun

    2011-12-01

    The microbial community (bacterial, archaeal, and fungi) and eight genes involved in the nitrogen biogeochemical cycle (nifH, nitrogen fixation; bacterial and archaeal amoA, ammonia oxidation; narG, nitrate reduction; nirS, nirK, nitrite reduction; norB, nitric oxide reduction; and nosZ, nitrous oxide reduction) were quantitatively assessed in this study, via real-time PCR with DNA extracted from three Antarctic soils. Interestingly, AOB amoA was found to be more abundant than AOA amoA in Antarctic soils. The results of microcosm studies revealed that the fungal and archaeal communities were diminished in response to warming temperatures (10 °C) and that the archaeal community was less sensitive to nitrogen addition, which suggests that those two communities are well-adapted to colder temperatures. AOA amoA and norB genes were reduced with warming temperatures. The abundance of only the nifH and nirK genes increased with both warming and the addition of nitrogen. NirS-type denitrifying bacteria outnumbered NirK-type denitrifiers regardless of the treatment used. Interestingly, dramatic increases in both NirS and NirK-types denitrifiers were observed with nitrogen addition. NirK types increase with warming, but NirS-type denitrifiers tend to be less sensitive to warming. Our findings indicated that the Antarctic microbial nitrogen cycle could be dramatically altered by temperature and nitrogen, and that warming may be detrimental to the ammonia-oxidizing archaeal community. To the best of our knowledge, this is the first report to investigate genes associated with each process of the nitrogen biogeochemical cycle in an Antarctic terrestrial soil environment.

  3. Genome-wide meta-analysis of maize heterosis reveals the potential role of additive gene expression at pericentromeric loci

    PubMed Central

    2014-01-01

    Background The identification of QTL involved in heterosis formation is one approach to unravel the not yet fully understood genetic basis of heterosis - the improved agronomic performance of hybrid F1 plants compared to their inbred parents. The identification of candidate genes underlying a QTL is important both for developing markers and determining the molecular genetic basis of a trait, but remains difficult owing to the large number of genes often contained within individual QTL. To address this problem in heterosis analysis, we applied a meta-analysis strategy for grain yield (GY) of Zea mays L. as example, incorporating QTL-, hybrid field-, and parental gene expression data. Results For the identification of genes underlying known heterotic QTL, we made use of tight associations between gene expression pattern and the trait of interest, identified by correlation analyses. Using this approach genes strongly associated with heterosis for GY were discovered to be clustered in pericentromeric regions of the complex maize genome. This suggests that expression differences of sequences in recombination-suppressed regions are important in the establishment of heterosis for GY in F1 hybrids and also in the conservation of heterosis for GY across genotypes. Importantly functional analysis of heterosis-associated genes from these genomic regions revealed over-representation of a number of functional classes, identifying key processes contributing to heterosis for GY. Based on the finding that the majority of the analyzed heterosis-associated genes were addtitively expressed, we propose a model referring to the influence of cis-regulatory variation on heterosis for GY by the compensation of fixed detrimental expression levels in parents. Conclusions The study highlights the utility of a meta-analysis approach that integrates phenotypic and multi-level molecular data to unravel complex traits in plants. It provides prospects for the identification of genes relevant for

  4. Transcription repressor HANABA TARANU controls flower development by integrating the actions of multiple hormones, floral organ specification genes, and GATA3 family genes in Arabidopsis.

    PubMed

    Zhang, Xiaolan; Zhou, Yun; Ding, Lian; Wu, Zhigang; Liu, Renyi; Meyerowitz, Elliot M

    2013-01-01

    Plant inflorescence meristems and floral meristems possess specific boundary domains that result in proper floral organ separation and specification. HANABA TARANU (HAN) encodes a boundary-expressed GATA3-type transcription factor that regulates shoot meristem organization and flower development in Arabidopsis thaliana, but the underlying mechanism remains unclear. Through time-course microarray analyses following transient overexpression of HAN, we found that HAN represses hundreds of genes, especially genes involved in hormone responses and floral organ specification. Transient overexpression of HAN also represses the expression of HAN and three other GATA3 family genes, HANL2 (HAN-LIKE 2), GNC (GATA, NITRATE-INDUCIBLE, CARBON-METABOLISM-INVOLVED), and GNL (GNC-LIKE), forming a negative regulatory feedback loop. Genetic analysis indicates that HAN and the three GATA3 family genes coordinately regulate floral development, and their expression patterns are partially overlapping. HAN can homodimerize and heterodimerize with the three proteins encoded by these genes, and HAN directly binds to its own promoter and the GNC promoter in vivo. These findings, along with the fact that constitutive overexpression of HAN produces an even stronger phenotype than the loss-of-function mutation, support the hypothesis that HAN functions as a key repressor that regulates floral development via regulatory networks involving genes in the GATA3 family, along with genes involved in hormone action and floral organ specification.

  5. Influence of temperature, mixing, and addition of microcystin-LR on microcystin gene expression in Microcystis aeruginosa.

    PubMed

    Scherer, Pia I; Raeder, Uta; Geist, Juergen; Zwirglmaier, Katrin

    2017-02-01

    Cyanobacteria, such as the toxin producer Microcystis aeruginosa, are predicted to be favored by global warming both directly, through elevated water temperatures, and indirectly, through factors such as prolonged stratification of waterbodies. M. aeruginosa is able to produce the hepatotoxin microcystin, which causes great concern in freshwater management worldwide. However, little is known about the expression of microcystin synthesis genes in response to climate change-related factors. In this study, a new RT-qPCR assay employing four reference genes (GAPDH, gltA, rpoC1, and rpoD) was developed to assess the expression of two target genes (the microcystin synthesis genes mcyB and mcyD). This assay was used to investigate changes in mcyB and mcyD expression in response to selected environmental factors associated with global warming. A 10°C rise in temperature significantly increased mcyB expression, but not mcyD expression. Neither mixing nor the addition of microcystin-LR (10 μg L(-1) or 60 μg L(-1) ) significantly altered mcyB and mcyD expression. The expression levels of mcyB and mcyD were correlated but not identical.

  6. Sequence Analysis of Insecticide Action and Detoxification-Related Genes in the Insect Pest Natural Enemy Pardosa pseudoannulata

    PubMed Central

    Bao, Haibo; Liu, Zewen

    2015-01-01

    The pond wolf spider Pardosa pseudoannulata, an important natural predatory enemy of rice planthoppers, is found widely distributed in paddy fields. However, data on the genes involved in insecticide action, detoxification, and response are very limited for P. pseudoannulata, which inhibits the development and appropriate use of selective insecticides to control insect pests on rice. We used transcriptome construction from adult spider cephalothoraxes to analyze and manually identify genes enconding metabolic enzymes and target receptors related to insecticide action and detoxification, including 90 cytochrome P450s, 14 glutathione S-transferases (GSTs), 17 acetylcholinesterases (AChEs), 17 nicotinic acetylcholine receptors (nAChRs), and 17 gamma-aminobutyric acid (GABA) receptors, as well as 12 glutamate-gated chloride channel (GluCl) unigenes. Sequence alignment and phylogenetic analysis revealed the different subclassifications of P450s and GSTs, some important sequence diversities in nAChRs and GABA receptors, polymorphism in AChEs, and high similarities in GluCls. For P450s in P. pseudoannulata, the number of unigenes belonging to the CYP2 clade was much higher than that in CYP3 and CYP4 clades. The results differed from insects in which most P450 genes were in CYP3 and CYP4 clades. For GSTs, most unigenes belonged to the delta and sigma classes, and no epsilon GST class gene was found, which differed from the findings for insects and acarina. Our results will be useful for studies on insecticide action, selectivity, and detoxification in the spider and other related animals, and the sequence differences in target genes between the spider and insects will provide important information for the design of selective insecticides. PMID:25923714

  7. Sequence Analysis of Insecticide Action and Detoxification-Related Genes in the Insect Pest Natural Enemy Pardosa pseudoannulata.

    PubMed

    Meng, Xiangkun; Zhang, Yixi; Bao, Haibo; Liu, Zewen

    2015-01-01

    The pond wolf spider Pardosa pseudoannulata, an important natural predatory enemy of rice planthoppers, is found widely distributed in paddy fields. However, data on the genes involved in insecticide action, detoxification, and response are very limited for P. pseudoannulata, which inhibits the development and appropriate use of selective insecticides to control insect pests on rice. We used transcriptome construction from adult spider cephalothoraxes to analyze and manually identify genes enconding metabolic enzymes and target receptors related to insecticide action and detoxification, including 90 cytochrome P450s, 14 glutathione S-transferases (GSTs), 17 acetylcholinesterases (AChEs), 17 nicotinic acetylcholine receptors (nAChRs), and 17 gamma-aminobutyric acid (GABA) receptors, as well as 12 glutamate-gated chloride channel (GluCl) unigenes. Sequence alignment and phylogenetic analysis revealed the different subclassifications of P450s and GSTs, some important sequence diversities in nAChRs and GABA receptors, polymorphism in AChEs, and high similarities in GluCls. For P450s in P. pseudoannulata, the number of unigenes belonging to the CYP2 clade was much higher than that in CYP3 and CYP4 clades. The results differed from insects in which most P450 genes were in CYP3 and CYP4 clades. For GSTs, most unigenes belonged to the delta and sigma classes, and no epsilon GST class gene was found, which differed from the findings for insects and acarina. Our results will be useful for studies on insecticide action, selectivity, and detoxification in the spider and other related animals, and the sequence differences in target genes between the spider and insects will provide important information for the design of selective insecticides.

  8. The Symbiotic Performance of Chickpea Rhizobia Can Be Improved by Additional Copies of the clpB Chaperone Gene.

    PubMed

    Paço, Ana; Brígido, Clarisse; Alexandre, Ana; Mateos, Pedro F; Oliveira, Solange

    2016-01-01

    The ClpB chaperone is known to be involved in bacterial stress response. Moreover, recent studies suggest that this protein has also a role in the chickpea-rhizobia symbiosis. In order to improve both stress tolerance and symbiotic performance of a chickpea microsymbiont, the Mesorhizobium mediterraneum UPM-Ca36T strain was genetically transformed with pPHU231 containing an extra-copy of the clpB gene. To investigate if the clpB-transformed strain displays an improved stress tolerance, bacterial growth was evaluated under heat and acid stress conditions. In addition, the effect of the extra-copies of the clpB gene in the symbiotic performance was evaluated using plant growth assays (hydroponic and pot trials). The clpB-transformed strain is more tolerant to heat shock than the strain transformed with pPHU231, supporting the involvement of ClpB in rhizobia heat shock tolerance. Both plant growth assays showed that ClpB has an important role in chickpea-rhizobia symbiosis. The nodulation kinetics analysis showed a higher rate of nodule appearance with the clpB-transformed strain. This strain also induced a greater number of nodules and, more notably, its symbiotic effectiveness increased ~60% at pH5 and 83% at pH7, compared to the wild-type strain. Furthermore, a higher frequency of root hair curling was also observed in plants inoculated with the clpB-transformed strain, compared to the wild-type strain. The superior root hair curling induction, nodulation ability and symbiotic effectiveness of the clpB-transformed strain may be explained by an increased expression of symbiosis genes. Indeed, higher transcript levels of the nodulation genes nodA and nodC (~3 folds) were detected in the clpB-transformed strain. The improvement of rhizobia by addition of extra-copies of the clpB gene may be a promising strategy to obtain strains with enhanced stress tolerance and symbiotic effectiveness, thus contributing to their success as crop inoculants, particularly under

  9. Anti-carcinogenic action of ellagic acid mediated via modulation of oxidative stress regulated genes in Dalton lymphoma bearing mice.

    PubMed

    Mishra, Sudha; Vinayak, Manjula

    2011-11-01

    An elevated level of reactive oxygen species (ROS) in a cancerous condition causes oxidative stress which in turn activates a number of genes, and therefore an interruption in the oxidative microenvironment should be able to inactivate these genes, contributing to cancer prevention. The present work was designed to evaluate the role of ellagic acid in the modulation of protein kinase Cα (PKCα) activity and expression and its correlation with the oncogene, c-Myc, and tumor suppressor gene, transforming growth factor-β (TGF-β1), in lymphoma bearing mice. We also evaluated its implication for cell viability. Our results show that ellagic acid leads to down-regulation of the expression and activity of PKCα via decreasing the oxidative stress, measured in terms of lipid peroxidation and protein carbonylation. It also reduces c-Myc expression and improves TGF-β1 expression besides decreasing cell viability in Dalton lymphoma bearing mice, which supports its anti-carcinogenic action.

  10. Evidence for susceptibility genes to familial Wilms tumour in addition to WT1, FWT1 and FWT2

    PubMed Central

    Rapley, E A; Barfoot, R; Bonaïti-Pellié, C; Chompret, A; Foulkes, W; Perusinghe, N; Reeve, A; Royer-Pokora, B; Schumacher, V; Shelling, A; Skeen, J; Tourreil, S de; Weirich, A; Pritchard-Jones, K; Stratton, M R; Rahman, N

    2000-01-01

    Three loci have been implicated in familial Wilms tumour: WT1 located on chromosome 11p13, FWT1 on 17q12-q21, and FWT2 on 19q13. Two out of 19 Wilms tumour families evaluated showed strong evidence against linkage at all three loci. Both of these families contained at least three cases of Wilms tumour indicating that they were highly likely to be due to genetic susceptibility and therefore that one or more additional familial Wilms tumour susceptibility genes remain to be found. © 2000 Cancer Research Campaign PMID:10901367

  11. Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview.

    PubMed

    Tardito, Daniela; Perez, Jorge; Tiraboschi, Ettore; Musazzi, Laura; Racagni, Giorgio; Popoli, Maurizio

    2006-03-01

    Regulation of gene expression represents a major component in antidepressant drug action. The effect of antidepressant treatments on the function of cAMP-responsive element binding protein (CREB), a transcription factor that regulates expression of several genes involved in neuroplasticity, cell survival, and cognition, has been extensively studied. Although there is general agreement that chronic antidepressants stimulate CREB function, conflicting results suggest that different effects may depend on drug type, drug dosage, and different experimental paradigms. CREB function is activated by a vast array of physiological stimuli, conveyed through a number of signaling pathways acting in concert, but thus far the effects of antidepressants on CREB have been analyzed mostly with regard to the cAMP-protein kinase A pathway. A growing body of data shows that other major pathways, such as the calcium/calmodulin-dependent kinase and the mitogen-activated kinase cascades, are involved in activity-dependent regulation of gene expression and may also be implicated in the mechanism of action of antidepressants. In this article the available evidence is reviewed with an attempt to identify the reasons for experimental discrepancies and possible directions for future research. Particularemphasis is given to the regulation of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene, which has been implicated in both the pathophysiology and pharmacology of mood disorders. The array of different results obtained by various groups is analyzed with an eye on recent advancements in the regulation of BDNF transcription, in an attempt to understand better the mechanisms of drug action and dissect molecular requirements for faster and more efficient antidepressant treatment.

  12. Connecting gene expression data from connectivity map and in silico target predictions for small molecule mechanism-of-action analysis.

    PubMed

    Ravindranath, Aakash Chavan; Perualila-Tan, Nolen; Kasim, Adetayo; Drakakis, Georgios; Liggi, Sonia; Brewerton, Suzanne C; Mason, Daniel; Bodkin, Michael J; Evans, David A; Bhagwat, Aditya; Talloen, Willem; Göhlmann, Hinrich W H; Shkedy, Ziv; Bender, Andreas

    2015-01-01

    Integrating gene expression profiles with certain proteins can improve our understanding of the fundamental mechanisms in protein-ligand binding. This paper spotlights the integration of gene expression data and target prediction scores, providing insight into mechanism of action (MoA). Compounds are clustered based upon the similarity of their predicted protein targets and each cluster is linked to gene sets using Linear Models for Microarray Data. MLP analysis is used to generate gene sets based upon their biological processes and a qualitative search is performed on the homogeneous target-based compound clusters to identify pathways. Genes and proteins were linked through pathways for 6 of the 8 MCF7 and 6 of the 11 PC3 clusters. Three compound clusters are studied; (i) the target-driven cluster involving HSP90 inhibitors, geldanamycin and tanespimycin induces differential expression for HSP90-related genes and overlap with pathway response to unfolded protein. Gene expression results are in agreement with target prediction and pathway annotations add information to enable understanding of MoA. (ii) The antipsychotic cluster shows differential expression for genes LDLR and INSIG-1 and is predicted to target CYP2D6. Pathway steroid metabolic process links the protein and respective genes, hypothesizing the MoA for antipsychotics. A sub-cluster (verepamil and dexverepamil), although sharing similar protein targets with the antipsychotic drug cluster, has a lower intensity of expression profile on related genes, indicating that this method distinguishes close sub-clusters and suggests differences in their MoA. Lastly, (iii) the thiazolidinediones drug cluster predicted peroxisome proliferator activated receptor (PPAR) PPAR-alpha, PPAR-gamma, acyl CoA desaturase and significant differential expression of genes ANGPTL4, FABP4 and PRKCD. The targets and genes are linked via PPAR signalling pathway and induction of apoptosis, generating a hypothesis for the MoA of

  13. Evidence for an Additive Neurorestorative Effect of Simultaneously Administered CDNF and GDNF in Hemiparkinsonian Rats: Implications for Different Mechanism of Action

    PubMed Central

    De Lorenzo, Francesca; Stepanova, Polina; Bäck, Susanne; Yu, Li-Ying; Pörsti, Eeva; Männistö, Pekka T.; Tuominen, Raimo K.

    2017-01-01

    Abstract Parkinson’s disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic (DAergic) neurons of the substantia nigra (SN) and the accumulation of intracellular inclusions containing α-synuclein. Current therapies do not stop the progression of the disease, and the efficacy of these treatments wanes over time. Neurotrophic factors (NTFs) are naturally occurring proteins promoting the survival and differentiation of neurons and the maintenance of neuronal contacts. CDNF (cerebral dopamine NTF) and GDNF (glial cell line-derived NTF) are able to protect DAergic neurons against toxin-induced degeneration in experimental models of PD. Here, we report an additive neurorestorative effect of coadministration of CDNF and GDNF in the unilateral 6-hydroxydopamine (6-OHDA) lesion model of PD in rats. NTFs were given into the striatum four weeks after unilateral intrastriatal injection of 6-OHDA (20 µg). Amphetamine-induced (2.5 mg/kg, i.p.) rotational behavior was measured every two weeks. Number of tyrosine hydroxylase (TH)-positive cells from SN pars compacta (SNpc) and density of TH-positive fibers in the striatum were analyzed at 12 weeks after lesion. CDNF and GDNF alone restored the DAergic function, and one specific dose combination had an additive effect: CDNF (2.5µg) and GDNF (1µg) coadministration led to a stronger trophic effect relative to either of the single treatments alone. The additive effect may indicate different mechanism of action for the NTFs. Indeed, both NTFs activated the survival promoting PI3 kinase (PI3K)-Akt signaling pathway, but only CDNF decreased the expression level of tested endoplasmatic reticulum (ER) stress markers ATF6, glucose-regulated protein 78 (GRP78), and phosphorylation of eukaryotic initiation factor 2α subunit (eIF2α). PMID:28303260

  14. Cloning and characterization of a gene involved in triacylglycerol biosynthesis and identification of additional homologous genes in the oleaginous bacterium Rhodococcus opacus PD630.

    PubMed

    Alvarez, Adrian F; Alvarez, Héctor M; Kalscheuer, Rainer; Wältermann, Marc; Steinbüchel, Alexander

    2008-08-01

    The oleaginous bacterium Rhodococus opacus strain PD630 serves as a model organism to investigate the metabolism of storage triacylglycerols (TAGs) in bacteria. The key enzyme catalysing the last step of TAG biosynthesis in bacteria is a promiscuous acyltransferase (Atf), exhibiting acyl-CoA acyltransferase activity to both diacylglycerols (DGAT activity) and fatty alcohols (wax ester synthase, WS activity). An 800 bp PCR product was obtained from chromosomal DNA of strain PD630 by using degenerate primers designed from conserved stretches of Atf proteins of Acinetobacter baylyi strain ADP1 and Mycobacterium smegmatis mc(2)155. The atf fragment was used as a probe on a strain PD630 gene library, resulting in the identification of a 3948 bp chromosomal DNA fragment containing the complete atf1 gene. An atf1 disruption mutant of strain PD630 exhibited a TAG-leaky phenotype and accumulated up to 50 % less fatty acids than the wild-type, with significantly reduced oleic acid content when cultivated in the presence of gluconate or oleic acid. Whereas DGAT activity was drastically reduced in comparison to the wild-type, WS activity remained almost unchanged in the mutant. RT-PCR analysis of gluconate-grown cells of strain PD630 showed that there is expression of atf1 under conditions of TAG synthesis. To identify additional Atfs in strain PD630, PCR employing non-degenerate primers deduced from Rhodococcus jostii RHA1 sequence data was used. This yielded nine additional atf-homologous genes exhibiting 88-99 % sequence identity to the corresponding strain RHA1 enzymes. Besides Atf1 only Atf2 exhibited high DGAT and/or WS activity when heterologously expressed in Escherichia coli.

  15. Novel glycol chitosan-based polymeric gene carrier synthesized by a Michael addition reaction with low molecular weight polyethylenimine.

    PubMed

    Lee, Young Hwa; Park, Hae In; Choi, Joon Sig

    2016-02-10

    A glycol chitosan-based polymer that spontaneously assembles with plasmid DNA into nanorods was evaluated as a non-viral vector for gene delivery. Glycol chitosan-methyl acrylate-polyethylenimine (GMP) was synthesized by grafting polyethylenimine onto glycol chitosan via amidation after Michael addition using methyl acrylate. Gel retardation and PicoGreen assay experiments showed complete complex formation with plasmid DNA. GMP/pDNA complexes were characterized using biophysical techniques and were found to be positively charged rod-shape structures with widths in the nanometer scale and lengths in the micrometer scale. Transfection efficiency and cytotoxicity of GMP polymer was evaluated in human epithelial ovary carcinoma (HeLa) cells, human embryonic kidney 293 (HEK293) cells, and human hepatocellular liver carcinoma (HepG2) cells, in comparison to high molecular weight polyethylenimine, a commonly used transfection reagent. Intracellular polymer uptake was compared and confirmed by confocal microscopy. The results demonstrate that GMP, a hybrid polymer of glycol chitosan grafted with branched polyethylenimine, may serve as a promising vehicle for efficient gene delivery.

  16. Classifying chemical mode of action using gene networks and machine learning: a case study with the herbicide linuron.

    PubMed

    Ornostay, Anna; Cowie, Andrew M; Hindle, Matthew; Baker, Christopher J O; Martyniuk, Christopher J

    2013-12-01

    The herbicide linuron (LIN) is an endocrine disruptor with an anti-androgenic mode of action. The objectives of this study were to (1) improve knowledge of androgen and anti-androgen signaling in the teleostean ovary and to (2) assess the ability of gene networks and machine learning to classify LIN as an anti-androgen using transcriptomic data. Ovarian explants from vitellogenic fathead minnows (FHMs) were exposed to three concentrations of either 5α-dihydrotestosterone (DHT), flutamide (FLUT), or LIN for 12h. Ovaries exposed to DHT showed a significant increase in 17β-estradiol (E2) production while FLUT and LIN had no effect on E2. To improve understanding of androgen receptor signaling in the ovary, a reciprocal gene expression network was constructed for DHT and FLUT using pathway analysis and these data suggested that steroid metabolism, translation, and DNA replication are processes regulated through AR signaling in the ovary. Sub-network enrichment analysis revealed that FLUT and LIN shared more regulated gene networks in common compared to DHT. Using transcriptomic datasets from different fish species, machine learning algorithms classified LIN successfully with other anti-androgens. This study advances knowledge regarding molecular signaling cascades in the ovary that are responsive to androgens and anti-androgens and provides proof of concept that gene network analysis and machine learning can classify priority chemicals using experimental transcriptomic data collected from different fish species.

  17. Transcriptomic analysis of genetically defined autism candidate genes reveals common mechanisms of action

    PubMed Central

    2013-01-01

    Background Austism spectrum disorder (ASD) is a heterogeneous behavioral disorder or condition characterized by severe impairment of social engagement and the presence of repetitive activities. The molecular etiology of ASD is still largely unknown despite a strong genetic component. Part of the difficulty in turning genetics into disease mechanisms and potentially new therapeutics is the sheer number and diversity of the genes that have been associated with ASD and ASD symptoms. The goal of this work is to use shRNA-generated models of genetic defects proposed as causative for ASD to identify the common pathways that might explain how they produce a core clinical disability. Methods Transcript levels of Mecp2, Mef2a, Mef2d, Fmr1, Nlgn1, Nlgn3, Pten, and Shank3 were knocked-down in mouse primary neuron cultures using shRNA constructs. Whole genome expression analysis was conducted for each of the knockdown cultures as well as a mock-transduced culture and a culture exposed to a lentivirus expressing an anti-luciferase shRNA. Gene set enrichment and a causal reasoning engine was employed to identify pathway level perturbations generated by the transcript knockdown. Results Quantification of the shRNA targets confirmed the successful knockdown at the transcript and protein levels of at least 75% for each of the genes. After subtracting out potential artifacts caused by viral infection, gene set enrichment and causal reasoning engine analysis showed that a significant number of gene expression changes mapped to pathways associated with neurogenesis, long-term potentiation, and synaptic activity. Conclusions This work demonstrates that despite the complex genetic nature of ASD, there are common molecular mechanisms that connect many of the best established autism candidate genes. By identifying the key regulatory checkpoints in the interlinking transcriptional networks underlying autism, we are better able to discover the ideal points of intervention that provide the

  18. Next-generation sequencing identifies high frequency of mutations in potentially clinically actionable genes in sebaceous carcinoma.

    PubMed

    Tetzlaff, Michael T; Singh, Rajesh R; Seviour, Elena G; Curry, Jonathan L; Hudgens, Courtney W; Bell, Diana; Wimmer, Daniel A; Ning, Jing; Czerniak, Bogdan A; Zhang, Li; Davies, Michael A; Prieto, Victor G; Broaddus, Russell R; Ram, Prahlad; Luthra, Rajyalakshmi; Esmaeli, Bita

    2016-09-01

    Sebaceous carcinoma (SC) is a rare but aggressive malignancy with frequent recurrence and metastases. Surgery is the mainstay of therapy, but effective systemic therapies are lacking because the molecular alterations driving SC remain poorly understood. To identify these, we performed whole-exome next-generation sequencing of 409 cancer-associated genes on 27 SCs (18 primary/locally recurrent ocular, 5 paired metastatic ocular, and 4 primary extraocular) from 20 patients. In ocular SC, we identified 139 non-synonymous somatic mutations (median/lesion 3; range 0-23). Twenty-five of 139 mutations (18%) occurred in potentially clinically actionable genes in 6 of 16 patients. The most common mutations were mutations in TP53 (n = 9), RB1 (n = 6), PIK3CA (n = 2), PTEN (n = 2), ERBB2 (n = 2), and NF1 (n = 2). TP53 and RB1 mutations were restricted to ocular SC and correlated with aberrant TP53 and RB protein expression. Systematic pathway analyses demonstrated convergence of these mutations to activation of the PI3K signalling cascade, and PI3K pathway activation was confirmed in tumours with PTEN and/or PIK3CA mutations. Considerable inter-tumoural heterogeneity was observed between paired primary and metastatic ocular SCs. In primary extraocular SC, we identified 77 non-synonymous somatic mutations (median/lesion 22.5; range 3-29). This overall higher mutational load was attributed to a microsatellite instability phenotype in three of four patients and somatically acquired mutations in mismatch repair genes in two of four patients. Eighteen of 77 mutations (23%) were in potentially clinically actionable genes in three of four patients, including BTK, FGFR2, PDGFRB, HRAS, and NF1 mutations. Identification of potentially clinically actionable mutations in 9 of 20 SC patients (45%) underscores the importance of next-generation sequencing to expand the spectrum of genotype-matched targeted therapies. Frequent activation of PI3K signalling pathways provides a strong

  19. Norepinephrine transporter knock-out alters expression of the genes connected with antidepressant drugs action.

    PubMed

    Solich, Joanna; Kolasa, Magdalena; Kusmider, Maciej; Faron-Gorecka, Agata; Pabian, Paulina; Zurawek, Dariusz; Szafran-Pilch, Kinga; Dziedzicka-Wasylewska, Marta

    2015-01-12

    Norepinephrine transporter knock-out mice (NET-KO) exhibit depression-resistant phenotypes. They manifest significantly shorter immobility times in both the forced swim test and the tail suspension test. Moreover, biochemical studies have revealed the up-regulation of other monoamine transporters (dopamine and serotonin) in the brains of NET-KO mice, similar to the phenomenon observed after the chronic pharmacological blockade of norepinephrine transporter by desipramine in wild-type (WT) animals. NET-KO mice are also resistant to stress, as we demonstrated previously by measuring plasma corticosterone concentration. In the present study, we used a microdissection technique to separate target brain regions and the TaqMan Low Density Array approach to test the expression of a group of genes in the NET-KO mice compared with WT animals. A group of genes with altered expression were identified in four brain structures (frontal and cingulate cortices, dentate gyrus of hippocampus and basal-lateral amygdala) of NET-KO mice compared with WT mice. These genes are known to be altered by antidepressant drugs administration. The most interesting gene is Crh-bp, which modulates the activity of corticotrophin--releasing hormone (CRH) and several CRH-family members. Generally, genetic disturbances within noradrenergic neurons result in biological changes, such as in signal transduction and intercellular communication, and may be linked to changes in noradrenaline levels in the brains of NET-KO mice.

  20. Elevational speciation in action? Restricted gene flow associated with adaptive divergence across an altitudinal gradient

    USGS Publications Warehouse

    Funk, W. C.; Murphy, M.A.; Hoke, K. L.; Muths, Erin L.; Amburgey, Staci M.; Lemmon, Emily M.; Lemmon, A. R.

    2016-01-01

    Evolutionary theory predicts that divergent selection pressures across elevational gradients could cause adaptive divergence and reproductive isolation in the process of ecological speciation. Although there is substantial evidence for adaptive divergence across elevation, there is less evidence that this restricts gene flow. Previous work in the boreal chorus frog (Pseudacris maculata) has demonstrated adaptive divergence in morphological, life history and physiological traits across an elevational gradient from approximately 1500–3000 m in the Colorado Front Range, USA. We tested whether this adaptive divergence is associated with restricted gene flow across elevation – as would be expected if incipient speciation were occurring – and, if so, whether behavioural isolation contributes to reproductive isolation. Our analysis of 12 microsatellite loci in 797 frogs from 53 populations revealed restricted gene flow across elevation, even after controlling for geographic distance and topography. Calls also varied significantly across elevation in dominant frequency, pulse number and pulse duration, which was partly, but not entirely, due to variation in body size and temperature across elevation. However, call variation did not result in strong behavioural isolation: in phonotaxis experiments, low-elevation females tended to prefer an average low-elevation call over a high-elevation call, and vice versa for high-elevation females, but this trend was not statistically significant. In summary, our results show that adaptive divergence across elevation restricts gene flow in P. maculata, but the mechanisms for this potential incipient speciation remain open.

  1. Histamine H1 Receptor Gene Expression and Drug Action of Antihistamines.

    PubMed

    Fukui, Hiroyuki; Mizuguchi, Hiroyuki; Nemoto, Hisao; Kitamura, Yoshiaki; Kashiwada, Yoshiki; Takeda, Noriaki

    2016-11-25

    The upregulation mechanism of histamine H1 receptor through the activation of protein kinase C-δ (PKCδ) and the receptor gene expression was discovered. Levels of histamine H1 receptor mRNA and IL-4 mRNA in nasal mucosa were elevated by the provocation of nasal hypersensitivity model rats. Pretreatment with antihistamines suppressed the elevation of mRNA levels. Scores of nasal symptoms were correlatively alleviated to the suppression level of mRNAs above. A correlation between scores of nasal symptoms and levels of histamine H1 receptor mRNA in the nasal mucosa was observed in patients with pollinosis. Both scores of nasal symptoms and the level of histamine H1 receptor mRNA were improved by prophylactic treatment of antihistamines. Similar to the antihistamines, pretreatment with antiallergic natural medicines showed alleviation of nasal symptoms with correlative suppression of gene expression in nasal hypersensitivity model rats through the suppression of PKCδ. Similar effects of antihistamines and antiallergic natural medicines support that histamine H1 receptor-mediated activation of histamine H1 receptor gene expression is an important signaling pathway for the symptoms of allergic diseases. Antihistamines with inverse agonist activity showed the suppression of constitutive histamine H1 receptor gene expression, suggesting the advantage of therapeutic effect.

  2. Elevational speciation in action? Restricted gene flow associated with adaptive divergence across an altitudinal gradient.

    PubMed

    Funk, W C; Murphy, M A; Hoke, K L; Muths, E; Amburgey, S M; Lemmon, E M; Lemmon, A R

    2016-02-01

    Evolutionary theory predicts that divergent selection pressures across elevational gradients could cause adaptive divergence and reproductive isolation in the process of ecological speciation. Although there is substantial evidence for adaptive divergence across elevation, there is less evidence that this restricts gene flow. Previous work in the boreal chorus frog (Pseudacris maculata) has demonstrated adaptive divergence in morphological, life history and physiological traits across an elevational gradient from approximately 1500-3000 m in the Colorado Front Range, USA. We tested whether this adaptive divergence is associated with restricted gene flow across elevation - as would be expected if incipient speciation were occurring - and, if so, whether behavioural isolation contributes to reproductive isolation. Our analysis of 12 microsatellite loci in 797 frogs from 53 populations revealed restricted gene flow across elevation, even after controlling for geographic distance and topography. Calls also varied significantly across elevation in dominant frequency, pulse number and pulse duration, which was partly, but not entirely, due to variation in body size and temperature across elevation. However, call variation did not result in strong behavioural isolation: in phonotaxis experiments, low-elevation females tended to prefer an average low-elevation call over a high-elevation call, and vice versa for high-elevation females, but this trend was not statistically significant. In summary, our results show that adaptive divergence across elevation restricts gene flow in P. maculata, but the mechanisms for this potential incipient speciation remain open.

  3. The facilitating roles and uses of gene banks in addressing the global plan of action

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Contractions of livestock genetic resources are occurring as countries strive to meet increasing demand for livestock products. The Global Plan of Action’s (GPA) Strategic Priority Area 3 – Conservation, calls for governments to establish gene banks for ex-situ cryogenic conservation. Establishment ...

  4. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

    PubMed Central

    van der Put, N M; Gabreëls, F; Stevens, E M; Smeitink, J A; Trijbels, F J; Eskes, T K; van den Heuvel, L P; Blom, H J

    1998-01-01

    Recently, we showed that homozygosity for the common 677(C-->T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A-->C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an MboII recognition site and has an allele frequency of .33. This 1298(A-->C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P < .0001), which is more pronounced in the homozygous than heterozygous state. Neither the homozygous nor the heterozygous state is associated with higher plasma homocysteine (Hcy) or a lower plasma folate concentration-phenomena that are evident with homozygosity for the 677(C-->T) mutation. However, there appears to be an interaction between these two common mutations. When compared with heterozygosity for either the 677(C-->T) or 1298(A-->C) mutations, the combined heterozygosity for the 1298(A-->C) and 677(C-->T) mutations was associated with reduced MTHFR specific activity (ANOVA P < .0001), higher Hcy, and decreased plasma folate levels (ANOVA P <.03). Thus, combined heterozygosity for both MTHFR mutations results in similar features as observed in homozygotes for the 677(C-->T) mutation. This combined heterozygosity was observed in 28% (n =86) of the NTD patients compared with 20% (n =403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9-4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C-->T) mutation, and can be an additional genetic risk factor for NTDs. PMID:9545395

  5. Addition of ammonia or amino acids to a nitrogen-depleted medium affects gene expression patterns in yeast cells during alcoholic fermentation.

    PubMed

    Jiménez-Martí, Elena; del Olmo, Marcel Lí

    2008-03-01

    Yeast cells require nitrogen and are capable of selectively using good nitrogen sources in preference to poor ones by means of the regulatory mechanism known as nitrogen catabolite repression (NCR). Herein, the effect of ammonia or amino acid addition to nitrogen-depleted medium on global yeast expression patterns in yeast cells was studied using alcoholic fermentation as a system. The results indicate that there is a differential reprogramming of the gene expression depending on the nitrogen source added. Ammonia addition resulted in a higher expression of genes involved in amino acids biosynthesis while amino acid addition prepares the cells for protein biosynthesis. Therefore, a high percentage of the genes regulated by the transcription factors involved in the regulation of amino acid biosynthesis are more expressed during the first hours after ammonia addition compared with amino acid addition. The opposite occurs for those genes regulated by the transcription factor Sfp1p, related to ribosome biosynthesis. Although both additions include rich nitrogen sources, most NCR-regulated genes are more expressed after adding ammonia than amino acids. One of the differentially expressed genes, YBR174W, is required for optimal growth in synthetic medium.

  6. Corn gluten hydrolysate and capsaicin have complimentary actions on body weight reduction and lipid-related genes in diet-induced obese rats.

    PubMed

    Mun, Joo-Mi; Ok, Hyang Mok; Kwon, Oran

    2014-05-01

    The aim of this study was to test the hypothesis that a combination of corn gluten hydrolysate (CGH) and capsaicin may have an additive or synergistic effect on body weight reduction. For 13 weeks, male Sprague-Dawley rats were provided a diet to induce obesity. Afterward, the rats were randomly divided into 5 dietary groups: the normal control (n = 5), the high-fat control (n = 8), the high-fat diet (HFD) containing 35% CGH (n = 7), the HFD containing 0.02% capsaicin (HF-P) (n = 8), and the HFD containing both CGH and capsaicin (HF-CP) (n = 7) for an additional 4 weeks. Administration of CGH plus capsaicin, along with a HFD, led to significant decreases in body weight, fat mass, lipids in the liver, and plasma leptin as well as increases in plasma adiponectin. The pattern of gene expression was different in each target organ. In the liver, up-regulation of peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1α, and acyl-coenzyme A oxidase was found in the HF-CP group. In contrast, down-regulation of peroxisome proliferator-activated receptor γ was found in both the HFD containing 35% CGH and HF-CP groups. In skeletal muscle, up-regulation of insulin receptor and uncoupling protein 3 was found in the HF-P group only, whereas up-regulation of the glucose transporter 4 gene was observed in both the HF-CP and HF-P groups. In adipose tissue, up-regulation of peroxisome proliferator-activated receptor γ and hormone-sensitive lipase was only found in the HF-CP group. In summary, this study suggests that CGH and capsaicin perform complementary actions on food intake, lipid metabolism, and insulin sensitivity by a coordinated control of energy metabolism in the liver, adipose tissue, and skeletal muscle, thus exerting an additive effect on body weight reduction.

  7. Concerted action of the MutLβ heterodimer and Mer3 helicase regulates the global extent of meiotic gene conversion

    PubMed Central

    Duroc, Yann; Kumar, Rajeev; Ranjha, Lepakshi; Adam, Céline; Guérois, Raphaël; Md Muntaz, Khan; Marsolier-Kergoat, Marie-Claude; Dingli, Florent; Laureau, Raphaëlle; Loew, Damarys; Llorente, Bertrand; Charbonnier, Jean-Baptiste; Cejka, Petr; Borde, Valérie

    2017-01-01

    Gene conversions resulting from meiotic recombination are critical in shaping genome diversification and evolution. How the extent of gene conversions is regulated is unknown. Here we show that the budding yeast mismatch repair related MutLβ complex, Mlh1-Mlh2, specifically interacts with the conserved meiotic Mer3 helicase, which recruits it to recombination hotspots, independently of mismatch recognition. This recruitment is essential to limit gene conversion tract lengths genome-wide, without affecting crossover formation. Contrary to expectations, Mer3 helicase activity, proposed to extend the displacement loop (D-loop) recombination intermediate, does not influence the length of gene conversion events, revealing non-catalytical roles of Mer3. In addition, both purified Mer3 and MutLβ preferentially recognize D-loops, providing a mechanism for limiting gene conversion in vivo. These findings show that MutLβ is an integral part of a new regulatory step of meiotic recombination, which has implications to prevent rapid allele fixation and hotspot erosion in populations. DOI: http://dx.doi.org/10.7554/eLife.21900.001 PMID:28051769

  8. Concerted action of the MutLβ heterodimer and Mer3 helicase regulates the global extent of meiotic gene conversion.

    PubMed

    Duroc, Yann; Kumar, Rajeev; Ranjha, Lepakshi; Adam, Céline; Guérois, Raphaël; Md Muntaz, Khan; Marsolier-Kergoat, Marie-Claude; Dingli, Florent; Laureau, Raphaëlle; Loew, Damarys; Llorente, Bertrand; Charbonnier, Jean-Baptiste; Cejka, Petr; Borde, Valérie

    2017-01-04

    Gene conversions resulting from meiotic recombination are critical in shaping genome diversification and evolution. How the extent of gene conversions is regulated is unknown. Here we show that the budding yeast mismatch repair related MutLβ complex, Mlh1-Mlh2, specifically interacts with the conserved meiotic Mer3 helicase, which recruits it to recombination hotspots, independently of mismatch recognition. This recruitment is essential to limit gene conversion tract lengths genome-wide, without affecting crossover formation. Contrary to expectations, Mer3 helicase activity, proposed to extend the displacement loop (D-loop) recombination intermediate, does not influence the length of gene conversion events, revealing non-catalytical roles of Mer3. In addition, both purified Mer3 and MutLβ preferentially recognize D-loops, providing a mechanism for limiting gene conversion in vivo. These findings show that MutLβ is an integral part of a new regulatory step of meiotic recombination, which has implications to prevent rapid allele fixation and hotspot erosion in populations.

  9. Differential action of glucocorticoids on apolipoprotein E gene expression in macrophages and hepatocytes

    PubMed Central

    Trusca, Violeta Georgeta; Fuior, Elena Valeria; Fenyo, Ioana Madalina; Kardassis, Dimitris; Simionescu, Maya

    2017-01-01

    Apolipoprotein E (apoE) has anti-atherosclerotic properties, being involved in the transport and clearance of cholesterol-rich lipoproteins as well as in cholesterol efflux from cells. We hypothesized that glucocorticoids may exert anti-inflammatory properties by increasing the level of macrophage-derived apoE. Our data showed that glucocorticoids increased apoE expression in macrophages in vitro as well as in vivo. Dexamethasone increased ~6 fold apoE mRNA levels in cultured peritoneal macrophages and RAW 264.7 cells. Administered to C57BL/6J mice, dexamethasone induced a two-fold increase in apoE expression in peritoneal macrophages. By contrast, glucocorticoids did not influence apoE expression in hepatocytes, in vitro and in vivo. Moreover, dexamethasone enhanced apoE promoter transcriptional activity in RAW 264.7 macrophages, but not in HepG2 cells, as tested by transient transfections. Analysis of apoE proximal promoter deletion mutants, complemented by protein-DNA interaction assays demonstrated the functionality of a putative glucocorticoid receptors (GR) binding site predicted by in silico analysis in the -111/-104 region of the human apoE promoter. In hepatocytes, GR can bind to their specific site within apoE promoter but are not able to modulate the gene expression. The modulatory blockade in hepatocytes is a consequence of partial involvement of transcription factors and other signaling molecules activated through MEK1/2 and PLA2/PLC pathways. In conclusion, our study indicates that glucocorticoids (1) differentially target apoE gene expression; (2) induce a significant increase in apoE level specifically in macrophages. The local increase of apoE gene expression in macrophages at the level of the atheromatous plaque may have therapeutic implications in atherosclerosis. PMID:28355284

  10. Branching in Pea (Action of Genes Rms3 and Rms4).

    PubMed Central

    Beveridge, C. A.; Ross, J. J.; Murfet, I. C.

    1996-01-01

    The nonallelic ramosus mutations rms3-2 and rms4 of pea (Pisum sativum L.) cause extensive release of vegetative axillary buds and lateral growth in comparison with wild-type (cv Torsdag) plants, in which axillary buds are not normally released under the conditions utilized. Grafting studies showed that the expression of the rms4 mutation in the shoot is independent of the genotype of the root-stock. In contrast, the length of the branches at certain nodes of rms3-2 plants was reduced by grafting to wild-type stocks, indicating that the wild-type Rms3 gene may control the level of a mobile substance produced in the root. This substance also appears to be produced in the shoot because Rms3 shoots did not branch when grafted to mutant rms3-2 rootstocks. However, the end product of the Rms3 gene appears to differ from that of the Rms2 gene (C.A. Beveridge, J.J. Ross, and I.C. Murfet [1994] Plant Physiol 104: 953-959) because reciprocal grafts between rms3-2 and rms2 seedlings produced mature shoots with apical dominance similar to that of rms3-2 and rms2 shoots grafted to wild-type stocks. Indole-3-acetic acid levels were not reduced in apical or nodal portions of rms4 plants and were actually elevated (up to 2-fold) in rms3-2 plants. It is suggested that further studies with these branching mutants may enable significant progress in understanding the normal control of apical dominance and the related communication between the root and shoot. PMID:12226224

  11. Testicular development involves the spatiotemporal control of PDGFs and PDGF receptors gene expression and action

    PubMed Central

    1995-01-01

    Platelet-derived growth factors (PDGFs) are growth-regulatory molecules that stimulate chemotaxis, proliferation and metabolism primarily of cells of mesenchymal origin. In this study, we found high levels of PDGFs and PDGFs receptors (PDGFRs) mRNAs, and specific immunostaining for the corresponding proteins in the rat testis. PDGFs and PDGFRs expression was shown to be developmentally regulated and tissue specific. Expression of PDGFs and PDGFRs genes was observed in whole testis RNA 2 d before birth, increased through postnatal day 5 and fell to low levels in adult. The predominant cell population expressing transcripts of the PDGFs and PDGFRs genes during prenatal and early postnatal periods were Sertoli cells and peritubular myoid cells (PMC) or their precursors, respectively, while in adult animals PDGFs and PDGFRs were confined in Leydig cells. We also found that early postnatal Sertoli cells produce PDGF-like substances and that this production is inhibited dose dependently by follicle-stimulating hormone (FSH). The expression of PDGFRs by PMC and of PDGFs by Sertoli cells corresponds in temporal sequence to the developmental period of PMC proliferation and migration from the interstitium to the peritubulum. Moreover, we observed that all the PDGF isoforms and the medium conditioned by early postnatal Sertoli cells show a strong chemotactic activity for PMC which is inhibited by anti-PDGF antibodies. These data indicate that, through the spatiotemporal pattern of PDGF ligands and receptors expression, PDGF may play a role in testicular development and homeostasis. PMID:7490286

  12. Regulation of corticosteroid receptor gene expression in depression and antidepressant action.

    PubMed Central

    Barden, N

    1999-01-01

    OBJECTIVE: Major alterations of the hypothalamic-pituitary-adrenocortical (HPA) system are often seen in patients with depression, and can be reversed by successful antidepressant therapy. Persuasive evidence points to the involvement of a dysfunctional glucocorticoid receptor system in these changes. The authors developed a transgenic mouse to determine the mechanism for these changes. DESIGN: In vivo and in vitro animal experiments. ANIMALS: Transgenic mice expressing glucocorticoid receptor antisense RNA and control mice. INTERVENTIONS: In vivo: hormone assays and dexamethasone suppression tests; in vitro: cell transfection, chloramphenicol acetyl transferase assay, Northern blot analysis, binding assays of cytosolic receptor. OUTCOME MEASURES: Indicators of depressive disorder in transgenic mice, effect of antidepressant therapy on dexamethasone binding in transgenic mouse hippocampus, mouse behaviour, and glucocorticoid receptor activity. RESULTS: Transgenic mice showed no suppression of corticosterone with a dose of 2 mg per 100 g body weight dexamethasone. Treatment with amitriptyline reduced levels of corticotropin and corticosterone, increased glucocorticoid receptor mRNA concentrations and glucocorticoid binding capacity of several brain areas, and reversed behavioural changes. In vitro experiments also showed that desipramine increased glucocorticoid receptor mRNA. CONCLUSION: These transgenic mice have numerous neuroendocrine characteristics of human depression as well as altered behaviour. Many of these neuroendocrinologic and behavioural characteristics are reversed by antidepressants. The antidepressant-induced increase in glucocorticoid receptor activity may render the HPA axis more sensitive to glucocorticoid feedback. This new insight into antidepressant drug action suggests a novel approach to the development of new antidepressant drugs. Images Fig. 5. PMID:9987205

  13. Control of Gene Expression by RNA Binding Protein Action on Alternative Translation Initiation Sites

    PubMed Central

    Re, Angela; Waldron, Levi; Quattrone, Alessandro

    2016-01-01

    Transcript levels do not faithfully predict protein levels, due to post-transcriptional regulation of gene expression mediated by RNA binding proteins (RBPs) and non-coding RNAs. We developed a multivariate linear regression model integrating RBP levels and predicted RBP-mRNA regulatory interactions from matched transcript and protein datasets. RBPs significantly improved the accuracy in predicting protein abundance of a portion of the total modeled mRNAs in three panels of tissues and cells and for different methods employed in the detection of mRNA and protein. The presence of upstream translation initiation sites (uTISs) at the mRNA 5’ untranslated regions was strongly associated with improvement in predictive accuracy. On the basis of these observations, we propose that the recently discovered widespread uTISs in the human genome can be a previously unappreciated substrate of translational control mediated by RBPs. PMID:27923063

  14. Physiological basis of tolerance to complete submergence in rice involves genetic factors in addition to the SUB1 gene

    PubMed Central

    Singh, Sudhanshu; Mackill, David J.; Ismail, Abdelbagi M.

    2014-01-01

    Recurring floods in Asia cause poor crop establishment. Yields decline drastically when plants are completely submerged for a few days. Traditional rice cultivars predominate because they have acquired moderate tolerance to flooding but they carry the penalty of inherently lower grain yields. In contrast, modern high-yielding varieties are highly susceptible to flooding. Cultivars with tolerance to complete submergence were recently developed in the background of popular varieties by transferring the submergence tolerance gene SUBMERGENCE1 (SUB1) from the highly tolerant Indian landrace FR13A. The present study evaluated three pairs of Sub1 near-isogenic lines (NILs) together with FR13A and two of its submergence-tolerant derivatives under field conditions to assess the survival and growth processes occurring during submergence and recovery that are associated with SUB1. Under control conditions, the NILs showed similar growth and biomass accumulation, indicating that SUB1 had no apparent effects. Submergence substantially decreased biomass accumulation but with greater reduction in the genotypes lacking SUB1, particularly when submergence was prolonged for 17 days. When submerged, the lines lacking SUB1 showed greater elongation and lower or negative biomass accumulation. Sub1 lines maintained higher chlorophyll concentrations during submergence and lost less non-structural carbohydrates (NSC) after submergence. This indicates that the introgression of SUB1 resulted in better regulation of NSC during submergence and that high pre-submergence NSC is not essential for the submergence tolerance conferred by SUB1. During recovery, chlorophyll degradation was faster in genotypes lacking SUB1 and any surviving plants showed poorer and delayed emergence of tillers and leaves. Sub1 lines restored new leaf and tiller production faster. During submergence, FR13A showed not only slower leaf elongation but also accumulated extra biomass and was able to recover faster than Sub

  15. Physiological basis of tolerance to complete submergence in rice involves genetic factors in addition to the SUB1 gene.

    PubMed

    Singh, Sudhanshu; Mackill, David J; Ismail, Abdelbagi M

    2014-10-03

    Recurring floods in Asia cause poor crop establishment. Yields decline drastically when plants are completely submerged for a few days. Traditional rice cultivars predominate because they have acquired moderate tolerance to flooding but they carry the penalty of inherently lower grain yields. In contrast, modern high-yielding varieties are highly susceptible to flooding. Cultivars with tolerance to complete submergence were recently developed in the background of popular varieties by transferring the submergence tolerance gene SUBMERGENCE1 (SUB1) from the highly tolerant Indian landrace FR13A. The present study evaluated three pairs of Sub1 near-isogenic lines (NILs) together with FR13A and two of its submergence-tolerant derivatives under field conditions to assess the survival and growth processes occurring during submergence and recovery that are associated with SUB1. Under control conditions, the NILs showed similar growth and biomass accumulation, indicating that SUB1 had no apparent effects. Submergence substantially decreased biomass accumulation but with greater reduction in the genotypes lacking SUB1, particularly when submergence was prolonged for 17 days. When submerged, the lines lacking SUB1 showed greater elongation and lower or negative biomass accumulation. Sub1 lines maintained higher chlorophyll concentrations during submergence and lost less non-structural carbohydrates (NSC) after submergence. This indicates that the introgression of SUB1 resulted in better regulation of NSC during submergence and that high pre-submergence NSC is not essential for the submergence tolerance conferred by SUB1. During recovery, chlorophyll degradation was faster in genotypes lacking SUB1 and any surviving plants showed poorer and delayed emergence of tillers and leaves. Sub1 lines restored new leaf and tiller production faster. During submergence, FR13A showed not only slower leaf elongation but also accumulated extra biomass and was able to recover faster than Sub

  16. Protein thiol modification by 15-deoxy-Delta12,14-prostaglandin J2 addition in mesangial cells: role in the inhibition of pro-inflammatory genes.

    PubMed

    Sánchez-Gómez, Francisco J; Cernuda-Morollón, Eva; Stamatakis, Konstantinos; Pérez-Sala, Dolores

    2004-11-01

    The cyclopentenone prostaglandin and PPARgamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) displays anti-inflammatory effects in several experimental models. Direct modification of protein thiols is arising as an important mechanism of cyclopentenone prostaglandin action. However, little is known about the extent or specificity of this process. Mesangial cells (MC) play a key role in glomerulonephritis. In this work, we have studied the selectivity of protein modification by 15d-PGJ(2) in MC, and the correlation with the modulation of several proinflammatory genes. MC incubation with biotinylated 15d-PGJ(2) results in the labeling of a distinct set of proteins as evidenced by two-dimensional electrophoresis. 15d-PGJ(2) binds to nuclear and cytosolic targets as detected by fluorescence microscopy and subcellular fractionation. The pattern of biotinylated 15d-PGJ(2)-modified polypeptides is readily distinguishable from that of total protein staining or labeling with biotinylated iodoacetamide. 15d-PGJ(2) addition requires the double bond in the cyclopentane ring. 9,10-Dihydro-15d-PGJ(2), a 15d-PGJ(2) analog that shows the same potency as peroxisome proliferator-activated receptor (PPAR) agonist in MC but lacks the cyclopentenone moiety, displays reduced ability to modify proteins and to block 15d-PGJ(2) binding. Micromolar concentrations of 15d-PGJ(2) inhibit cytokine-elicited levels of inducible nitricoxide synthase, cyclooxygenase-2, and intercellular adhesion molecule-1 in MC. In contrast, 9,10-dihydro-15d-PGJ(2) does not reproduce this inhibition. 15d-PGJ(2) effect is not blocked by the PPARgamma antagonist 2-chloro-5-nitro-N-phenylbenzamide (GW9662). Moreover, compounds possessing an alpha,beta-unsaturated carbonyl group, like 2-cyclopenten-1-one and 2-cyclohexen-1-one, reduce pro-inflammatory gene expression. These observations indicate that covalent modification of cellular thiols by 15d-PGJ(2) is a selective process that plays an important

  17. A Meta-Analytic Review of the Theories of Reasoned Action and Planned Behavior in Physical Activity: Predictive Validity and the Contribution of Additional Variables.

    ERIC Educational Resources Information Center

    Hagger, Martin S.; Chatzisarantis, Nikos L. D.; Biddle, Stuart J. H.

    2002-01-01

    Examined relations between behavior, intentions, attitudes, subjective norms, perceived behavioral control, self-efficacy, and past behaviors using the Theories of Reasoned Action (TRA) and Planned Behavior (TPB) in physical activity. This quantitative integration of the physical activity literature supported the major relationships of the…

  18. Comparison of mouse and human genomes followed by experimental verification yields an estimated 1,019 additional genes.

    PubMed

    Guigo, Roderic; Dermitzakis, Emmanouil T; Agarwal, Pankaj; Ponting, Chris P; Parra, Genis; Reymond, Alexandre; Abril, Josep F; Keibler, Evan; Lyle, Robert; Ucla, Catherine; Antonarakis, Stylianos E; Brent, Michael R

    2003-02-04

    A primary motivation for sequencing the mouse genome was to accelerate the discovery of mammalian genes by using sequence conservation between mouse and human to identify coding exons. Achieving this goal proved challenging because of the large proportion of the mouse and human genomes that is apparently conserved but apparently does not code for protein. We developed a two-stage procedure that exploits the mouse and human genome sequences to produce a set of genes with a much higher rate of experimental verification than previously reported prediction methods. RT-PCR amplification and direct sequencing applied to an initial sample of mouse predictions that do not overlap previously known genes verified the regions flanking one intron in 139 predictions, with verification rates reaching 76%. On average, the confirmed predictions show more restricted expression patterns than the mouse orthologs of known human genes, and two-thirds lack homologs in fish genomes, demonstrating the sensitivity of this dual-genome approach to hard-to-find genes. We verified 112 previously unknown homologs of known proteins, including two homeobox proteins relevant to developmental biology, an aquaporin, and a homolog of dystrophin. We estimate that transcription and splicing can be verified for >1,000 gene predictions identified by this method that do not overlap known genes. This is likely to constitute a significant fraction of the previously unknown, multiexon mammalian genes.

  19. Mitochondrial genome sequence and gene order of Sipunculus nudus give additional support for an inclusion of Sipuncula into Annelida

    PubMed Central

    Mwinyi, Adina; Meyer, Achim; Bleidorn, Christoph; Lieb, Bernhard; Bartolomaeus, Thomas; Podsiadlowski, Lars

    2009-01-01

    Background Mitochondrial genomes are a valuable source of data for analysing phylogenetic relationships. Besides sequence information, mitochondrial gene order may add phylogenetically useful information, too. Sipuncula are unsegmented marine worms, traditionally placed in their own phylum. Recent molecular and morphological findings suggest a close affinity to the segmented Annelida. Results The first complete mitochondrial genome of a member of Sipuncula, Sipunculus nudus, is presented. All 37 genes characteristic for metazoan mtDNA were detected and are encoded on the same strand. The mitochondrial gene order (protein-coding and ribosomal RNA genes) resembles that of annelids, but shows several derivations so far found only in Sipuncula. Sequence based phylogenetic analysis of mitochondrial protein-coding genes results in significant bootstrap support for Annelida sensu lato, combining Annelida together with Sipuncula, Echiura, Pogonophora and Myzostomida. Conclusion The mitochondrial sequence data support a close relationship of Annelida and Sipuncula. Also the most parsimonious explanation of changes in gene order favours a derivation from the annelid gene order. These results complement findings from recent phylogenetic analyses of nuclear encoded genes as well as a report of a segmental neural patterning in Sipuncula. PMID:19149868

  20. Identification of Gene Expression Signatures in the Chicken Intestinal Intraepithelial Lymphocytes in Response to Herb Additive Supplementations

    PubMed Central

    Won, Kyeong-Hye; Song, Ki-Duk; Park, Jong-Eun; Kim, Duk-Kyung; Na, Chong-Sam

    2016-01-01

    Anethole and garlic have an immune modulatory effects on avian coccidiosis, and these effects are correlated with gene expression changes in intestinal epithelial lymphocytes (IELs). In this study, we integrated gene expression datasets from two independent experiments and investigated gene expression profile changes by anethole and garlic respectively, and identified gene expression signatures, which are common targets of these herbs as they might be used for the evaluation of the effect of plant herbs on immunity toward avian coccidiosis. We identified 4,382 and 371 genes, which were differentially expressed in IELs of chickens supplemented with garlic and anethole respectively. The gene ontology (GO) term of differentially expressed genes (DEGs) from garlic treatment resulted in the biological processes (BPs) related to proteolysis, e.g., “modification-dependent protein catabolic process”, “proteolysis involved in cellular protein catabolic process”, “cellular protein catabolic process”, “protein catabolic process”, and “ubiquitin-dependent protein catabolic process”. In GO analysis, one BP term, “Proteolysis”, was obtained. Among DEGs, 300 genes were differentially regulated in response to both garlic and anethole, and 234 and 59 genes were either up- or down-regulated in supplementation with both herbs. Pathway analysis resulted in enrichment of the pathways related to digestion such as “Starch and sucrose metabolism” and “Insulin signaling pathway”. Taken together, the results obtained in the present study could contribute to the effective development of evaluation system of plant herbs based on molecular signatures related with their immunological functions in chicken IELs. PMID:26954117

  1. Microarray Analysis of Gene Expression in Saccharomyces cerevisiae kap108Δ Mutants upon Addition of Oxidative Stress.

    PubMed

    Belanger, Kenneth D; Larson, Nathaniel; Kahn, Jonathan; Tkachev, Dmitry; Ay, Ahmet

    2016-04-07

    Protein transport between the nucleus and cytoplasm of eukaryotic cells is tightly regulated, providing a mechanism for controlling intracellular localization of proteins, and regulating gene expression. In this study, we have investigated the importance of nucleocytoplasmic transport mediated by the karyopherin Kap108 in regulating cellular responses to oxidative stress in Saccharomyces cerevisiae We carried out microarray analyses on wild-type and kap108 mutant cells grown under normal conditions, shortly after introduction of oxidative stress, after 1 hr of oxidative stress, and 1 hr after oxidative stress was removed. We observe more than 500 genes that undergo a 40% or greater change in differential expression between wild-type and kap108Δ cells under at least one of these conditions. Genes undergoing changes in expression can be categorized in two general groups: 1) those that are differentially expressed between wild-type and kap108Δ cells, no matter the oxidative stress conditions; and 2) those that have patterns of response dependent upon both the absence of Kap108, and introduction or removal of oxidative stress. Gene ontology analysis reveals that, among the genes whose expression is reduced in the absence of Kap108 are those involved in stress response and intracellular transport, while those overexpressed are largely involved in mating and pheromone response. We also identified 25 clusters of genes that undergo similar patterns of change in gene expression when oxidative stresses are added and subsequently removed, including genes involved in stress response, oxidation-reduction processing, iron homeostasis, ascospore wall assembly, transmembrane transport, and cell fusion during mating. These data suggest that Kap108 is important for regulating expression of genes involved in a variety of specific cell functions.

  2. Inhibition of DNA and Histone Methylation by 5-Aza-2′-Deoxycytidine (Decitabine) and 3-Deazaneplanocin-A on Antineoplastic Action and Gene Expression in Myeloid Leukemic Cells

    PubMed Central

    Momparler, Richard L.; Côté, Sylvie; Momparler, Louise F.; Idaghdour, Youssef

    2017-01-01

    Epigenetic alterations play an important role in the development of acute myeloid leukemia (AML) by silencing of genes that suppress leukemogenesis and differentiation. One of the key epigenetic changes in AML is gene silencing by DNA methylation. The importance of this alteration is illustrated by the induction of remissions in AML by 5-aza-2′-deoxycytidine (5-AZA-CdR, decitabine), a potent inhibitor of DNA methylation. However, most patients induced into remission by 5-AZA-CdR will relapse, suggesting that a second agent should be sought to increase the efficacy of this epigenetic therapy. An interesting candidate for this purpose is 3-deazaneplanocin A (DZNep). This analog inhibits EZH2, a histone methyltransferase that trimethylates lysine 27 histone H3 (H3K27me3), a marker for gene silencing. This second epigenetic silencing mechanism also plays an important role in leukemogenesis as shown in preclinical studies where DZNep exhibits potent inhibition of colony formation by AML cells. We reported previously that 5-AZA-CdR in combination with DZNep exhibits a synergistic antineoplastic action against human HL-60 AML cells and the synergistic activation of several tumor suppressor genes. In this report, we showed that this combination also induced a synergistic activation of apoptosis in HL-60 cells. The synergistic antineoplastic action of 5-AZA-CdR plus DZNep was also observed on a second human myeloid leukemia cell line, AML-3. In addition, 5-AZA-CdR in combination with the specific inhibitors of EZH2, GSK-126, or GSK-343, also exhibited a synergistic antineoplastic action on both HL-60 and AML-3. The combined action of 5-AZA-CdR and DZNep on global gene expression in HL-60 cells was investigated in greater depth using RNA sequencing analysis. We observed that this combination of epigenetic agents exhibited a synergistic activation of hundreds of genes. The synergistic activation of so many genes that suppress malignancy by 5-AZA-CdR plus DZNep suggests that

  3. Disrupting actions of bisphenol A and malachite green on growth hormone receptor gene expression and signal transduction in seabream.

    PubMed

    Jiao, Baowei; Cheng, Christopher H K

    2010-06-01

    Environmental estrogen could mimic natural estrogens thereby disrupting the endocrine systems of human and animals. The actions of such endocrine disruptors have been studied mainly on reproduction and development. However, estrogen could also affect the somatotropic axis via multiple targets such as growth hormone (GH). In the present study, two endocrine disruptors were chosen to investigate their effects on the expression level and signal transduction of growth hormone receptor (GHR) in fish. Using real-time PCR, it was found that exposure to both the estrogenic (bisphenol A) and anti-estrogenic (malachite green) compounds could attenuate the expression levels of GHR1 and GHR2 in black seabream (Acanthopagrus schlegeli) hepatocytes. The expression level of IGF-I, the downstream effector of GHR activation in the liver, was decreased by bisphenol A but not by malachite green. Luciferase reporter assay of the beta-casein promoter was used to monitor GHR signaling in transfected cells. In the fish liver cell line Hepa-T1, both GHR1 and GHR2 signaling were attenuated by bisphenol A and malachite green. This attenuation could only occur in the presence of estrogen receptor, indicating that these agents probably produce their actions via the estrogen receptor. Results of the present study demonstrated that estrogenic or anti-estrogenic compounds could down-regulate the somatotropic axis in fish by affecting both the gene expression and signaling of GHR. In view of the increasing prevalence of these compounds in the environment, the impact on fish growth and development both in the wild and in aquaculture would be considerable.

  4. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis.

    PubMed

    Kao, Hsiao-Wen; Liang, D Cherng; Kuo, Ming-Chung; Wu, Jin-Hou; Dunn, Po; Wang, Po-Nan; Lin, Tung-Liang; Shih, Yu-Shu; Liang, Sung-Tzu; Lin, Tung-Huei; Lai, Chen-Yu; Lin, Chun-Hui; Shih, Lee-Yung

    2015-10-20

    The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML.

  5. A chimeric mouse histone H4 gene containing either an intron or poly(A) addition signal behaves like a basal histone.

    PubMed Central

    Seiler-Tuyns, A; Paterson, B M

    1986-01-01

    We have modified the basic structure of the mouse H4 histone gene by introducing, in one case, the IVS-II of the human beta globin gene in the middle of the H4 coding region and, in the second case, the poly(A) addition signal from either the chicken vimentin gene or the alpha globin gene, displacing the hairpin loop structure in the 3' direction. Constructs were placed into the vector, PSV2gpt, and stably transformed into L cells. Pools of 100-500 independent transformants were analyzed for H4 expression. Even though the intron is processed correctly, the growth regulated expression of the modified gene is lost and the gene is now expressed at a constant basal level. Furthermore, unprocessed transcripts accumulate in the nucleus of Go cells when compared to exponentially growing cultures. Polyadenylated H4 RNA is correctly processed but expressed at reduced levels (30 fold) in a constitutive manner, independent of the growth state of the cell. The altered expression of these chimeric H4 genes compared to the endogenous copy or the transfected wild type gene suggests a structural model to explain the cell cycle independent expression of the basal histones. Images PMID:3024121

  6. DOSE RESPONSE FROM HIGH THROUGHPUT GENE EXPRESSION STUDIES AND THE INFLUENCE OF TIME AND CELL LINE ON INFERRED MODE OF ACTION BY ONTOLOGIC ENRICHMENT (SOT)

    EPA Science Inventory

    Gene expression with ontologic enrichment and connectivity mapping tools is widely used to infer modes of action (MOA) for therapeutic drugs. Despite progress in high-throughput (HT) genomic systems, strategies suitable to identify industrial chemical MOA are needed. The L1000 is...

  7. Simvastatin and Dipentyl Phthalate Display Different Mechanisms of Action but Exhibit Dose Additive Effects on Fetal Testicular Testosterone Production in Sprague Dawley Rats

    EPA Science Inventory

    Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero exposure to some phthalate esters (PEs) alters fetal Leydig cell differentiation, reducing the expression of several genes associated with steroid synthesis/tr...

  8. SBERIA: Set Based gene EnviRonment InterAction test for rare and common variants in complex diseases

    PubMed Central

    Jiao, Shuo; Hsu, Li; Bézieau, Stéphane; Brenner, Hermann; Chan, Andrew T.; Chang-Claude, Jenny; Le Marchand, Loic; Lemire, Mathieu; Newcomb, Polly A.; Slattery, Martha L.; Peters, Ulrike

    2013-01-01

    Identification of gene-environment interaction (GxE) is important in understanding the etiology of complex diseases. However, partially due to the lack of power, there have been very few replicated GxE findings compared to the success in marginal association studies. The existing GxE testing methods mainly focus on improving the power for individual markers. In this paper, we took a different strategy and proposed a Set Based gene EnviRonment InterAction test (SBERIA), which can improve the power by reducing the multiple testing burdens and aggregating signals within a set. The major challenge of the signal aggregation within a set is how to tell signals from noise and how to determine the direction of the signals. SBERIA takes advantage of the established correlation screening for GxE to guide the aggregation of genotypes within a marker set. The correlation screening has been shown to be an efficient way of selecting potential GxE candidate SNPs in case-control studies for complex diseases. Importantly, the correlation screening in case-control combined samples is independent of the interaction test. With this desirable feature, SBERIA maintains the correct type I error level and can be easily implemented in a regular logistic regression setting. We showed that SBERIA had higher power than benchmark methods in various simulation scenarios, both for common and rare variants. We also applied SBERIA to real GWAS data of 10,729 colorectal cancer cases and 13,328 controls and found evidence of interaction between the set of known colorectal cancer susceptibility loci and smoking. PMID:23720162

  9. Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans

    PubMed Central

    Alink, Gerrit M.; Scherjon, Fulco; MacDonald, Katharine; Smith, Alison C.; Nijveen, Harm; Roebroeks, Wil

    2016-01-01

    Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions. PMID:27655273

  10. Fire Usage and Ancient Hominin Detoxification Genes: Protective Ancestral Variants Dominate While Additional Derived Risk Variants Appear in Modern Humans.

    PubMed

    Aarts, Jac M M J G; Alink, Gerrit M; Scherjon, Fulco; MacDonald, Katharine; Smith, Alison C; Nijveen, Harm; Roebroeks, Wil

    Studies of the defence capacity of ancient hominins against toxic substances may contribute importantly to the reconstruction of their niche, including their diets and use of fire. Fire usage implies frequent exposure to hazardous compounds from smoke and heated food, known to affect general health and fertility, probably resulting in genetic selection for improved detoxification. To investigate whether such genetic selection occurred, we investigated the alleles in Neanderthals, Denisovans and modern humans at gene polymorphisms well-known to be relevant from modern human epidemiological studies of habitual tobacco smoke exposure and mechanistic evidence. We compared these with the alleles in chimpanzees and gorillas. Neanderthal and Denisovan hominins predominantly possess gene variants conferring increased resistance to these toxic compounds. Surprisingly, we observed the same in chimpanzees and gorillas, implying that less efficient variants are derived and mainly evolved in modern humans. Less efficient variants are observable from the first early Upper Palaeolithic hunter-gatherers onwards. While not clarifying the deep history of fire use, our results highlight the long-term stability of the genes under consideration despite major changes in the hominin dietary niche. Specifically for detoxification gene variants characterised as deleterious by epidemiological studies, our results confirm the predominantly recent appearance reported for deleterious human gene variants, suggesting substantial impact of recent human population history, including pre-Holocene expansions.

  11. [Study on action mechanism and material base of compound Danshen dripping pills in treatment of carotid atherosclerosis based on techniques of gene expression profile and molecular fingerprint].

    PubMed

    Zhou, Wei; Song, Xiang-gang; Chen, Chao; Wang, Shu-mei; Liang, Sheng-wang

    2015-08-01

    Action mechanism and material base of compound Danshen dripping pills in treatment of carotid atherosclerosis were discussed based on gene expression profile and molecular fingerprint in this paper. First, gene expression profiles of atherosclerotic carotid artery tissues and histologically normal tissues in human body were collected, and were screened using significance analysis of microarray (SAM) to screen out differential gene expressions; then differential genes were analyzed by Gene Ontology (GO) analysis and KEGG pathway analysis; to avoid some genes with non-outstanding differential expression but biologically importance, Gene Set Enrichment Analysis (GSEA) were performed, and 7 chemical ingredients with higher negative enrichment score were obtained by Cmap method, implying that they could reversely regulate the gene expression profiles of pathological tissues; and last, based on the hypotheses that similar structures have similar activities, 336 ingredients of compound Danshen dripping pills were compared with 7 drug molecules in 2D molecular fingerprints method. The results showed that 147 differential genes including 60 up-regulated genes and 87 down regulated genes were screened out by SAM. And in GO analysis, Biological Process ( BP) is mainly concerned with biological adhesion, response to wounding and inflammatory response; Cellular Component (CC) is mainly concerned with extracellular region, extracellular space and plasma membrane; while Molecular Function (MF) is mainly concerned with antigen binding, metalloendopeptidase activity and peptide binding. KEGG pathway analysis is mainly concerned with JAK-STAT, RIG-I like receptor and PPAR signaling pathway. There were 10 compounds, such as hexadecane, with Tanimoto coefficients greater than 0.85, which implied that they may be the active ingredients (AIs) of compound Danshen dripping pills in treatment of carotid atherosclerosis (CAs). The present method can be applied to the research on material

  12. Tandem oleosin genes in a cluster acquired in Brassicaceae created tapetosomes and conferred additive benefit of pollen vigor

    PubMed Central

    Huang, Chien Yu; Chen, Pei-Ying; Huang, Ming-Der; Tsou, Chih-Hua; Jane, Wann-Neng; Huang, Anthony H. C.

    2013-01-01

    During evolution, genomes expanded via whole-genome, segmental, tandem, and individual-gene duplications, and the emerged redundant paralogs would be eliminated or retained owing to selective neutrality or adaptive benefit and further functional divergence. Here we show that tandem paralogs can contribute adaptive quantitative benefit and thus have been retained in a lineage-specific manner. In Brassicaceae, a tandem oleosin gene cluster of five to nine paralogs encodes ample tapetum-specific oleosins located in abundant organelles called tapetosomes in flower anthers. Tapetosomes coordinate the storage of lipids and flavonoids and their transport to the adjacent maturing pollen as the coat to serve various functions. Transfer-DNA and siRNA mutants of Arabidopsis thaliana with knockout and knockdown of different tandem oleosin paralogs had quantitative and correlated loss of organized structures of the tapetosomes, pollen-coat materials, and pollen tolerance to dehydration. Complementation with the knockout paralog restored the losses. Cleomaceae is the family closest to Brassicaceae. Cleome species did not contain the tandem oleosin gene cluster, tapetum oleosin transcripts, tapetosomes, or pollen tolerant to dehydration. Cleome hassleriana transformed with an Arabidopsis oleosin gene for tapetum expression possessed primitive tapetosomes and pollen tolerant to dehydration. We propose that during early evolution of Brassicaceae, a duplicate oleosin gene mutated from expression in seed to the tapetum. The tapetum oleosin generated primitive tapetosomes that organized stored lipids and flavonoids for their effective transfer to the pollen surface for greater pollen vitality. The resulting adaptive benefit led to retention of tandem-duplicated oleosin genes for production of more oleosin and modern tapetosomes. PMID:23940319

  13. Testing the efficiency of plant artificial microRNAs by transient expression in Nicotiana benthamiana reveals additional action at the translational level

    PubMed Central

    Yu, Shi; Pilot, Guillaume

    2014-01-01

    Artificial microRNAs (amiRNAs) have become an important tool to assess gene functions due to their high efficiency and specificity to decrease target gene expression. Based on the observed degree of complementarity between microRNAs (miRNAs) and their targets, it was widely accepted that plant miRNAs act at the mRNA stability level, while the animal miRNAs act at the translational level. Contrary to these canonical dogmas, recent evidence suggests that both plant and animal miRNAs act at both levels. Nevertheless, it is still impossible to predict the effect of an artificial miRNA on the stability or translation of the target mRNA in plants. Consequently, identifying and discarding inefficient amiRNAs prior to stable plant transformation would help getting suppressed mutants faster and at reduced cost. We designed and tested a method using transient expression of amiRNAs and the corresponding target genes in Nicotiana benthamiana leaves to test the efficacy of amiRNAs for suppression of the target protein accumulation. The ability of the amiRNAs to suppress the target gene expression in N. benthamiana was then compared to that in stably transformed Arabidopsis. It was found that the efficacy of 16 amiRNAs, targeting a total of four genes, varied greatly. The effects of amiRNAs on target mRNA accumulation did not always correlate with target protein accumulation or the corresponding phenotypes, while a similar trend of the silencing efficacy of amiRNAs could be observed between N. benthamiana and stably transformed Arabidopsis. Our results showed that, similar to endogenous plant miRNAs, plant amiRNAs could act at the translational level, a property needed to be taken into account when testing the efficacy of individual amiRNAs. Preliminary tests in N. benthamiana can help determine which amiRNA would be the most likely to suppress target gene expression in stably transformed plants. PMID:25477887

  14. Complete sequence of a plasmid from a bovine methicillin-resistant Staphylococcus aureus harbouring a novel ica-like gene cluster in addition to antimicrobial and heavy metal resistance genes.

    PubMed

    Feßler, Andrea T; Zhao, Qin; Schoenfelder, Sonja; Kadlec, Kristina; Brenner Michael, Geovana; Wang, Yang; Ziebuhr, Wilma; Shen, Jianzhong; Schwarz, Stefan

    2017-02-01

    The multiresistance plasmid pAFS11, obtained from a bovine methicillin-resistant Staphylococcus aureus (MRSA) isolate, was completely sequenced and analysed for its structure and organisation. Moreover, the susceptibility to the heavy metals cadmium and copper was determined by broth macrodilution. The 49,189-bp plasmid harboured the apramycin resistance gene apmA, two copies of the macrolide/lincosamide/streptogramin B resistance gene erm(B) (both located on remnants of a truncated transposon Tn917), the kanamycin/neomycin resistance gene aadD, the tetracycline resistance gene tet(L) and the trimethoprim resistance gene dfrK. The latter three genes were part of a 7,284-bp segment which was bracketed by two copies of IS431. In addition, the cadmium resistance operon cadDX as well as the copper resistance genes copA and mco were located on the plasmid and mediated a reduced susceptibility to cadmium and copper. Moreover, a complete novel ica-like gene cluster of so far unknown genetic origin was detected on this plasmid. The ica-like gene cluster comprised four different genes whose products showed 64.4-76.9% homology to the Ica proteins known to be involved in biofilm formation of the S. aureus strains Mu50, Mu3 and N315. However, 96.2-99.4% homology was seen to proteins from S. sciuri NS1 indicating an S. sciuri origin. The finding of five different antibiotic resistance genes co-located on a plasmid with heavy metal resistance genes and an ica-like gene cluster is alarming. With the acquisition of this plasmid, antimicrobial multiresistance, heavy metal resistances and potential virulence properties may be co-selected and spread via a single horizontal gene transfer event.

  15. Effect of red mud addition on tetracycline and copper resistance genes and microbial community during the full scale swine manure composting.

    PubMed

    Wang, Rui; Zhang, Junya; Sui, Qianwen; Wan, Hefeng; Tong, Juan; Chen, Meixue; Wei, Yuansong; Wei, Dongbin

    2016-09-01

    Swine manure has been considered as the reservoir of antibiotic resistance genes (ARGs). Composting is one of the most suitable technologies for treating livestock manures, and red mud was proved to have a positive effect on nitrogen conservation during composting. This study investigated the abundance of eight tetracycline and three copper resistance genes, the bacterial community during the full scale swine manure composting with or without addition of red mud. The results showed that ARGs in swine manure could be effectively removed through composting (reduced by 2.4log copies/g TS), especially during the thermophilic phase (reduced by 1.5log copies/g TS), which the main contributor might be temperature. Additionally, evolution of bacterial community could also have a great influence on ARGs. Although addition of red mud could enhance nitrogen conservation, it obviously hindered removal of ARGs (reduced by 1.7log copies/g TS) and affected shaping of bacterial community during composting.

  16. Identification of an additional ferric-siderophore uptake gene clustered with receptor, biosynthesis, and fur-like regulatory genes in fluorescent Pseudomonas sp. strain M114.

    PubMed Central

    O'Sullivan, D J; Morris, J; O'Gara, F

    1990-01-01

    Five cosmid clones with insert sizes averaging 22.6 kilobases (kb) were isolated after complementation of 22 Tn5-induced Sid- mutants of Pseudomonas sp. strain M114. One of these plasmids (pMS639) was also shown to encode ferric-siderophore receptor and dissociation functions. The receptor gene was located on this plasmid since introduction of the plasmid into three wild-type fluorescent pseudomonads enabled them to utilize the ferric-siderophore from strain M114. The presence of an extra iron-regulated protein in the outer membrane profile of one of these strains was detected by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A ferric-siderophore dissociation gene was attributed to pMS639 since it complemented the ferric-siderophore uptake mutation in strain M114FR2. This mutant was not defective in the outer membrane receptor for ferric-siderophore but apparently accumulated ferric-siderophore internally. Since ferric-citrate alleviated the iron stress of the mutant, there was no defect in iron metabolism subsequent to release of iron from the ferric-siderophore complex. Consequently, this mutant was defective in ferric-siderophore dissociation. A fur-like regulatory gene also present on pMS639 was subcloned to a 7.0-kb BglII insert of pCUP5 and was located approximately 7.3 kb from the receptor region. These results established that the 27.2-kb insert of pMS639 encoded at least two siderophore biosynthesis genes, ferric-siderophore receptor and dissociation genes, and a fur-like regulatory gene from the biocontrol fluorescent Pseudomonas sp. strain M114. Images PMID:2143887

  17. Effects of Copper Addition on Copper Resistance, Antibiotic Resistance Genes, and intl1 during Swine Manure Composting

    PubMed Central

    Yin, Yanan; Gu, Jie; Wang, Xiaojuan; Song, Wen; Zhang, Kaiyu; Sun, Wei; Zhang, Xin; Zhang, Yajun; Li, Haichao

    2017-01-01

    Copper is one of the most abundant heavy metals present in swine manure. In this study, a laboratory-scale aerobic composting system was amended with Cu at three levels (0, 200, and 2000 mg kg-1, i.e., control, Cu200, and Cu2000 treatments, respectively) to determine its effect on the fate of copper resistance genes [copper resistance genes (CRGs): pcoA, cusA, copA, and tcrB], antibiotic resistance genes [antibiotic resistance genes (ARGs): erm(A) and erm(B)], and intl1. The results showed that the absolute abundances of pcoA, tcrB, erm(A), erm(B), and intl1 were reduced, whereas those of copA and cusA increased after swine manure composting. Redundancy analysis showed that temperature significantly affected the variations in CRGs, ARGs, and intl1. The decreases in CRGs, ARGs, and intI1 were positively correlated with the exchangeable Cu levels. The bacterial community could be grouped according to the composting time under different treatments, where the high concentration of copper had a more persistent effect on the bacterial community. Network analysis determined that the co-occurrence of CRGs, ARGs, and intI1, and the bacterial community were the main contributors to the changes in CRGs, ARG, and intl1. Thus, temperature, copper, and changes in the bacterial community composition had important effects on the variations in CRGs, ARGs, and intl1 during manure composting in the presence of added copper. PMID:28316595

  18. Effects of Copper Addition on Copper Resistance, Antibiotic Resistance Genes, and intl1 during Swine Manure Composting.

    PubMed

    Yin, Yanan; Gu, Jie; Wang, Xiaojuan; Song, Wen; Zhang, Kaiyu; Sun, Wei; Zhang, Xin; Zhang, Yajun; Li, Haichao

    2017-01-01

    Copper is one of the most abundant heavy metals present in swine manure. In this study, a laboratory-scale aerobic composting system was amended with Cu at three levels (0, 200, and 2000 mg kg(-1), i.e., control, Cu200, and Cu2000 treatments, respectively) to determine its effect on the fate of copper resistance genes [copper resistance genes (CRGs): pcoA, cusA, copA, and tcrB], antibiotic resistance genes [antibiotic resistance genes (ARGs): erm(A) and erm(B)], and intl1. The results showed that the absolute abundances of pcoA, tcrB, erm(A), erm(B), and intl1 were reduced, whereas those of copA and cusA increased after swine manure composting. Redundancy analysis showed that temperature significantly affected the variations in CRGs, ARGs, and intl1. The decreases in CRGs, ARGs, and intI1 were positively correlated with the exchangeable Cu levels. The bacterial community could be grouped according to the composting time under different treatments, where the high concentration of copper had a more persistent effect on the bacterial community. Network analysis determined that the co-occurrence of CRGs, ARGs, and intI1, and the bacterial community were the main contributors to the changes in CRGs, ARG, and intl1. Thus, temperature, copper, and changes in the bacterial community composition had important effects on the variations in CRGs, ARGs, and intl1 during manure composting in the presence of added copper.

  19. Addition of Escherichia coli K-12 Growth Observation and Gene Essentiality Data to the EcoCyc Database

    PubMed Central

    Mackie, Amanda; Paley, Suzanne; Keseler, Ingrid M.; Shearer, Alexander; Paulsen, Ian T.

    2014-01-01

    The sets of compounds that can support growth of an organism are defined by the presence of transporters and metabolic pathways that convert nutrient sources into cellular components and energy for growth. A collection of known nutrient sources can therefore serve both as an impetus for investigating new metabolic pathways and transporters and as a reference for computational modeling of known metabolic pathways. To establish such a collection for Escherichia coli K-12, we have integrated data on the growth or nongrowth of E. coli K-12 obtained from published observations using a variety of individual media and from high-throughput phenotype microarrays into the EcoCyc database. The assembled collection revealed a substantial number of discrepancies between the high-throughput data sets, which we investigated where possible using low-throughput growth assays on soft agar and in liquid culture. We also integrated six data sets describing 16,119 observations of the growth of single-gene knockout mutants of E. coli K-12 into EcoCyc, which are relevant to antimicrobial drug design, provide clues regarding the roles of genes of unknown function, and are useful for validating metabolic models. To make this information easily accessible to EcoCyc users, we developed software for capturing, querying, and visualizing cellular growth assays and gene essentiality data. PMID:24363340

  20. HSP70 and modified HPV 16 E7 fusion gene without the addition of a signal peptide gene sequence as a candidate therapeutic tumor vaccine.

    PubMed

    Zong, Jinbao; Wang, Changyuan; Wang, Qingyong; Peng, Qinglin; Xu, Yufei; Xie, Xixiu; Xu, Xuemei

    2013-12-01

    Millions of women are currently infected with high-risk human papillomavirus (HPV), which is considered to be a major risk factor for cervical cancer. Thus, it is urgent to develop therapeutic vaccines to eliminate the established infections or HPV-related diseases. In the present study, using the mycobacterium tuberculosis heat shock protein 70 (MtHSP70) gene linked to the modified HPV 16 E7 (mE7) gene, we generated two potential therapeutic HPV DNA vaccines, mE7/MtHSP70 and SigmE7/MtHSP70, the latter was linked to the signal peptide gene sequence of human CD33 at the upstream of the fusion gene. We found that vaccination with the mE7/MtHSP70 DNA vaccine induced a stronger E7-specific CD8+ T cell response and resulted in a more significant therapeutic effect against E7-expressing tumor cells in mice. Our results demonstrated that HSP70 can play a more important role in mE7 and MtHSP70 fusion DNA vaccine without the help of a signal peptide. This may facilitate the use of HSP70 and serve as a significant reference for future study.

  1. Scripts, Tricks and Capability Theory: Using an Empirical Window into the Logic of Achievement to Illustrate How a Critical Addition to Capability Theory Might Work to Guide Action

    ERIC Educational Resources Information Center

    Corrado, Gail

    2016-01-01

    Capability theory improves our understanding of well being because it takes account of the "conversion" problem: income/wealth/commodities. (IWCs) need to be made effectively available to really increase well being. However, just as IWCs need to be converted into functionings in order to be effective in bringing additional possibilities…

  2. Smoking and polymorphisms in xenobiotic metabolism and DNA repair genes are additive risk factors affecting bladder cancer in Northern Tunisia.

    PubMed

    Rouissi, Kamel; Ouerhani, Slah; Hamrita, Bechr; Bougatef, Karim; Marrakchi, Raja; Cherif, Mohamed; Ben Slama, Mohamed Riadh; Bouzouita, Mohamed; Chebil, Mohamed; Ben Ammar Elgaaied, Amel

    2011-12-01

    Cancer epidemiology has undergone marked development since the nineteen-fifties. One of the most spectacular and specific contributions was the demonstration of the massive effect of smoking and genetic polymorphisms on the occurrence of bladder cancer. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of N-acetyltransferases (NAT) and glutathione S-transferases (GST). DNA repair is essential to an individual's ability to respond to damage caused by tobacco carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to this environmental exposure. Polymorphisms in NAT2, GST and DNA repair genes alter the ability of these enzymes to metabolize carcinogens or to repair alterations caused by this process. We have conducted a case-control study to assess the role of smoking, slow NAT2 variants, GSTM1 and GSTT1 null, and XPC, XPD, XPG nucleotide excision-repair (NER) genotypes in bladder cancer development in North Tunisia. Taken alone, each gene unless NAT2 did not appear to be a factor affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotypes, the NAT2*5/*7 diplotype was found to have a 7-fold increased risk to develop bladder cancer (OR = 7.14; 95% CI: 1.30-51.41). However, in tobacco consumers, we have shown that Null GSTM1, Wild GSTT1, Slow NAT2, XPC (CC) and XPG (CC) are genetic risk factors for the disease. When combined together in susceptible individuals compared to protected individuals these risk factors give an elevated OR (OR = 61). So, we have shown a strong cumulative effect of tobacco and different combinations of studied genetic risk factors which lead to a great susceptibility to bladder cancer.

  3. High frequency of additional gene mutations in acute myeloid leukemia with MLL partial tandem duplication: DNMT3A mutation is associated with poor prognosis

    PubMed Central

    Kao, Hsiao-Wen; Liang, Der-Cherng; Kuo, Ming-Chung; Wu, Jin-Hou; Dunn, Po; Wang, Po-Nan; Lin, Tung-Liang; Shih, Yu-Shu; Liang, Sung-Tzu; Lin, Tung-Huei; Lai, Chen-Yu; Lin, Chun-Hui; Shih, Lee-Yung

    2015-01-01

    The mutational profiles of acute myeloid leukemia (AML) with partial tandem duplication of mixed-lineage leukemia gene (MLL-PTD) have not been comprehensively studied. We studied 19 gene mutations for 98 patients with MLL-PTD AML to determine the mutation frequency and clinical correlations. MLL-PTD was screened by reverse-transcriptase PCR and confirmed by real-time quantitative PCR. The mutational analyses were performed with PCR-based assays followed by direct sequencing. Gene mutations of signaling pathways occurred in 63.3% of patients, with FLT3-ITD (44.9%) and FLT3-TKD (13.3%) being the most frequent. 66% of patients had gene mutations involving epigenetic regulation, and DNMT3A (32.7%), IDH2 (18.4%), TET2 (18.4%), and IDH1 (10.2%) mutations were most common. Genes of transcription pathways and tumor suppressors accounted for 23.5% and 10.2% of patients. RUNX1 mutation occurred in 23.5% of patients, while none had NPM1 or double CEBPA mutation. 90.8% of MLL-PTD AML patients had at least one additional gene mutation. Of 55 MLL-PTD AML patients who received standard chemotherapy, age older than 50 years and DNMT3A mutation were associated with inferior outcome. In conclusion, gene mutations involving DNA methylation and activated signaling pathway were common co-existed gene mutations. DNMT3A mutation was a poor prognostic factor in MLL-PTD AML. PMID:26375248

  4. Reference Gene Selection for qPCR Analysis in Tomato-Bipartite Begomovirus Interaction and Validation in Additional Tomato-Virus Pathosystems

    PubMed Central

    Lacerda, Ana L. M.; Fonseca, Leonardo N.; Blawid, Rosana; Boiteux, Leonardo S.; Ribeiro, Simone G.; Brasileiro, Ana C. M.

    2015-01-01

    Quantitative Polymerase Chain Reaction (qPCR) is currently the most sensitive technique used for absolute and relative quantification of a target gene transcript, requiring the use of appropriated reference genes for data normalization. To accurately estimate the relative expression of target tomato (Solanum lycopersicum L.) genes responsive to several virus species in reverse transcription qPCR analysis, the identification of reliable reference genes is mandatory. In the present study, ten reference genes were analyzed across a set of eight samples: two tomato contrasting genotypes (‘Santa Clara’, susceptible, and its near-isogenic line ‘LAM 157’, resistant); subjected to two treatments (inoculation with Tomato chlorotic mottle virus (ToCMoV) and its mock-inoculated control) and in two distinct times after inoculation (early and late). Reference genes stability was estimated by three statistical programs (geNorm, NormFinder and BestKeeper). To validate the results over broader experimental conditions, a set of ten samples, corresponding to additional three tomato-virus pathosystems that included tospovirus, crinivirus and tymovirus + tobamovirus, was analyzed together with the tomato-ToCMoV pathosystem dataset, using the same algorithms. Taking into account the combined analyses of the ranking order outputs from the three algorithms, TIP41 and EF1 were identified as the most stable genes for tomato-ToCMoV pathosystem, and TIP41 and EXP for the four pathosystems together, and selected to be used as reference in the forthcoming expression qPCR analysis of target genes in experimental conditions involving the aforementioned tomato-virus pathosystems. PMID:26317870

  5. Action perception predicts action performance

    PubMed Central

    Bailey, Heather R.; Kurby, Christopher A.; Giovannetti, Tania; Zacks, Jeffrey M.

    2013-01-01

    Everyday action impairments often are observed in demented older adults, and they are common potential barriers to functional independence. We evaluated whether the ability to segment and efficiently encode activities is related to the ability to execute activities. Further, we evaluated whether brain regions important for segmentation also were important for action performance. Cognitively healthy older adults and those with very mild or mild dementia of the Alzheimer's type watched and segmented movies of everyday activities and then completed the Naturalistic Action Test. Structural MRI was used to measure volume in the dorsolateral prefrontal cortex (DLPFC), medial temporal lobes (MTL), posterior cortex, and anterior cingulate cortex (ACC). Dementia status and the ability to segment everyday activities strongly predicted naturalistic action performance, and MTL volume largely accounted for this relationship. In addition, the current results supported the Omission-Commission Model: Different cognitive and neurological mechanisms predicted different types of action error. Segmentation, dementia severity, and MTL volume predicted everyday omission errors, DLPFC volume predicted commission errors, and ACC volume predicted action additions. These findings suggest that event segmentation may be critical for effective action production, and that the segmentation and production of activities may recruit the same event representation system. PMID:23851113

  6. Action perception predicts action performance.

    PubMed

    Bailey, Heather R; Kurby, Christopher A; Giovannetti, Tania; Zacks, Jeffrey M

    2013-09-01

    Everyday action impairments often are observed in demented older adults, and they are common potential barriers to functional independence. We evaluated whether the ability to segment and efficiently encode activities is related to the ability to execute activities. Further, we evaluated whether brain regions important for segmentation also were important for action performance. Cognitively healthy older adults and those with very mild or mild dementia of the Alzheimer's type watched and segmented movies of everyday activities and then completed the Naturalistic Action Test. Structural MRI was used to measure volume in the dorsolateral prefrontal cortex (DLPFC), medial temporal lobes (MTL), posterior cortex, and anterior cingulate cortex (ACC). Dementia status and the ability to segment everyday activities strongly predicted naturalistic action performance, and MTL volume largely accounted for this relationship. In addition, the current results supported the Omission-Commission Model: Different cognitive and neurological mechanisms predicted different types of action error. Segmentation, dementia severity, and MTL volume predicted everyday omission errors, DLPFC volume predicted commission errors, and ACC volume predicted action additions. These findings suggest that event segmentation may be critical for effective action production, and that the segmentation and production of activities may recruit the same event representation system.

  7. Combined action of time-delay and colored cross-associated multiplicative and additive noises on stability and stochastic resonance for a stochastic metapopulation system

    NASA Astrophysics Data System (ADS)

    Wang, Kang-Kang; Zong, De-Cai; Wang, Ya-Jun; Li, Sheng-Hong

    2016-05-01

    In this paper, the transition between the stable state of a big density and the extinction state and stochastic resonance (SR) for a time-delayed metapopulation system disturbed by colored cross-correlated noises are investigated. By applying the fast descent method, the small time-delay approximation and McNamara and Wiesenfeld's SR theory, we investigate the impacts of time-delay, the multiplicative, additive noises and colored cross-correlated noise on the SNR and the shift between the two states of the system. Numerical results show that the multiplicative, additive noises and time-delay can all speed up the transition from the stable state to the extinction state, while the correlation noise and its correlation time can slow down the extinction process of the population system. With respect to SNR, the multiplicative noise always weakens the SR effect, while noise correlation time plays a dual role in motivating the SR phenomenon. Meanwhile, time-delay mainly plays a negative role in stimulating the SR phenomenon. Conversely, it could motivate the SR effect to increase the strength of the cross-correlation noise in the SNR-β plot, while the increase of additive noise intensity will firstly excite SR, and then suppress the SR effect.

  8. Skin epidermis lacking the c-myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional lossof the p21Cip1 gene

    PubMed Central

    Oskarsson, Thordur; Essers, Marieke Alida Gertruda; Dubois, Nicole; Offner, Sandra; Dubey, Christelle; Roger, Catherine; Metzger, Daniel; Chambon, Pierre; Hummler, Edith; Beard, Peter; Trumpp, Andreas

    2006-01-01

    The target gene(s) required for Myc-mediated tumorigenesis are still elusive. Here we show that while endogenous c-Myc is surprisingly dispensable for skin homeostasis and TPA-induced hyperplasia, c-Myc-deficient epidermis is resistant to Ras-mediated DMBA/TPAinduced tumorigenesis. This is mechanistically linked to p21Cip1, which is induced in tumors by the activated Ras–ERK pathway but repressed by c-Myc. Acute elimination of c-Myc in established tumors leads to the up-regulation of p21Cip1, and epidermis lacking both p21Cip1 and c-Myc reacquires normal sensitivity to DMBA/TPA-induced tumorigenesis. This identifies c-Myc-mediated repression of p21Cip1 as a key step for Ras-driven epidermal tumorigenesis. PMID:16882980

  9. An Additional Regulatory Gene for Actinorhodin Production in Streptomyces lividans Involves a LysR-Type Transcriptional Regulator

    PubMed Central

    Martínez-Costa, Oscar H.; Martín-Triana, Angel J.; Martínez, Eduardo; Fernández-Moreno, Miguel A.; Malpartida, Francisco

    1999-01-01

    The sequence of a 4.8-kbp DNA fragment adjacent to the right-hand end of the actinorhodin biosynthetic (act) cluster downstream of actVB-orf6 from Streptomyces coelicolor A3(2) reveals six complete open reading frames, named orf7 to orf12. The deduced amino acid sequences from orf7, orf10, and orf11 show significant similarities with the following products in the databases: a putative protein from the S. coelicolor SCP3 plasmid, LysR-type transcriptional regulators, and proteins belonging to the family of short-chain dehydrogenases/reductases, respectively. The deduced product of orf8 reveals low similarities with several methyltransferases from different sources, while orf9 and orf12 products show no similarities with other known proteins. Disruptions of orf10 and orf11 genes in S. coelicolor appear to have no significant effect on the production of actinorhodin. Nevertheless, disruption or deletion of orf10 in Streptomyces lividans causes actinorhodin overproduction. The introduction of extra copies of orf10 and orf11 genes in an S. coelicolor actIII mutant restores the ability to produce actinorhodin. Transcriptional analysis and DNA footprinting indicate that Orf10 represses its own transcription and regulates orf11 transcription, expression of which might require the presence of an unknown inducer. No DNA target for Orf10 protein was found within the act cluster. PMID:10400594

  10. Evolution of the CD4 family: teleost fish possess two divergent forms of CD4 in addition to lymphocyte activation gene-3

    USGS Publications Warehouse

    Laing, K.J.; Zou, J.J.; Purcell, M.K.; Phillips, R.; Secombes, C.J.; Hansen, J.D.

    2006-01-01

    The T cell coreceptor CD4 is a transmembrane glycoprotein belonging to the Ig superfamily and is essential for cell-mediated immunity. Two different genes were identified in rainbow trout that resemble mammalian CD4. One (trout CD4) encodes four extracellular Ig domains reminiscent off mammalian CD4, whereas the other (CD4REL) codes for two Ig domains. Structural motifs within the amino acid sequences suggest that the two Ig domains of CD4REL duplicated to generate the four-domain molecule of CD4 and the related gene, lymphocyte activation gene-3. Here we present evidence that both of these molecules in trout are homologous to mammalian CD4 and that teleosts encode an additional CD4 family member, lymphocyte activation gene-3, which is a marker for activated T cells. The syntenic relationships of similar genes in other teleost and non-fish genomes provide evidence for the likely evolution of CD4-related molecules in vertebrates, with CD4REL likely representing the primordial form in fish. Expression of both CD4 genes is highest in the thymus and spleen, and mRNA expression of these genes is limited to surface IgM- lymphocytes, consistent with a role for T cell functionality. Finally, the intracellular regions of both CD4 and CD4REL possess the canonical CXC motif involved in the interaction off CD4 with p56LCK, implying that similar mechanisms for CD4 + T cell activation are present in all vertebrates. Our results therefore raise new questions about T cell development and functionality in lower vertebrates that cannot be answered by current mammalian models and, thus, is of fundamental importance for understanding the evolution of cell-mediated immunity in gnathosomes. Copyright ?? 2006 by The American Association of Immunologists, Inc.

  11. The effect of nitrate addition on abundance of nirK, nirS and gln genes in acidified Norway spruce forest soil

    NASA Astrophysics Data System (ADS)

    Bárta, Jiří; Tahovská, Karolina; Kaåa, Jiří; Antrå¯Čková, Hana Å.

    2010-05-01

    The denitrification is the main biotic process leading to loses of fixed nitrogen as well as removal of excess of nitrate (NO3-) from the soil environment. The reduction of NO2- to nitric oxide (NO) distinguishes the 'true' denitrifiers from other nitrate-respiring bacteria. This reaction is catalyzed by two different types of nitrite reductases, either a cytochrome cd1 encoded by nirS gene (nirS denitrifiers) or a Cu-containing enzyme encoded by nirK gene (nirK denitrifiers). The nirS denitrifiers are located mostly in rhizosphere, while the nirK denitrifiers are more abundant in bulk soil. These two groups can be also classified as markers of denitrification. Glutamine synthetase is one of the main bacterial NH4+ assimilating enzymes; it is coded by glnI gene. Glutamine synthetase is mostly active when N is the limiting factor for bacterial growth. There is recent evidence that the activity may be affected by the presence of alternative N source (i.e. NO3-). However, in anaerobic condition NO3- can be used also by the denitrifying bacteria so there may be strong competition for this nutrient. The laboratory experiment was performed to evaluate the effect of nitrates (NO3-) on abundance of nirK, nirS and gln gene copy numbers. The amount of NO3- corresponded to the actual atmospheric depositions on experimental sites in the Bohemian Forest. Litter organic layer (0-5cm of soil) was used for laboratory incubation experiment. Four replicates of control (no addition of NO3-), and NO3-addition were incubated anaerobically for one month. After the incubation DNA was extracted and the number of nirK, nirS and gln gene copies was determined using qPCR (SYBRGreen methodology). Results showed that the addition of NO3- significantly increased the number of nirK and nirS denitrifiers from 5.9x106 to 1.1x107 and from not detectable amount to 1.4x106, respectively. The gln gene copy number was also higher after NO3-addition. However, the difference was not statistically

  12. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease.

    PubMed

    De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi; Li, Linhong; Wu, Xiaolin; Su, Ling; Raley, Castle; Theobald, Narda; Choi, Uimook; Song, Alexander H; Chan, Andy; Pearl, Jocelynn R; Paschon, David E; Lee, Janet; Newcombe, Hannah; Koontz, Sherry; Sweeney, Colin; Shivak, David A; Zarember, Kol A; Peshwa, Madhusudan V; Gregory, Philip D; Urnov, Fyodor D; Malech, Harry L

    2016-04-01

    Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ∼15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases.

  13. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

    PubMed

    Fan, Qiao; Verhoeven, Virginie J M; Wojciechowski, Robert; Barathi, Veluchamy A; Hysi, Pirro G; Guggenheim, Jeremy A; Höhn, René; Vitart, Veronique; Khawaja, Anthony P; Yamashiro, Kenji; Hosseini, S Mohsen; Lehtimäki, Terho; Lu, Yi; Haller, Toomas; Xie, Jing; Delcourt, Cécile; Pirastu, Mario; Wedenoja, Juho; Gharahkhani, Puya; Venturini, Cristina; Miyake, Masahiro; Hewitt, Alex W; Guo, Xiaobo; Mazur, Johanna; Huffman, Jenifer E; Williams, Katie M; Polasek, Ozren; Campbell, Harry; Rudan, Igor; Vatavuk, Zoran; Wilson, James F; Joshi, Peter K; McMahon, George; St Pourcain, Beate; Evans, David M; Simpson, Claire L; Schwantes-An, Tae-Hwi; Igo, Robert P; Mirshahi, Alireza; Cougnard-Gregoire, Audrey; Bellenguez, Céline; Blettner, Maria; Raitakari, Olli; Kähönen, Mika; Seppala, Ilkka; Zeller, Tanja; Meitinger, Thomas; Ried, Janina S; Gieger, Christian; Portas, Laura; van Leeuwen, Elisabeth M; Amin, Najaf; Uitterlinden, André G; Rivadeneira, Fernando; Hofman, Albert; Vingerling, Johannes R; Wang, Ya Xing; Wang, Xu; Tai-Hui Boh, Eileen; Ikram, M Kamran; Sabanayagam, Charumathi; Gupta, Preeti; Tan, Vincent; Zhou, Lei; Ho, Candice E H; Lim, Wan'e; Beuerman, Roger W; Siantar, Rosalynn; Tai, E-Shyong; Vithana, Eranga; Mihailov, Evelin; Khor, Chiea-Chuen; Hayward, Caroline; Luben, Robert N; Foster, Paul J; Klein, Barbara E K; Klein, Ronald; Wong, Hoi-Suen; Mitchell, Paul; Metspalu, Andres; Aung, Tin; Young, Terri L; He, Mingguang; Pärssinen, Olavi; van Duijn, Cornelia M; Jin Wang, Jie; Williams, Cathy; Jonas, Jost B; Teo, Yik-Ying; Mackey, David A; Oexle, Konrad; Yoshimura, Nagahisa; Paterson, Andrew D; Pfeiffer, Norbert; Wong, Tien-Yin; Baird, Paul N; Stambolian, Dwight; Wilson, Joan E Bailey; Cheng, Ching-Yu; Hammond, Christopher J; Klaver, Caroline C W; Saw, Seang-Mei; Rahi, Jugnoo S; Korobelnik, Jean-François; Kemp, John P; Timpson, Nicholas J; Smith, George Davey; Craig, Jamie E; Burdon, Kathryn P; Fogarty, Rhys D; Iyengar, Sudha K; Chew, Emily; Janmahasatian, Sarayut; Martin, Nicholas G; MacGregor, Stuart; Xu, Liang; Schache, Maria; Nangia, Vinay; Panda-Jonas, Songhomitra; Wright, Alan F; Fondran, Jeremy R; Lass, Jonathan H; Feng, Sheng; Zhao, Jing Hua; Khaw, Kay-Tee; Wareham, Nick J; Rantanen, Taina; Kaprio, Jaakko; Pang, Chi Pui; Chen, Li Jia; Tam, Pancy O; Jhanji, Vishal; Young, Alvin L; Döring, Angela; Raffel, Leslie J; Cotch, Mary-Frances; Li, Xiaohui; Yip, Shea Ping; Yap, Maurice K H; Biino, Ginevra; Vaccargiu, Simona; Fossarello, Maurizio; Fleck, Brian; Yazar, Seyhan; Tideman, Jan Willem L; Tedja, Milly; Deangelis, Margaret M; Morrison, Margaux; Farrer, Lindsay; Zhou, Xiangtian; Chen, Wei; Mizuki, Nobuhisa; Meguro, Akira; Mäkelä, Kari Matti

    2016-03-29

    Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

  14. Gene expression suggests double-segmental and single-segmental patterning mechanisms during posterior segment addition in the beetle Tribolium castaneum.

    PubMed

    Janssen, Ralf

    2014-01-01

    In the model arthropod Drosophila, all segments are patterned simultaneously in the blastoderm. In most other arthropods, however, posterior segments are added sequentially from a posterior segment addition zone. Posterior addition of single segments likely represents the ancestral mode of arthropod segmentation, although in Drosophila, segments are patterned in pairs by the pair-rule genes. It has been shown that in the new model insect, the beetle Tribolium, a segmentation clock operates that apparently patterns all segments in pairs as well. Here, I report on the expression of the segment polarity gene H15/midline in Tribolium. In the anterior embryo, segmental stripes of H15 appear in pairs, but in the posterior of the embryo stripes appear in a single-segmental periodicity. This implies that either two completely different segmentation-mechanisms may act in the germ band of Tribolium, that the segmentation clock changes its periodicity during development, or that the speed in which posterior segments are patterned changes. In any case, the data suggest the presence of another (or modified), yet undiscovered, mechanism of posterior segment addition in one of the best-understood arthropod models. The finding of a hitherto unrecognized segmentation mechanism in Tribolium may have major implications for the understanding of the origin of segmentation mechanisms, including the origin of pair rule patterning. It also calls for (re)-investigation of posterior segment addition in Tribolium and other previously studied arthropod models.

  15. Action of multiple intra-QTL genes concerted around a co-localized transcription factor underpins a large effect QTL

    PubMed Central

    Dixit, Shalabh; Kumar Biswal, Akshaya; Min, Aye; Henry, Amelia; Oane, Rowena H.; Raorane, Manish L.; Longkumer, Toshisangba; Pabuayon, Isaiah M.; Mutte, Sumanth K.; Vardarajan, Adithi R.; Miro, Berta; Govindan, Ganesan; Albano-Enriquez, Blesilda; Pueffeld, Mandy; Sreenivasulu, Nese; Slamet-Loedin, Inez; Sundarvelpandian, Kalaipandian; Tsai, Yuan-Ching; Raghuvanshi, Saurabh; Hsing, Yue-Ie C.; Kumar, Arvind; Kohli, Ajay

    2015-01-01

    Sub-QTLs and multiple intra-QTL genes are hypothesized to underpin large-effect QTLs. Known QTLs over gene families, biosynthetic pathways or certain traits represent functional gene-clusters of genes of the same gene ontology (GO). Gene-clusters containing genes of different GO have not been elaborated, except in silico as coexpressed genes within QTLs. Here we demonstrate the requirement of multiple intra-QTL genes for the full impact of QTL qDTY12.1 on rice yield under drought. Multiple evidences are presented for the need of the transcription factor ‘no apical meristem’ (OsNAM12.1) and its co-localized target genes of separate GO categories for qDTY12.1 function, raising a regulon-like model of genetic architecture. The molecular underpinnings of qDTY12.1 support its effectiveness in further improving a drought tolerant genotype and for its validity in multiple genotypes/ecosystems/environments. Resolving the combinatorial value of OsNAM12.1 with individual intra-QTL genes notwithstanding, identification and analyses of qDTY12.1has fast-tracked rice improvement towards food security. PMID:26507552

  16. Individual and Additive Effects of the CNR1 and FAAH Genes on Brain Response to Marijuana Cues

    PubMed Central

    Filbey, Francesca M; Schacht, Joseph P; Myers, Ursula S; Chavez, Robert S; Hutchison, Kent E

    2010-01-01

    As previous work has highlighted the significance of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes with respect to cannabis dependence (CD), this study sought to characterize the neural mechanisms that underlie these genetic effects. To this end, we collected DNA samples and fMRI data using a cue-elicited craving paradigm in thirty-seven 3-day-abstinent regular marijuana users. The participants were grouped according to their genotype on two single-nucleotide polymorphisms (SNPs) earlier associated with CD phenotypes: rs2023239 in CNR1 and rs324420 in FAAH. Between-group comparisons showed that carriers of the CNR1 rs2023239 G allele had significantly greater activity in reward-related areas of the brain, such as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate gyrus (ACG), during exposure to marijuana cues, as compared with those with the A/A genotype for this SNP. The FAAH group contrasts showed that FAAH rs324420 C homozygotes also had greater activation in widespread areas within the reward circuit, specifically in the OFC, ACG, and nucleus accumbens (NAc), as compared with the FAAH A-allele carriers. Moreover, there was a positive correlation between neural response in OFC and NAc and the total number of risk alleles (cluster-corrected p<0.05). These findings are in accord with earlier reported associations between CNR1 and FAAH and CD intermediate phenotypes, and suggest that the underlying mechanism of these genetic effects may be enhanced neural response in reward areas of the brain in carriers of the CNR1 G allele and FAAH C/C genotype in response to marijuana cues. PMID:20010552

  17. Individual and additive effects of the CNR1 and FAAH genes on brain response to marijuana cues.

    PubMed

    Filbey, Francesca M; Schacht, Joseph P; Myers, Ursula S; Chavez, Robert S; Hutchison, Kent E

    2010-03-01

    As previous work has highlighted the significance of the cannabinoid receptor 1 (CNR1) and fatty acid amide hydrolase (FAAH) genes with respect to cannabis dependence (CD), this study sought to characterize the neural mechanisms that underlie these genetic effects. To this end, we collected DNA samples and fMRI data using a cue-elicited craving paradigm in thirty-seven 3-day-abstinent regular marijuana users. The participants were grouped according to their genotype on two single-nucleotide polymorphisms (SNPs) earlier associated with CD phenotypes: rs2023239 in CNR1 and rs324420 in FAAH. Between-group comparisons showed that carriers of the CNR1 rs2023239 G allele had significantly greater activity in reward-related areas of the brain, such as the orbitofrontal cortex (OFC), inferior frontal gyrus (IFG), and anterior cingulate gyrus (ACG), during exposure to marijuana cues, as compared with those with the A/A genotype for this SNP. The FAAH group contrasts showed that FAAH rs324420 C homozygotes also had greater activation in widespread areas within the reward circuit, specifically in the OFC, ACG, and nucleus accumbens (NAc), as compared with the FAAH A-allele carriers. Moreover, there was a positive correlation between neural response in OFC and NAc and the total number of risk alleles (cluster-corrected p<0.05). These findings are in accord with earlier reported associations between CNR1 and FAAH and CD intermediate phenotypes, and suggest that the underlying mechanism of these genetic effects may be enhanced neural response in reward areas of the brain in carriers of the CNR1 G allele and FAAH C/C genotype in response to marijuana cues.

  18. Impacts of addition of natural zeolite or a nitrification inhibitor on antibiotic resistance genes during sludge composting.

    PubMed

    Zhang, Junya; Chen, Meixue; Sui, Qianwen; Tong, Juan; Jiang, Chao; Lu, Xueting; Zhang, Yuxiu; Wei, Yuansong

    2016-03-15

    Composting is commonly used for the treatment and resource utilization of sewage sludge, and natural zeolite and nitrification inhibitors can be used for nitrogen conservation during sludge composting, while their impacts on ARGs control are still unclear. Therefore, three lab-scale composting reactors, A (the control), B (natural zeolite addition) and C (nitrification inhibitor addition of 3,4-dimethylpyrazole phosphate, DMPP), were established. The impacts of natural zeolite and DMPP on the levels of ARGs were investigated, as were the roles that heavy metals, mobile genetic elements (MGEs) and the bacterial community play in ARGs evolution. The results showed that total ARGs copies were enriched 2.04 and 1.95 times in reactors A and C, respectively, but were reduced by 1.5% in reactor B due to the reduction of conjugation and co-selection of heavy metals caused by natural zeolite. Although some ARGs (blaCTX-M, blaTEM, ermB, ereA and tetW) were reduced by 0.3-2 logs, others (ermF, sulI, sulII, tetG, tetX, mefA and aac(6')-Ib-cr) increased by 0.3-1.3 logs after sludge composting. Although the contributors for the ARGs profiles in different stages were quite different, the results of a partial redundancy analysis, Mantel test and Procrustes analysis showed that the bacterial community was the main contributor to the changes in ARGs compared to MGEs and heavy metals. Network analysis determined the potential host bacteria for various ARGs and further confirmed our results.

  19. The UV filter benzophenone 3 (BP-3) activates hormonal genes mimicking the action of ecdysone and alters embryo development in the insect Chironomus riparius (Diptera).

    PubMed

    Ozáez, Irene; Martínez-Guitarte, José Luis; Morcillo, Gloria

    2014-09-01

    Numerous studies have evaluated the endocrine effects of UV filters in vertebrates, but little attention has been paid to their possible hormonal activity in invertebrates. We examined the effects of benzophenone-3 (BP-3), one of the most common sunscreen agents, in Chironomus riparius (Insecta), a reference organism in aquatic toxicology. Salivary glands from larvae were treated with either the hormone ecdysone or BP-3 to compare the response of endocrine genes. It was found that BP-3 elicits the same effects as the natural hormone activating the expression of a set of ecdysone responsive genes. BP-3 also activated the stress gene hsp70. Interestingly, similar effects have been confirmed in vivo in embryos. Moreover, BP-3 also altered embryogenesis delaying hatching. This is the first demonstration of hormonal activity of UV filters in invertebrates, showing a mode of action similar to ecdysteroid hormones. This finding highlights the potential endocrine disruptive effects of these emergent pollutants.

  20. Chromosomal locations and modes of action of genes of the retinoid (vitamin A) system support their involvement in the etiology of schizophrenia

    SciTech Connect

    Goodman, A.B.

    1995-08-14

    Vitamin A (retinoid), an essential nutrient for fetal and subsequent mammalian development, is involved in gene expression, cell differentiation, proliferation, migration, and death. Retinoic acid (RA) the morphogenic derivative of vitamin A is highly teratogenic. In humans retinoid excess or deficit can result in brain anomalies and psychosis. This review discusses chromosomal loci of genes that control the retinoid cascade in relation to some candidate genes in schizophrenia. The paper relates the knowledge about the transport, delivery, and action of retinoids to what is presently known about the pathology of schizophrenia, with particular reference to the dopamine hypothesis, neurotransmitters, the glutamate hypothesis, neurotransmitters, the glutamate hypothesis, retinitis pigmentosa, dermatologic disorders, and craniofacial anomalies. 201 refs., 1 tab.

  1. Additional regulatory activities of MrkH for the transcriptional expression of the Klebsiella pneumoniae mrk genes: Antagonist of H-NS and repressor

    PubMed Central

    Ares, Miguel A.; Fernández-Vázquez, José L.; Pacheco, Sabino; Martínez-Santos, Verónica I.; Jarillo-Quijada, Ma. Dolores; Torres, Javier; Alcántar-Curiel, María D.; González-y-Merchand, Jorge A.; De la Cruz, Miguel A.

    2017-01-01

    Klebsiella pneumoniae is a common opportunistic pathogen causing nosocomial infections. One of the main virulence determinants of K. pneumoniae is the type 3 pilus (T3P). T3P helps the bacterial interaction to both abiotic and biotic surfaces and it is crucial for the biofilm formation. T3P is genetically organized in three transcriptional units: the mrkABCDF polycistronic operon, the mrkHI bicistronic operon and the mrkJ gene. MrkH is a regulatory protein encoded in the mrkHI operon, which positively regulates the mrkA pilin gene and its own expression. In contrast, the H-NS nucleoid protein represses the transcriptional expression of T3P. Here we reported that MrkH and H-NS positively and negatively regulate mrkJ expression, respectively, by binding to the promoter of mrkJ. MrkH protein recognized a sequence located at position -63.5 relative to the transcriptional start site of mrkJ gene. Interestingly, our results show that, in addition to its known function as classic transcriptional activator, MrkH also positively controls the expression of mrk genes by acting as an anti-repressor of H-NS; moreover, our results support the notion that high levels of MrkH repress T3P expression. Our data provide new insights about the complex regulatory role of the MrkH protein on the transcriptional control of T3P in K. pneumoniae. PMID:28278272

  2. Additional regulatory activities of MrkH for the transcriptional expression of the Klebsiella pneumoniae mrk genes: Antagonist of H-NS and repressor.

    PubMed

    Ares, Miguel A; Fernández-Vázquez, José L; Pacheco, Sabino; Martínez-Santos, Verónica I; Jarillo-Quijada, Ma Dolores; Torres, Javier; Alcántar-Curiel, María D; González-Y-Merchand, Jorge A; De la Cruz, Miguel A

    2017-01-01

    Klebsiella pneumoniae is a common opportunistic pathogen causing nosocomial infections. One of the main virulence determinants of K. pneumoniae is the type 3 pilus (T3P). T3P helps the bacterial interaction to both abiotic and biotic surfaces and it is crucial for the biofilm formation. T3P is genetically organized in three transcriptional units: the mrkABCDF polycistronic operon, the mrkHI bicistronic operon and the mrkJ gene. MrkH is a regulatory protein encoded in the mrkHI operon, which positively regulates the mrkA pilin gene and its own expression. In contrast, the H-NS nucleoid protein represses the transcriptional expression of T3P. Here we reported that MrkH and H-NS positively and negatively regulate mrkJ expression, respectively, by binding to the promoter of mrkJ. MrkH protein recognized a sequence located at position -63.5 relative to the transcriptional start site of mrkJ gene. Interestingly, our results show that, in addition to its known function as classic transcriptional activator, MrkH also positively controls the expression of mrk genes by acting as an anti-repressor of H-NS; moreover, our results support the notion that high levels of MrkH repress T3P expression. Our data provide new insights about the complex regulatory role of the MrkH protein on the transcriptional control of T3P in K. pneumoniae.

  3. Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action.

    PubMed

    Vonderlin, Nadine; Fischer, Fathima; Zitron, Edgar; Seyler, Claudia; Scherer, Daniel; Thomas, Dierk; Katus, Hugo A; Scholz, Eberhard P

    2015-01-01

    Midazolam is a short-acting benzodiazepine that is in wide clinical use as an anxiolytic, sedative, hypnotic, and anticonvulsant. Midazolam has been shown to inhibit ion channels, including calcium and potassium channels. So far, the effects of midazolam on cardiac human ether-à-go-go-related gene (hERG) channels have not been analyzed. The inhibitory effects of midazolam on heterologously expressed hERG channels were analyzed in Xenopus oocytes using the double-electrode voltage clamp technique. We found that midazolam inhibits hERG channels in a concentration-dependent manner, yielding an IC50 of 170 μM in Xenopus oocytes. When analyzed in a HEK 293 cell line using the patch-clamp technique, the IC50 was 13.6 μM. Midazolam resulted in a small negative shift of the activation curve of hERG channels. However, steady-state inactivation was not significantly affected. We further show that inhibition is state-dependent, occurring within the open and inactivated but not in the closed state. There was no frequency dependence of block. Using the hERG pore mutants F656A and Y652A we provide evidence that midazolam uses a classical binding site within the channel pore. Analyzing the subacute effects of midazolam on hERG channel trafficking, we further found that midazolam does not affect channel surface expression. Taken together, we show that the anesthetic midazolam is a low-affinity inhibitor of cardiac hERG channels without additional effects on channel surface expression. These data add to the current understanding of the pharmacological profile of the anesthetic midazolam.

  4. Additive roles of PthAs in bacterial growth and pathogenicity associated with nucleotide polymorphisms in effector-binding elements of citrus canker susceptibility genes.

    PubMed

    Abe, Valeria Yukari; Benedetti, Celso Eduardo

    2016-10-01

    Citrus canker, caused by Xanthomonas citri, affects most commercial citrus varieties. All X. citri strains possess at least one transcription activator-like effector of the PthA family that activates host disease susceptibility (S) genes. The X. citri strain 306 encodes four PthA effectors; nevertheless, only PthA4 is known to elicit cankers on citrus. As none of the PthAs act as avirulence factors on citrus, we hypothesized that PthAs 1-3 might also contribute to pathogenicity on certain hosts. Here, we show that, although PthA4 is indispensable for canker formation in six Brazilian citrus varieties, PthAs 1 and 3 contribute to canker development in 'Pera' sweet orange, but not in 'Tahiti' lemon. Deletions in two or more pthA genes reduce bacterial growth in planta more pronouncedly than single deletions, suggesting an additive role of PthAs in pathogenicity and bacterial fitness. The contribution of PthAs 1 and 3 in canker formation in 'Pera' plants does not correlate with the activation of the canker S gene, LOB1 (LATERAL ORGAN BOUNDARIES 1), but with the induction of other PthA targets, including LOB2 and citrus dioxygenase (DIOX). LOB1, LOB2 and DIOX show differential PthA-dependent expression between 'Pera' and 'Tahiti' plants that appears to be associated with nucleotide polymorphisms found at or near PthA-binding sites. We also present evidence that LOB1 activation alone is not sufficient to elicit cankers on citrus, and that DIOX acts as a canker S gene in 'Pera', but not 'Tahiti', plants. Our results suggest that the activation of multiple S genes, such as LOB1 and DIOX, is necessary for full canker development.

  5. Association in alcoholic patients between psychopathic traits and the additive effect of allelic forms of the CNR1 and FAAH endocannabinoid genes, and the 3' region of the DRD2 gene.

    PubMed

    Hoenicka, Janet; Ponce, Guillermo; Jiménez-Arriero, Miguel A; Ampuero, Israel; Rodríguez-Jiménez, Roberto; Rubio, Gabriel; Aragüés, Maria; Ramos, Jose A; Palomo, Tomás

    2007-01-01

    Little is known about the genetic factors that underlie the comorbidity between alcohol use disorder and antisocial personality disorder. Previous studies have associated both, dopaminergic and endocannabinoid systems to severe alcoholism with non-adaptive disrupted behaviours. In this work we have examined some gene variants involved in such systems in a sample of alcoholic patients to test whether there is a relationship with antisocial traits. The genetic analysis involved the genotyping of the single nucleotide polymorphism (SNP) TaqIA located nearby the DRD2 gene, the 10-repeat allele of a variable number tandem repeats (VNTR) of the SLC6A3 gene, the C385A FAAH SNP and the 3'-UTR microsatellite of CNR1 gene. The clinical study was performed in 137 Spanish alcohol dependent males. Antisocial Personality Disorder (DSM-IV) diagnosis was made by applying the International Personality Disorder Examination, and psychopathic traits were evaluated by the Hare's Psychopathy Checklist revised (PCL-R). The genotype distribution indicates there is a relationship between the TaqIA SNP, CNR1 and FAAH genes and PCL-R's Factor 1 in alcoholic patients. This relationship seems to be additive and independent and might be responsible for 11.4% of the variance in this PCL-R subscale. Our results suggest the implication of the dopaminergic and endocannabinoid systems in those processes leading to the comorbidity of alcoholism and antisocial behaviour.

  6. Gene Regulation of Intestinal Porcine Epithelial Cells IPEC-J2 Is Dependent on the Site of Deoxynivalenol Toxicological Action

    PubMed Central

    Diesing, Anne-Kathrin; Nossol, Constanze; Ponsuksili, Siriluck; Wimmers, Klaus; Kluess, Jeannette; Walk, Nicole; Post, Andreas; Rothkötter, Hermann-Josef; Kahlert, Stefan

    2012-01-01

    The intestinal epithelial cell layer represents the border between the luminal and systemic side of the gut. The decision between absorption and exclusion of substances is the quintessential function of the gut and varies along the gut axis. Consequently, potentially toxic substances may reach the basolateral domain of the epithelial cell layer via blood stream. The mycotoxin deoxynivalenol (DON) is a Fusarium derived secondary metabolite known to enter the blood stream and displaying a striking toxicity on the basolateral side of polarised epithelial cell layers in vitro. Here we analysed potential mechanisms of apical and basolateral DON toxicity reflected in the gene expression. We used the jejunum-derived, polarised intestinal porcine epithelial cell line IPEC-J2 as an in vitro cell culture model. Luminal and systemic DON challenge of the epithelial cell layer was mimicked by a DON application from the apical or basolateral compartment of membrane inserts for 72 h. We compared the genome-wide gene expression of untreated and DON-treated IPEC-J2 cells with the GeneChip® Porcine Genome Array of Affymetrix. Low basolateral DON (200 ng/mL) application triggered 10 times more gene transcripts in comparison to the corresponding apical application (2539 versus 267) despite the intactness of the challenged cell layer as measured by transepithelial electrical resistance. Analysis of the regulated genes by bioinformatic resource DAVID identified several groups of biochemical pathways modulated by concentration and orientation of DON application. Selected genes representing pathways of the cellular metabolism, information processing and structural design were analysed in detail by quantitative PCR. Our findings clearly show that apical and basolateral challenge of epithelial cell layers trigger different gene response profiles paralleled with a higher susceptibility towards basolateral challenge. The evaluation of toxicological potentials of mycotoxins should take this

  7. The action of a dietary retinoid on gene expression and cancer induction in electron-irradiated rat skin

    NASA Technical Reports Server (NTRS)

    Burns, Fredric J.; Chen, Shuaili; Xu, Guijuan; Wu, Feng; Tang, Moon-Shong

    2002-01-01

    Current models of radiation carcinogenesis generally assume that the DNA is damaged in a variety of ways by the radiation and that subsequent cell divisions contribute to the conversion of the damage to heritable mutations. Cancer may seem complex and intractable, but its complexity provides multiple opportunities for preventive interventions. Mitotic inhibitors are among the strongest cancer preventive agents, not only slowing the growth rate of preneoplasias but also increasing the fidelity of DNA repair processes. Ionizing radiation, including electrons, is a strong inducer of cancer in rat skin, and dietary retinoids have shown potent cancer preventive activity in the same system. A non-toxic dietary dose of retinyl acetate altered gene expression levels 24 hours after electron irradiation of rat skin. Of the 8740 genes on an Affymetrix rat expression array, the radiation significantly (5 fold or higher) altered 188, while the retinoid altered 231, including 16 radiation-altered genes that were reversely altered. While radiation strongly affected the expression of stress response, immune/inflammation and nucleic acid metabolism genes, the retinoid most strongly affected proliferation-related genes, including some significant reversals, such as, keratin 14, retinol binding protein, and calcium binding proteins. These results point to reversal of proliferation-relevant genes as a likely basis for the anti-radiogenic effects of dietary retinyl acetate.

  8. Copy number changes of clinically actionable genes in melanoma, non-small cell lung cancer and colorectal cancer-A survey across 822 routine diagnostic cases.

    PubMed

    Pfarr, Nicole; Penzel, Roland; Klauschen, Frederick; Heim, Daniel; Brandt, Regine; Kazdal, Daniel; Jesinghaus, Moritz; Herpel, Esther; Schirmacher, Peter; Warth, Arne; Weichert, Wilko; Endris, Volker; Stenzinger, Albrecht

    2016-11-01

    Targeted deep massive parallel sequencing has been implemented in routine molecular diagnostics for high-throughput genetic profiling of formalin-fixed paraffin-embedded (FFPE) cancer samples. This approach is widely used to interrogate simple somatic mutations but experience with the analysis of copy number variations (CNV) is limited. Here, we retrospectively analyzed CNV in 822 cancer cases (135 melanoma, 468 non-small cell lung cancers (NSCLC), 219 colorectal cancers (CRC)). We observed a decreasing frequency of CNV in clinically actionable genes from melanoma to NSCLC to CRC. The overall cohort displayed 168 (20%) amplifications in 17 druggable targets. The majority of BRAF mutant melanomas (54%) showed co-occurring CNV in other genes, mainly affecting CDKN2A. Subsets showed clustered deletions in ABL1, NOTCH1, RET or STK11, GNA11, and JAK3. Most NRAS mutant melanomas (49%) harbored CNVs in other genes with CDKN2A and FGFR3 being most frequently affected. Five BRAF/NRASwt tumors had co-amplifications of KDR, KIT, PDGFRA and another six mutated KIT. Among all NSCLC, we identified 14 EGFRamp (with ten EGFRmut) and eight KRASamp (with seven KRASmut). KRASmut tumors displayed frequent amplifications of MYC (n = 10) and MDM2 (n = 5). Fifteen KRAS/EGFR/BRAFwt tumors had MET mutations/amplifications. In CRC, amplified IGF2 was most prevalent (n = 13) followed by MYC (n = 9). Two cases showed amplified KRAS wildtype alleles. Two of the KRASmut cases harbored amplifications of NRAS and three KRASwt cases amplification of EGFR. In conclusion, we demonstrate that our approach i) facilitates detection of CNV, ii) enables detection of known CNV patterns, and iii) uncovers new CNV of clinically actionable genes in FFPE tissue samples across cancers. © 2016 Wiley Periodicals, Inc.

  9. Co-addition of manure increases the dissipation rates of tylosin A and the numbers of resistance genes in laboratory incubation experiments.

    PubMed

    Li, Qian; Wang, Yan; Zou, Yong-De; Liao, Xin-Di; Liang, Juan-Boo; Xin, Wen; Wu, Yin-Bao

    2015-09-15

    The behavior of veterinary antibiotics in the soil is commonly studied using the following methods to add antibiotics to the soil: (A) adding manure collected from animals fed a diet that includes antibiotics; (B) adding antibiotic-free animal manure spiked with antibiotics; and (C) the direct addition of antibiotics. However, most studies have only used methods (B) and (C) in their research, and few studies have simultaneously compared the different antibiotic addition methods. This study used tylosin A (TYLA) as a model antibiotic to compare the effects of these three commonly used antibiotic addition methods on the dissipation rates of TYLA and the numbers of resistance genes in laboratory incubation experiments. The results showed that the three treatment methods produced similar TYLA degradation trends; however, there were significant differences (P<0.05) in the TYLA degradation half-life (t1/2) among the three methods. The half-life of TYLA degradation in treatments A, B and C was 2.44 ± 0.04, 1.21 ± 0.03 and 5.13 ± 0.11 days, respectively. The presence of manure resulted in a higher electrical conductivity (EC), higher relative abundance of Citrobacter amalonaticus, higher macrolide resistant gene (ermB, ermF and ermT) count and lower ecological toxicity in the soil, which could partially explain the higher TYLA degradation rate in the treatments containing manure. The higher degradation rate of TYLA in treatment B when compared to treatment A could be due to the lower concentrations of tylosin B (TYLB) and tylosin D (TYLD). The main route for veterinary antibiotics to enter the soil is via the manure of animals that have been administered antibiotics. Therefore, the more appropriate method to study the degradation and ecotoxicity of antibiotic residues in the soil is by using manure from animals fed/administered the particular antibiotic rather than by adding the antibiotic directly to the soil.

  10. Neuroblast lineage identification and lineage-specific Hox gene action during postembryonic development of the subesophageal ganglion in the Drosophila central brain.

    PubMed

    Kuert, Philipp A; Hartenstein, Volker; Bello, Bruno C; Lovick, Jennifer K; Reichert, Heinrich

    2014-06-15

    The central brain of Drosophila consists of the supraesophageal ganglion (SPG) and the subesophageal ganglion (SEG), both of which are generated by neural stem cell-like neuroblasts during embryonic and postembryonic development. Considerable information has been obtained on postembryonic development of the neuroblasts and their lineages in the SPG. In contrast, very little is known about neuroblasts, neural lineages, or any other aspect of the postembryonic development in the SEG. Here we characterize the neuroanatomy of the larval SEG in terms of tracts, commissures, and other landmark features as compared to a thoracic ganglion. We then use clonal MARCM labeling to identify all adult-specific neuroblast lineages in the late larval SEG and find a surprisingly small number of neuroblast lineages, 13 paired and one unpaired. The Hox genes Dfd, Scr, and Antp are expressed in a lineage-specific manner in these lineages during postembryonic development. Hox gene loss-of-function causes lineage-specific defects in axonal targeting and reduction in neural cell numbers. Moreover, it results in the formation of novel ectopic neuroblast lineages. Apoptosis block also results in ectopic lineages suggesting that Hox genes are required for lineage-specific termination of proliferation through programmed cell death. Taken together, our findings show that postembryonic development in the SEG is mediated by a surprisingly small set of identified lineages and requires lineage-specific Hox gene action to ensure the correct formation of adult-specific neurons in the Drosophila brain.

  11. Transcriptome analysis of genes related to resistance against powdery mildew in wheat-Thinopyrum alien addition disomic line germplasm SN6306.

    PubMed

    Li, Quanquan; Niu, Zubiao; Bao, Yinguang; Tian, Qiuju; Wang, Honggang; Kong, Lingrang; Feng, Deshun

    2016-09-15

    Wheat powdery mildew, which is mainly caused by Blumeria graminis f. sp. tritici (Bgt), seriously damages wheat production. The wheat-Thinopyrum intermedium alien addition disomic line germplasm SN6306, being one of the important sources of genes for wheat resistance, is highly resistant to Bgt E09 and to many other powdery mildew physiological races. However, knowledge on the resistance mechanism of SN6306 remains limited. Our study employed high-throughput RNA sequencing based on next-generation sequencing technology (Illumina) to obtain an overview of the transcriptome characteristics of SN6306 and its parent wheat Yannong 15 (YN15) during Bgt infection. The sequencing generated 104,773 unigenes, 9909 of which showed varied expression levels. Among the 9909 unigenes, 1678 unigenes showed 0 reads in YN15. The expression levels in Bgt-inoculated SN6306 and YN15 of exactly 39 unigenes that showed 0 or considerably low reads in YN15 were validated to identify the genes involved in Bgt resistance. Among the 39 unigenes, 12 unigenes were upregulated in SN6306 by 3-45 times. These unigenes mainly encoded kinase, synthase, proteases, and signal transduction proteins, which may play an important role in the resistance against Bgt. To confirm whether the unigenes that showed 0 reads in YN15 are really unique to SN6306, 8 unigenes were cloned and sequenced. Results showed that the selected unigenes are more similar to SN6306 and Th. intermedium than to the wheat cultivar YN15. The sequencing results further confirmed that the unigenes showing 0 reads in YN15 are unique to SN6306 and are most likely derived from Th. intermedium (Host) Nevski. Thus, the genes from Th. intermedium most probably conferred the resistance of SN6306 to Bgt.

  12. Pro-inflammatory NF-κB and early growth response gene 1 regulate epithelial barrier disruption by food additive carrageenan in human intestinal epithelial cells.

    PubMed

    Choi, Hye Jin; Kim, Juil; Park, Seong-Hwan; Do, Kee Hun; Yang, Hyun; Moon, Yuseok

    2012-06-20

    The widely used food additive carrageenan (CGN) has been shown to induce intestinal inflammation, ulcerative colitis-like symptoms, or neoplasm in the gut epithelia in animal models, which are also clinical features of human inflammatory bowel disease. In this study, the effects of CGN on pro-inflammatory transcription factors NF-κB and early growth response gene 1 product (EGR-1) were evaluated in terms of human intestinal epithelial barrier integrity. Both pro-inflammatory transcription factors were elevated by CGN and only NF-κB activation was shown to be involved in the induction of pro-inflammatory cytokine interleukin-8. Moreover, the integrity of the in vitro epithelial monolayer under the CGN insult was maintained by both activated pro-inflammatory transcription factors NF-κB and EGR-1. Suppression of NF-κB or EGR-1 aggravated barrier disruption by CGN, which was associated with the reduced gene expression of tight junction component zonula occludens 1 and its irregular localization in the epithelial monolayer.

  13. Re-sequencing of the APOL1-APOL4 and MYH9 gene regions in African Americans does not identify additional risks for CKD progression

    PubMed Central

    Hawkins, Gregory A.; Friedman, David J.; Lu, Lingyi; McWilliams, David R.; Chou, Jeff W.; Sajuthi, Satria; Divers, Jasmin; Parekh, Rulan; Li, Man; Genovese, Giulio; Pollak, Martin R.; Hicks, Pamela J.; Bowden, Donald W.; Ma, Lijun; Freedman, Barry I.; Langefeld, Carl D.

    2015-01-01

    Background APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants. Methods Re-sequencing was performed across a ~275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant. Results Sequencing identified 3246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions (InDels). No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1571 AA ESKD cases and 1334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p=0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes (FIND) did not replicate this association. Conclusion Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles. PMID:26343748

  14. Gene cuisine or Frankenfood? The theory of reasoned action as an audience segmentation strategy for messages about genetically modified foods.

    PubMed

    Silk, Kami J; Weiner, Judith; Parrott, Roxanne L

    2005-12-01

    Genetically modified (GM) foods are currently a controversial topic about which the lay public in the United States knows little. Formative research has demonstrated that the lay public is uncertain and concerned about GM foods. This study (N = 858) extends focus group research by using the Theory of Reasoned Action (TRA) to examine attitudes and subjective norms related to GM foods as a theoretical strategy for audience segmentation. A hierarchical cluster analysis revealed four unique audiences based on their attitude and subjective norm toward GM foods (ambivalent-biotech, antibiotech, biotech-normer, and biotech individual). Results are discussed in terms of the theoretical and practical significance for audience segmentation.

  15. Alcohol Regulates Genes that Are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells.

    PubMed

    Candelaria, Nicholes R; Weldon, Ryan; Muthusamy, Selvaraj; Nguyen-Vu, Trang; Addanki, Sridevi; Yoffou, Paule-Helena; Karaboga, Husna; Blessing, Alicia M; Bollu, Lakshmi Reddy; Miranda, Rajesh C; Lin, Chin-Yo

    2015-01-01

    Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. Alcohol consumption is a modifiable behavior that is linked to increased breast cancer risks and is associated with the development of hormone-dependent breast cancers as well as disease progression and recurrence following endocrine treatment. In this study we examined the molecular mechanisms of action of alcohol by applying molecular, genetic, and genomic approaches in characterizing its effects on estrogen receptor (ER)-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1 but not the canonical target TFF1/pS2. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, including those which function in apoptotic and cell proliferation pathways. Furthermore, expression profiles of the responsive gene sets in tumors were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics.

  16. Induced mutagenesis of plasmid and chromosomal genes inserted into the plasmid DNA. II. Mutagenic action of chemical factors

    SciTech Connect

    Esipova, V.V.; Vedunova, S.L.; Kriviskii, A.S.

    1986-02-01

    Following the study of the mutagenic action of UV and ..gamma..-radiation on plasmid DNA in vitro, they investigated the induction of mutations under the influence of chemical mutagens on the same DNA of plasmid RSF2124, determining the synthesis of colicine E1 and resistance to ampicillin. The inactivating action of the mutagen was assessed from the yield of transformants resistant to the antibiotic and the mutagenic effect from the loss by colonies of transformants that were capable of releasing colicine into the external medium. In these experiments they mainly used chemical compounds whose mutagenic effect if well known in other systems (transforming and transfecting DNA, microbial viruses). As a result all mutagens tested for their activity were divided into four groups: first group, those exceeding the level of mutagenesis by more than 100-fold above the spontaneous background (hydroxylamine, O-methylhydroxylamine); second group, those exceeding it by a factor of 10 (UV radiation (lambda = 254 nm), W-mutagenesis, ionizing radiation, nitrous acid, mitomycin C); third group, those exceeding it by a factor of <10 (indirect UV mutagenesis, nitrous acid, ..beta..-chloroethyldiethylamine hydrochloride, nitrosoguanidine); fourth group, no mutagenic effect (acridine orange, ethyl methane sulfonate, sodium azide, 0-..beta..-diethylaminoethylhydroxylamine).

  17. Actions of HSVtk and connexin43 gene delivery on gap junctional communication and drug sensitization in hepatocellular carcinoma.

    PubMed

    Ghoumari, A M; Mouawad, R; Zerrouqi, A; Nizard, C; Provost, N; Khayat, D; Naus, C C; Soubrane, C

    1998-08-01

    We have previously demonstrated that transfected hepatocellular carcinoma cells (Hepa1-6) with one copy (pAGO) and two copies (pYED) of the HSVtk gene, using liposomes, induced cell death of untransfected cells in the presence of ganciclovir (GCV). This phenomenon is called the 'bystander effect'. To determine whether an elevated level of connexin43 increases the bystander effect, we have cotransfected Hepa1-6 cells with a plasmid containing the HSVtk gene driven by the alpha-fetoprotein promoter (pFTK) or pAGO or pYED and connexin43. The results showed that, after GCV treatment, the percentage of growth inhibition was higher (25-30%) in cells cotransfected with HSVtk and connexin43 than in cells transfected only with HSVtk gene. The IC50 of GCV on cells transfected with pFTK/Connexin43 was 17.85-fold lower than cells transfected with pFTK alone. To improve these results, stable connexin43 transduced Hepa1-6 cells were transfected with pFTK followed by GCV treatment. In this case, the cell growth was markedly inhibited as compared with parental cells. Furthermore, we have studied the correlation between the expression of the HSVtk and the connexin43 proteins. Using flow cytometric analysis, scrape loading/dye transfer and immunoblotting assay we found that the cells transfected separately by pAGO, pYED, pFTK and pLTR-Cx43 showed an increase of connexin43 protein. This study indicates that transfecting Hepa1-6 cells with both connexin43 and HSVtk genes up-regulates connexin43 expression which enhances the bystander effect and subsequently tumor cell death.

  18. Gene cloning and characterization of a thermostable phytase from Bacillus subtilis US417 and assessment of its potential as a feed additive in comparison with a commercial enzyme.

    PubMed

    Farhat, Ameny; Chouayekh, Hichem; Ben Farhat, Mounira; Bouchaala, Kameleddine; Bejar, Samir

    2008-10-01

    An extracellular phytase from Bacillus subtilis US417 (PHY US417) was purified and characterized. The purified enzyme of 41 kDa was calcium-dependent and optimally active at pH 7.5 and 55 degrees C. The thermal stability of PHY US417 was drastically improved by calcium. Indeed, it recovered 77% of its original activity after denaturation for 10 min at 75 degrees C in the presence of 5 mM CaCl2, while it retained only 22% of activity when incubated for 10 min at 60 degrees C without calcium. In addition, PHY US417 was found to be highly specific for phytate and exhibited pH stability similar to Phyzyme, a commercial phytase with optimal activity at pH 5.5 and 60 degrees C. The phytase gene was cloned by PCR from Bacillus subtilis US417. Sequence analysis of the encoded polypeptide revealed one residue difference from PhyC of Bacillus subtilis VTTE-68013 (substitution of arginine in position 257 by proline in PHY US417) which was reported to exhibit lower thermostability especially in the absence of calcium. With its neutral pH optimum as well as its great pH and thermal stability, the PHY US417 enzyme presumed to be predominantly active in the intestine has a high potential for use as feed additive.

  19. Addition of transcription activator-like effector binding sites to a pathogen strain-specific rice bacterial blight resistance gene makes it effective against additional strains and against bacterial leaf streak.

    PubMed

    Hummel, Aaron W; Doyle, Erin L; Bogdanove, Adam J

    2012-09-01

    Xanthomonas transcription activator-like (TAL) effectors promote disease in plants by binding to and activating host susceptibility genes. Plants counter with TAL effector-activated executor resistance genes, which cause host cell death and block disease progression. We asked whether the functional specificity of an executor gene could be broadened by adding different TAL effector binding elements (EBEs) to it. We added six EBEs to the rice Xa27 gene, which confers resistance to strains of the bacterial blight pathogen Xanthomonas oryzae pv. oryzae (Xoo) that deliver the TAL effector AvrXa27. The EBEs correspond to three other effectors from Xoo strain PXO99(A) and three from strain BLS256 of the bacterial leaf streak pathogen Xanthomonas oryzae pv. oryzicola (Xoc). Stable integration into rice produced healthy lines exhibiting gene activation by each TAL effector, and resistance to PXO99(A) , a PXO99(A) derivative lacking AvrXa27, and BLS256, as well as two other Xoo and 10 Xoc strains virulent toward wildtype Xa27 plants. Transcripts initiated primarily at a common site. Sequences in the EBEs were found to occur nonrandomly in rice promoters, suggesting an overlap with endogenous regulatory sequences. Thus, executor gene specificity can be broadened by adding EBEs, but caution is warranted because of the possible coincident introduction of endogenous regulatory elements.

  20. Gene expression profiles following exposure to a developmental neurotoxicant, Aroclor 1254: Pathway analysis for possible mode(s) of action

    SciTech Connect

    Royland, Joyce E.; Kodavanti, Prasada Rao S.

    2008-09-01

    Epidemiological studies indicate that low levels of polychlorinated biphenyl (PCB) exposure can adversely affect neurocognitive development. In animal models, perturbations in calcium signaling, neurotransmitters, and thyroid hormones have been postulated as potential mechanisms for PCB-induced developmental neurotoxicity. In order to understand the role of these proposed mechanisms and to identify other mechanisms in PCB-induced neurotoxicity, we have chosen a global approach utilizing oligonucleotide microarrays to examine gene expression profiles in the brain following developmental exposure to Aroclor 1254 (0 or 6 mg/kg/day from gestation day 6 through postnatal day (PND) 21) in Long-Evans rats. Gene expression levels in the cerebellum and hippocampus from PNDs 7 and 14 animals were determined on Affymetrix rat 230A{sub 2}.0 chips. In the cerebellum, 87 transcripts were altered at PND7 compared to 27 transcripts at PND14 by Aroclor 1254 exposure, with only one transcript affected at both ages. In hippocampus, 175 transcripts and 50 transcripts were altered at PND7 and PND14, respectively, by Aroclor 1254 exposure with five genes commonly affected. Functional analysis suggests that pathways related to calcium homeostasis (Gng3, Ryr2, Trdn, Cacna1a), intracellular signaling (Camk2d, Stk17b, Pacsin2, Ryr2, Trio, Fert2, Ptk2b), axonal guidance (Lum, Mxd3, Akap11, Gucy1b3), aryl hydrocarbon receptor signaling (Nfia, Col1a2), and transcripts involved in cell proliferation (Gspt2, Cdkn1c, Ptk2b) and differentiation (Ifitm31, Hpca, Zfp260, Igsf4a, Hes5) leading to the development of nervous system were significantly altered by Aroclor 1254 exposure. Of the two brain regions examined, Aroclor 1254-induced genomic changes were greater in the hippocampus than the cerebellum. The genomic data suggests that PCB-induced neurotoxic effects were due to disruption of normal ontogenetic pattern of nervous system growth and development by altering intracellular signaling pathways

  1. Two additional human serum proteins structurally related to complement factor H: Evidence for a family of factor H-related genes

    SciTech Connect

    Skerka, C.; Timmann, C.; Horstmann, R.D. ); Zipfel, P.F.

    1992-05-15

    The authors identify and characterize two human serum proteins with an apparent molecular mass of 24 and 29 kDa, which are antigenically related to complement factor H. These proteins represent differently glycosylated forms and are encoded by the same mRNA. The corresponding cDNA clone is 1051 bp in size and hybridized to a 1.4-kb mRNA derived from human liver. The predicted translation product represents a protein of 270 amino acids, which displays a hydrophobic leader sequence, indicative of a secreted protein. The secreted part is organized in four short consensus repeats (SCR) and has a single putative N-linked glycosylation site. The predicted sequence is closely related to that of the previously described factor H-related proteins h37 and h42, which are also derived from a 1.4-kb mRNA. Amino acid comparison of these factor H-related proteins showed identical leader sequences, an exchange of three amino acids in SCR1, identical sequences of SCR2, and a lower degree of homology between SCR3-4 (h24 and h29) and SCR4-5 (h37 and h42). In addition, SCR3-4 of h24 and h29 display homology to SCR19-20 of human complement factor H. The relatedness of structural elements of the factor H-related proteins h24, h29, h37, and h42 and of factor H, suggests a function common to these proteins and indicates the existence of a gene family consisting of factor H and at least two factor H-related genes. 28 refs., 7 figs., 1 tab.

  2. Addition of fish oil to diets for dairy cows. II. Effects on milk fat and gene expression of mammary lipogenic enzymes.

    PubMed

    Ahnadi, Charaf E; Beswick, Naomi; Delbecchi, Louis; Kennelly, John J; Lacasse, Pierre

    2002-11-01

    Sixteen Holstein cows in mid-lactation were used to determine whether alterations of mammary fatty acid metabolism are responsible for the milk fat depression associated with consumption of fish oil. Cows were given a total mixed ration with no added fish oil (control), unprotected fish oil (3.7 % of dry matter), or glutaraldehyde-protected microcapsules of fish oil (1.5% or 3.0% of dry matter) for 4 weeks. Milk samples were taken once a week and a mammary biopsy was taken from a rear quarter at the end of the treatment period. Milk fat content was lower in cows given unprotected fish oil (26.0 g/kg), 1.5% protected fish oil (24.6 g/kg) and 3% protected fish oil (20.4 g/kg) than in cows fed the control diet (36.0 g/kg). This was mainly due to a decrease in the synthesis of short-chain fatty acids. Consumption of protected fish oil decreased the abundance of lipogenic enzymes mRNA in the mammary gland. Acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase mRNAs for cows given 3% protected fish oil averaged only 30%, 25% and 25% of control values, respectively. Dietary addition of unprotected fish oil slightly decreased mRNA abundance of these enzymes but markedly reduced the amount of lipoprotein lipase mRNA. Milk fat content was significantly correlated with gene expression of acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase but not lipoprotein lipase. These results suggest that fish oil reduces milk fat percentage by inhibiting gene expression of mammary lipogenic enzymes.

  3. STAT4 Associates with SLE Through Two Independent Effects that Correlate with Gene Expression and Act Additively with IRF5 to Increase Risk

    PubMed Central

    Abelson, Anna-Karin; Delgado-Vega, Angélica M.; Kozyrev, Sergey V.; Sánchez, Elena; Velázquez-Cruz, Rafael; Eriksson, Niclas; Wojcik, Jerome; Reddy, Prasad Linga; Lima, Guadalupe; D’Alfonso, Sandra; Migliaresi, Sergio; Baca, Vicente; Orozco, Lorena; Witte, Torsten; Ortego-Centeno, Norberto; Abderrahim, Hadi; Pons-Estel, Bernardo A.; Gutiérrez, Carmen; Suárez, Ana; González-Escribano, Maria Francisca; Martin, Javier; Alarcón-Riquelme, Marta E.

    2013-01-01

    Objectives To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. Methods 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5’-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. Results In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis. Conclusions These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE. PMID:19019891

  4. The Neurospora crassa cyt-20 gene encodes cytosolic and mitochondrial valyl-tRNA synthetases and may have a second function in addition to protein synthesis.

    PubMed Central

    Kubelik, A R; Turcq, B; Lambowitz, A M

    1991-01-01

    The cyt-20-1 mutant of Neurospora crassa is a temperature-sensitive, cytochrome b- and aa3-deficient strain that is severely deficient in both mitochondrial and cytosolic protein synthesis (R.A. Collins, H. Bertrand, R.J. LaPolla, and A.M. Lambowitz, Mol. Gen. Genet. 177:73-84, 1979). We cloned the cyt-20+ gene by complementation of the cyt-20-1 mutation and found that it contains a 1,093-amino-acid open reading frame (ORF) that encodes both the cytosolic and mitochondrial valyl-tRNA synthetases (vaIRSs). A second mutation, un-3, which is allelic with cyt-20-1, also results in temperature-sensitive growth, but not in gross deficiencies in cytochromes b and aa3 or protein synthesis. The un-3 mutant had also been reported to have pleiotropic defects in cellular transport process, resulting in resistance to amino acid analogs (M.S. Kappy and R.L. Metzenberg, J. Bacteriol. 94:1629-1637, 1967), but this resistance phenotype is separable from the temperature sensitivity in crosses and may result from a mutation in a different gene. The 1,093-amino-acid ORF encoding vaIRSs is the site of missense mutations resulting in temperature sensitivity in both cyt-20-1 and un-3 and is required for the transformation of both mutants. The opposite strand of the cyt-20 gene encodes an overlapping ORF of 532 amino acids, which may also be functional but is not required for transformation of either mutant. The cyt-20-1 mutation in the vaIRS ORF results in severe deficiencies of both mitochondrial and cytosolic vaIRS activities, whereas the un-3 mutation does not appear to result in a deficiency of these activities or of mitochondrial or cytosolic protein synthesis sufficient to account for its temperature-sensitive growth. The phenotype of the un-3 mutant raises the possibility that the vaIRS ORF has a second function in addition to protein synthesis. PMID:1830127

  5. Flavobacterium johnsoniae sprB Is Part of an Operon Spanning the Additional Gliding Motility Genes sprC, sprD, and sprF ▿ †

    PubMed Central

    Rhodes, Ryan G.; Nelson, Shawn S.; Pochiraju, Soumya; McBride, Mark J.

    2011-01-01

    Cells of Flavobacterium johnsoniae move rapidly over surfaces by a process known as gliding motility. Gld proteins are thought to comprise the gliding motor that propels cell surface adhesins, such as the 669-kDa SprB. A novel protein secretion apparatus called the Por secretion system (PorSS) is required for assembly of SprB on the cell surface. Genetic and molecular analyses revealed that sprB is part of a seven-gene operon spanning 29.3 kbp of DNA. In addition to sprB, three other genes of this operon (sprC, sprD, and sprF) are involved in gliding. Mutations in sprB, sprC, sprD, and sprF resulted in cells that failed to form spreading colonies on agar but that exhibited some motility on glass in wet mounts. SprF exhibits some similarity to Porphyromonas gingivalis PorP, which is required for secretion of gingipain protease virulence factors via the P. gingivalis PorSS. F. johnsoniae sprF mutants produced SprB protein but were defective in localization of SprB to the cell surface, suggesting a role for SprF in secretion of SprB. The F. johnsoniae PorSS is involved in secretion of extracellular chitinase in addition to its role in secretion of SprB. SprF was not needed for chitinase secretion and may be specifically required for SprB secretion by the PorSS. Cells with nonpolar mutations in sprC or sprD produced and secreted SprB and propelled it rapidly along the cell surface. Multiple paralogs of sprB, sprC, sprD, and sprF are present in the genome, which may explain why mutations in sprB, sprC, sprD, and sprF do not result in complete loss of motility and suggests the possibility that semiredundant SprB-like adhesins may allow movement of cells over different surfaces. PMID:21131497

  6. Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma.

    PubMed

    Kim, Eun Young; Cho, Eun Na; Park, Heae Surng; Hong, Ji Young; Lim, Seri; Youn, Jong Pil; Hwang, Seung Yong; Chang, Yoon Soo

    2016-01-01

    Compound EGFR mutations, defined as double or multiple mutations in the EGFR tyrosine kinase domain, are frequently detected with advances in sequencing technology but its clinical significance is unclear. This study analyzed 61 cases of EGFR mutation positive lung adenocarcinoma using next-generation sequencing (NGS) based repeated deep sequencing panel of 16 genes that contain actionable mutations and investigated clinical implication of compound EGFR mutations. Compound EGFR mutation was detected in 15 (24.6%) of 61 cases of EGFR mutation-positive lung adenocarcinoma. The majority (12/15) of compound mutations are combination of the atypical mutation and typical mutations such as exon19 deletion, L858R or G719X substitutions, or exon 20 insertion whereas 3 were combinations of rare atypical mutations. The patients with compound mutation showed shorter overall survival than those with simple mutations (83.7 vs. 72.8 mo; P = 0.020, Breslow test). Among the 115 missense mutations discovered in the tested genes, a few number of actionable mutations were detected irrelevant to the subtype of EGFR mutations, including ALK rearrangement, BCL2L11 intron 2 deletion, KRAS c.35G>A, PIK3CA c.1633G>A which are possible target of crizotinib, BH3 mimetics, MEK inhibitors, and PI3K-tyrosine kinase inhibitors, respectively. 31 missense mutations were detected in the cases with simple mutations whereas 84 in those with compound mutation, showing that the cases with compound missense mutation have higher burden of missense mutations (P = 0.001, independent sample t-test). Compound EGFR mutations are detected at a high frequency using NGS-based repeated deep sequencing. Because patients with compound EGFR mutations showed poor clinical outcomes, they should be closely monitored during follow-up.

  7. Actions of sex steroids on kisspeptin expression and other reproduction-related genes in the brain of the teleost fish European sea bass.

    PubMed

    Alvarado, M V; Servili, A; Molés, G; Gueguen, M M; Carrillo, M; Kah, O; Felip, A

    2016-11-01

    Kisspeptins are well known as mediators of the coordinated communication between the brain-pituitary axis and the gonads in many vertebrates. To test the hypothesis that gonadal steroids regulate kiss1 and kiss2 mRNA expression in European sea bass (a teleost fish), we examined the brains of gonad-intact (control) and castrated animals, as well as castrated males (GDX) and ovariectomized females (OVX) that received testosterone (T) and estradiol (E2) replacement, respectively, during recrudescence. In GDX males, low expression of kiss1 mRNA is observed by in situ hybridization in the caudal hypothalamus (CH) and the mediobasal hypothalamus (MBH), although hypothalamic changes in kiss1 mRNA levels were not statistically different among the groups, as revealed by real-time PCR. However, T strongly decreased kiss2 expression levels in the hypothalamus, which was documented in the MBH and the nucleus of the lateral recess (NRLd) in GDX T-treated sea bass males. Conversely, it appears that E2 evokes low kiss1 mRNA in the CH, while there were cells expressing kiss2 in the MBH and NRLd in these OVX females. These results demonstrate that kisspeptin neurons are presumably sensitive to the feedback actions of sex steroids in the sea bass, suggesting that the MBH represents a major site for sex steroid actions on kisspeptins in this species. Also, recent data provide evidence that both positive and negative actions occur in key factors involved in sea bass reproductive function, including changes in the expression of gnrh-1/gonadotropin, cyp19b, er and ar genes and sex steroid and gonadotropin plasma levels in this teleost fish.

  8. Food additives

    PubMed Central

    Spencer, Michael

    1974-01-01

    Food additives are discussed from the food technology point of view. The reasons for their use are summarized: (1) to protect food from chemical and microbiological attack; (2) to even out seasonal supplies; (3) to improve their eating quality; (4) to improve their nutritional value. The various types of food additives are considered, e.g. colours, flavours, emulsifiers, bread and flour additives, preservatives, and nutritional additives. The paper concludes with consideration of those circumstances in which the use of additives is (a) justified and (b) unjustified. PMID:4467857

  9. Bacterial RNA Polymerase-DNA Interaction—The Driving Force of Gene Expression and the Target for Drug Action

    PubMed Central

    Lee, Jookyung; Borukhov, Sergei

    2016-01-01

    DNA-dependent multisubunit RNA polymerase (RNAP) is the key enzyme of gene expression and a target of regulation in all kingdoms of life. It is a complex multifunctional molecular machine which, unlike other DNA-binding proteins, engages in extensive and dynamic interactions (both specific and nonspecific) with DNA, and maintains them over a distance. These interactions are controlled by DNA sequences, DNA topology, and a host of regulatory factors. Here, we summarize key recent structural and biochemical studies that elucidate the fine details of RNAP-DNA interactions during initiation. The findings of these studies help unravel the molecular mechanisms of promoter recognition and open complex formation, initiation of transcript synthesis and promoter escape. We also discuss most current advances in the studies of drugs that specifically target RNAP-DNA interactions during transcription initiation and elongation. PMID:27882317

  10. Antagonistic and cooperative actions of the EGFR and Dpp pathways on the iroquois genes regulate Drosophila mesothorax specification and patterning.

    PubMed

    Letizia, Annalisa; Barrio, Rosa; Campuzano, Sonsoles

    2007-04-01

    In Drosophila, restricted expression of the Iroquois complex (Iro-C) genes in the proximal region of the wing imaginal disc contributes to its territorial subdivision, specifying first the development of the notum versus the wing hinge, and subsequently, that of the lateral versus medial notum. Iro-C expression is under the control of the EGFR and Dpp signalling pathways. To analyze how both pathways cooperate in the regulation of Iro-C, we isolated several wing disc-specific cis-regulatory elements of the complex. One of these (IroRE(2)) integrates competing inputs of the EGFR and Dpp pathways, mediated by the transcription factors Pointed (downstream of EGFR pathway) and Pannier/U-shaped and Mothers against Dpp (Mad), in the case of Dpp. By contrast, a second element (IroRE(1)) mediates activation by both the EGFR and Dpp pathways, thus promoting expression of Iro-C in a region of elevated levels of Dpp signalling, the prospective lateral notum near the anterior-posterior compartment boundary. These results help define the molecular mechanisms of the interplay between the EGFR and Dpp pathways in the specification and patterning of the notum.

  11. Food additives

    MedlinePlus

    ... or natural. Natural food additives include: Herbs or spices to add flavor to foods Vinegar for pickling ... Certain colors improve the appearance of foods. Many spices, as well as natural and man-made flavors, ...

  12. ISR meets SAR outside: additive action of the endophyte Bacillus pumilus INR7 and the chemical inducer, benzothiadiazole, on induced resistance against bacterial spot in field-grown pepper.

    PubMed

    Yi, Hwe-Su; Yang, Jung Wook; Ryu, Choong-Min

    2013-01-01

    Induced resistance has been recognized as an attractive tool for plant disease management in modern agriculture. During the last two decades, studies on chemically- and biologically elicited induced resistance have revealed previously unknown features of the plant defense response including defense priming. As a biological trigger for induced resistance, plant growth-promoting rhizobacteria (PGPR) are a group of root-associated bacteria that can reduce plant disease severity and incidence, and augment plant growth and yield under greenhouse and field conditions. We evaluated the potential of an endophytic PGPR, Bacillus pumilus INR7, to induce systemic resistance against bacterial spot caused by Xanthomonas axonopodis pv. vesicatoria in pepper. Trials in the greenhouse showed significantly less symptom development in pepper plants inoculated with strain INR7 compared to a water treatment. Furthermore, a single dipping treatment with INR7 before transplantation of pepper plants into the field elicited an induced systemic resistance response against bacterial spot caused by artificially infiltration of X. axonopodis pv. vesicatoria and even against naturally occurring bacterial spot disease. We identified an additive effect on induced resistance after administration of a combination treatment composed of strain INR7 with a chemical inducer, benzothiadiazole (BTH) in the field. The combination treatment stimulated expression of pepper defense marker genes CaPR1, CaTin1, and CaPR4 to a greater extent than did treatment with either agent alone. Similar experiments conducted with tobacco revealed no additive effects under field conditions. Interestingly, co-application of plants with INR7 lifted the growth repressing effect of BTH. Application of BTH onto pepper and tobacco did not affect rhizosphere colonization but supported a higher population density inside plant roots when compared to water-treated control plants. Our results indicate that PGPR can be used in

  13. ISR meets SAR outside: additive action of the endophyte Bacillus pumilus INR7 and the chemical inducer, benzothiadiazole, on induced resistance against bacterial spot in field-grown pepper

    PubMed Central

    Yi, Hwe-Su; Yang, Jung Wook; Ryu, Choong-Min

    2013-01-01

    Induced resistance has been recognized as an attractive tool for plant disease management in modern agriculture. During the last two decades, studies on chemically- and biologically elicited induced resistance have revealed previously unknown features of the plant defense response including defense priming. As a biological trigger for induced resistance, plant growth-promoting rhizobacteria (PGPR) are a group of root-associated bacteria that can reduce plant disease severity and incidence, and augment plant growth and yield under greenhouse and field conditions. We evaluated the potential of an endophytic PGPR, Bacillus pumilus INR7, to induce systemic resistance against bacterial spot caused by Xanthomonas axonopodis pv. vesicatoria in pepper. Trials in the greenhouse showed significantly less symptom development in pepper plants inoculated with strain INR7 compared to a water treatment. Furthermore, a single dipping treatment with INR7 before transplantation of pepper plants into the field elicited an induced systemic resistance response against bacterial spot caused by artificially infiltration of X. axonopodis pv. vesicatoria and even against naturally occurring bacterial spot disease. We identified an additive effect on induced resistance after administration of a combination treatment composed of strain INR7 with a chemical inducer, benzothiadiazole (BTH) in the field. The combination treatment stimulated expression of pepper defense marker genes CaPR1, CaTin1, and CaPR4 to a greater extent than did treatment with either agent alone. Similar experiments conducted with tobacco revealed no additive effects under field conditions. Interestingly, co-application of plants with INR7 lifted the growth repressing effect of BTH. Application of BTH onto pepper and tobacco did not affect rhizosphere colonization but supported a higher population density inside plant roots when compared to water-treated control plants. Our results indicate that PGPR can be used in

  14. Choosing Actions

    PubMed Central

    Rosenbaum, David A.; Chapman, Kate M.; Coelho, Chase J.; Gong, Lanyun; Studenka, Breanna E.

    2013-01-01

    Actions that are chosen have properties that distinguish them from actions that are not. Of the nearly infinite possible actions that can achieve any given task, many of the unchosen actions are irrelevant, incorrect, or inappropriate. Others are relevant, correct, or appropriate but are disfavored for other reasons. Our research focuses on the question of what distinguishes actions that are chosen from actions that are possible but are not. We review studies that use simple preference methods to identify factors that contribute to action choices, especially for object-manipulation tasks. We can determine which factors are especially important through simple behavioral experiments. PMID:23761769

  15. Action semantics modulate action prediction.

    PubMed

    Springer, Anne; Prinz, Wolfgang

    2010-11-01

    Previous studies have demonstrated that action prediction involves an internal action simulation that runs time-locked to the real action. The present study replicates and extends these findings by indicating a real-time simulation process (Graf et al., 2007), which can be differentiated from a similarity-based evaluation of internal action representations. Moreover, results showed that action semantics modulate action prediction accuracy. The semantic effect was specified by the processing of action verbs and concrete nouns (Experiment 1) and, more specifically, by the dynamics described by action verbs (Experiment 2) and the speed described by the verbs (e.g., "to catch" vs. "to grasp" vs. "to stretch"; Experiment 3). These results propose a linkage between action simulation and action semantics as two yet unrelated domains, a view that coincides with a recent notion of a close link between motor processes and the understanding of action language.

  16. Cytotoxicity, genotoxicity and mechanism of action (via gene expression analysis) of the indole alkaloid aspidospermine (antiparasitic) extracted from Aspidosperma polyneuron in HepG2 cells.

    PubMed

    Coatti, Giuliana Castello; Marcarini, Juliana Cristina; Sartori, Daniele; Fidelis, Queli Cristina; Ferreira, Dalva Trevisan; Mantovani, Mário Sérgio

    2016-08-01

    Aspidospermine is an indole alkaloid with biological properties associated with combating parasites included in the genera Plasmodium, Leishmania and Trypanossoma. The present study evaluated the cytotoxicity (resazurin test), genotoxicity (comet assay) and mechanism of action (gene expression analysis via qRT-PCR) of this alkaloid in human HepG2 cells. The results demonstrated that treatment with aspidospermine was both cytotoxic (starting at 75 μM) and genotoxic (starting at 50 μM). There was no significant modulation of the expression of the following genes: GSTP1 and GPX1 (xenobiotic metabolism); CAT (oxidative stress); TP53 and CCNA2 (cell cycle); HSPA5, ERN1, EIF2AK3 and TRAF2 (endoplasmic reticulum stress); CASP8, CASP9, CASP3, CASP7, BCL-2, BCL-XL BAX and BAX (apoptosis); and PCBP4, ERCC4, OGG1, RAD21 and MLH1 (DNA repair). At a concentration of 50 μM (non-cytotoxic, but genotoxic), there was a significant increase in the expression of CYP1A1 (xenobiotic metabolism) and APC (cell cycle), and at a concentration of 100 μM, a significant increase in the expression of CYP1A1 (xenobiotic metabolism), GADD153 (endoplasmic reticulum stress) and SOD (oxidative stress) was detected, with repression of the expression of GR (xenobiotic metabolism and oxidative stress). The results of treatment with aspidospermine at a 100 μM concentration (the dose indicated in the literature to achieve 89 % reduction of the growth of L. amazonensis) suggest that increased oxidative stress and an unfolded protein response (UPR) occurred in HepG2 cells. For the therapeutic use of aspidospermine (antiparasitic), chemical alteration of the molecule to achieve a lower cytotoxicity/genotoxicity in host cells is recommended.

  17. Expression of the nir and nor genes for denitrification of Pseudomonas aeruginosa requires a novel CRP/FNR-related transcriptional regulator, DNR, in addition to ANR.

    PubMed

    Arai, H; Igarashi, Y; Kodama, T

    1995-08-28

    A gene, designated dnr, was identified in the vicinity of the structural genes for nitrite reductase (nirS) and nitric oxide reductase (norCB), and the gene for activation of the reductases (nirQ) from Pseudomonas aeruginosa. It encodes a protein of 227 amino acids homologous with the CRP/FNR-family transcriptional regulators. Promoter activities for nirS, nirQ and norCB were considerably reduced in the dnr mutant as well as in the mutant of anr, the other fnr-like regulatory gene from P. aeruginosa. This is the first finding that two CRP/FNR-related regulators are involved in denitrification in one strain.

  18. Potlining Additives

    SciTech Connect

    Rudolf Keller

    2004-08-10

    In this project, a concept to improve the performance of aluminum production cells by introducing potlining additives was examined and tested. Boron oxide was added to cathode blocks, and titanium was dissolved in the metal pool; this resulted in the formation of titanium diboride and caused the molten aluminum to wet the carbonaceous cathode surface. Such wetting reportedly leads to operational improvements and extended cell life. In addition, boron oxide suppresses cyanide formation. This final report presents and discusses the results of this project. Substantial economic benefits for the practical implementation of the technology are projected, especially for modern cells with graphitized blocks. For example, with an energy savings of about 5% and an increase in pot life from 1500 to 2500 days, a cost savings of $ 0.023 per pound of aluminum produced is projected for a 200 kA pot.

  19. Phosphazene additives

    DOEpatents

    Harrup, Mason K; Rollins, Harry W

    2013-11-26

    An additive comprising a phosphazene compound that has at least two reactive functional groups and at least one capping functional group bonded to phosphorus atoms of the phosphazene compound. One of the at least two reactive functional groups is configured to react with cellulose and the other of the at least two reactive functional groups is configured to react with a resin, such as an amine resin of a polycarboxylic acid resin. The at least one capping functional group is selected from the group consisting of a short chain ether group, an alkoxy group, or an aryloxy group. Also disclosed are an additive-resin admixture, a method of treating a wood product, and a wood product.

  20. Antiviral Actions of Interferons

    PubMed Central

    Samuel, Charles E.

    2001-01-01

    Tremendous progress has been made in understanding the molecular basis of the antiviral actions of interferons (IFNs), as well as strategies evolved by viruses to antagonize the actions of IFNs. Furthermore, advances made while elucidating the IFN system have contributed significantly to our understanding in multiple areas of virology and molecular cell biology, ranging from pathways of signal transduction to the biochemical mechanisms of transcriptional and translational control to the molecular basis of viral pathogenesis. IFNs are approved therapeutics and have moved from the basic research laboratory to the clinic. Among the IFN-induced proteins important in the antiviral actions of IFNs are the RNA-dependent protein kinase (PKR), the 2′,5′-oligoadenylate synthetase (OAS) and RNase L, and the Mx protein GTPases. Double-stranded RNA plays a central role in modulating protein phosphorylation and RNA degradation catalyzed by the IFN-inducible PKR kinase and the 2′-5′-oligoadenylate-dependent RNase L, respectively, and also in RNA editing by the IFN-inducible RNA-specific adenosine deaminase (ADAR1). IFN also induces a form of inducible nitric oxide synthase (iNOS2) and the major histocompatibility complex class I and II proteins, all of which play important roles in immune response to infections. Several additional genes whose expression profiles are altered in response to IFN treatment and virus infection have been identified by microarray analyses. The availability of cDNA and genomic clones for many of the components of the IFN system, including IFN-α, IFN-β, and IFN-γ, their receptors, Jak and Stat and IRF signal transduction components, and proteins such as PKR, 2′,5′-OAS, Mx, and ADAR, whose expression is regulated by IFNs, has permitted the generation of mutant proteins, cells that overexpress different forms of the proteins, and animals in which their expression has been disrupted by targeted gene disruption. The use of these IFN system

  1. Action principles in nature

    NASA Astrophysics Data System (ADS)

    Barrow, John D.; Tipler, Frank J.

    1988-01-01

    Physical theories have their most fundamental expression as action integrals. This suggests that the total action of the universe is the most fundamental physical quantity, and hence finite. In this article it is argued that finite universal action implies that the universe is spatially closed. Further, the possible spatial topologies, the types of matter that can dominate the early universe dynamics, and the form of any quadratic additions to the lagrangian of general relativity are constrained. Initial and final cosmological curvature singularities are required to avoid a universal action singularity.

  2. Mechanism of action of nalidixic acid: Purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme

    PubMed Central

    Sugino, Akio; Peebles, Craig L.; Kreuzer, Kenneth N.; Cozzarelli, Nicholas R.

    1977-01-01

    A target protein for nalidixic and oxolinic acids in Escherichia coli, the nalA gene product (Pnal), was purified to homogeneity as judged by gel electrophoresis, using an in vitro complementation assay. It is a dimer of identical 110,000-dalton subunits. A polypeptide of this molecular weight is uniquely induced by a λ nalA transducing phage, thereby showing that the purified Pnal is a product of the nalA gene. Nalidixic and oxolinic acids inhibit DNA gyrase activity and induce formation of a relaxation complex analogue. Treatment of the complex with sodium dodecyl sulfate causes a doublestrand break in the DNA substrate and the resulting linear molecule seems covalently bound to protein. Complex formation, unlike the introduction of supertwists, does not require ATP or relaxed circular DNA and is insensitive to novobiocin. DNA gyrase from a strain with a nalA mutation conferring drug resistance (nalAr) is 1/100 as sensitive to oxolinic and nalidixic acids with respect to inhibition of supertwisting and induction of the pre-linearization complex. Addition of Pnal restores drug sensitivity and stimulates DNA gyrase activity. DNA gyrase preparations and Pnal catalyze a third reaction sensitive to nalidixic and oxolinic acids, the ATP-independent relaxation of supertwister DNA. Relaxation by gyrase from nalAr cells is drug resistant. The nicking-closing activity is distinct from E. coli ω protein in several properties, including the ability to relax positively supertwisted DNA. We postulate that the nalA gene product occurs in two molecular forms, as Pnal and as a gyrase component. Both forms catalyze nicking-closing, and inhibition of this activity by nalidixic and oxolinic acids may account for the inhibition of DNA synthesis by these drugs. Images PMID:200930

  3. Joint analysis of additive, dominant and first-order epistatic effects of four genes (IGF2, MC4R, PRKAG3 and LEPR) with known effects on fat content and fat distribution in pigs.

    PubMed

    López-Buesa, P; Burgos, C; Galve, A; Varona, L

    2014-02-01

    LEPR, MC4R, IGF2 and PRKAG3 are genes with known effects on fat content and distribution in pig carcass and pork. In a study performed with Duroc × Landrace/Large White pigs, we have found that IGF2 has strong additive effects on several carcass conformational traits and on fatty acid composition in several anatomical locations. MC4R shows additive effects on saturated fatty acid content in several muscles. On the other side, almost no additive effect has been found for PRKAG3 and very few for LEPR. In this work, no dominant effect has been found for any of the four genes. Using a Bayesian Lasso approach, we have been able now to find first-order epistatic (mainly dominant-additive) effects between LEPR and PRKAG3 for intramuscular fat content and for saturated fatty acid content in L. dorsii, B. femoralis, Ps. major and whole ham. The presence of interactions between genes in the shaping of traits of such importance as intramuscular fat content and composition highlights the complexity of heritable traits and the difficulty of gene-assisted selection for such traits.

  4. Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: The additive and subtractive effect of the three dopaminergic genes - DRD2, D{beta}H, and DAT1

    SciTech Connect

    Comings, D.E.; Wu, S.; Chiu, C.; Ring, R.H.; Gade, R.; Ahn, C.; Dietz, G.; Muhleman, D.

    1996-05-31

    Polymorphisms of three different dopaminergic genes, dopamine D{sub 2} receptor (DRD2), dopamine {beta}-hydroxylase (D{beta}H), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and subtractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order, attention deficit hyperactivity disorder (ADHD), stuttering, oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse, and general anxiety - behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering, oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique. 144 refs., 2 figs., 13 tabs.

  5. Action physics

    NASA Astrophysics Data System (ADS)

    McGinness, Lachlan P.; Savage, C. M.

    2016-09-01

    More than a decade ago, Edwin Taylor issued a "call to action" that presented the case for basing introductory university mechanics teaching around the principle of stationary action [E. F. Taylor, Am. J. Phys. 71, 423-425 (2003)]. We report on our response to that call in the form of an investigation of the teaching and learning of the stationary action formulation of physics in a first-year university course. Our action physics instruction proceeded from the many-paths approach to quantum physics to ray optics, classical mechanics, and relativity. Despite the challenges presented by action physics, students reported it to be accessible, interesting, motivational, and valuable.

  6. Simvastatin and Dipentyl Phthalate Lower Ex vivo Testicular Testosterone Production and Exhibit Additive Effects on Testicular Testosterone and Gene Expression Via Distinct Mechanistic Pathways in the Fetal Rat

    EPA Science Inventory

    Sex differentiation of the male reproductive tract in mammals is driven, in part, by fetal androgen production. In utero, some phthalate esters (PEs) alter fetal Leydig cell differentiation, reducing the expression of several genes associated with steroid synthesis/transport, and...

  7. Association Between Single-Nucleotide Polymorphisms in Hormone Metabolism and DNA Repair Genes and Epithelial Ovarian Cancer: Results from Two Australian Studies and an Additional Validation Set

    PubMed Central

    Beesley, Jonathan; Jordan, Susan J.; Spurdle, Amanda B.; Song, Honglin; Ramus, Susan J.; Kjaer, Suzanne Kruger; Hogdall, Estrid; DiCioccio, Richard A.; McGuire, Valerie; Whittemore, Alice S.; Gayther, Simon A.; Pharoah, Paul D.P.; Webb, Penelope M.; Chenevix-Trench, Georgia

    2009-01-01

    Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148; r2 = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation samples, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition. PMID:18086758

  8. Complementary actions.

    PubMed

    Sartori, Luisa; Betti, Sonia

    2015-01-01

    Complementary colors are color pairs which, when combined in the right proportions, produce white or black. Complementary actions refer here to forms of social interaction wherein individuals adapt their joint actions according to a common aim. Notably, complementary actions are incongruent actions. But being incongruent is not sufficient to be complementary (i.e., to complete the action of another person). Successful complementary interactions are founded on the abilities: (i) to simulate another person's movements, (ii) to predict another person's future action/s, (iii) to produce an appropriate incongruent response which differ, while interacting, with observed ones, and (iv) to complete the social interaction by integrating the predicted effects of one's own action with those of another person. This definition clearly alludes to the functional importance of complementary actions in the perception-action cycle and prompts us to scrutinize what is taking place behind the scenes. Preliminary data on this topic have been provided by recent cutting-edge studies utilizing different research methods. This mini-review aims to provide an up-to-date overview of the processes and the specific activations underlying complementary actions.

  9. Complementary actions

    PubMed Central

    Sartori, Luisa; Betti, Sonia

    2015-01-01

    Complementary colors are color pairs which, when combined in the right proportions, produce white or black. Complementary actions refer here to forms of social interaction wherein individuals adapt their joint actions according to a common aim. Notably, complementary actions are incongruent actions. But being incongruent is not sufficient to be complementary (i.e., to complete the action of another person). Successful complementary interactions are founded on the abilities: (i) to simulate another person’s movements, (ii) to predict another person’s future action/s, (iii) to produce an appropriate incongruent response which differ, while interacting, with observed ones, and (iv) to complete the social interaction by integrating the predicted effects of one’s own action with those of another person. This definition clearly alludes to the functional importance of complementary actions in the perception–action cycle and prompts us to scrutinize what is taking place behind the scenes. Preliminary data on this topic have been provided by recent cutting-edge studies utilizing different research methods. This mini-review aims to provide an up-to-date overview of the processes and the specific activations underlying complementary actions. PMID:25983717

  10. Genes

    MedlinePlus

    ... Search Search MedlinePlus GO GO About MedlinePlus Site Map FAQs Customer Support Health Topics Drugs & Supplements Videos & Tools Español You Are Here: Home → Medical Encyclopedia → Genes URL of this page: //medlineplus.gov/ency/article/ ...

  11. Calcitonin gene-related peptide protects rats from cerebral ischemia/reperfusion injury via a mechanism of action in the MAPK pathway

    PubMed Central

    YANG, SI; YUAN, YONGJIE; JIAO, SHAN; LUO, QI; YU, JINLU

    2016-01-01

    The aim of the present study was to investigate the protective function and underlying mechanism of calcitonin gene-related peptide (CGRP) on cerebral ischemia/reperfusion damage in rats. Adult male Wistar rats were selected for the establishment of an ischemia/reperfusion injury model through the application of a middle cerebral artery occlusion. Animals were randomly divided into 6 groups of 24 animals. Drugs were administered according to the design of each group; animals were administered CGRP, CGRP8–37, PD98059 and SB20358. The neurobehavioral scores of the rat cerebral ischemia model in each group were calculated. The infarction range of the rat brain tissues was observed by 2,3,5-triphenyltetrazolium chloride staining. The expression levels of three proteins, phosphorylated c-Jun N-terminal kinase (JNK)/JNK, phosphorylated extracellular signal-regulated protein kinase (ERK)/ERK and p-p38/p38, in the mitogen-activated protein kinase (MAPK) pathway in the brain tissues was detected by western blotting. The results showed that CGRP could improve the neurobehavioral function of the ischemic rats and reduce the infarction range. Western blotting results confirmed that the function of the CGRP was mediated mainly through the reduction of the JNK and p38 phosphorylation and the promotion of ERK phosphorylation. Therefore, the present study confirmed that an increase in the exogenous CRGP could effectively improve ischemia/reperfusion injury of the brain tissue. The mechanisms of action were achieved through a reduction in JNK and p38 phosphorylation and an increase in ERL phosphorylation in the MAPK pathway. These mechanisms were interdependent. PMID:27284409

  12. Non-genomic actions of estrogens and their interaction with genomic actions in the brain.

    PubMed

    Vasudevan, Nandini; Pfaff, Donald W

    2008-05-01

    Ligands for the nuclear receptor superfamily have at least two mechanisms of action: (a) classical transcriptional regulation of target genes (genomic mechanisms); and (b) non-genomic actions, which are initiated at the cell membrane, which could also impact transcription. Though transcriptional mechanisms are increasingly well understood, membrane-initiated actions of these ligands are incompletely understood. This has led to considerable debate over the physiological relevance of membrane-initiated actions of hormones versus genomic actions of hormones, with genomic actions predominating in the endocrine field. There is good evidence that the membrane-limited actions of hormones, particularly estrogens, involve the rapid activation of kinases and the release of calcium and that these are linked to physiologically relevant scenarios in the brain. We show evidence in this review, that membrane actions of estrogens, which activate these rapid signaling cascades, can also potentiate nuclear transcription in both the central nervous system and in non-neuronal cell lines. We present a theoretical scenario which can be used to understand this phenomenon. These signaling cascades may occur in parallel or in series but subsequently, converge at the modification of transcriptionally relevant molecules such as nuclear receptors and/or coactivators. In addition, other non-cognate hormones or neurotransmitters may also activate cascades to crosstalk with estrogen receptor-mediated transcription, though the relevance of this is less clear. The idea that coupling between membrane-initiated and genomic actions of hormones is a novel idea in neuroendocrinology and provides us with a unified view of hormone action in the central nervous system.

  13. Direct comparison between genomic constitution and flavonoid contents in Allium multiple alien addition lines reveals chromosomal locations of genes related to biosynthesis from dihydrokaempferol to quercetin glucosides in scaly leaf of shallot (Allium cepa L.).

    PubMed

    Masuzaki, S; Shigyo, M; Yamauchi, N

    2006-02-01

    The extrachromosome 5A of shallot (Allium cepa L., genomes AA) has an important role in flavonoid biosynthesis in the scaly leaf of Allium fistulosum-shallot monosomic addition lines (FF+nA). This study deals with the production and biochemical characterisation of A. fistulosum-shallot multiple alien addition lines carrying at least 5A to determine the chromosomal locations of genes for quercetin formation. The multiple alien additions were selected from the crossing between allotriploid FFA (female symbol) and A. fistulosum (male symbol). The 113 plants obtained from this cross were analysed by a chromosome 5A-specific PGI isozyme marker of shallot. Thirty plants were preliminarily selected for an alien addition carrying 5A. The chromosome numbers of the 30 plants varied from 18 to 23. The other extrachromosomes in 19 plants were completely identified by using seven other chromosome markers of shallot. High-performance liquid chromatography analyses of the 19 multiple additions were conducted to identify the flavonoid compounds produced in the scaly leaves. Direct comparisons between the chromosomal constitution and the flavonoid contents of the multiple alien additions revealed that a flavonoid 3'-hydroxylase (F3'H) gene for the synthesis of quercetin from kaempferol was located on 7A and that an anonymous gene involved in the glucosidation of quercetin was on 3A or 4A. As a result of supplemental SCAR analyses by using genomic DNAs from two complete sets of A. fistulosum-shallot monosomic additions, we have assigned F3'H to 7A and flavonol synthase to 4A.

  14. Massively parallel sequencing of phyllodes tumours of the breast reveals actionable mutations, and TERT promoter hotspot mutations and TERT gene amplification as likely drivers of progression

    PubMed Central

    Piscuoglio, Salvatore; Ng, Charlotte K Y; Murray, Melissa; Burke, Kathleen A; Edelweiss, Marcia; Geyer, Felipe C; Macedo, Gabriel S; Inagaki, Akiko; Papanastasiou, Anastasios D; Martelotto, Luciano G; Marchio, Caterina; Lim, Raymond S; Ioris, Rafael A; Nahar, Pooja K; De Bruijn, Ino; Smyth, Lillian; Akram, Muzaffar; Ross, Dara; Petrini, John H; Norton, Larry; Solit, David B; Baselga, Jose; Brogi, Edi; Ladanyi, Marc; Weigelt, Britta; Reis-Filho, Jorge S

    2015-01-01

    Phyllodes tumours (PTs) are breast fibroepithelial lesions that are graded based on histological criteria as benign, borderline or malignant. PTs may recur locally. Borderline PTs and malignant PTs may metastasize to distant sites. Breast fibroepithelial lesions, including PTs and fibroadenomas, are characterized by recurrent MED12 exon 2 somatic mutations. We sought to define the repertoire of somatic genetic alterations in PTs and whether these may assist in the differential diagnosis of these lesions. We collected 100 fibroadenomas, 40 benign PTs, 14 borderline PTs and 22 malignant PTs. Six, 6 and 13 benign, borderline and malignant PTs respectively and their matched normal tissue were subjected to targeted massively parallel sequencing (MPS) using the MSK-IMPACT sequencing assay. Recurrent MED12 mutations were found in 56% of PTs; in addition, mutations affecting cancer genes (e.g. TP53, RB1, SETD2 and EGFR) were exclusively detected in borderline and malignant PTs. We found a novel recurrent clonal hotspot mutation in the TERT promoter (−124 C>T) in 52% and TERT gene amplification in 4% of PTs. Laser capture microdissection revealed that these mutations were restricted to the mesenchymal component of PTs. Sequencing analysis of the entire cohort revealed that the frequency of TERT alterations increased from benign (18%), to borderline (57%) and to malignant PTs (68%; P<0.01), and TERT alterations were associated with increased levels of TERT mRNA (P<0.001). No TERT alterations were observed in fibroadenomas. An analysis of TERT promoter sequencing and gene amplification distinguished PTs from fibroadenomas with a sensitivity and a positive predictive value of 100% (CI 95.38%–100%) and 100% (CI 85.86%–100%), respectively, and a sensitivity and a negative predictive value of 39% (CI 28.65%–51.36%) and 68% (CI 60.21%–75.78%), respectively. Our results suggest that TERT alterations may drive the progression of PTs, and may assist in the differential

  15. Long-term nutrient addition differentially alters community composition and diversity of genes that control nitrous oxide flux from salt marsh sediments

    NASA Astrophysics Data System (ADS)

    Kearns, Patrick J.; Angell, John H.; Feinman, Sarah G.; Bowen, Jennifer L.

    2015-03-01

    Enrichment of natural waters, soils, and sediments by inorganic nutrients, including nitrogen, is occurring at an increasing rate and has fundamentally altered global biogeochemical cycles. Salt marshes are critical for the removal of land-derived nitrogen before it enters coastal waters. This is accomplished via multiple microbially mediated pathways, including denitrification. Many of these pathways, however, are also a source of the greenhouse gas nitrous oxide (N2O). We used clone libraries and quantative PCR (qPCR) to examine the effect of fertilization on the diversity and abundance of two functional genes associated with denitrification and N2O production (norB and nosZ) in experimental plots at the Great Sippewissett Salt Marsh (Falmouth, MA, USA) that have been enriched with nutrients for over 40 years. Our data showed distinct nosZ and norB community structures at different nitrogen loads, especially at the highest level of fertilization. Furthermore, calculations of the Shannon Diversity Index and Chao1 Richness Estimator indicated that nosZ gene diversity and richness increased with increased nitrogen supply, however no such relationship existed with regard to richness and diversity of the norB gene. Results from qPCR demonstrated that nosZ gene abundance was an order of magnitude lower in the extra-highly fertilized plots compared to the other plots, but the abundance of norB was not affected by fertilization. The majority of sequences obtained from the marsh plots had no close cultured relatives and they were divergent from previously sequenced norB and nosZ fragments. Despite their divergence from any cultured representatives, most of the norB and nosZ sequences appeared to be from members of the Alpha- and Betaproteobacteria, suggesting that these classes are particularly important in salt marsh nitrogen cycling. Our results suggest that both norB and nosZ containing microbes are affected by fertilization and that the Great Sippewissett Marsh may

  16. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes

    PubMed Central

    Harold, Denise; Abraham, Richard; Hollingworth, Paul; Sims, Rebecca; Gerrish, Amy; Hamshere, Marian; Singh Pahwa, Jaspreet; Moskvina, Valentina; Dowzell, Kimberley; Williams, Amy; Jones, Nicola; Thomas, Charlene; Stretton, Alexandra; Morgan, Angharad; Lovestone, Simon; Powell, John; Proitsi, Petroula; Lupton, Michelle K; Brayne, Carol; Rubinsztein, David C.; Gill, Michael; Lawlor, Brian; Lynch, Aoibhinn; Morgan, Kevin; Brown, Kristelle; Passmore, Peter; Craig, David; McGuinness, Bernadette; Todd, Stephen; Holmes, Clive; Mann, David; Smith, A. David; Love, Seth; Kehoe, Patrick G.; Hardy, John; Mead, Simon; Fox, Nick; Rossor, Martin; Collinge, John; Maier, Wolfgang; Jessen, Frank; Schürmann, Britta; van den Bussche, Hendrik; Heuser, Isabella; Kornhuber, Johannes; Wiltfang, Jens; Dichgans, Martin; Frölich, Lutz; Hampel, Harald; Hüll, Michael; Rujescu, Dan; Goate, Alison; Kauwe, John S.K.; Cruchaga, Carlos; Nowotny, Petra; Morris, John C.; Mayo, Kevin; Sleegers, Kristel; Bettens, Karolien; Engelborghs, Sebastiaan; De Deyn, Peter; van Broeckhoven, Christine; Livingston, Gill; Bass, Nicholas J.; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panagiotis; Al-Chalabi, Ammar; Shaw, Christopher E.; Tsolaki, Magda; Singleton, Andrew; Guerreiro, Rita; Mühleisen, Thomas W.; Nöthen, Markus M.; Moebus, Susanne; Jöckel, Karl-Heinz; Klopp, Norman; Wichmann, H-Erich; Carrasquillo, Minerva M.; Pankratz, V. Shane; Younkin, Steven G.; Holmans, Peter; O'Donovan, Michael; Owen, Michael J.; Williams, Julie

    2010-01-01

    We undertook a two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the APOE locus (most significant SNP: rs2075650, p= 1.8×10−157) and observed genome-wide significant association with SNPs at two novel loci: rs11136000 in the CLU or APOJ gene (p= 1.4×10−9) and rs3851179, a SNP 5′ to the PICALM gene (p= 1.9×10−8). Both novel associations were supported in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with AD in the combined dataset (rs11136000: p= 8.5×10−10, odds ratio= 0.86; rs3851179: p= 1.3×10−9, odds ratio= 0.86). We also observed more variants associated at p< 1×10−5 than expected by chance (p=7.5×10−6), including polymorphisms at the BIN1, DAB1 and CR1 loci. PMID:19734902

  17. Action Learning.

    ERIC Educational Resources Information Center

    1996

    These four papers were presented at a symposium on action learning moderated by Lex Dilworth at the 1996 conference of the Academy of Human Resource Development. "Developing an Infrastructure for Individual and Organizational Change: Transfer of Learning from an Action Reflection Learning (ARL) Program" (ARL Inquiry) reports findings…

  18. The Effect of a Newly Developed Oat-Banana Fermented Beverage with a Beta-glucan Additive on ldhL Gene Expression in Streptococcus thermophilus TKM3 KKP 2030p.

    PubMed

    Goncerzewicz, Anna; Misiewicz, Anna; Owczarek, Lubomiła; Jasińska, Urszula; Skąpska, Sylwia

    2016-12-01

    The number of people who cannot consume dairy products due to intolerance or allergies to food components is increasing. Consumers are increasingly searching for alternative, nondairy beverages which have an advantageous effect on the body and which stimulate gut microflora. Previous studies have shown that Streptococcus thermophilus TKM3 KKP 2030p can be an efficient starter culture for the fermentation of plant material and can also ensure an acceptable sensory profile and a high number of lactic acid bacteria during 4 week cold storage. The aim of this study was to determine the relative gene expression of the L-lactate dehydrogenase gene (ldhL) in selected strain using the RT qPCR technique at particular time points. The gene expression experiments were conducted in laboratory broth (LABm) and fruit-cereal (OBPromOat) matrix with a beta-glucan additive. Levels of gene relative expression in the selected strain in these two media were correlated with the amount of L-lactate produced. The results showed that the plant matrix stimulated stronger ldhL gene expression in the first 4 h of the experiment (although the synthesis of L-lactate was less than in laboratory broth). This study broadens existing knowledge of the transcriptional mechanisms which arise from the adaptation of the analyzed strain to different habitats during L-lactate synthesis. This could contribute to the development of new alternative food products for people who show intolerance to milk proteins or lactose.

  19. Food additives: Sodium benzoate, potassium sorbate, azorubine, and tartrazine modify the expression of NFκB, GADD45α, and MAPK8 genes.

    PubMed

    Raposa, B; Pónusz, R; Gerencsér, G; Budán, F; Gyöngyi, Z; Tibold, A; Hegyi, D; Kiss, I; Koller, Á; Varjas, T

    2016-09-01

    It has been reported that some of the food additives may cause sensitization, inflammation of tissues, and potentially risk factors in the development of several chronic diseases. Thus, we hypothesized that expressions of common inflammatory molecules - known to be involved in the development of various inflammatory conditions and cancers - are affected by these food additives. We investigated the effects of commonly used food preservatives and artificial food colorants based on the expressions of NFκB, GADD45α, and MAPK8 (JNK1) from the tissues of liver. RNA was isolated based on Trizol protocol and the activation levels were compared between the treated and the control groups. Tartrazine alone could elicit effects on the expressions of NFκB (p = 0.013) and MAPK8 (p = 0.022). Azorubine also resulted in apoptosis according to MAPK8 expression (p = 0.009). Preservatives were anti-apoptotic in high dose. Sodium benzoate (from low to high doses) dose-dependently silenced MAPK8 expression (p = 0.004 to p = 0.002). Addition of the two preservatives together elicited significantly greater expression of MAPK8 at half-fold dose (p = 0.002) and at fivefold dose (p = 0.008). This study suggests that some of the food preservatives and colorants can contribute to the activation of inflammatory pathways.

  20. Effects of Addition of Linseed and Marine Algae to the Diet on Adipose Tissue Development, Fatty Acid Profile, Lipogenic Gene Expression, and Meat Quality in Lambs

    PubMed Central

    Urrutia, Olaia; Mendizabal, José Antonio; Insausti, Kizkitza; Soret, Beatriz; Purroy, Antonio; Arana, Ana

    2016-01-01

    This study examined the effect of linseed and algae on growth and carcass parameters, adipocyte cellularity, fatty acid profile and meat quality and gene expression in subcutaneous and intramuscular adipose tissues (AT) in lambs. After weaning, 33 lambs were fed three diets up to 26.7 ± 0.3 kg: Control diet (barley and soybean); L diet (barley, soybean and 10% linseed) and L-A diet (barley, soybean, 5% linseed and 3.89% algae). Lambs fed L-A diet showed lower average daily gain and greater slaughter age compared to Control and L (P < 0.001). Carcass traits were not affected by L and L-A diets, but a trend towards greater adipocyte diameter was observed in L and L-A in the subcutaneous AT (P = 0.057). Adding either linseed or linseed and algae increased α-linolenic acid and eicosapentaenoic acid contents in both AT (P < 0.001); however, docosahexaenoic acid was increased by L-A (P < 0.001). The n-6/n-3 ratio decreased in L and L-A (P < 0.001). Algae had adverse effects on meat quality, with greater lipid oxidation and reduced ratings for odor and flavor. The expression of lipogenic genes was downregulated in the subcutaneous AT (P < 0.05): acetyl-CoA carboxylase 1 (ACACA) in L and L-A and lipoprotein lipase (LPL) and stearoyl-CoA desaturase (SCD) in L-A. Fatty acid desaturase 1 (FADS1), fatty acid desaturase 2 (FADS2) and fatty acid elongase 5 (ELOVL5) were unaffected. In the subcutaneous AT, supplementing either L or L-A increased peroxisome proliferator-activated receptor gamma (PPARG) and CAAT-enhancer binding protein alpha (CEBPA) (P < 0.05), although it had no effect on sterol regulatory element-binding factor 1 (SREBF1). In the intramuscular AT, expression of ACACA, SCD, FADS1 and FADS2 decreased in L and L-A (P < 0.001) and LPL in L (P < 0.01), but PPARG, CEBPA and SREBF1 were unaffected. PMID:27253325

  1. Alien genes introgression and development of alien monosomic addition lines from a threatened species, Allium roylei Stearn, to Allium cepa L.

    PubMed

    Vu, Hoa Q; Yoshimatsu, Yasuyuki; Khrustaleva, Ludmila I; Yamauchi, Naoki; Shigyo, Masayoshi

    2012-05-01

    To produce alien monosomic addition lines (AMALs) of Allium cepa (genomes CC, 2n = 2x = 16) carrying extrachromosomes from Allium roylei (RR, 2n = 2x = 16), reciprocal backcrossing of allotriploids (2n = 24, CCR) with diploids (2n = 16, CC) and selfing of a single allotriploid were carried out. The chromosome numbers in the BC(2)F(1) and BC(1)F(2) progenies ranged from 16 to 32. Forty-eight plants were recorded to possess 2n = 17 among a total of 169 plants in observation. Through the analyses of isozymes, expressed sequence tag (EST) markers, and karyotypes, all eight possible types of A. cepa-A. roylei monosomic addition lines (CC+1R-CC+8R) could be identified. Seven types of representative AMALs (without CC+2R) were used for the GISH analysis of somatic chromosomes. Except for CC+6R, all AMALs showed an entire (unrecombined) extrachromosome from A. roylei in the integral diploid background of A. cepa. A single recombination between A. cepa and A. roylei was observed on the extrachromosome in the remaining type. All alloplasmic AMALs possessing A. roylei cytoplasm showed high or complete pollen sterility. Only the autoplasmic CC+4R with A. cepa cytoplasm possessed relatively high pollen fertility. The bulbs of CC+4R displayed the distinct ovoid shape that discriminates them from spherical or oval ones in other AMALs. Downy mildew screening in the field showed higher resistance in A. roylei, a hypo-allotriploid (CCR-nR, 2n = 23), and an allotriploid (CCR, 2n = 24). Meanwhile, no complete resistance was found in some AMALs examined. This was the first trial toward the establishment of a complete set of A. cepa-A. roylei monosomic additions.

  2. Common symbiosis genes CERBERUS and NSP1 provide additional insight into the establishment of arbuscular mycorrhizal and root nodule symbioses in Lotus japonicus.

    PubMed

    Nagae, Miwa; Takeda, Naoya; Kawaguchi, Masayoshi

    2014-01-01

    Arbuscular mycorrhizal symbiosis (AMS) and root nodule symbiosis (RNS) share several common symbiotic components, and many of the common symbiosis mutants block the entry of symbionts into the roots. We recently reported that CERBERUS (an E3 ubiquitin ligase) and NSP1 (a GRAS family transcription factor), required for RNS, also modulate AMS development in Lotus japonicus. The novel common symbiosis mutants, cerberus and nsp1, have low colonization of arbuscular mycorrhiza (AM) fungi, caused by a defect in internal hyphal elongation and by a decreased fungal entry into the roots, respectively. Here, we showed that CERBERUS was induced at the sites of symbiotic fungal or bacterial infection. NSP1 has been implicated in a strigolactone biosynthesis gene DWARF27 expression. Nevertheless, in nsp1, DWARF27 was induced by inoculation with AM fungi, implying the existence of a NSP1-independent regulatory mechanism of strigolactone biosynthesis during AMS establishment. These results support functional analysis of CERBERUS and NSP1, and also contribute to elucidation of common mechanisms in AMS and RNS.

  3. Targeted Gene Addition to a Safe Harbor locus in human CD34+ Hematopoietic Stem Cells for Correction of X-linked Chronic Granulomatous Disease

    PubMed Central

    De Ravin, Suk See; Reik, Andreas; Liu, Pei-Qi; Li, Linhong; Wu, Xiaolin; Su, Ling; Raley, Castle; Theobald, Narda; Choi, Uimook; Song, Alexander H.; Chan, Andy; Pearl, Jocelynn R.; Paschon, David E.; Lee, Janet; Newcombe, Hannah; Koontz, Sherry; Sweeney, Colin; Shivak, David A.; Zarember, Kol A.; Peshwa, Madhusudan V.; Gregory, Philip D.; Urnov, Fyodor D.; Malech, Harry L.

    2016-01-01

    Gene therapy with genetically modified human CD34+ hematopoietic stem cells (HSCs) may be safer using targeted integration (TI) of transgenes into a genomic ‘safe harbor’ site than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno associated virus (AAV) 6 delivery of donor constructs in human HSCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus-positive HSCs with 6–16% human cell marking were observed following engraftment into mice. In HSCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 in resulted in ~15% gp91phox expression and increased NADPH oxidase activity in ex vivo–derived neutrophils. In mice transplanted with corrected HSCs, 4–11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases. PMID:26950749

  4. Neotropical Monogenoidea. 58. Three new species of Gyrodactylus (Gyrodactylidae) from Scleromystax spp. (Callichthyidae) and the proposal of COII gene as an additional fragment for barcoding gyrodactylids.

    PubMed

    Bueno-Silva, Marlus; Boeger, Walter A

    2014-06-01

    Based on molecular markers (COII and ITS1-ITS2) and morphological data, we describe three new Neotropical species of Gyrodactylus von Nordmann, 1832 from Scleromystax barbatus (Quoy et Gaimard) and Scleromystax macropterus (Regan) from southern Brazil. The three new species can be distinguished from each other by sequences of both molecular markers and morphology of hooks and anchors. Gyrodactylus bueni sp. n. is characterised by having hook with shaft curved, heel straight, shelf straight, toe pointed, anchor with superficial root slender, elongate and male copulatory organ armed with two rows of spinelets. Gyrodactylus major sp. n. presents hook with shaft, point curved, proximal shaft straight, heel convex, shelf convex, toe concave, anchor with superficial root robust and male copulatory organ armed with two rows of spinelets. Gyrodactylus scleromystaci sp. n. presents hook with shaft, point recurved, heel convex, shelf convex, toe pointed, anchor with superficial root curved and male copulatory organ armed with two rows of spinelets. These species appear to be closely related to other species of Gyrodactylus known from other species of Callichthyidae. These new species, however, differ by the comparative morphology of the haptoral hard structures and molecular data. Comparative analysis of sequences from these species of Gyrodactylus suggests that the COII gene may represent an important marker for the taxonomy of species of Gyrodactylidae and, perhaps, for species of other lineages of Monogenoidea.

  5. Common symbiosis genes CERBERUS and NSP1 provide additional insight into the establishment of arbuscular mycorrhizal and root nodule symbioses in Lotus japonicus

    PubMed Central

    Nagae, Miwa; Takeda, Naoya; Kawaguchi, Masayoshi

    2014-01-01

    Arbuscular mycorrhizal symbiosis (AMS) and root nodule symbiosis (RNS) share several common symbiotic components, and many of the common symbiosis mutants block the entry of symbionts into the roots. We recently reported that CERBERUS (an E3 ubiquitin ligase) and NSP1 (a GRAS family transcription factor), required for RNS, also modulate AMS development in Lotus japonicus. The novel common symbiosis mutants, cerberus and nsp1, have low colonization of arbuscular mycorrhiza (AM) fungi, caused by a defect in internal hyphal elongation and by a decreased fungal entry into the roots, respectively. Here, we showed that CERBERUS was induced at the sites of symbiotic fungal or bacterial infection. NSP1 has been implicated in a strigolactone biosynthesis gene DWARF27 expression. Nevertheless, in nsp1, DWARF27 was induced by inoculation with AM fungi, implying the existence of a NSP1-independent regulatory mechanism of strigolactone biosynthesis during AMS establishment. These results support functional analysis of CERBERUS and NSP1, and also contribute to elucidation of common mechanisms in AMS and RNS. PMID:24705023

  6. Differences in the induction of cyp1A and related genes in cultured rainbow trout Oncorhynchus mykiss. Additional considerations for the use of EROD activity as a biomarker.

    PubMed

    Valdehita, A; Fernández-Cruz, M L; Torrent, F; Sericano, J L; Navas, J M

    2012-07-01

    Two rainbow trout Oncorhynchus mykiss fish farms were repeatedly sampled in order to observe the variability of ethoxyresorufin-O-deethylase (EROD) activity and of related genes in the liver. Fish coming from fish farm A exhibited EROD levels that could be considered as basal according to the scientific literature, however, EROD activity in fish coming from fish farm B was significantly increased. This was accompanied by augmented aryl hydrocarbon receptor (ahr) and cytochrome P4501A (cyp1A) messenger RNA expression and reduced oestrogen receptor (er) and vitellogenin (vtg) transcription. Only sediment extracts from the entry channel of fish farm B induced EROD activity in O. mykiss cultured cells, however, this induction could not be explained by the levels of polyaromatic hydrocarbons (PAH) and polychlorinated biphenyls (PCB) measured in the sediments. The results of this study point out that O. mykiss cultured in fish farms could be used as sentinels for indication of pollution. In this particular work, however, no conclusive evidence has been found for a relationship between the presence of PAHs and PCBs and the observed EROD induction.

  7. Replication of a gene-environment interaction Via Multimodel inference: additive-genetic variance in adolescents' general cognitive ability increases with family-of-origin socioeconomic status.

    PubMed

    Kirkpatrick, Robert M; McGue, Matt; Iacono, William G

    2015-03-01

    The present study of general cognitive ability attempts to replicate and extend previous investigations of a biometric moderator, family-of-origin socioeconomic status (SES), in a sample of 2,494 pairs of adolescent twins, non-twin biological siblings, and adoptive siblings assessed with individually administered IQ tests. We hypothesized that SES would covary positively with additive-genetic variance and negatively with shared-environmental variance. Important potential confounds unaddressed in some past studies, such as twin-specific effects, assortative mating, and differential heritability by trait level, were found to be negligible. In our main analysis, we compared models by their sample-size corrected AIC, and base our statistical inference on model-averaged point estimates and standard errors. Additive-genetic variance increased with SES-an effect that was statistically significant and robust to model specification. We found no evidence that SES moderated shared-environmental influence. We attempt to explain the inconsistent replication record of these effects, and provide suggestions for future research.

  8. Replication of a Gene-Environment Interaction via Multimodel Inference: Additive-Genetic Variance in Adolescents’ General Cognitive Ability Increases with Family-of-Origin Socioeconomic Status

    PubMed Central

    Kirkpatrick, Robert M.; McGue, Matt; Iacono, William G.

    2015-01-01

    The present study of general cognitive ability attempts to replicate and extend previous investigations of a biometric moderator, family-of-origin socioeconomic status (SES), in a sample of 2,494 pairs of adolescent twins, non-twin biological siblings, and adoptive siblings assessed with individually administered IQ tests. We hypothesized that SES would covary positively with additive-genetic variance and negatively with shared-environmental variance. Important potential confounds unaddressed in some past studies, such as twin-specific effects, assortative mating, and differential heritability by trait level, were found to be negligible. In our main analysis, we compared models by their sample-size corrected AIC, and base our statistical inference on model-averaged point estimates and standard errors. Additive-genetic variance increased with SES—an effect that was statistically significant and robust to model specification. We found no evidence that SES moderated shared-environmental influence. We attempt to explain the inconsistent replication record of these effects, and provide suggestions for future research. PMID:25539975

  9. Non-additive hepatic gene expression elicited by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) co-treatment in C57BL/6 mice

    SciTech Connect

    Kopec, Anna K.; D'Souza, Michelle L.; Mets, Bryan D.; Burgoon, Lyle D.; Reese, Sarah E.; Archer, Kellie J.; Potter, Dave; Tashiro, Colleen; Sharratt, Bonnie; Harkema, Jack R.; Zacharewski, Timothy R.

    2011-10-15

    Interactions between environmental contaminants can lead to non-additive effects that may affect the toxicity and risk assessment of a mixture. Comprehensive time course and dose-response studies with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), non-dioxin-like 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and their mixture were performed in immature, ovariectomized C57BL/6 mice. Mice were gavaged once with 30 {mu}g/kg TCDD, 300 mg/kg PCB153, a mixture of 30 {mu}g/kg TCDD with 300 mg/kg PCB153 (MIX) or sesame oil vehicle for 4,12, 24,72 or 168 h. In the 24 h dose-response study, animals were gavaged with TCDD (0.3,1, 3, 6, 10, 15, 30, 45 {mu}g/kg), PCB153 (3,10, 30, 60, 100, 150, 300, 450 mg/kg), MIX (0.3 + 3, 1 + 10, 3 + 30, 6 + 60, 10 + 100, 15 + 150, 30 + 300, 45 {mu}g/kg TCDD + 450 mg/kg PCB153, respectively) or vehicle. All three treatments significantly increased relative liver weights (RLW), with MIX eliciting significantly greater increases compared to TCDD and PCB153 alone. Histologically, MIX induced hepatocellular hypertrophy, vacuolization, inflammation, hyperplasia and necrosis, a combination of TCDD and PCB153 responses. Complementary lipid analyses identified significant increases in hepatic triglycerides in MIX and TCDD samples, while PCB153 had no effect on lipids. Hepatic PCB153 levels were also significantly increased with TCDD co-treatment. Microarray analysis identified 167 TCDD, 185 PCB153 and 388 MIX unique differentially expressed genes. Statistical modeling of quantitative real-time PCR analysis of Pla2g12a, Serpinb6a, Nqo1, Srxn1, and Dysf verified non-additive expression following MIX treatment compared to TCDD and PCB153 alone. In summary, TCDD and PCB153 co-treatment elicited specific non-additive gene expression effects that are consistent with RLW increases, histopathology, and hepatic lipid accumulation. - Graphical abstract: Display Omitted Highlights: > MIX (TCDD:PCB153 at 1:10,000 ratio) exposure leads to non-additive gene expression

  10. Morphology and small subunit (SSU) rRNA gene sequence of the new brackish water ciliate Neobakuella flava n. g., n. sp. (Ciliophora, Spirotricha, Bakuellidae) and SSU rRNA gene sequences of six additional hypotrichs from Korea.

    PubMed

    Li, Liqiong; Khan, Sadia Nawroz; Ji, Daode; Shin, Mann Kyoon; Berger, Helmut

    2011-01-01

    The morphology and the small subunit (SSU) rRNA gene sequence of the hypotrich Neobakuella flava n. g., n. sp. from the estuary of the Taehwagang River (Ulsan, South Korea) were investigated. The three frontal cirri, the composition of the midventral complex of cirral pairs and rows, and the simple dorsal kinety pattern of three bipolar kineties assign it to the urostyloid taxon Bakuellidae. The increased number of buccal and parabuccal cirri, the presence of transverse cirri, and more than one left marginal row, as well as the lack of caudal cirri separate Neobakuella n. g. from the other bakuellids. Neobakuella flava n. sp. has many 0.3 μm sized green and/or yellow usually dark-green cortical granules and some sparsely distributed, 2 × 1 μm sized grass green with yellowish shimmer granules. The gene sequence data indicate a close relationship with Diaxonella and a distinct separation from the bakuellid Metaurostylopsis and parabirojimid Parabirojimia. The SSU rRNA gene sequences of four further urostyloids (i.e. Diaxonella pseudorubra, Anteholosticha monilata, Metaurostylopsis struederkypkeae, Pseudourostyla cristata) and two stylonychines (i.e. Sterkiella cavicola, Sterkiella histriomuscorum) from Korea were analyzed. Anteholosticha monilata, type of the genus, is clearly separated from the Holosticha clade, supporting the morphological separation from Holosticha. Sterkiella cavicola, type of Sterkiella, clusters within the stylonychines and is obviously closely related with S. histriomuscorum.

  11. Increased yield of actionable mutations using multi-gene panels to assess hereditary cancer susceptibility in an ethnically diverse clinical cohort.

    PubMed

    Ricker, Charité; Culver, Julie O; Lowstuter, Katrina; Sturgeon, Duveen; Sturgeon, Julia D; Chanock, Christopher R; Gauderman, William J; McDonnell, Kevin J; Idos, Gregory E; Gruber, Stephen B

    2016-04-01

    This study aims to assess multi-gene panel testing in an ethnically diverse clinical cancer genetics practice. We conducted a retrospective study of individuals with a personal or family history of cancer undergoing clinically indicated multi-gene panel tests of 6-110 genes, from six commercial laboratories. The 475 patients in the study included 228 Hispanics (47.6%), 166 non-Hispanic Whites (35.4%), 55 Asians (11.6%), 19 Blacks (4.0%), and seven others (1.5%). Panel testing found that 15.6% (74/475) of patients carried deleterious mutations for a total of 79 mutations identified. This included 7.4% (35/475) of patients who had a mutation identified that would not have been tested with a gene-by-gene approach. The identification of a panel-added mutation impacted clinical management for most of cases (69%, 24/35), and genetic testing was recommended for the first degree relatives of nearly all of them (91%, 32/35). Variants of uncertain significance (VUSs) were identified in a higher proportion of tests performed in ethnic minorities. Multi-gene panel testing increases the yield of mutations detected and adds to the capability of providing individualized cancer risk assessment. VUSs represent an interpretive challenge due to less data available outside of White, non-Hispanic populations. Further studies are necessary to expand understanding of the implementation and utilization of panels across broad clinical settings and patient populations.

  12. Evidence for an additional intracellular site of action of probucol in the prevention of oxidative modification of low density lipoprotein. Use of a new water-soluble probucol derivative.

    PubMed Central

    Parthasarathy, S

    1992-01-01

    Oxidative modification of low density lipoprotein (LDL) renders it more atherogenic. Probucol, a highly nonpolar antioxidant, is transported in lipoproteins, including LDL, and inhibits oxidative modification of LDL in vitro. The ability of probucol to inhibit atherogenesis in the LDL receptor-deficient rabbit has been attributed to its antioxidant effect. We report synthesis of a new water-soluble analogue of probucol that is very effective in preventing cell-induced LDL oxidation. The polar probucol derivative, diglutaryl probucol, is efficiently taken up by endothelial cells and macrophages in culture and is hydrolyzed to release the active antioxidant, probucol. The treated cells, after thorough washing, show a marked decrease in their capacity to oxidize LDL during a subsequent incubation. At high concentrations of the derivative, the cells also released free probucol into the medium. Thus, the effectiveness of probucol in vivo may be related both to its presence in LDL, acting as a nonspecific antioxidant, and to an additional ability to inhibit cell-mediated oxidation of LDL by virtue of its uptake into cells. PMID:1569200

  13. Cardiac action potential imaging

    NASA Astrophysics Data System (ADS)

    Tian, Qinghai; Lipp, Peter; Kaestner, Lars

    2013-06-01

    Action potentials in cardiac myocytes have durations in the order of magnitude of 100 milliseconds. In biomedical investigations the documentation of the occurrence of action potentials is often not sufficient, but a recording of the shape of an action potential allows a functional estimation of several molecular players. Therefore a temporal resolution of around 500 images per second is compulsory. In the past such measurements have been performed with photometric approaches limiting the measurement to one cell at a time. In contrast, imaging allows reading out several cells at a time with additional spatial information. Recent developments in camera technologies allow the acquisition with the required speed and sensitivity. We performed action potential imaging on isolated adult cardiomyocytes of guinea pigs utilizing the fluorescent membrane potential sensor di-8-ANEPPS and latest electron-multiplication CCD as well as scientific CMOS cameras of several manufacturers. Furthermore, we characterized the signal to noise ratio of action potential signals of varying sets of cameras, dye concentrations and objective lenses. We ensured that di-8-ANEPPS itself did not alter action potentials by avoiding concentrations above 5 μM. Based on these results we can conclude that imaging is a reliable method to read out action potentials. Compared to conventional current-clamp experiments, this optical approach allows a much higher throughput and due to its contact free concept leaving the cell to a much higher degree undisturbed. Action potential imaging based on isolated adult cardiomyocytes can be utilized in pharmacological cardiac safety screens bearing numerous advantages over approaches based on heterologous expression of hERG channels in cell lines.

  14. The Non-Genomic Actions of Vitamin D

    PubMed Central

    Hii, Charles S; Ferrante, Antonio

    2016-01-01

    Since its discovery in 1920, a great deal of effort has gone into investigating the physiological actions of vitamin D and the impact its deficiency has on human health. Despite this intense interest, there is still disagreement on what constitutes the lower boundary of adequacy and on the Recommended Dietary Allowance. There has also been a major push to elucidate the biochemistry of vitamin D, its metabolic pathways and the mechanisms that mediate its action. Originally thought to act by altering the expression of target genes, it was realized in the mid-1980s that some of the actions of vitamin D were too rapid to be accounted for by changes at the genomic level. These rapid non-genomic actions have attracted as much interest as the genomic actions and they have spawned additional questions in an already busy field. This mini-review attempts to summarise the in vitro and in vivo work that has been conducted to characterise the rapid non-genomic actions, the mechanisms that give rise to these properties and the roles that these play in the overall action of vitamin D at the cellular level. Understanding the effects of vitamin D at the cellular level should enable the design of elegant human studies to extract the full potential of vitamin D to benefit human health. PMID:26950144

  15. Citizen's actions

    NASA Technical Reports Server (NTRS)

    1975-01-01

    The role played by individual citizens as consumers of energy was examined, with emphasis on studying ways in which their action could result in energy conservation. It was shown that there are ways that energy can be conserved in this way, with citizens acting either individually or in groups. The potential savings are significant, but the actual savings may be quite small. The citizens need to be motivated to save and to believe in a conservation ethic; developing such an ethic is difficult, and perhaps not responsive to the shotgun approach now being attempted. The true course of action may be to synthesize new societal structures that provide the maximum evolution of culture within the limitation of scarce energy resources.

  16. A novel gene EaF82a from variegated Epipremnum aureum and its potential involvement in light associated auxin action in shoot meristems

    Technology Transfer Automated Retrieval System (TEKTRAN)

    EaF82, a gene identified in previous studies of the variegated plant Epipremnum aureum, exhibited a unique expression pattern with greater transcript abundance in yellow sectors than green sectors of variegated leaves, but lower abundance in regenerated pale yellow plants than in green plants derive...

  17. Screening somatic cell nuclear transfer parameters for generation of transgenic cloned cattle with intragenomic integration of additional gene copies that encode bovine adipocyte-type fatty acid-binding protein (A-FABP).

    PubMed

    Guo, Yong; Li, Hejuan; Wang, Ying; Yan, Xingrong; Sheng, Xihui; Chang, Di; Qi, Xiaolong; Wang, Xiangguo; Liu, Yunhai; Li, Junya; Ni, Hemin

    2017-02-01

    Somatic cell nuclear transfer (SCNT) is frequently used to produce transgenic cloned livestock, but it is still associated with low success rates. To our knowledge, we are the first to report successful production of transgenic cattle that overexpress bovine adipocyte-type fatty acid binding proteins (A-FABPs) with the aid of SCNT. Intragenomic integration of additional A-FABP gene copies has been found to be positively correlated with the intramuscular fat content in different farm livestock species. First, we optimized the cloning parameters to produce bovine embryos integrated with A-FABP by SCNT, such as applied voltage field strength and pulse duration for electrofusion, morphology and size of donor cells, and number of donor cells passages. Then, bovine fibroblast cells from Qinchuan cattle were transfected with A-FABP and used as donor cells for SCNT. Hybrids of Simmental and Luxi local cattle were selected as the recipient females for A-FABP transgenic SCNT-derived embryos. The results showed that a field strength of 2.5 kV/cm with two 10-μs duration electrical pulses was ideal for electrofusion, and 4-6th generation circular smooth type donor cells with diameters of 15-25 μm were optimal for producing transgenic bovine embryos by SCNT, and resulted in higher fusion (80%), cleavage (73%), and blastocyst (27%) rates. In addition, we obtained two transgenic cloned calves that expressed additional bovine A-FABP gene copies, as detected by PCR-amplified cDNA sequencing. We proposed a set of optimal protocols to produce transgenic SCNT-derived cattle with intragenomic integration of ectopic A-FABP-inherited exon sequences.

  18. Conscious Action/Zombie Action

    PubMed Central

    Shepherd, Joshua

    2015-01-01

    Abstract I argue that the neural realizers of experiences of trying (that is, experiences of directing effort towards the satisfaction of an intention) are not distinct from the neural realizers of actual trying (that is, actual effort directed towards the satisfaction of an intention). I then ask how experiences of trying might relate to the perceptual experiences one has while acting. First, I assess recent zombie action arguments regarding conscious visual experience, and I argue that contrary to what some have claimed, conscious visual experience plays a causal role for action control in some circumstances. Second, I propose a multimodal account of the experience of acting. According to this account, the experience of acting is (at the very least) a temporally extended, co‐conscious collection of agentive and perceptual experiences, functionally integrated and structured both by multimodal perceptual processing as well as by what an agent is, at the time, trying to do. PMID:27667859

  19. Conscious Action/Zombie Action.

    PubMed

    Shepherd, Joshua

    2016-06-01

    I argue that the neural realizers of experiences of trying (that is, experiences of directing effort towards the satisfaction of an intention) are not distinct from the neural realizers of actual trying (that is, actual effort directed towards the satisfaction of an intention). I then ask how experiences of trying might relate to the perceptual experiences one has while acting. First, I assess recent zombie action arguments regarding conscious visual experience, and I argue that contrary to what some have claimed, conscious visual experience plays a causal role for action control in some circumstances. Second, I propose a multimodal account of the experience of acting. According to this account, the experience of acting is (at the very least) a temporally extended, co-conscious collection of agentive and perceptual experiences, functionally integrated and structured both by multimodal perceptual processing as well as by what an agent is, at the time, trying to do.

  20. ES H action plan

    SciTech Connect

    Not Available

    1991-01-01

    This document contains planned actions to correct the deficiencies identified in the Pre-Tiger Team Self-Assessment (PTTSA), January 1991, of Sandia National Laboratories (SNL -- Albuquerque, New Mexico; Tonopah, Nevada; and Kauai, Hawaii). The Self-Assessment was conducted by a Self-Assessment Working Group consisting of 19 department managers, with support from Environment, Safety, and Health (ES H) professionals, from October through December 1990. Findings from other past audits, dating back to 1985, were reviewed and compared with the PTTSA findings to determine if additional findings, key findings, or root causes were warranted. The resulting ES H Action Plan and individual planned actions were prepared by the ES H Action Plan Project Group with assistance from the Program owners/authors during February and March 1991. The plan was reviewed by SNL Management in April 1991. This document serves as a planning instrument for the Laboratories to aid in the scoping and sizing of activities related to ES H compliance for the coming five years. It will be modified as required to ensure a workload/funding balance and to address the findings resulting from the Tiger Team assessment at SNL, Albuquerque. The process of producing this document has served well to prepare SNL, Albuquerque, for the coming task of producing the required post-Tiger Team action plan document. 8 tabs.

  1. Comparison of the temporary dynamics of NGF and BDNF gene expression in rat hippocampus, frontal cortex, and retina under Semax action.

    PubMed

    Shadrina, Maria; Kolomin, Timur; Agapova, Tamara; Agniullin, Yan; Shram, Stanislav; Slominsky, Petr; Lymborska, Svetlana; Myasoedov, Nikolay

    2010-05-01

    Neurotrophins are a family of structurally related proteins that regulate the survival, differentiation, and maintenance of function of different neuron populations. Some peptides are able to affect the production and activity of neurotrophins. One of these synthetic peptides is heptapeptide Semax, an analog of the N-terminal adrenocorticotropic hormone fragment 4-10. It is known that Semax has effects on learning and memory formation and exerts some neuroprotective effects in rodents and humans. Male Wistar rats were treated for 20 min, 40 min, 90 min, 3 h, 8 h, and 24 h with Semax. Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) gene expression in rat brain and retina was analyzed by real-time polymerase chain reaction. It was revealed that after Semax administration the multidirectional activation of the expression of the genes under investigation in the hippocampus, frontal cortex, and retina was observed. The expression of both neurotrophin genes was decreased in rat hippocampus and retina 20 min after Semax administration and was increased in the frontal cortex. The expression levels of NGF remained practically constant in the retina at the initial stage, whereas the expression levels of BDNF were significantly increased 90 min after Semax administration.

  2. Action Learning: Avoiding Conflict or Enabling Action

    ERIC Educational Resources Information Center

    Corley, Aileen; Thorne, Ann

    2006-01-01

    Action learning is based on the premise that action and learning are inextricably entwined and it is this potential, to enable action, which has contributed to the growth of action learning within education and management development programmes. However has this growth in action learning lead to an evolution or a dilution of Revan's classical…

  3. Differential action of 13-HPODE on PPARalpha downstream genes in rat Fao and human HepG2 hepatoma cell lines.

    PubMed

    König, Bettina; Eder, Klaus

    2006-06-01

    In rats, oxidized fats activate the peroxisome proliferator-activated receptor alpha (PPARalpha), leading to reduced triglyceride concentrations in liver, plasma and very low density lipoproteins. Oxidation products of linoleic acid constitute an important portion of oxidized dietary fats. This study was conducted to check whether the primary lipid peroxidation product of linoleic acid, 13-hydroperoxy-9,11-octadecadienoic acid (13-HPODE), might be involved in the PPARalpha-activating effect of oxidized fats. Therefore, we examined the effect of 13-HPODE on the expression of PPARalpha target genes in the rat Fao and the human HepG2 hepatoma cell lines. In Fao cells, 13-HPODE increased the mRNA concentration of the PPARalpha target genes acyl-CoA oxidase (ACO), cytochrome P450 4A1 and carnitine-palmitoyltransferase 1A (CPT1A). Furthermore, the concentration of cellular and secreted triglycerides was reduced in Fao cells treated with 13-HPODE. Because PPARalpha mRNA was not influenced, we conclude that these effects are due to an activation of PPARalpha by 13-HPODE. In contrast, HepG2 cells seemed to be resistant to PPARalpha activation by 13-HPODE because no remarkable induction of the PPARalpha target genes ACO, CPT1A, mitochondrial HMG-CoA synthase and delta9-desaturase was observed. Consequently, cellular and secreted triglyceride levels were not changed after incubation of HepG2 cells with 13-HPODE. In conclusion, this study shows that 13-HPODE activates PPARalpha in rat Fao but not in human HepG2 hepatoma cells.

  4. Anti-proliferative and pro-apoptotic actions of a novel human and mouse ovarian tumor-associated gene OTAG-12: downregulation, alternative splicing and drug sensitization.

    PubMed

    Chen, X; Zhang, H; Aravindakshan, J P; Gotlieb, W H; Sairam, M R

    2011-06-23

    In studying the age dependence and chronology of ovarian tumors in follicle stimulating hormone receptor knockout mice, we identified a novel ovarian tumor associated gene-12 (OTAG-12), which is progressively downregulated and maps to Chr. 8B3.3. OTAG-12 protein overexpression in mouse ovarian and mammary tumor cells suggested powerful anti-proliferative effects. In human epithelial ovarian cancers (OCs) and OC cell lines, OTAG-12 mRNA expression is downregulated in comparison with normal ovaries. Cloning and identification revealed that human OTAG-12 mapping to gene-rich Chr. 19p13.12 is expressed in three spliced forms: hOTAG-12a, hOTAG-12b and hOTAG-12c, of which b is predominant in the normal ovary. Functionally active hOTAG-12b is a simple protein with no disulfide bonds and a nuclear localization signal is present in all variants. Transfection of OTAG-12 variants in OC and tumorigenic HEK293 cells confirmed nuclear localization. hOTAG-12b overexpression in OC and HEK293 cells effectively suppressed cell growth, anchorage-dependent and independent colony formation followed by apoptosis, whereas hOTAG-12a and hOTAG-12c had no such effects. Deletion mutants identified the critical importance of carboxyl terminus for hOTAG-12b function. Doxycycline-inducible growth inhibition of HEK293 cells by hOTAG-12a was associated with effects on G2 cell cycle arrest and apoptosis induction. hOTAG-12b expression rendered tumorigenic cells more sensitive to four apoptotic stimuli including etoposide-a topoisomerase-II inhibitor. Doxycycline-induced hOTAG-12b expression blocked xenograft tumor growth in nude mice, whereas hOTAG-12a was ineffective. Although p53-pathway-dependent apoptotic agents could upregulate endogenous hOTAG-12b and p53 in UCI-101/107 OC cells, hOTAG-12b could also induce apoptosis in p53-null and platinum-resistant SKOV3 OC cells and Doxycycline-induced hOTAG-12b did not alter p53. Further study showed that hOTAG-12b increases mRNAs of pro-apoptotic genes

  5. Additive lattice kirigami.

    PubMed

    Castle, Toen; Sussman, Daniel M; Tanis, Michael; Kamien, Randall D

    2016-09-01

    Kirigami uses bending, folding, cutting, and pasting to create complex three-dimensional (3D) structures from a flat sheet. In the case of lattice kirigami, this cutting and rejoining introduces defects into an underlying 2D lattice in the form of points of nonzero Gaussian curvature. A set of simple rules was previously used to generate a wide variety of stepped structures; we now pare back these rules to their minimum. This allows us to describe a set of techniques that unify a wide variety of cut-and-paste actions under the rubric of lattice kirigami, including adding new material and rejoining material across arbitrary cuts in the sheet. We also explore the use of more complex lattices and the different structures that consequently arise. Regardless of the choice of lattice, creating complex structures may require multiple overlapping kirigami cuts, where subsequent cuts are not performed on a locally flat lattice. Our additive kirigami method describes such cuts, providing a simple methodology and a set of techniques to build a huge variety of complex 3D shapes.

  6. Additive lattice kirigami

    PubMed Central

    Castle, Toen; Sussman, Daniel M.; Tanis, Michael; Kamien, Randall D.

    2016-01-01

    Kirigami uses bending, folding, cutting, and pasting to create complex three-dimensional (3D) structures from a flat sheet. In the case of lattice kirigami, this cutting and rejoining introduces defects into an underlying 2D lattice in the form of points of nonzero Gaussian curvature. A set of simple rules was previously used to generate a wide variety of stepped structures; we now pare back these rules to their minimum. This allows us to describe a set of techniques that unify a wide variety of cut-and-paste actions under the rubric of lattice kirigami, including adding new material and rejoining material across arbitrary cuts in the sheet. We also explore the use of more complex lattices and the different structures that consequently arise. Regardless of the choice of lattice, creating complex structures may require multiple overlapping kirigami cuts, where subsequent cuts are not performed on a locally flat lattice. Our additive kirigami method describes such cuts, providing a simple methodology and a set of techniques to build a huge variety of complex 3D shapes. PMID:27679822

  7. Gene based therapies for kidney regeneration.

    PubMed

    Janssen, Manoe J; Arcolino, Fanny O; Schoor, Perry; Kok, Robbert Jan; Mastrobattista, Enrico

    2016-11-05

    In this review we provide an overview of the expanding molecular toolbox that is available for gene based therapies and how these therapies can be used for a large variety of kidney diseases. Gene based therapies range from restoring gene function in genetic kidney diseases to steering complex molecular pathways in chronic kidney disorders, and can provide a treatment or cure for diseases that otherwise may not be targeted. This approach involves the delivery of recombinant DNA sequences harboring therapeutic genes to improve cell function and thereby promote kidney regeneration. Depending on the therapy, the recombinant DNA will express a gene that directly plays a role in the function of the cell (gene addition), that regulates the expression of an endogenous gene (gene regulation), or that even changes the DNA sequence of endogenous genes (gene editing). Some interventions involve permanent changes in the genome whereas others are only temporary and leave no trace. Efficient and safe delivery are important steps for all gene based therapies and also depend on the mode of action of the therapeutic gene. Here we provide examples on how the different methods can be used to treat various diseases, which technologies are now emerging (such as gene repair through CRISPR/Cas9) and what the opportunities, perspectives, potential and the limitations of these therapies are for the treatment of kidney diseases.

  8. Epistasis and Quantitative Traits: Using Model Organisms to Study Gene-Gene Interactions

    PubMed Central

    Mackay, Trudy F. C.

    2014-01-01

    Summary The role of epistasis in the genetic architecture of quantitative traits is controversial, despite the biological plausibility that non-linear molecular interactions underpin the genotype-phenotype map. This controversy arises because most genetic variation for quantitative traits is additive. However, additive variance is consistent with pervasive epistatic gene action. Here, I discuss experimental designs to detect the contribution of epistasis to quantitative trait phenotypes in model organisms. These studies indicate that epistatic gene action is common, and that additivity can be an emergent property of underlying genetic interaction networks. Epistasis causes hidden quantitative genetic variation in natural populations and could be responsible for the small additive effects, missing heritability and lack of replication typically observed for human complex traits. PMID:24296533

  9. Social Action As An Objective of Social Studies Instruction.

    ERIC Educational Resources Information Center

    Curtis, Charles K.

    This paper presents a rationale for making social action a major goal of elementary and secondary school social studies education. In addition, it describes social action models, suggests social action approaches appropriate for students at various grade levels, and reviews literature on social action by public school students. Social action is…

  10. Role of angiotensin converting enzyme and angiotensinogen gene polymorphisms in angiotensin converting enzyme inhibitor-mediated antiproteinuric action in type 2 diabetic nephropathy patients

    PubMed Central

    Aggarwal, Neerja; Kare, Pawan Kumar; Varshney, Parul; Kalra, Om Prakash; Madhu, Sri Venkata; Banerjee, Basu Dev; Yadav, Anil; Raizada, Alpana; Tripathi, Ashok Kumar

    2017-01-01

    AIM To investigate the role of genetic variants of angiotensin converting enzyme (ACE) and angiotensinogen (AGT) genes in the antiproteinuric efficacy of ACE inhibitor therapy in diabetic nephropathy (DN) patients. METHODS In the present study, 270 type 2 diabetes mellitus patients with nephropathy were enrolled and treated with ACE inhibitor (ramipril) and followed at 6 mo for renal function and albumin excretion by estimating serum creatinine, end stage renal disease, and albumin/creatinine ratio (ACR) in urine. Genotyping of ACE I/D and AGT M235T polymorphisms were performed by using primer specific polymerase chain reaction (PCR) and PCR-RFLP techniques, respectively. RESULTS Forty-eight percent of DN patients (responders) benefited with respect to proteinuria from ACE inhibitor therapy at 6 mo follow-up. A significant reduction in ACR was observed after 6 mo treatment with ACE inhibitor irrespective of whether DN patients were micro-albuminuric (≥ 30 and < 300 mg/g creatinine) or macro-albuminuric (≥ 300 mg/g creatinine) at the time of enrollment. However, macro-albuminuric patients (55%) showed better response to therapy. A reduction in urinary ACR was found independent of genotypes of ACE I/D and AGT M235T polymorphisms although macro-albuminuric patients having TT genotype showed statistically insignificant increased response (72%). CONCLUSION ACE inhibitor therapy reduced urinary ACR by ≥ 30% in 50% of DN patients and the response is independent of ACE I/D and AGT M235T polymorphisms. PMID:28344754

  11. Deoxynivalenol impairs hepatic and intestinal gene expression of selected oxidative stress, tight junction and inflammation proteins in broiler chickens, but addition of an adsorbing agent shifts the effects to the distal parts of the small intestine.

    PubMed

    Osselaere, Ann; Santos, Regiane; Hautekiet, Veerle; De Backer, Patrick; Chiers, Koen; Ducatelle, Richard; Croubels, Siska

    2013-01-01

    Broiler chickens are rather resistant to deoxynivalenol and thus, clinical signs are rarely seen. However, effects of subclinical concentrations of deoxynivalenol on both the intestine and the liver are less frequently studied at the molecular level. During our study, we investigated the effects of three weeks of feeding deoxynivalenol on the gut wall morphology, intestinal barrier function and inflammation in broiler chickens. In addition, oxidative stress was evaluated in both the liver and intestine. Besides, the effect of a clay-based mycotoxin adsorbing agent on these different aspects was also studied. Our results show that feeding deoxynivalenol affects the gut wall morphology both in duodenum and jejenum of broiler chickens. A qRT-PCR analysis revealed that deoxynivalenol acts in a very specific way on the intestinal barrier, since only an up-regulation in mRNA expression of claudin 5 in jejunum was observed, while no effects were seen on claudin 1, zona occludens 1 and 2. Addition of an adsorbing agent resulted in an up-regulation of all the investigated genes coding for the intestinal barrier in the ileum. Up-regulation of Toll-like receptor 4 and two markers of oxidative stress (heme-oxigenase or HMOX and xanthine oxidoreductase or XOR) were mainly seen in the jejunum and to a lesser extent in the ileum in response to deoxynivalenol, while in combination with an adsorbing agent main effect was seen in the ileum. These results suggest that an adsorbing agent may lead to higher concentrations of deoxynivalenol in the more distal parts of the small intestine. In the liver, XOR was up-regulated due to DON exposure. HMOX and HIF-1α (hypoxia-inducible factor 1α) were down-regulated due to feeding DON but also due to feeding the adsorbing agent alone or in combination with DON.

  12. Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development

    PubMed Central

    Chan, Yingleong; Salem, Rany M.; Hsu, Yu-Han H.; McMahon, George; Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Guo, Michael H.; Lim, Elaine T.; Franke, Lude; Smith, George Davey; Strachan, David P.; Hirschhorn, Joel N.

    2015-01-01

    Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r2 ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10−8) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10−40). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases. PMID:25865494

  13. Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development.

    PubMed

    Chan, Yingleong; Salem, Rany M; Hsu, Yu-Han H; McMahon, George; Pers, Tune H; Vedantam, Sailaja; Esko, Tonu; Guo, Michael H; Lim, Elaine T; Franke, Lude; Smith, George Davey; Strachan, David P; Hirschhorn, Joel N

    2015-05-07

    Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r(2) ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10(-8)) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10(-40)). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases.

  14. 77 FR 47823 - Procurement List; Proposed Addition

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-10

    ... Administration, New York, NY Coverage: A-List for the Total Government Requirement as aggregated by the General... PEOPLE WHO ARE BLIND OR SEVERELY DISABLED Procurement List; Proposed Addition AGENCY: Committee for Purchase From People Who Are Blind or Severely Disabled. ACTION: Proposed Addition to the Procurement...

  15. 78 FR 45183 - Procurement List Additions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-26

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    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

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  20. 78 FR 22209 - Additional Synthetic Drug Testing

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  1. Molecular mechanisms of glucocorticoid action in mast cells.

    PubMed

    Oppong, Emmanuel; Flink, Nesrin; Cato, Andrew C B

    2013-11-05

    Glucocorticoids are compounds that have successfully been used over the years in the treatment of inflammatory disorders. They are known to exhibit their effects through the glucocorticoid receptor (GR) that acts to downregulate the action of proinflammatory transcription factors such as AP-1 and NF-κB. The GR also exerts anti-inflammatory effects through activation of distinct genes. In addition to their anti-inflammatory actions, glucocorticoids are also potent antiallergic compounds that are widely used in conditions such as asthma and anaphylaxis. Nevertheless the mechanism of action of this hormone in these disorders is not known. In this article, we have reviewed reports on the effects of glucocorticoids in mast cells, one of the important immune cells in allergy. Building on the knowledge of the molecular action of glucocorticoids and the GR in the treatment of inflammation in other cell types, we have made suggestions as to the likely mechanisms of action of glucocorticoids in mast cells. We have further identified some important questions and research directions that need to be addressed in future studies to improve the treatment of allergic disorders.

  2. The role of action prediction and inhibitory control for joint action coordination in toddlers.

    PubMed

    Meyer, M; Bekkering, H; Haartsen, R; Stapel, J C; Hunnius, S

    2015-11-01

    From early in life, young children eagerly engage in social interactions. Yet, they still have difficulties in performing well-coordinated joint actions with others. Adult literature suggests that two processes are important for smooth joint action coordination: action prediction and inhibitory control. The aim of the current study was to disentangle the potential role of these processes in the early development of joint action coordination. Using a simple turn-taking game, we assessed 2½-year-old toddlers' joint action coordination, focusing on timing variability and turn-taking accuracy. In two additional tasks, we examined their action prediction capabilities with an eye-tracking paradigm and examined their inhibitory control capabilities with a classic executive functioning task (gift delay task). We found that individual differences in action prediction and inhibitory action control were distinctly related to the two aspects of joint action coordination. Toddlers who showed more precision in their action predictions were less variable in their action timing during the joint play. Furthermore, toddlers who showed more inhibitory control in an individual context were more accurate in their turn-taking performance during the joint action. On the other hand, no relation between timing variability and inhibitory control or between turn-taking accuracy and action prediction was found. The current results highlight the distinct role of action prediction and inhibitory action control for the quality of joint action coordination in toddlers. Underlying neurocognitive mechanisms and implications for processes involved in joint action coordination in general are discussed.

  3. Ol-Prx 3, a member of an additional class of homeobox genes, is unimodally expressed in several domains of the developing and adult central nervous system of the medaka (Oryzias latipes).

    PubMed

    Joly, J S; Bourrat, F; Nguyen, V; Chourrout, D

    1997-11-25

    Large-scale genetic screens for mutations affecting early neurogenesis of vertebrates have recently been performed with an aquarium fish, the zebrafish. Later stages of neural morphogenesis have attracted less attention in small fish species, partly because of the lack of molecular markers of developing structures that may facilitate the detection of discrete structural alterations. In this context, we report the characterization of Ol-Prx 3 (Oryzias latipes-Prx 3). This gene was isolated in the course of a large-scale screen for brain cDNAs containing a highly conserved DNA binding region, the homeobox helix-three. Sequence analysis revealed that this gene belongs to another class of homeobox genes, together with a previously isolated mouse ortholog, called OG-12 [Rovescalli, A. C., Asoh, S. & Nirenberg, M. (1996) Proc. Natl. Acad. Sci. USA 93, 10691-10696] and with the human SHOX gene [Rao, E., Weiss, B., Fukami, M., Rump, A., Niesler, B., et al. (1997) Nat. Genet. 16, 54-62], thought to be involved in the short-stature phenotype of Turner syndrome patients. These three genes exhibit a moderate level of identity in the homeobox with the other genes of the paired-related (PRX) gene family. Ol-Prx 3, as well as the PRX genes, are expressed in various cartilaginous structures of head and limbs. These genes might thus be involved in common regulatory pathways during the morphogenesis of these structures. Moreover, this paper reports a complex and monophasic pattern of Ol-Prx 3 expression in the central nervous system, which differs markedly from the patterns reported for the PRX genes, Prx 3 excluded: this gene begins to be expressed in a variety of central nervous system territories at late neurula stage. Strikingly, it remains turned on in some of the derivatives of each territory during the entire life of the fish. We hope this work will thus help identify common features for the PRX 3 family of homeobox genes.

  4. RNA polymerase beta subunit (rpoB) gene and the 16S-23S rRNA intergenic transcribed spacer region (ITS) as complementary molecular markers in addition to the 16S rRNA gene for phylogenetic analysis and identification of the species of the family Mycoplasmataceae.

    PubMed

    Volokhov, Dmitriy V; Simonyan, Vahan; Davidson, Maureen K; Chizhikov, Vladimir E

    2012-01-01

    Conventional classification of the species in the family Mycoplasmataceae is mainly based on phenotypic criteria, which are complicated, can be difficult to measure, and have the potential to be hampered by phenotypic deviations among the isolates. The number of biochemical reactions suitable for phenotypic characterization of the Mycoplasmataceae is also very limited and therefore the strategy for the final identification of the Mycoplasmataceae species is based on comparative serological results. However, serological testing of the Mycoplasmataceae species requires a performance panel of hyperimmune sera which contains anti-serum to each known species of the family, a high level of technical expertise, and can only be properly performed by mycoplasma-reference laboratories. In addition, the existence of uncultivated and fastidious Mycoplasmataceae species/isolates in clinical materials significantly complicates, or even makes impossible, the application of conventional bacteriological tests. The analysis of available genetic markers is an additional approach for the primary identification and phylogenetic classification of cultivable species and uncultivable or fastidious organisms in standard microbiological laboratories. The partial nucleotide sequences of the RNA polymerase β-subunit gene (rpoB) and the 16S-23S rRNA intergenic transcribed spacer (ITS) were determined for all known type strains and the available non-type strains of the Mycoplasmataceae species. In addition to the available 16S rRNA gene data, the ITS and rpoB sequences were used to infer phylogenetic relationships among these species and to enable identification of the Mycoplasmataceae isolates to the species level. The comparison of the ITS and rpoB phylogenetic trees with the 16S rRNA reference phylogenetic tree revealed a similar clustering patterns for the Mycoplasmataceae species, with minor discrepancies for a few species that demonstrated higher divergence of their ITS and rpoB in

  5. Sexually Dimorphic Actions of Glucocorticoids Provide a Link to Inflammatory Diseases with Gender Differences in Prevalence

    PubMed Central

    Duma, Danielle; Collins, Jennifer B.; Chou, Jeff W.; Cidlowski, John A.

    2016-01-01

    Males and females show differences in the prevalence of many major diseases that have important inflammatory components to their etiology. These gender-specific diseases, which include autoimmune diseases, hepatocellular carcinoma, diabetes, and osteoporosis, are largely considered to reflect the actions of sex hormones on the susceptibility to inflammatory stimuli. However, inflammation reflects a balance between pro- and anti-inflammatory signals, and investigation of gender-specific responses to the latter has been neglected. Glucocorticoids are the primary physiological anti-inflammatory hormones in mammals, and synthetic derivatives of these hormones are prescribed as anti-inflammatory agents, irrespective of patient gender. We explored the possibility that sexually dimorphic actions of glucocorticoid regulation of gene expression may contribute to the dimorphic basis of inflammatory disease by evaluating the rat liver, a classic glucocorticoid-responsive organ. Surprisingly, glucocorticoid administration expanded the set of hepatic sexually dimorphic genes. Eight distinct patterns of glucocorticoid-regulated gene expression were identified, which included sex-specific genes. Our experiments also defined specific genes with altered expression in response to glucocorticoid treatment in both sexes, but in opposite directions. Pathway analysis identified sex-specific glucocorticoid-regulated gene expression in several canonical pathways involved in susceptibility to and progression of diseases with gender differences in prevalence. Moreover, a comparison of the number of genes involved in inflammatory disorders between sexes revealed 84 additional glucocorticoid-responsive genes in the male, suggesting that the anti-inflammatory actions of glucocorticoids are more effective in males. These gender-specific actions of glucocorticoids in liver were substantiated in vivo with a sepsis model of systemic inflammation. PMID:20940427

  6. ICDF Complex Remedial Action Report

    SciTech Connect

    W. M. Heileson

    2007-09-26

    This Idaho CERCLA Disposal Facility (ICDF) Remedial Action Report has been prepared in accordance with the requirements of Section 6.2 of the INEEL CERCLA Disposal Facility Remedial Action Work Plan. The agency prefinal inspection of the ICDF Staging, Storage, Sizing, and Treatment Facility (SSSTF) was completed in June of 2005. Accordingly, this report has been developed to describe the construction activities completed at the ICDF along with a description of any modifications to the design originally approved for the facility. In addition, this report provides a summary of the major documents prepared for the design and construction of the ICDF, a discussion of relevant requirements and remedial action objectives, the total costs associated with the development and operation of the facility to date, and identification of necessary changes to the Agency-approved INEEL CERCLA Disposal Facility Remedial Action Work Plan and the ICDF Complex Operations and Maintenance Plan.

  7. Protective Action Guides (PAGs)

    EPA Pesticide Factsheets

    The Protective Action Guide (PAG) manual contains radiation dose guidelines that would trigger public safety measures. EPA developed Protective Action Guides to help responders plan for radiation emergencies.

  8. The +37 kb Cebpa Enhancer Is Critical for Cebpa Myeloid Gene Expression and Contains Functional Sites that Bind SCL, GATA2, C/EBPα, PU.1, and Additional Ets Factors.

    PubMed

    Cooper, Stacy; Guo, Hong; Friedman, Alan D

    2015-01-01

    The murine Cebpa gene contains an evolutionarily conserved 453 bp enhancer located at +37 kb that, together with its promoter, directs expression to myeloid progenitors and to long-term hematopoietic stem cells in transgenic mice. In human acute myeloid leukemia cases, the enhancer lacks point mutations but binds the RUNX1-ETO oncoprotein. The enhancer contains the H3K4me1 and H3K27Ac histone modifications, denoting an active enhancer, at progressively increasing levels as long-term hematopoietic stem cells transition to granulocyte-monocyte progenitors. We previously identified four enhancer sites that bind RUNX1 and demonstrated that their integrity is required for maximal enhancer activity in 32Dcl3 myeloid cells. The +37 kb Cebpa enhancer also contains C/EBP, Ets factor, Myb, GATA, and E-box consensus sites conserved in the human +42 kb CEBPA enhancer. Mutation of the two C/EBP, seven Ets, one Myb, two GATA, or two E-box sites reduces activity of an enhancer-promoter reporter in 32Dcl3 cells. In 293T gel shift assays, exogenous C/EBPα binds both C/EBP sites, c-Myb binds the Myb site, PU.1 binds the second Ets site, PU.1, Fli-1, ERG, and Ets1 bind the sixth Ets site, GATA2 binds both GATA sites, and SCL binds the second E-box. Endogenous hematopoietic RUNX1, PU.1, Fli-1, ERG, C/EBPα, GATA2, and SCL were previously shown to bind the enhancer, and we find that endogenous PU.1 binds the second Ets site in 32Dcl3 cells. Using CRISPR/Cas9, we developed 32Dcl3 lines in which the wild-type enhancer alleles are replaced with a variant mutant in the seven Ets sites. These lines have 20-fold reduced Cebpa mRNA when cultured in IL-3 or G-CSF, demonstrating a critical requirement for enhancer integrity for optimal Cebpa expression. In addition, these results indicate that the +37 kb Cebpa enhancer is the focus of multiple regulatory transcriptional pathways that impact its expression during normal hematopoiesis and potentially during myeloid transformation.

  9. Disorders of androgen action.

    PubMed

    Sultan, Charles; Lumbroso, Serge; Paris, Françoise; Jeandel, Claire; Terouanne, B; Belon, Charles; Audran, F; Poujol, N; Georget, V; Gobinet, J; Jalaguier, S; Auzou, G; Nicolas, J C

    2002-08-01

    Disorders of androgen action are the main cause of male pseudohermaphroditism and include 5alphaR deficiency and androgen receptor defects. 5alphaR deficiency is characterized by female genitalia with some degree of masculinization, clitoromegaly, and severely bifid scrotum corresponding to the so-called pseudovaginal perineoscrotal hypospadias. At the onset of puberty, increased muscle mass, development of pubic hair, and phallic growth are associated with the acquisition of male gender identity. Normal or increased levels of testosterone and an elevated testosterone-to-dihydrotestosterone ratio after human chorionic gonadotropin stimulation testing suggest 5alphareductase deficiency, and the diagnosis can be ascertained by identifying the mutation in the 5alphaR-2 gene. Whatever the patient's age at diagnosis, psychological evaluation with 5alphaRD is vital. Androgen receptor defects encompass two clinical expressions: the complete and partial androgen insensitivity syndromes. Complete androgen insensitivity syndrome should be suspected at birth in the presence of inguinal hernia in a girl without genital ambiguity. At puberty, the sign of alert is primary amenorrhea with normal female phenotype and harmonious mammary development but no pubic hair growth. Partial androgen insensitivity syndrome covers a wide spectrum of undervirilized phenotypes ranging from clitoromegaly at birth to infertile men. In all cases, complementary investigations should include plasma testosterone and luteinizing hormone as well as androgen-binding capacity in cultured genital skin fibroblasts. Diagnosis is confirmed by identification of the androgen receptor gene mutation. Although patients with complete androgen insensitivity syndrome are raised as females, patients with partial androgen insensitivity syndrome should be managed according to age at diagnosis, response to treatment with exogenous androgens, and the presence of an androgen gene mutation. Gonadectomy in complete androgen

  10. Pathway-based network modeling finds hidden genes in shRNA screen for regulators of acute lymphoblastic leukemia† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ib00040a Click here for additional data file. Click here for additional data file.

    PubMed Central

    Wilson, Jennifer L.; Dalin, Simona; Gosline, Sara; Hemann, Michael

    2016-01-01

    Data integration stands to improve interpretation of RNAi screens which, as a result of off-target effects, typically yield numerous gene hits of which only a few validate. These off-target effects can result from seed matches to unintended gene targets (reagent-based) or cellular pathways, which can compensate for gene perturbations (biology-based). We focus on the biology-based effects and use network modeling tools to discover pathways de novo around RNAi hits. By looking at hits in a functional context, we can uncover novel biology not identified from any individual ‘omics measurement. We leverage multiple ‘omic measurements using the Simultaneous Analysis of Multiple Networks (SAMNet) computational framework to model a genome scale shRNA screen investigating Acute Lymphoblastic Leukemia (ALL) progression in vivo. Our network model is enriched for cellular processes associated with hematopoietic differentiation and homeostasis even though none of the individual ‘omic sets showed this enrichment. The model identifies genes associated with the TGF-beta pathway and predicts a role in ALL progression for many genes without this functional annotation. We further experimentally validate the hidden genes – Wwp1, a ubiquitin ligase, and Hgs, a multi-vesicular body associated protein – for their role in ALL progression. Our ALL pathway model includes genes with roles in multiple types of leukemia and roles in hematological development. We identify a tumor suppressor role for Wwp1 in ALL progression. This work demonstrates that network integration approaches can compensate for off-target effects, and that these methods can uncover novel biology retroactively on existing screening data. We anticipate that this framework will be valuable to multiple functional genomic technologies – siRNA, shRNA, and CRISPR – generally, and will improve the utility of functional genomic studies. PMID:27315426

  11. Additive Similarity Trees

    ERIC Educational Resources Information Center

    Sattath, Shmuel; Tversky, Amos

    1977-01-01

    Tree representations of similarity data are investigated. Hierarchical clustering is critically examined, and a more general procedure, called the additive tree, is presented. The additive tree representation is then compared to multidimensional scaling. (Author/JKS)

  12. Action Research: Rethinking Lewin.

    ERIC Educational Resources Information Center

    Dickens, Linda; Watkins, Karen

    1999-01-01

    Explores both historical and contemporary definitions of action research. Describes the process and goals of action research in the tradition of Lewin. Presents a case study of an action-research project involving two teams in a high-technology corporation that depicts the process in action. (Author/CCM)

  13. Polyimide processing additives

    NASA Technical Reports Server (NTRS)

    Pratt, J. R.; St. Clair, T. L.; Burks, H. D.; Stoakley, D. M.

    1987-01-01

    A method has been found for enhancing the melt flow of thermoplastic polyimides during processing. A high molecular weight 422 copoly(amic acid) or copolyimide was fused with approximately 0.05 to 5 pct by weight of a low molecular weight amic acid or imide additive, and this melt was studied by capillary rheometry. Excellent flow and improved composite properties on graphite resulted from the addition of a PMDA-aniline additive to LARC-TPI. Solution viscosity studies imply that amic acid additives temporarily lower molecular weight and, hence, enlarge the processing window. Thus, compositions containing the additive have a lower melt viscosity for a longer time than those unmodified.

  14. [Food additives and healthiness].

    PubMed

    Heinonen, Marina

    2014-01-01

    Additives are used for improving food structure or preventing its spoilage, for example. Many substances used as additives are also naturally present in food. The safety of additives is evaluated according to commonly agreed principles. If high concentrations of an additive cause adverse health effects for humans, a limit of acceptable daily intake (ADI) is set for it. An additive is a risk only when ADI is exceeded. The healthiness of food is measured on the basis of nutrient density and scientifically proven effects.

  15. Attention and its coupling to action.

    PubMed

    Humphreys, Glyn W; Yoon, Eun Young; Kumar, Sanjay; Lestou, Vaia; Kitadono, Keiko; Roberts, Katherine L; Jane Riddoch, M

    2010-05-01

    We discuss two commentaries that we have received on our target article (Humphreys et al., 2010). We elaborate on the evidence for action effects on extinction and discuss whether these effects occur pre or post the selection of a response. In addition, we discuss the neural basis of the effects of action relations on extinction and on the generalization of results on action relations to real-world examples.

  16. The actions of in ovo cortisol on egg fertility, embryo development and the expression of growth-related genes in rainbow trout embryos, and the growth performance of juveniles.

    PubMed

    Li, Mao; Bureau, Dominique P; King, W Allan; Leatherland, John F

    2010-10-01

    Rainbow trout (Oncorhynchus mykiss) oocytes were incubated for 3 hr in ovarian fluid alone (CC), or cortisol-enriched ovarian fluid [100 or 1,000 ng ml(-1) (CL and CH, respectively)], after which they were fertilized; the growth and development of the embryos reared from these oocytes was monitored until first feed, and the juveniles were monitored for 9 months. The hatching rates of the CH group were significantly reduced, but the overall survival as measured at 40-week post-fertilization was similar in the three treatment groups. In addition, significant apparently biphasic changes relative to the CC group were found in the expression of some key growth-related genes in the CL and CH treatment groups, particularly IGF-1, IGF-2, GH1, GH2, GH receptors, and thyroid hormone receptors (TRα and TRβ). Moreover, the juveniles of the CL (but not the CH treatment group) exhibited enhanced growth; the enhanced growth could not be explained on the basis of increased feed conversion efficiency or changes in serum GH levels at the juvenile stage. Additionally, relative growth rates from the three treatment groups were similar, suggesting that the biphasic growth-enhancing effects of cortisol occurred very early in embryogenesis.

  17. Mechanism of action of and resistance to quinolones.

    PubMed

    Fàbrega, Anna; Madurga, Sergi; Giralt, Ernest; Vila, Jordi

    2009-01-01

    Fluoroquinolones are an important class of wide-spectrum antibacterial agents. The first quinolone described was nalidixic acid, which showed a narrow spectrum of activity. The evolution of quinolones to more potent molecules was based on changes at positions 1, 6, 7 and 8 of the chemical structure of nalidixic acid. Quinolones inhibit DNA gyrase and topoisomerase IV activities, two enzymes essential for bacteria viability. The acquisition of quinolone resistance is frequently related to (i) chromosomal mutations such as those in the genes encoding the A and B subunits of the protein targets (gyrA, gyrB, parC and parE), or mutations causing reduced drug accumulation, either by a decreased uptake or by an increased efflux, and (ii) quinolone resistance genes associated with plasmids have been also described, i.e. the qnr gene that encodes a pentapeptide, which blocks the action of quinolones on the DNA gyrase and topoisomerase IV; the aac(6')-Ib-cr gene that encodes an acetylase that modifies the amino group of the piperazin ring of the fluoroquinolones and efflux pump encoded by the qepA gene that decreases intracellular drug levels. These plasmid-mediated mechanisms of resistance confer low levels of resistance but provide a favourable background in which selection of additional chromosomally encoded quinolone resistance mechanisms can occur.

  18. Words and actions.

    PubMed

    Kissling, F

    1999-01-01

    This is an editorial that appeared in the journal Conscience. Church leaders have long employed a rhetoric that stigmatizes those who perform abortions and women who have abortions. According to many men in the Church, women who have abortions are either mindless victims or are devoid of moral sensibility. In addition to treating abortion as if it were murder, church leaders also brand it as evil. With this kind of language coming from the church, British Columbia Catholic editor Paul Schratz's assertion that something positive might come from killing a doctor who has provided an abortion can hardly be seen as aberrant. Presently, the reaction of those engaged in the abortion wars is to reject any notion that their language contributes in any way to murders, injuries, and bombings. But language leads to action and violent rhetoric can engender violent deeds.

  19. Inferences about Action Engage Action Systems

    ERIC Educational Resources Information Center

    Taylor, Lawrence J.; Lev-Ari, Shiri; Zwaan, Rolf A.

    2008-01-01

    Verbal descriptions of actions activate compatible motor responses [Glenberg, A. M., & Kaschak, M. P. (2002). Grounding language in action. "Psychonomic Bulletin & Review, 9", 558-565]. Previous studies have found that the motor processes for manual rotation are engaged in a direction-specific manner when a verb disambiguates the direction of…

  20. The SU(2) action-angle variables

    NASA Technical Reports Server (NTRS)

    Ellinas, Demosthenes

    1993-01-01

    Operator angle-action variables are studied in the frame of the SU(2) algebra, and their eigenstates and coherent states are discussed. The quantum mechanical addition of action-angle variables is shown to lead to a noncommutative Hopf algebra. The group contraction is used to make the connection with the harmonic oscillator.

  1. 75 FR 52724 - Procurement List Additions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-27

    .... Services Service Type/Location: Custodial Service, National Weather Service, 587 Aero Drive, Buffalo, NY... action adds products and services to the Procurement List that will be furnished by nonprofit agencies... the products and services and impact of the additions on the current or most recent contractors,...

  2. 75 FR 72815 - Procurement List Additions

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    2010-11-26

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  3. 78 FR 16476 - Procurement List Additions

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-15

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  4. Polylactides in additive biomanufacturing.

    PubMed

    Poh, Patrina S P; Chhaya, Mohit P; Wunner, Felix M; De-Juan-Pardo, Elena M; Schilling, Arndt F; Schantz, Jan-Thorsten; van Griensven, Martijn; Hutmacher, Dietmar W

    2016-12-15

    New advanced manufacturing technologies under the alias of additive biomanufacturing allow the design and fabrication of a range of products from pre-operative models, cutting guides and medical devices to scaffolds. The process of printing in 3 dimensions of cells, extracellular matrix (ECM) and biomaterials (bioinks, powders, etc.) to generate in vitro and/or in vivo tissue analogue structures has been termed bioprinting. To further advance in additive biomanufacturing, there are many aspects that we can learn from the wider additive manufacturing (AM) industry, which have progressed tremendously since its introduction into the manufacturing sector. First, this review gives an overview of additive manufacturing and both industry and academia efforts in addressing specific challenges in the AM technologies to drive toward AM-enabled industrial revolution. After which, considerations of poly(lactides) as a biomaterial in additive biomanufacturing are discussed. Challenges in wider additive biomanufacturing field are discussed in terms of (a) biomaterials; (b) computer-aided design, engineering and manufacturing; (c) AM and additive biomanufacturing printers hardware; and (d) system integration. Finally, the outlook for additive biomanufacturing was discussed.

  5. Additive Manufactured Product Integrity

    NASA Technical Reports Server (NTRS)

    Waller, Jess; Wells, Doug; James, Steve; Nichols, Charles

    2017-01-01

    NASA is providing key leadership in an international effort linking NASA and non-NASA resources to speed adoption of additive manufacturing (AM) to meet NASA's mission goals. Participants include industry, NASA's space partners, other government agencies, standards organizations and academia. Nondestructive Evaluation (NDE) is identified as a universal need for all aspects of additive manufacturing.

  6. The interaction of attention and action: from seeing action to acting on perception.

    PubMed

    Humphreys, Glyn W; Yoon, Eun Young; Kumar, Sanjay; Lestou, Vaia; Kitadono, Keiko; Roberts, Katherine L; Riddoch, M Jane

    2010-05-01

    We discuss evidence indicating that human visual attention is strongly modulated by the potential of objects for action. The possibility of action between multiple objects enables the objects to be attended as a single group, and the fit between individual objects in a group and the action that can be performed influences responses to group members. In addition, having a goal state to perform a particular action affects the stimuli that are selected along with the features and area of space that is attended. These effects of action may reflect statistical learning between environmental cues that are linked by action and/or the coupling between perception and action systems in the brain. The data support the argument that visual selection is a flexible process that emerges as a need to prioritize objects for action.

  7. Methyl Jasmonate Regulates Podophyllotoxin Accumulation in Podophyllum hexandrum by Altering the ROS-Responsive Podophyllotoxin Pathway Gene Expression Additionally through the Down Regulation of Few Interfering miRNAs.

    PubMed

    Hazra, Saptarshi; Bhattacharyya, Dipto; Chattopadhyay, Sharmila

    2017-01-01

    Podophylloxin (ptox), primarily obtained from Podophyllum hexandrum, is the precursor for semi-synthetic anticancer drugs viz. etoposide, etopophos, and teniposide. Previous studies established that methyl jasmonate (MeJA) treated cell culture of P. hexandrum accumulate ptox significantly. However, the molecular mechanism of MeJA induced ptox accumulation is yet to be explored. Here, we demonstrate that MeJA induces reactive oxygen species (ROS) production, which stimulates ptox accumulation significantly and up regulates three ROS-responsive ptox biosynthetic genes, namely, PhCAD3, PhCAD4 (cinnamyl alcohol dehydrogenase), and NAC3 by increasing their mRNA stability. Classic uncoupler of oxidative phosphorylation, carbonylcyanide m-chlorophenylhydrazone, as well as H2O2 treatment induced the ROS generation and consequently, enhanced the ptox production. However, when the ROS was inhibited with NADPH oxidase inhibitor diphenylene iodonium and Superoxide dismutase inhibitor diethyldithio-carbamic acid, the ROS inhibiting agent, the ptox production was decreased significantly. We also noted that, MeJA up regulated other ptox biosynthetic pathway genes which are not affected by the MeJA induced ROS. Further, these ROS non-responsive genes were controlled by MeJA through the down regulation of five secondary metabolites biosynthesis specific miRNAs viz. miR172i, miR035, miR1438, miR2275, and miR8291. Finally, this study suggested two possible mechanisms through which MeJA modulates the ptox biosynthesis: primarily by increasing the mRNA stability of ROS-responsive genes and secondly, by the up regulation of ROS non-responsive genes through the down regulation of some ROS non-responsive miRNAs.

  8. Methyl Jasmonate Regulates Podophyllotoxin Accumulation in Podophyllum hexandrum by Altering the ROS-Responsive Podophyllotoxin Pathway Gene Expression Additionally through the Down Regulation of Few Interfering miRNAs

    PubMed Central

    Hazra, Saptarshi; Bhattacharyya, Dipto; Chattopadhyay, Sharmila

    2017-01-01

    Podophylloxin (ptox), primarily obtained from Podophyllum hexandrum, is the precursor for semi-synthetic anticancer drugs viz. etoposide, etopophos, and teniposide. Previous studies established that methyl jasmonate (MeJA) treated cell culture of P. hexandrum accumulate ptox significantly. However, the molecular mechanism of MeJA induced ptox accumulation is yet to be explored. Here, we demonstrate that MeJA induces reactive oxygen species (ROS) production, which stimulates ptox accumulation significantly and up regulates three ROS-responsive ptox biosynthetic genes, namely, PhCAD3, PhCAD4 (cinnamyl alcohol dehydrogenase), and NAC3 by increasing their mRNA stability. Classic uncoupler of oxidative phosphorylation, carbonylcyanide m-chlorophenylhydrazone, as well as H2O2 treatment induced the ROS generation and consequently, enhanced the ptox production. However, when the ROS was inhibited with NADPH oxidase inhibitor diphenylene iodonium and Superoxide dismutase inhibitor diethyldithio-carbamic acid, the ROS inhibiting agent, the ptox production was decreased significantly. We also noted that, MeJA up regulated other ptox biosynthetic pathway genes which are not affected by the MeJA induced ROS. Further, these ROS non-responsive genes were controlled by MeJA through the down regulation of five secondary metabolites biosynthesis specific miRNAs viz. miR172i, miR035, miR1438, miR2275, and miR8291. Finally, this study suggested two possible mechanisms through which MeJA modulates the ptox biosynthesis: primarily by increasing the mRNA stability of ROS-responsive genes and secondly, by the up regulation of ROS non-responsive genes through the down regulation of some ROS non-responsive miRNAs. PMID:28261233

  9. Objects tell us what action we can expect: dissociating brain areas for retrieval and exploitation of action knowledge during action observation in fMRI

    PubMed Central

    Schubotz, Ricarda I.; Wurm, Moritz F.; Wittmann, Marco K.; von Cramon, D. Yves

    2014-01-01

    Objects are reminiscent of actions often performed with them: knife and apple remind us on peeling the apple or cutting it. Mnemonic representations of object-related actions (action codes) evoked by the sight of an object may constrain and hence facilitate recognition of unrolling actions. The present fMRI study investigated if and how action codes influence brain activation during action observation. The average number of action codes (NAC) of 51 sets of objects was rated by a group of n = 24 participants. In an fMRI study, different volunteers were asked to recognize actions performed with the same objects presented in short videos. To disentangle areas reflecting the storage of action codes from those exploiting them, we showed object-compatible and object-incompatible (pantomime) actions. Areas storing action codes were considered to positively co-vary with NAC in both object-compatible and object-incompatible action; due to its role in tool-related tasks, we here hypothesized left anterior inferior parietal cortex (aIPL). In contrast, areas exploiting action codes were expected to show this correlation only in object-compatible but not incompatible action, as only object-compatible actions match one of the active action codes. For this interaction, we hypothesized ventrolateral premotor cortex (PMv) to join aIPL due to its role in biasing competition in IPL. We found left anterior intraparietal sulcus (IPS) and left posterior middle temporal gyrus (pMTG) to co-vary with NAC. In addition to these areas, action codes increased activity in object-compatible action in bilateral PMv, right IPS, and lateral occipital cortex (LO). Findings suggest that during action observation, the brain derives possible actions from perceived objects, and uses this information to shape action recognition. In particular, the number of expectable actions quantifies the activity level at PMv, IPL, and pMTG, but only PMv reflects their biased competition while observed action unfolds

  10. Action plan for the Tiger Team assessment report

    SciTech Connect

    Not Available

    1990-08-30

    This document contains responses and planned actions that address the findings of the Tiger Team Assessment of Brookhaven National Laboratory, June 1990. In addition, the document contains descriptions of the management and organizational structure to be used in conducting planned actions, root causes for the problems identified in the findings, responses, planned actions, schedules and milestones for completing planned actions, and, where known, costs associated with planned actions.

  11. From genes to brain development to phenotypic behavior: "dorsal-stream vulnerability" in relation to spatial cognition, attention, and planning of actions in Williams syndrome (WS) and other developmental disorders.

    PubMed

    Atkinson, Janette; Braddick, Oliver

    2011-01-01

    Visual information is believed to be processed through two distinct, yet interacting cortical streams. The ventral stream performs the computations needed for recognition of objects and faces ("what" and "who"?) and the dorsal stream the computations for registering spatial relationships and for controlling visually guided actions ("where" and "how"?). We initially proposed a model of spatial deficits in Williams syndrome (WS) in which visual abilities subserved by the ventral stream, such as face recognition, are relatively well developed (although not necessarily in exactly the same way as in typical development), whereas dorsal-stream functions, such as visuospatial actions, are markedly impaired. Since these initial findings in WS, deficits of motion coherence sensitivity, a dorsal-stream function has been found in other genetic disorders such as Fragile X and autism, and as a consequence of perinatal events (in hemiplegia, perinatal brain anomalies following very premature birth), leading to the proposal of a general "dorsal-stream vulnerability" in many different conditions of abnormal human development. In addition, dorsal-stream systems provide information used in tasks of visuospatial memory and locomotor planning, and these systems are closely coupled to networks for attentional control. We and several other research groups have previously shown deficits of frontal and parietal lobe function in WS individuals for specific attention tasks [e.g., Atkinson, J., Braddick, O., Anker, S., Curran, W., & Andrew, R. (2003). Neurobiological models of visuospatial cognition in children with Williams Syndrome: Measures of dorsal-stream and frontal function. Developmental Neuropsychology, 23(1/2), 141-174.]. We have used the Test of Everyday Attention for Children (TEA-Ch) which aims to attempt to separate components of attention with distinct brain networks (selective attention, sustained attention, and attention control-executive function) testing a group of older

  12. Polyimide processing additives

    NASA Technical Reports Server (NTRS)

    Fletcher, James C. (Inventor); Pratt, J. Richard (Inventor); St.clair, Terry L. (Inventor); Stoakley, Diane M. (Inventor); Burks, Harold D. (Inventor)

    1992-01-01

    A process for preparing polyimides having enhanced melt flow properties is described. The process consists of heating a mixture of a high molecular weight poly-(amic acid) or polyimide with a low molecular weight amic acid or imide additive in the range of 0.05 to 15 percent by weight of additive. The polyimide powders so obtained show improved processability, as evidenced by lower melt viscosity by capillary rheometry. Likewise, films prepared from mixtures of polymers with additives show improved processability with earlier onset of stretching by TMA.

  13. Polyimide processing additives

    NASA Technical Reports Server (NTRS)

    Pratt, J. Richard (Inventor); St.clair, Terry L. (Inventor); Stoakley, Diane M. (Inventor); Burks, Harold D. (Inventor)

    1993-01-01

    A process for preparing polyimides having enhanced melt flow properties is described. The process consists of heating a mixture of a high molecular weight poly-(amic acid) or polyimide with a low molecular weight amic acid or imide additive in the range of 0.05 to 15 percent by weight of the additive. The polyimide powders so obtained show improved processability, as evidenced by lower melt viscosity by capillary rheometry. Likewise, films prepared from mixtures of polymers with additives show improved processability with earlier onset of stretching by TMA.

  14. Set Goals & Select Actions

    EPA Pesticide Factsheets

    This phase of the Local Climate Action Framework will help users articulate the goals for their climate, energy, and sustainability programs, as well as to identify the actions that are most appropriate to help meet those goals.

  15. American Lead Action Memorandum

    EPA Pesticide Factsheets

    ACTION MEMORANDUM— Request for a Time-Critical Removal Action andExemption from the $2 Million and 12-Month Statutory Limits at the AmericanLead Site, Indianapolis, Marion County, Indiana (Site ID #B56J)

  16. Food Additives and Hyperkinesis

    ERIC Educational Resources Information Center

    Wender, Ester H.

    1977-01-01

    The hypothesis that food additives are causally associated with hyperkinesis and learning disabilities in children is reviewed, and available data are summarized. Available from: American Medical Association 535 North Dearborn Street Chicago, Illinois 60610. (JG)

  17. Smog control fuel additives

    SciTech Connect

    Lundby, W.

    1993-06-29

    A method is described of controlling, reducing or eliminating, ozone and related smog resulting from photochemical reactions between ozone and automotive or industrial gases comprising the addition of iodine or compounds of iodine to hydrocarbon-base fuels prior to or during combustion in an amount of about 1 part iodine per 240 to 10,000,000 parts fuel, by weight, to be accomplished by: (a) the addition of these inhibitors during or after the refining or manufacturing process of liquid fuels; (b) the production of these inhibitors for addition into fuel tanks, such as automotive or industrial tanks; or (c) the addition of these inhibitors into combustion chambers of equipment utilizing solid fuels for the purpose of reducing ozone.

  18. Gravitational action with null boundaries

    NASA Astrophysics Data System (ADS)

    Lehner, Luis; Myers, Robert C.; Poisson, Eric; Sorkin, Rafael D.

    2016-10-01

    We present a complete discussion of the boundary term in the action functional of general relativity when the boundary includes null segments in addition to the more usual timelike and spacelike segments. We confirm that ambiguities appear in the contribution from a null segment, because it depends on an arbitrary choice of parametrization for the generators. We also show that similar ambiguities appear in the contribution from a codimension-two surface at which a null segment is joined to another (spacelike, timelike, or null) segment. The parametrization ambiguity can be tamed by insisting that the null generators be affinely parametrized; this forces each null contribution to the boundary action to vanish, but leaves intact the fredom to rescale the affine parameter by a constant factor on each generator. Once a choice of parametrization is made, the ambiguity in the joint contributions can be eliminated by formulating well-motivated rules that ensure the additivity of the gravitational action. Enforcing these rules, we calculate the time rate of change of the action when it is evaluated for a so-called "Wheeler-DeWitt patch" of a black hole in asymptotically anti de Sitter space. We recover a number of results cited in the literature, obtained with a less complete analysis.

  19. Clinical actionability enhanced through deep targeted sequencing of solid tumors

    PubMed Central

    Chen, Ken; Meric-Bernstam, Funda; Zhao, Hao; Zhang, Qingxiu; Ezzeddine, Nader; Tang, Lin-ya; Qi, Yuan; Mao, Yong; Chen, Tenghui; Chong, Zechen; Zhou, Wanding; Zheng, Xiaofeng; Johnson, Amber; Aldape, Kenneth D.; Routbort, Mark J.; Luthra, Rajyalakshmi; Kopetz, Scott; Davies, Michael A.; de Groot, John; Moulder, Stacy; Vinod, Ravi; Farhangfar, Carol J.; Shaw, Kenna Mills; Mendelsohn, John; Mills, Gordon B.; Eterovic, Agda Karina

    2015-01-01

    Background Further advances of targeted cancer therapy require comprehensive in-depth profiling of somatic mutations that are present in subpopulations of tumor cells in a clinical tumor sample. However, it is unclear to what extent such intra-tumor heterogeneity is present and whether it may affect clinical decision making. To unravel this challenge, we established a deep targeted sequencing platform to identify potentially actionable DNA alterations in tumor samples. Methods We assayed 515 FFPE tumor samples and matched germline (475 patients) from 11 disease sites by capturing and sequencing all the exons in 201 cancer related genes. Mutations, indels and copy number data were reported. Results We obtained a 1000-fold average sequencing depth and identified 4794 non-synonymous mutations in the samples analyzed, which 15.2% were present at less than 10% allele frequency. Most of these low level mutations occurred at known oncogenic hotspots and are likely functional. Identifying low level mutations improved identification of mutations in actionable genes in 118 (24.84%) patients, among which 47 (9.8%) would otherwise be unactionable. In addition, acquiring ultra-high depth also ensured a low false discovery rate (less than 2.2%) from FFPE samples. Conclusion Our results were as accurate as a commercially available CLIA-compliant hotspot panel, but allowed the detection of a higher number of mutations in actionable genes. Our study revealed the critical importance of acquiring and utilizing high depth in profiling clinical tumor samples and presented a very useful platform for implementing routine sequencing in a cancer care institution. PMID:25626406

  20. Action in Development

    ERIC Educational Resources Information Center

    von Hofsten, Claes

    2007-01-01

    It is argued that cognitive development has to be understood in the functional perspective provided by actions. Actions reflect all aspects of cognitive development including the motives of the child, the problems to be solved, and the constraints and possibilities of the child's body and sensorimotor system. Actions are directed into the future…

  1. Putting Action in Perspective

    ERIC Educational Resources Information Center

    Lozano, Sandra C.; Hard, Bridgette Martin; Tversky, Barbara

    2007-01-01

    Embodied approaches to cognition propose that our own actions influence our understanding of the world. Do other people's actions also have this influence? The present studies show that perceiving another person's actions changes the way people think about objects in a scene. In Study 1, participants viewed a photograph and answered a question…

  2. Action Learning at Work.

    ERIC Educational Resources Information Center

    Mumford, Alan, Ed.

    This book contains 34 papers examining the theory, process, and outcomes of action learning at work. The following papers are included: "An Introduction to the Text" (Alan Mumford); "The Learning Equation" (Reg Revans); "Action Learning as a Vehicle for Learning" (Alan Mumford); "Placing Action Learning and…

  3. Conservation Action Handbook.

    ERIC Educational Resources Information Center

    National Rifle Association, Washington, DC.

    Conservation problems are identified, with some suggestions for action. General areas covered are: Wildlife Conservation, Soil Conservation, Clean Water, Air Pollution Action, and Outdoor Recreation Action. Appendices list private organizations or agencies concerned with natural resource use and/or management, congressional committees considering…

  4. Planning as Action Research

    ERIC Educational Resources Information Center

    de Gonzalez, Carmen Beatriz; Hernandez, Teresa; Kusch, Jim; Ryan, Charly

    2004-01-01

    Planning contains so much more than the written plan. Early in 2000, an invitation came from the Collaborative Action Research Network (CARN), to people experienced in action research who might want to help plan and present an action research event for elementary school science teachers in Venezuela, South America, in Autumn 2000. This article…

  5. Participatory Action Research.

    ERIC Educational Resources Information Center

    Walker, Martha Lentz

    1993-01-01

    Describes aspects of participatory action research and considers advantages of using participatory action research in research by disabilities and rehabilitation researchers. Notes that participatory action research can be built into any rehabilitation research design but that it rests upon the recognition of persons with disabilities as integral…

  6. Group Sparse Additive Models

    PubMed Central

    Yin, Junming; Chen, Xi; Xing, Eric P.

    2016-01-01

    We consider the problem of sparse variable selection in nonparametric additive models, with the prior knowledge of the structure among the covariates to encourage those variables within a group to be selected jointly. Previous works either study the group sparsity in the parametric setting (e.g., group lasso), or address the problem in the nonparametric setting without exploiting the structural information (e.g., sparse additive models). In this paper, we present a new method, called group sparse additive models (GroupSpAM), which can handle group sparsity in additive models. We generalize the ℓ1/ℓ2 norm to Hilbert spaces as the sparsity-inducing penalty in GroupSpAM. Moreover, we derive a novel thresholding condition for identifying the functional sparsity at the group level, and propose an efficient block coordinate descent algorithm for constructing the estimate. We demonstrate by simulation that GroupSpAM substantially outperforms the competing methods in terms of support recovery and prediction accuracy in additive models, and also conduct a comparative experiment on a real breast cancer dataset.

  7. Additive Manufacturing Infrared Inspection

    NASA Technical Reports Server (NTRS)

    Gaddy, Darrell

    2014-01-01

    Additive manufacturing is a rapid prototyping technology that allows parts to be built in a series of thin layers from plastic, ceramics, and metallics. Metallic additive manufacturing is an emerging form of rapid prototyping that allows complex structures to be built using various metallic powders. Significant time and cost savings have also been observed using the metallic additive manufacturing compared with traditional techniques. Development of the metallic additive manufacturing technology has advanced significantly over the last decade, although many of the techniques to inspect parts made from these processes have not advanced significantly or have limitations. Several external geometry inspection techniques exist such as Coordinate Measurement Machines (CMM), Laser Scanners, Structured Light Scanning Systems, or even traditional calipers and gages. All of the aforementioned techniques are limited to external geometry and contours or must use a contact probe to inspect limited internal dimensions. This presentation will document the development of a process for real-time dimensional inspection technique and digital quality record of the additive manufacturing process using Infrared camera imaging and processing techniques.

  8. Response to selection in finite locus models with non-additive effects.

    PubMed

    Esfandyari, Hadi; Henryon, Mark; Berg, Peer; Thomasen, Jorn Rind; Bijma, Piter; Sørensen, Anders Christian

    2017-01-12

    Under the finite-locus model in the absence of mutation, the additive genetic variation is expected to decrease when directional selection is acting on a population, according to quantitative-genetic theory. However, some theoretical studies of selection suggest that the level of additive variance can be sustained or even increased when non-additive genetic effects are present. We tested the hypothesis that finite-locus models with both additive and non-additive genetic effects maintain more additive genetic variance (V_A) and realize larger medium-to-long term genetic gains than models with only additive effects when the trait under selection is subject to truncation selection. Four genetic models that included additive, dominance, and additive-by-additive epistatic effects were simulated. The simulated genome for individuals consisted of 25 chromosomes, each with a length of 1M. One hundred bi-allelic QTL, four on each chromosome, were considered. In each generation, 100 sires and 100 dams were mated, producing five progeny per mating. The population was selected for a single trait (h(2)=0.1) for 100 discrete generations with selection on phenotype or BLUP-EBV. V_A decreased with directional truncation selection even in presence of non-additive genetic effects. Non-additive effects influenced long-term response to selection and among genetic models additive gene action had highest response to selection. In addition, in all genetic models, BLUP-EBV resulted in a greater fixation of favourable and unfavourable alleles and higher response than phenotypic selection. In conclusion, for the schemes we simulated, the presence of non-additive genetic effects had little effect in changes of additive variance and V_A decreased by directional selection.

  9. Phenylethynyl Containing Reactive Additives

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Smith, Joseph G., Jr. (Inventor); Hergenrother, Paul M. (Inventor)

    2002-01-01

    Phenylethynyl containing reactive additives were prepared from aromatic diamine, containing phenylethvnvl groups and various ratios of phthalic anhydride and 4-phenylethynviphthalic anhydride in glacial acetic acid to form the imide in one step or in N-methyl-2-pvrrolidinone to form the amide acid intermediate. The reactive additives were mixed in various amounts (10% to 90%) with oligomers containing either terminal or pendent phenylethynyl groups (or both) to reduce the melt viscosity and thereby enhance processability. Upon thermal cure, the additives react and become chemically incorporated into the matrix and effect an increase in crosslink density relative to that of the host resin. This resultant increase in crosslink density has advantageous consequences on the cured resin properties such as higher glass transition temperature and higher modulus as compared to that of the host resin.

  10. Fused Lasso Additive Model

    PubMed Central

    Petersen, Ashley; Witten, Daniela; Simon, Noah

    2016-01-01

    We consider the problem of predicting an outcome variable using p covariates that are measured on n independent observations, in a setting in which additive, flexible, and interpretable fits are desired. We propose the fused lasso additive model (FLAM), in which each additive function is estimated to be piecewise constant with a small number of adaptively-chosen knots. FLAM is the solution to a convex optimization problem, for which a simple algorithm with guaranteed convergence to a global optimum is provided. FLAM is shown to be consistent in high dimensions, and an unbiased estimator of its degrees of freedom is proposed. We evaluate the performance of FLAM in a simulation study and on two data sets. Supplemental materials are available online, and the R package flam is available on CRAN. PMID:28239246

  11. Phenylethynyl Containing Reactive Additives

    NASA Technical Reports Server (NTRS)

    Connell, John W. (Inventor); Smith, Joseph G., Jr. (Inventor); Hergenrother, Paul M. (Inventor)

    2002-01-01

    Phenylethynyl containing reactive additives were prepared from aromatic diamines containing phenylethynyl groups and various ratios of phthalic anhydride and 4-phenylethynylphthalic anhydride in glacial acetic acid to form the imide in one step or in N-methyl-2-pyrrolidi none to form the amide acid intermediate. The reactive additives were mixed in various amounts (10% to 90%) with oligomers containing either terminal or pendent phenylethynyl groups (or both) to reduce the melt viscosity and thereby enhance processability. Upon thermal cure, the additives react and become chemically incorporated into the matrix and effect an increase in crosslink density relative to that of the host resin. This resultant increase in crosslink density has advantageous consequences on the cured resin properties such as higher glass transition temperature and higher modulus as compared to that of the host resin.

  12. Additives in plastics.

    PubMed Central

    Deanin, R D

    1975-01-01

    The polymers used in plastics are generally harmless. However, they are rarely used in pure form. In almost all commercial plastics, they are "compounded" with monomeric ingredients to improve their processing and end-use performance. In order of total volume used, these monomeric additives may be classified as follows: reinforcing fibers, fillers, and coupling agents; plasticizers; colorants; stabilizers (halogen stabilizers, antioxidants, ultraviolet absorbers, and biological preservatives); processing aids (lubricants, others, and flow controls); flame retardants, peroxides; and antistats. Some information is already available, and much more is needed, on potential toxicity and safe handling of these additives during processing and manufacture of plastics products. PMID:1175566

  13. Additives in plastics.

    PubMed

    Deanin, R D

    1975-06-01

    The polymers used in plastics are generally harmless. However, they are rarely used in pure form. In almost all commercial plastics, they are "compounded" with monomeric ingredients to improve their processing and end-use performance. In order of total volume used, these monomeric additives may be classified as follows: reinforcing fibers, fillers, and coupling agents; plasticizers; colorants; stabilizers (halogen stabilizers, antioxidants, ultraviolet absorbers, and biological preservatives); processing aids (lubricants, others, and flow controls); flame retardants, peroxides; and antistats. Some information is already available, and much more is needed, on potential toxicity and safe handling of these additives during processing and manufacture of plastics products.

  14. Gene therapy.

    PubMed

    Drugan, A; Miller, O J; Evans, M I

    1987-01-01

    Severe genetic disorders are potentially correctable by the addition of a normal gene into tissues. Although the technical problems involving integration, stable expression, and insertional damage to the treated cell are not yet fully solved, enough scientific progress has already been made to consider somatic cell gene therapy acceptable from both the ethical and scientific viewpoints. The resolutions to problems evolving from somatic cell gene therapy will help to overcome the technical difficulties encountered presently with germ line gene manipulation. This procedure would then become morally permissible as it will cause, in time, a reduction in the pool of abnormal genes in the population. Enhancement genetic engineering is technically feasible but morally unacceptable. Eugenic genetic engineering is not technically possible or ethically permissible in the foreseeable future.

  15. Representation of action in Parkinson's disease: imagining, observing, and naming actions.

    PubMed

    Poliakoff, Ellen

    2013-09-01

    People with Parkinson's disease (PD) exhibit slowed movements and difficulty in initiating movements. This review addresses the issue of whether or not cognitive representations of actions in PD are affected, alongside these motor problems. In healthy people, the motor system can be involved in tasks such as observing a graspable object or another person's action, or imagining and naming actions, in the absence of overt movement. As described in this review, the fact that the slowed real movements exhibited by PD patients are coupled with slower motor imagery and verb processing provides additional evidence for the involvement of the motor system in these processes. On the other hand, PD patients can still engage in motor imagery and action observation to some extent, which is encouraging for the use of these processes in rehabilitation. Findings across the different domains of action-representation reveal several important factors. First, the nature of action is critical: patients' performance in observation and naming tasks is influenced by whether or not the action is in their repertoire and by the extent of motion required to execute the action. Second, people with PD may use alternative or compensatory mechanisms to represent actions, such as relying more on a third-person perspective or a visual strategy. Third, people with PD show a lack of specificity, responding as strongly to stimuli related and unrelated to actions. Investigating action-representation in PD has implications for our understanding of both the symptoms of PD and the cognitive representation of actions in the healthy system.

  16. Genes and Gene Therapy

    MedlinePlus

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  17. Biobased lubricant additives

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fully biobased lubricants are those formulated using all biobased ingredients, i.e. biobased base oils and biobased additives. Such formulations provide the maximum environmental, safety, and economic benefits expected from a biobased product. Currently, there are a number of biobased base oils that...

  18. More Than Additional Space...

    ERIC Educational Resources Information Center

    CEFP Journal, 1973

    1973-01-01

    A much needed addition to the Jamestown Elementary School turned out to be more than an expansion of walls for more space. A new educational program, a limited budget, and a short time line were tackled on a team approach basis and were successfully resolved. (Author)

  19. Gene expression patterns in rainbow trout, Oncorhynchus mykiss, exposed to a suite of model toxicants.

    PubMed

    Hook, Sharon E; Skillman, Ann D; Small, Jack A; Schultz, Irvin R

    2006-05-25

    The increased availability and use of DNA microarrays has allowed the characterization of gene expression patterns associated with exposure to different toxicants. An important question is whether toxicant induced changes in gene expression in fish are sufficiently diverse to allow for identification of specific modes of action and/or specific contaminants. In theory, each class of toxicant may generate a gene expression profile unique to its mode of toxic action. In this study, isogenic (cloned) rainbow trout Oncorhynchus mykiss were exposed to sublethal levels of a series of model toxicants with varying modes of action, including ethynylestradiol (xeno-estrogen), 2,2,4,4'-tetrabromodiphenyl ether (BDE-47, thyroid active), diquat (oxidant stressor), chromium VI, and benzo[a]pyrene (BaP) for a period of 1-3 weeks. An additional experiment measured trenbolone (anabolic steroid; model androgen) induced gene expression changes in sexually mature female trout. Following exposure, fish were euthanized, livers removed and RNA extracted. Fluorescently labeled cDNA were generated and hybridized against a commercially available Atlantic Salmon/Trout array (GRASP project, University of Victoria) spotted with 16,000 cDNA's. The slides were scanned to measure abundance of a given transcript in each sample relative to controls. Data were analyzed via Genespring (Silicon Genetics) to identify a list of up- and downregulated genes, as well as to determine gene clustering patterns that can be used as "expression signatures". The results indicate each toxicant exposure caused between 64 and 222 genes to be significantly altered in expression. Most genes exhibiting altered expression responded to only one of the toxicants and relatively few were co-expressed in multiple treatments. For example, BaP and Diquat, both of which exert toxicity via oxidative stress, upregulated 28 of the same genes, of over 100 genes altered by either treatment. Other genes associated with steroidogenesis

  20. Vinyl capped addition polyimides

    NASA Technical Reports Server (NTRS)

    Vannucci, Raymond D. (Inventor); Malarik, Diane C. (Inventor); Delvigs, Peter (Inventor)

    1991-01-01

    Polyimide resins (PMR) are generally useful where high strength and temperature capabilities are required (at temperatures up to about 700 F). Polyimide resins are particularly useful in applications such as jet engine compressor components, for example, blades, vanes, air seals, air splitters, and engine casing parts. Aromatic vinyl capped addition polyimides are obtained by reacting a diamine, an ester of tetracarboxylic acid, and an aromatic vinyl compound. Low void materials with improved oxidative stability when exposed to 700 F air may be fabricated as fiber reinforced high molecular weight capped polyimide composites. The aromatic vinyl capped polyimides are provided with a more aromatic nature and are more thermally stable than highly aliphatic, norbornenyl-type end-capped polyimides employed in PMR resins. The substitution of aromatic vinyl end-caps for norbornenyl end-caps in addition polyimides results in polymers with improved oxidative stability.

  1. Electrophilic addition of astatine

    SciTech Connect

    Norseev, Yu.V.; Vasaros, L.; Nhan, D.D.; Huan, N.K.

    1988-03-01

    It has been shown for the first time that astatine is capable of undergoing addition reactions to unsaturated hydrocarbons. A new compound of astatine, viz., ethylene astatohydrin, has been obtained, and its retention numbers of squalane, Apiezon, and tricresyl phosphate have been found. The influence of various factors on the formation of ethylene astatohydrin has been studied. It has been concluded on the basis of the results obtained that the univalent cations of astatine in an acidic medium is protonated hypoastatous acid.

  2. Functional Generalized Additive Models.

    PubMed

    McLean, Mathew W; Hooker, Giles; Staicu, Ana-Maria; Scheipl, Fabian; Ruppert, David

    2014-01-01

    We introduce the functional generalized additive model (FGAM), a novel regression model for association studies between a scalar response and a functional predictor. We model the link-transformed mean response as the integral with respect to t of F{X(t), t} where F(·,·) is an unknown regression function and X(t) is a functional covariate. Rather than having an additive model in a finite number of principal components as in Müller and Yao (2008), our model incorporates the functional predictor directly and thus our model can be viewed as the natural functional extension of generalized additive models. We estimate F(·,·) using tensor-product B-splines with roughness penalties. A pointwise quantile transformation of the functional predictor is also considered to ensure each tensor-product B-spline has observed data on its support. The methods are evaluated using simulated data and their predictive performance is compared with other competing scalar-on-function regression alternatives. We illustrate the usefulness of our approach through an application to brain tractography, where X(t) is a signal from diffusion tensor imaging at position, t, along a tract in the brain. In one example, the response is disease-status (case or control) and in a second example, it is the score on a cognitive test. R code for performing the simulations and fitting the FGAM can be found in supplemental materials available online.

  3. Plan of action. Information.

    PubMed

    Leduc, J W

    1996-11-01

    This article provides information on WHO¿s strategic plan of action to aid countries around the world in detecting and controlling emerging infectious diseases. Activities are conducted through an organizational structure that ensures cost-sharing among all the 190 member states of WHO. Four major goals incorporating specific tasks are suggested: 1) the strengthening of global surveillance of infectious diseases through WHO collaborating centers; 2) the rebuilding of the international infrastructure to recognize, report, and respond to emerging and resurgent infectious diseases through laboratory and communication improvement 3) the fostering of applied research through greater practical use of the biotechnological revolution, and 4) the enhancement of the international capacity for infectious disease prevention and control through defined and practical public health steps. To implement this program, a workshop has been conducted and the WHONET program for laboratories has been introduced. In addition, clear guidance will be needed on the question of when to make changes in the antimicrobials recommended for specific diseases. The WHO strategy aims to enhance the capacity of local and national public health laboratories, to foster applied research to address practical problems, and to improve infectious disease prevention and control.

  4. Nonclassical vitamin D action.

    PubMed

    Zittermann, Armin; Gummert, Jan F

    2010-04-01

    It is becoming increasingly clear that vitamin D has a broad range of actions in the human body. Besides its well-known effects on calcium/phosphate homeostasis, vitamin D influences muscle function, cardiovascular homeostasis, nervous function, and the immune response. Vitamin D deficiency/insufficiency has been associated with muscle weakness and a high incidence of various chronic diseases such as cardiovascular disease, cancer, multiple sclerosis, and type 1 and 2 diabetes. Most importantly, low vitamin D status has been found to be an independent predictor of all-cause mortality. Several recent randomized controlled trials support the assumption that vitamin D can improve muscle strength, glucose homeostasis, and cardiovascular risk markers. In addition, vitamin D may reduce cancer incidence and elevated blood pressure. Since the prevalence of vitamin D deficiency/insufficiency is high throughout the world, there is a need to improve vitamin D status in the general adult population. However, the currently recommended daily vitamin D intake of 5-15 µg is too low to achieve an adequate vitamin D status in individuals with only modest skin synthesis. Thus, there is a need to recommend a vitamin D intake that is effective for achieving adequate circulating 25-hydroxyvitamin D concentrations (>75 nmol/L).

  5. Gene expression levels are correlated with synonymous codon usage, amino acid composition, and gene architecture in the red flour beetle, Tribolium castaneum.

    PubMed

    Williford, Anna; Demuth, Jeffery P

    2012-12-01

    Gene expression levels correlate with multiple aspects of gene sequence and gene structure in phylogenetically diverse taxa, suggesting an important role of gene expression levels in the evolution of protein-coding genes. Here we present results of a genome-wide study of the influence of gene expression on synonymous codon usage, amino acid composition, and gene structure in the red flour beetle, Tribolium castaneum. Consistent with the action of translational selection, we find that synonymous codon usage bias increases with gene expression. However, the correspondence between tRNA gene copy number and optimal codons is weak. At the amino acid level, translational selection is suggested by the positive correlation between tRNA gene numbers and amino acid usage, which is stronger for highly expressed genes. In addition, there is a clear trend for increased use of metabolically cheaper, less complex amino acids as gene expression increases. tRNA gene numbers also correlate negatively with amino acid size/complexity (S/C) score indicating the coupling between translational selection and selection to minimize the use of large/complex amino acids. Interestingly, the analysis of 10 additional genomes suggests that the correlation between tRNA gene numbers and amino acid S/C score is widespread and might be explained by selection against negative consequences of protein misfolding. At the level of gene structure, three major trends are detected: 1) complete coding region length increases across low and intermediate expression levels but decreases in highly expressed genes; 2) the average intron size shows the opposite trend, first decreasing with expression, followed by a slight increase in highly expressed genes; and 3) intron density remains nearly constant across all expression levels. These changes in gene architecture are only in partial agreement with selection favoring reduced cost of biosynthesis.

  6. National Biofuels Action Plan

    DTIC Science & Technology

    2008-10-01

    Leading the Federal Interagency Biomass Research and Development Initiative October 2008 National Biofuels Action Plan Biomass Research and...REPORT DATE OCT 2008 2. REPORT TYPE 3. DATES COVERED 00-00-2008 to 00-00-2008 4. TITLE AND SUBTITLE National Biofuels Action Plan 5a. CONTRACT...goal of the National Biofuels Action Plan is to maximize the environmental and economic benefi ts of biofuels use by advancing sustainable practices

  7. 78 FR 73434 - Food Additives Permitted for Direct Addition to Food for Human Consumption; Acacia (Gum Arabic)

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-06

    ... to Food for Human Consumption; Acacia (Gum Arabic) AGENCY: Food and Drug Administration, HHS. ACTION... regulations to provide for the expanded safe use of acacia (gum arabic) in foods. This action is in response... ] additive regulations in Sec. 172.780, Acacia (gum arabic) (21 CFR 172.780) to provide for the expanded...

  8. Stereoscopically Observing Manipulative Actions

    PubMed Central

    Ferri, S.; Pauwels, K.; Rizzolatti, G.; Orban, G. A.

    2016-01-01

    The purpose of this study was to investigate the contribution of stereopsis to the processing of observed manipulative actions. To this end, we first combined the factors “stimulus type” (action, static control, and dynamic control), “stereopsis” (present, absent) and “viewpoint” (frontal, lateral) into a single design. Four sites in premotor, retro-insular (2) and parietal cortex operated specifically when actions were viewed stereoscopically and frontally. A second experiment clarified that the stereo-action-specific regions were driven by actions moving out of the frontoparallel plane, an effect amplified by frontal viewing in premotor cortex. Analysis of single voxels and their discriminatory power showed that the representation of action in the stereo-action-specific areas was more accurate when stereopsis was active. Further analyses showed that the 4 stereo-action-specific sites form a closed network converging onto the premotor node, which connects to parietal and occipitotemporal regions outside the network. Several of the specific sites are known to process vestibular signals, suggesting that the network combines observed actions in peripersonal space with gravitational signals. These findings have wider implications for the function of premotor cortex and the role of stereopsis in human behavior. PMID:27252350

  9. Siloxane containing addition polyimides

    NASA Technical Reports Server (NTRS)

    Maudgal, S.; St. Clair, T. L.

    1984-01-01

    Addition polyimide oligomers have been synthesized from bis(gamma-aminopropyl) tetramethyldisiloxane and 3, 3', 4, 4'-benzophenonetetracarboxylic dianhydride using a variety of latent crosslinking groups as endcappers. The prepolymers were isolated and characterized for solubility (in amide, chlorinated and ether solvents), melt flow and cure properties. The most promising systems, maleimide and acetylene terminated prepolymers, were selected for detailed study. Graphite cloth reinforced composites were prepared and properties compared with those of graphite/Kerimid 601, a commercially available bismaleimide. Mixtures of the maleimide terminated system with Kerimid 601, in varying proportions, were also studied.

  10. Putting Actions in Context: Visual Action Adaptation Aftereffects Are Modulated by Social Contexts

    PubMed Central

    de la Rosa, Stephan; Streuber, Stephan; Giese, Martin; Bülthoff, Heinrich H.; Curio, Cristóbal

    2014-01-01

    The social context in which an action is embedded provides important information for the interpretation of an action. Is this social context integrated during the visual recognition of an action? We used a behavioural visual adaptation paradigm to address this question and measured participants’ perceptual bias of a test action after they were adapted to one of two adaptors (adaptation after-effect). The action adaptation after-effect was measured for the same set of adaptors in two different social contexts. Our results indicate that the size of the adaptation effect varied with social context (social context modulation) although the physical appearance of the adaptors remained unchanged. Three additional experiments provided evidence that the observed social context modulation of the adaptation effect are owed to the adaptation of visual action recognition processes. We found that adaptation is critical for the social context modulation (experiment 2). Moreover, the effect is not mediated by emotional content of the action alone (experiment 3) and visual information about the action seems to be critical for the emergence of action adaptation effects (experiment 4). Taken together these results suggest that processes underlying visual action recognition are sensitive to the social context of an action. PMID:24466123

  11. Food Additives Permitted for Direct Addition to Food for Human Consumption; Folic Acid. Final rule.

    PubMed

    2016-04-15

    The Food and Drug Administration (FDA or we) is amending the food additive regulations to provide for the safe use of folic acid in corn masa flour. We are taking this action in response to a food additive petition filed jointly by Gruma Corporation, Spina Bifida Association, March of Dimes Foundation, American Academy of Pediatrics, Royal DSM N.V., and National Council of La Raza.

  12. Integrating systems biology sources illuminates drug action

    PubMed Central

    Gottlieb, Assaf; Altman, Russ B.

    2014-01-01

    There are significant gaps in our understanding of the pathways by which drugs act. This incomplete knowledge limits our ability to use mechanistic molecular information rationally to repurpose drugs, understand their side effects, and predict their interactions with other drugs. Here we present DrugRouter: a novel method for generating drug-specific pathways of action by linking target genes, disease genes and pharmacogenes using gene interaction networks. We construct pathways for over a hundred drugs, and show that the genes included in our pathways (1) co-occur with the query drug in the literature, (2) significantly overlap or are adjacent to known drug-response pathways, and (3) are adjacent to genes that are hits in genome wide association studies assessing drug response. Finally, these computed pathways suggest novel drug repositioning opportunities (e.g., statins for follicular thyroid cancer), gene-side effect associations, and gene-drug interactions. Thus, DrugRouter generates hypotheses about drug actions using systems biology data. PMID:24577151

  13. Platelet additive solution - electrolytes.

    PubMed

    Azuma, Hiroshi; Hirayama, Junichi; Akino, Mitsuaki; Ikeda, Hisami

    2011-06-01

    Recent attention to solutions that replace most or all plasma in platelet concentrates, while maintaining satisfactory platelet function, is motivated by the potential of plasma reduction or depletion to mitigate various transfusion-related adverse events. This report considers the electrolytic composition of previously described platelet additive solutions, in order to draw general conclusions about what is required for platelet function and longevity. The optimal concentrations of Na(+) and Cl(-) are 69-115 mM. The presence of both K(+) and Mg(2+) in platelet suspension at nearly physiological concentrations (3-5mM and 1.5-3mM, respectively) is indispensable for good preservation capacity because both electrolytes are required to prevent platelet activation. In contrast to K(+) and Mg(2+), Ca(2+) may not be important because no free Ca(2+) is available in M-sol, which showed excellent platelet preservation capacity at less than 5% plasma concentration. The importance of bicarbonate (approximately 40 mM) can be recognized when the platelets are suspended in additive solution under less than 5% residual plasma concentration.

  14. Targeted gene repair: the ups and downs of a promising gene therapy approach.

    PubMed

    de Semir, David; Aran, Josep M

    2006-08-01

    As a novel form of molecular medicine based on direct actions over the genes, targeted gene repair has raised consideration recently above classical gene therapy strategies based on genetic augmentation or complementation. Targeted gene repair relies on the local induction of the cell's endogenous DNA repair mechanisms to attain a therapeutic gene conversion event within the genome of the diseased cell. Successful repair has been achieved both in vitro and in vivo with a variety of corrective molecules ranging from oligonucleotides (chimeraplasts, modified single-stranded oligonucleotides, triplex-forming oligonucleotides), to small DNA fragments (small fragment homologous replacement (SFHR)), and even viral vectors (AAV-based). However, controversy on the consistency and lack of reproducibility of early experiments regarding frequencies and persistence of targeted gene repair, particularly for chimeraplasty, has flecked the field. Nevertheless, several hurdles such as inefficient nuclear uptake of the corrective molecules, and misleading assessment of targeted repair frequencies have been identified and are being addressed. One of the key bottlenecks for exploiting the overall potential of the different targeted gene repair modalities is the lack of a detailed knowledge of their mechanisms of action at the molecular level. Several studies are now focusing on the assessment of the specific repair pathway(s) involved (homologous recombination, mismatch repair, etc.), devising additional strategies to increase their activity (using chemotherapeutic drugs, chimeric nucleases, etc.), and assessing the influence of the cell cycle in the regulation of the repair process. Until therapeutic correction frequencies for single gene disorders are reached both in cellular and animal models, precision and undesired side effects of this promising gene therapy approach will not be thoroughly evaluated.

  15. Gene interactions and genetics for yield and its attributes in grass pea (Lathyrus sativus L.).

    PubMed

    Parihar, A K; Dixit, G P; Singh, Deepak

    2016-12-01

    Grain yield is a complex character representing a multiplicative end product of many yield attributes. However, understanding the genetics and inheritance that underlies yield and its component characters pose a prerequisite to attain the actual yield potential of any crop species. The knowledge pertaining to gene actions and interactions is likely to direct and strengthen the crop breeding programmes. With this objective, the present investigation was undertaken by using six generations derived from three different crosses in grass pea. The study underscores the significance of additive-dominance model, gene action involved in inheritance of quantitative characters and heritability. Of note, nonallelic interactions influencing the traits were detected by both scaling test and joint scaling test, indicating the inadequacy of the additive-dominance model alone in explaining the manifestation of complex traits such as yield. Besides, additive (d) and dominance (h) gene effects, different types of interallelic interactions (i, j, l) contributed towards the inheritance of traits in the given crosses. Nevertheless, predominance of additive variance suggests a difference between homozygotes at a locus with positive and negative alleles being distributed between the parents. Duplicate epistasis was prevalent in most of the cases for traits like plant height, seeds/pod, 100-seed weight and pod width. In view of the diverse gene actions, i.e. additive, dominant and epistasis, playing important roles in the manifestation of complex traits like yield, we advocate implementation of population improvement techniques in particular reciprocal recurrent selection to improve productivity gains in grass pea.

  16. Caffeine's Vascular Mechanisms of Action

    PubMed Central

    Echeverri, Darío; Montes, Félix R.; Cabrera, Mariana; Galán, Angélica; Prieto, Angélica

    2010-01-01

    Caffeine is the most widely consumed stimulating substance in the world. It is found in coffee, tea, soft drinks, chocolate, and many medications. Caffeine is a xanthine with various effects and mechanisms of action in vascular tissue. In endothelial cells, it increases intracellular calcium stimulating the production of nitric oxide through the expression of the endothelial nitric oxide synthase enzyme. Nitric oxide is diffused to the vascular smooth muscle cell to produce vasodilation. In vascular smooth muscle cells its effect is predominantly a competitive inhibition of phosphodiesterase, producing an accumulation of cAMP and vasodilation. In addition, it blocks the adenosine receptors present in the vascular tissue to produce vasoconstriction. In this paper the main mechanisms of action of caffeine on the vascular tissue are described, in which it is shown that caffeine has some cardiovascular properties and effects which could be considered beneficial. PMID:21188209

  17. Additive composition, for gasoline

    SciTech Connect

    Vataru, M.

    1989-01-10

    An admixture is described that comprises Diesel fuel and an additive composition added thereto which is between about 0.05 to about 2.0 percent by weight of the fuel, the composition comprising: (a) between about 0.05 and 25% relative weight parts of an organic peroxide, and (b) between about 0.1 and 25% relative weight parts of detergent selected from the component group that consists of: (i) fatty amines; (ii) ethoxylated and propoxylated derivatives of fatty amines; (iii) fatty diamines; (iv) fatty imidazlines; (v) polymeric amines and derivatives thereof; (vi) combination of one or more of the (i) through (v) components with carboxylic acid or acids having from three to forth carbon atoms, (c) from about 99.0 to about 50% by weight of a hydrocarbon solvent.

  18. Teardrop bladder: additional considerations

    SciTech Connect

    Wechsler, R.J.; Brennan, R.E.

    1982-07-01

    Nine cases of teardrop bladder (TDB) seen at excretory urography are presented. In some of these patients, the iliopsoas muscles were at the upper limit of normal in size, and additional evaluation of the perivesical structures with computed tomography (CT) was necessary. CT demonstrated only hypertrophied muscles with or without perivesical fat. The psoas muscles and pelvic width were measured in 8 patients and compared with the measurements of a control group of males without TDB. Patients with TDB had large iliopsoas muscles and narrow pelves compared with the control group. The psoas muscle width/pelvic width ratio was significantly greater (p < 0.0005) in patients with TDB than in the control group, with values of 1.04 + 0.05 and 0.82 + 0.09, respectively. It is concluded that TDB is not an uncommon normal variant in black males. Both iliopsoas muscle hypertrophy and a narrow pelvis are factors that predispose a patient to TDB.

  19. New addition curing polyimides

    NASA Technical Reports Server (NTRS)

    Frimer, Aryeh A.; Cavano, Paul

    1991-01-01

    In an attempt to improve the thermal-oxidative stability (TOS) of PMR-type polymers, the use of 1,4-phenylenebis (phenylmaleic anhydride) PPMA, was evaluated. Two series of nadic end-capped addition curing polyimides were prepared by imidizing PPMA with either 4,4'-methylene dianiline or p-phenylenediamine. The first resulted in improved solubility and increased resin flow while the latter yielded a compression molded neat resin sample with a T(sub g) of 408 C, close to 70 C higher than PME-15. The performance of these materials in long term weight loss studies was below that of PMR-15, independent of post-cure conditions. These results can be rationalized in terms of the thermal lability of the pendant phenyl groups and the incomplete imidization of the sterically congested PPMA. The preparation of model compounds as well as future research directions are discussed.

  20. Perspectives on Additive Manufacturing

    NASA Astrophysics Data System (ADS)

    Bourell, David L.

    2016-07-01

    Additive manufacturing (AM) has skyrocketed in visibility commercially and in the public sector. This article describes the development of this field from early layered manufacturing approaches of photosculpture, topography, and material deposition. Certain precursors to modern AM processes are also briefly described. The growth of the field over the last 30 years is presented. Included is the standard delineation of AM technologies into seven broad categories. The economics of AM part generation is considered, and the impacts of the economics on application sectors are described. On the basis of current trends, the future outlook will include a convergence of AM fabricators, mass-produced AM fabricators, enabling of topology optimization designs, and specialization in the AM legal arena. Long-term developments with huge impact are organ printing and volume-based printing.

  1. Sewage sludge additive

    NASA Technical Reports Server (NTRS)

    Kalvinskas, J. J.; Mueller, W. A.; Ingham, J. D. (Inventor)

    1980-01-01

    The additive is for a raw sewage treatment process of the type where settling tanks are used for the purpose of permitting the suspended matter in the raw sewage to be settled as well as to permit adsorption of the dissolved contaminants in the water of the sewage. The sludge, which settles down to the bottom of the settling tank is extracted, pyrolyzed and activated to form activated carbon and ash which is mixed with the sewage prior to its introduction into the settling tank. The sludge does not provide all of the activated carbon and ash required for adequate treatment of the raw sewage. It is necessary to add carbon to the process and instead of expensive commercial carbon, coal is used to provide the carbon supplement.

  2. Global nutritional profiling for mutant and chemical mode-of-action analysis in filamentous fungi.

    PubMed

    Tanzer, Matthew M; Arst, Herbert N; Skalchunes, Amy R; Coffin, Marie; Darveaux, Blaise A; Heiniger, Ryan W; Shuster, Jeffrey R

    2003-12-01

    We describe a method for gene function discovery and chemical mode-of-action analysis via nutrient utilization using a high throughput Nutritional Profiling platform suitable for filamentous microorganisms. We have optimized the growth conditions for each fungal species to produce reproducible optical density growth measurements in microtiter plates. We validated the Nutritional Profiling platform using a nitrogen source utilization assay to analyze 21 Aspergillus nidulans strains with mutations in the master nitrogen regulatory gene, areA. Analysis of these data accurately reproduced expected results and provided new data to demonstrate that this platform is suitable for fine level phenotyping of filamentous fungi. Next, we analyzed the differential responses of two fungal species to a glutamine synthetase inhibitor, illustrating chemical mode-of-action analysis. Finally, a comparative phenotypic study was performed to characterize carbon catabolite repression in four fungal species using a carbon source utilization assay. The results demonstrate differentiation between two Aspergillus species and two diverse plant pathogens and provide a wealth of new data on fungal nutrient utilization. Thus, these assays can be used for gene function and chemical mode-of-action analysis at the whole organism level as well as interspecies comparisons in a variety of filamentous fungi. Additionally, because uniform distribution of growth within wells is maintained, comparisons between yeast and filamentous forms of a single organism can be performed.

  3. Action Learning in China

    ERIC Educational Resources Information Center

    Marquardt, Michael J.

    2015-01-01

    Action learning was introduced into China less than 20 years ago, but has rapidly become a valuable tool for organizations seeking to solve problems, develop their leaders, and become learning organizations. This article provides an historical overview of action learning in China, its cultural underpinnings, and five case studies. It concludes…

  4. Who Needs Affirmative Action.

    ERIC Educational Resources Information Center

    Ginger, Ann Fagan

    1979-01-01

    Affirmative action and reverse discrimination are discussed. Facts that were omitted from the court record on the Bakke case are examined. The need for encouraging minority students and women to continue to press for school admission and for lawyers to continue to press affirmative action suits is stressed. (MC)

  5. Renormalized action improvements

    SciTech Connect

    Zachos, C.

    1984-01-01

    Finite lattice spacing artifacts are suppressed on the renormalized actions. The renormalized action trajectories of SU(N) lattice gauge theories are considered from the standpoint of the Migdal-Kadanoff approximation. The minor renormalized trajectories which involve representations invariant under the center are discussed and quantified. 17 references.

  6. Training for Nonviolent Action.

    ERIC Educational Resources Information Center

    Olson, Theodore W.; Shivers, Lynne

    The theory and practice of nonviolent action training as it exists to date are reviewed in this pamphlet. A response to a renewal of interest in alternative forms of social action, the pamphlet results specifically from an international seminar of experienced organizers and trainers held at Preston Patrick, Westmorland, England, June 27 - July 2,…

  7. Affirmative Action Program Manual.

    ERIC Educational Resources Information Center

    Ventura County Community Coll. District, CA.

    Guidelines relating to the affirmative action program of the Ventura County Community College District are provided in this manual. Affirmative action is defined as, "A set of specific and result-oriented procedures to which a contractor commits himself/herself to apply every good faith effort. The objective of those procedures, plus such efforts,…

  8. 25 Action Learning Schools.

    ERIC Educational Resources Information Center

    National Association of Secondary School Principals, Reston, VA.

    This booklet on action-learning reflects an interest in preparing youth for the world of real experiences. Arranged in two major parts, the first offers information on the background and development of action-learning. Included in this section are the conclusions of the Panel on Youth of the President's Science Advisory Committee, the National…

  9. ACTION. 1977 Annual Report.

    ERIC Educational Resources Information Center

    ACTION, Washington, DC.

    In this report are described projects and activities undertaken by ACTION's volunteer programs in 1977. The first section concentrates on reviews conducted, including a major review of ACTION's domestic volunteer programs and the management systems supporting them and an assessment of its programs using the Zero-Base Budget approach called for by…

  10. Action Learning and Leadership.

    ERIC Educational Resources Information Center

    Marquardt, Michael J.

    2000-01-01

    Today's leaders perform the following roles: systems thinker, change agent, innovator, servant, polychronic coordinator, teacher-mentor, and visionary. The elements of action learning (real problems, teams, reflective inquiry, commitment to action, focus on learning) contribute to the development of these critical skills. (Author/SK)

  11. Handbook for Ecology Action.

    ERIC Educational Resources Information Center

    Eber, Ronald

    This handbook has been compiled to aid concerned individuals and ecology groups more adequately define their goals, initiate good programs, and take effective action. It examines the ways a group of working individuals can become involved in action programs for ecological change. Part 1 deals with organization, preliminary organizing, structuring,…

  12. Chiral Asymmetry and the Spectral Action

    NASA Astrophysics Data System (ADS)

    Pfäffle, Frank; Stephan, Christoph A.

    2013-07-01

    We consider orthogonal connections with arbitrary torsion on compact Riemannian manifolds. For the induced Dirac operators, twisted Dirac operators and Dirac operators of Chamseddine-Connes type we compute the spectral action. In addition to the Einstein-Hilbert action and the bosonic part of the Standard Model Lagrangian we find the Holst term from Loop Quantum Gravity, a coupling of the Holst term to the scalar curvature and a prediction for the value of the Barbero-Immirzi parameter.

  13. Reduced attentional capture in action video game players.

    PubMed

    Chisholm, Joseph D; Hickey, Clayton; Theeuwes, Jan; Kingstone, Alan

    2010-04-01

    Recent studies indicate that playing action video games improves performance on a number of attention-based tasks. However, it remains unclear whether action video game experience primarily affects endogenous or exogenous forms of spatial orienting. To examine this issue, action video game players and non-action video game players performed an attentional capture task. The results show that action video game players responded quicker than non-action video game players, both when a target appeared in isolation and when a salient, task-irrelevant distractor was present in the display. Action video game players additionally showed a smaller capture effect than did non-action video game players. When coupled with the findings of previous studies, the collective evidence indicates that extensive experience with action video games may enhance players' top-down attentional control, which, in turn, can modulate the negative effects of bottom-up attentional capture.

  14. The petunia MADS box gene FBP11 determines ovule identity.

    PubMed Central

    Colombo, L; Franken, J; Koetje, E; van Went, J; Dons, H J; Angenent, G C; van Tunen, A J

    1995-01-01

    In contrast to the wealth of information relating to genes regulating floral meristem and floral organ identity, only limited data are available concerning genes that are involved in determining and regulating the identity and development of an ovule. We have recently isolated the floral binding protein 11 (FBP11) MADS box gene from petunia and found that it is expressed exclusively in ovule primordia and subsequently in the ovules, suggesting a role for this gene in ovule formation. To test this hypothesis, we constructed a recombinant gene in which the full-size FBP11 cDNA was placed under the control of a strong cauliflower mosaic virus 35S promoter. Transgenic petunia plants expressing this chimeric gene have ovulelike structures on the adaxial side of the sepals and the abaxial side of the petals. Detailed morphological studies showed that these ovulelike structures are true ovules. RNA gel blot analysis was performed to investigate ectopic FBP11 expression in relation to the expression of the closely related FBP7 gene and the putative petunia class C-type homeotic genes FBP6 and pMADS3. Our results indicate that FBP11 represents an ovule identity gene. A new model describing the mode of action of FBP11 as an additional class D MADS box gene is presented. PMID:8535139

  15. Conscious Vision in Action.

    PubMed

    Briscoe, Robert; Schwenkler, John

    2015-09-01

    It is natural to assume that the fine-grained and highly accurate spatial information present in visual experience is often used to guide our bodily actions. Yet this assumption has been challenged by proponents of the Two Visual Systems Hypothesis (TVSH), according to which visuomotor programming is the responsibility of a "zombie" processing stream whose sources of bottom-up spatial information are entirely non-conscious (Clark, 2007, 2009; Goodale & Milner, 1992, 2004a; Milner & Goodale, 1995/2006, 2008). In many formulations of TVSH, the role of conscious vision in action is limited to "recognizing objects, selecting targets for action, and determining what kinds of action, broadly speaking, to perform" (Clark, 2007, p. 570). Our aim in this study is to show that the available evidence not only fails to support this dichotomous view but actually reveals a significant role for conscious vision in motor programming, especially for actions that require deliberate attention.

  16. Curvature and gravity actions for matrix models

    NASA Astrophysics Data System (ADS)

    Blaschke, Daniel N.; Steinacker, Harold

    2010-08-01

    We show how gravitational actions, in particular the Einstein-Hilbert action, can be obtained from additional terms in Yang-Mills matrix models. This is consistent with recent results on induced gravitational actions in these matrix models, realizing spacetime as four-dimensional brane solutions. It opens up the possibility for a controlled non-perturbative description of gravity through simple matrix models, with interesting perspectives for the problem of vacuum energy. The relation with UV/IR mixing and non-commutative gauge theory is discussed.

  17. Ceramics with Different Additives

    NASA Astrophysics Data System (ADS)

    Wang, Juanjuan; Feng, Lajun; Lei, Ali; Zhao, Kang; Yan, Aijun

    2014-09-01

    Li2CO3, MgCO3, BaCO3, and Bi2O3 dopants were introduced into CaCu3Ti4O12 (CCTO) ceramics in order to improve the dielectric properties. The CCTO ceramics were prepared by conventional solid-state reaction method. The phase structure, microstructure, and dielectric behavior were carefully investigated. The pure structure without any impurity phases can be confirmed by the x-ray diffraction patterns. Scanning Electron Microscopy (SEM) analysis illuminated that the grains of Ca0.90Li0.20Cu3Ti4O12 ceramics were greater than that of pure CCTO. It was important for the properties of the CCTO ceramics to study the additives in complex impedance spectroscopy. It was found that the Ca0.90Li0.20Cu3Ti4O12 ceramics had the higher permittivity (>45000), the lower dielectric loss (<0.025) than those of CCTO at 1 kHz at room temperature and good temperature stability from -30 to 75 °C.

  18. Corrective Action Investigation Plan for Corrective Action Unit 563: Septic Systems, Nevada Test Site, Nevada, with Errata Sheet, Revision 0

    SciTech Connect

    Alfred Wickline

    2007-01-01

    Corrective Action Unit 563, Septic Systems, is located in Areas 3 and 12 of the Nevada Test Site, which is 65 miles northwest of Las Vegas, Nevada. Corrective Action Unit 563 is comprised of the four corrective action sites (CASs) below: • 03-04-02, Area 3 Subdock Septic Tank • 03-59-05, Area 3 Subdock Cesspool • 12-59-01, Drilling/Welding Shop Septic Tanks • 12-60-01, Drilling/Welding Shop Outfalls These sites are being investigated because existing information on the nature and extent of potential contamination is insufficient to evaluate and recommend corrective action alternatives. Additional information will be obtained by conducting a corrective action investigation (CAI) before evaluating corrective action alternatives and selecting the appropriate corrective action for each CAS. The results of the field investigation will support a defensible evaluation of viable corrective action alternatives that will be presented in the Corrective Action Decision Document.

  19. Similarity of actions depends on the functionality of previously observed actions.

    PubMed

    Naber, Marnix; Eijgermans, Wessel; Herman, Anne-Sophie; Bergman, Annemiek; Hommel, Bernhard

    2016-05-01

    People have a tendency to imitate the behavior of others, sometimes even automatically. And yet, evidence suggests that many of our actions are controlled, mediated by current goals and careful considerations. Here, we investigated whether the observation and evaluation of previous actions of another person modulates the similarity of actions between people in present trials. We manipulated the functionality of a confederate's actions and the interactive context in 2 behavioral tasks, which consisted of games that participants played against a confederate or a virtual computer opponent. To measure effects of working memory load on imitation rates, participants additionally performed an easy or difficult auditory n-back task in parallel to the tasks. We show that participants occasionally produced rather bizarre and dysfunctional behavior when the confederate had done so as well. Even more importantly, results from both tasks show that participants most likely copied dysfunctional behavior in the present trial when the confederate performed functional actions in the previous trial. Thus, the positive evaluation of action consequences in previous trials increases the probability of similarity between the participant's and confederate's actions in present trials despite a chance to copy improper actions. Furthermore, we found a trend of increased action similarities when participants were under high working memory load in Experiment 1 but not in Experiment 2. These results suggest that copying an observed action is an efficient and effortless behavioral and social strategy to achieve similar goals as others, though with an increased risk of maladaptive behavior.

  20. Mixing kaons with mixed action chiral perturbation theory

    NASA Astrophysics Data System (ADS)

    Aubin, Christopher

    2006-12-01

    We calculate the neutral kaon mixing parameter, BK , to next-to-leading order in mixed action (domain-wall valence with staggered sea quarks) chiral perturbation theory. We find the expres- sion for BK in this mixed-action case only differs from the continuum partially quenched expres- sion by an additional analytic term. Additionally, in preparation for a lattice calculation of BK with a mixed action, we discuss quantitatively the effects of the taste violations as well as finite volume effects.

  1. Actions of prolactin on molecular research

    SciTech Connect

    Rillema, J.A.

    1987-01-01

    This book discusses the current understanding on the primary mechanisms by which prolactin regulates cellular proliferation and other metabolic processes (including gene expression) in its target cells. Reviews and analyzes information relative to the molecular events involved in the actions of prolactin on cells to provide a basis for determining the sequence of molecular reactions by which prolactin expresses its biological responses. The contents discussed are Activation of Molecular Events by Prolactin. Prolactin Interaction with its Receptors and Relationship to Subsequent Regulation of Metabolic Processes. Actions of Prolactin in the Brain. Models of Prolactin Action in Nonmmalian Vertebraes. Prolactin Regulation of Membrane Fludity and Prostglandin Formation. Role of Calcium Ions and Phospholipids in Prolactin Regulation of its Traget Cells. Synergistic Actions of Glucocorticoid and Prolactin in Murine Milk-Protein Gene Expression. Role of Polyamines in Prolactin Actions. Prolactin and the Regulation of Secretion Including Membrane Flow: Potential Roles for Tubulin and Microtubules. Protein Phosphorylation of Prlactin Target Tissue: Mammary Gland, Prolactin, Growth Factors, and Cell Growth.

  2. Role of Tet1 and 5-hydroxymethylcytosine in cocaine action.

    PubMed

    Feng, Jian; Shao, Ningyi; Szulwach, Keith E; Vialou, Vincent; Huynh, Jimmy; Zhong, Chun; Le, Thuc; Ferguson, Deveroux; Cahill, Michael E; Li, Yujing; Koo, Ja Wook; Ribeiro, Efrain; Labonte, Benoit; Laitman, Benjamin M; Estey, David; Stockman, Victoria; Kennedy, Pamela; Couroussé, Thomas; Mensah, Isaac; Turecki, Gustavo; Faull, Kym F; Ming, Guo-li; Song, Hongjun; Fan, Guoping; Casaccia, Patrizia; Shen, Li; Jin, Peng; Nestler, Eric J

    2015-04-01

    Ten-eleven translocation (TET) enzymes mediate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is enriched in brain, and its ultimate DNA demethylation. However, the influence of TET and 5hmC on gene transcription in brain remains elusive. We found that ten-eleven translocation protein 1 (TET1) was downregulated in mouse nucleus accumbens (NAc), a key brain reward structure, by repeated cocaine administration, which enhanced behavioral responses to cocaine. We then identified 5hmC induction in putative enhancers and coding regions of genes that have pivotal roles in drug addiction. Such induction of 5hmC, which occurred similarly following TET1 knockdown alone, correlated with increased expression of these genes as well as with their alternative splicing in response to cocaine administration. In addition, 5hmC alterations at certain loci persisted for at least 1 month after cocaine exposure. Together, these reveal a previously unknown epigenetic mechanism of cocaine action and provide new insight into how 5hmC regulates transcription in brain in vivo.

  3. Topological lattice actions

    NASA Astrophysics Data System (ADS)

    Bietenholz, W.; Gerber, U.; Pepe, M.; Wiese, U.-J.

    2010-12-01

    We consider lattice field theories with topological actions, which are invariant against small deformations of the fields. Some of these actions have infinite barriers separating different topological sectors. Topological actions do not have the correct classical continuum limit and they cannot be treated using perturbation theory, but they still yield the correct quantum continuum limit. To show this, we present analytic studies of the 1-d O(2) and O(3) model, as well as Monte Carlo simulations of the 2-d O(3) model using topological lattice actions. Some topological actions obey and others violate a lattice Schwarz inequality between the action and the topological charge Q. Irrespective of this, in the 2-d O(3) model the topological susceptibility {χ_t} = {{{left< {{Q^2}} rightrangle }} left/ {V} right.} is logarithmically divergent in the continuum limit. Still, at non-zero distance the correlator of the topological charge density has a finite continuum limit which is consistent with analytic predictions. Our study shows explicitly that some classically important features of an action are irrelevant for reaching the correct quantum continuum limit.

  4. Acute alteration of cardiac ECG, action potential, I{sub Kr} and the human ether-a-go-go-related gene (hERG) K{sup +} channel by PCB 126 and PCB 77

    SciTech Connect

    Park, Mi-Hyeong; Park, Won Sun; Jo, Su-Hyun

    2012-07-01

    Polychlorinated biphenyls (PCBs) have been known as serious persistent organic pollutants (POPs), causing developmental delays and motor dysfunction. We have investigated the effects of two PCB congeners, 3,3′,4,4′-tetrachlorobiphenyl (PCB 77) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on ECG, action potential, and the rapidly activating delayed rectifier K{sup +} current (I{sub Kr}) of guinea pigs' hearts, and hERG K{sup +} current expressed in Xenopus oocytes. PCB 126 shortened the corrected QT interval (QTc) of ECG and decreased the action potential duration at 90% (APD{sub 90}), and 50% of repolarization (APD{sub 50}) (P < 0.05) without changing the action potential duration at 20% (APD{sub 20}). PCB 77 decreased APD{sub 20} (P < 0.05) without affecting QTc, APD{sub 90}, and APD{sub 50}. The PCB 126 increased the I{sub Kr} in guinea-pig ventricular myocytes held at 36 °C and hERG K{sup +} current amplitude at the end of the voltage steps in voltage-dependent mode (P < 0.05); however, PCB 77 did not change the hERG K{sup +} current amplitude. The PCB 77 increased the diastolic Ca{sup 2+} and decreased Ca{sup 2+} transient amplitude (P < 0.05), however PCB 126 did not change. The results suggest that PCB 126 shortened the QTc and decreased the APD{sub 90} possibly by increasing I{sub Kr}, while PCB 77 decreased the APD{sub 20} possibly by other modulation related with intracellular Ca{sup 2+}. The present data indicate that the environmental toxicants, PCBs, can acutely affect cardiac electrophysiology including ECG, action potential, intracellular Ca{sup 2+}, and channel activity, resulting in toxic effects on the cardiac function in view of the possible accumulation of the PCBs in human body. -- Highlights: ► PCBs are known as serious environmental pollutants and developmental disruptors. ► PCB 126 shortened QT interval of ECG and action potential duration. ► PCB 126 increased human ether-a-go-go-related K{sup +} current and I{sub Kr}. ► PCB

  5. Spacelike brane actions.

    PubMed

    Hashimoto, Koji; Ho, Pei-Ming; Wang, John E

    2003-04-11

    We derive effective actions for "spacelike branes" (S-branes) and find a solution describing the formation of fundamental strings in the rolling tachyon background. The S-brane action is a Dirac-Born-Infeld action for Euclidean world volumes defined in the context of time-dependent tachyon condensation of non-BPS (Bogomol'nyi-Prasad-Sommerfield) branes. It includes gauge fields and, in particular, a scalar field associated with translation along the time direction. We show that the BIon spike solutions constructed in this system correspond to the production of a confined electric flux tube (a fundamental string) at late time of the rolling tachyon.

  6. Conscious Control over Action.

    PubMed

    Shepherd, Joshua

    2015-06-01

    The extensive involvement of nonconscious processes in human behaviour has led some to suggest that consciousness is much less important for the control of action than we might think. In this article I push against this trend, developing an understanding of conscious control that is sensitive to our best models of overt (that is, bodily) action control. Further, I assess the cogency of various zombie challenges-challenges that seek to demote the importance of conscious control for human agency. I argue that though nonconscious contributions to action control are evidently robust, these challenges are overblown.

  7. Conscious Control over Action

    PubMed Central

    Shepherd, Joshua

    2015-01-01

    The extensive involvement of nonconscious processes in human behaviour has led some to suggest that consciousness is much less important for the control of action than we might think. In this article I push against this trend, developing an understanding of conscious control that is sensitive to our best models of overt (that is, bodily) action control. Further, I assess the cogency of various zombie challenges—challenges that seek to demote the importance of conscious control for human agency. I argue that though nonconscious contributions to action control are evidently robust, these challenges are overblown. PMID:26113753

  8. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights.

    PubMed

    Bose, Prithviraj; Dai, Yun; Grant, Steven

    2014-09-01

    Initially regarded as "epigenetic modifiers" acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer.

  9. Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights

    PubMed Central

    Bose, Prithviraj; Dai, Yun; Grant, Steven

    2014-01-01

    Initially regarded as “epigenetic modifiers” acting predominantly through chromatin remodeling via histone acetylation, HDACIs, alternatively referred to as lysine deacetylase or simply deacetylase inhibitors, have since been recognized to exert multiple cytotoxic actions in cancer cells, often through acetylation of non-histone proteins. Some well-recognized mechanisms of HDACI lethality include, in addition to relaxation of DNA and de-repression of gene transcription, interference with chaperone protein function, free radical generation, induction of DNA damage, up-regulation of endogenous inhibitors of cell cycle progression, e.g., p21, and promotion of apoptosis. Intriguingly, this class of agents is relatively selective for transformed cells, at least in pre-clinical studies. In recent years, additional mechanisms of action of these agents have been uncovered. For example, HDACIs interfere with multiple DNA repair processes, as well as disrupt cell cycle checkpoints, critical to the maintenance of genomic integrity in the face of diverse genotoxic insults. Despite their pre-clinical potential, the clinical use of HDACIs remains restricted to certain subsets of T-cell lymphoma. Currently, it appears likely that the ultimate role of these agents will lie in rational combinations, only a few of which have been pursued in the clinic to date. This review focuses on relatively recently identified mechanisms of action of HDACIs, with particular emphasis on those that relate to the DNA damage response (DDR), and discuss synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use of HDACIs in patients with cancer. PMID:24769080

  10. Actions and mode of actions of FGF19 subfamily members.

    PubMed

    Fukumoto, Seiji

    2008-03-01

    Fibroblast growth factors (FGFs) are humoral factors with diverse biological functions. While most FGFs were shown to work as local factors regulating cell growth and differentiation, recent investigations indicated that FGF19 subfamily members, FGF15/19, FGF21 and FGF23 work as systemic factors. FGF15/19 produced by intestine inhibits bile acid synthesis and FGF21from liver is involved in carbohydrate and lipid metabolism. In addition, FGF23 was shown to be produced by bone and regulate phosphate and vitamin D metabolism. Furthermore, these FGFs require klotho or betaklotho for their actions in addition to canonical FGF receptors. It is possible that these FGFs together with their receptor systems might be targets for novel therapeutic measures in the future.

  11. Political action committee for scientists

    NASA Astrophysics Data System (ADS)

    Richman, Barbara T.

    Spurred by budget proposals that could severely reduce science funding (Eos, March 24, March 3, February 10), seven scientists currently serving as Congressional Science or State Department Fellows recently founded a political action committee (PAC) for scientists. The Science and Technology Political Action Committee (SCITEC-PAC) aims to make scientists more politically aware and better informed about potential legislative actions that affect research. It will also serve to ‘establish a political presence’ with respect to science, said Donald Stein, SCITEC-PAC's chairman.The organization is not a lobbying group, explained Stein, professor of neurology and psychology at Clark University and the University of Massachusetts Medical Center. ‘Lobbyists seek to influence officials by presenting information to them,’ he said, ‘while a PAC tries to influence the outcome of elections through campaign contributions of money, time, and effort in behalf of candidates that share similar goals and aspirations.’ In other words, the PAC will be a vehicle for promoting candidates for federal office who advocate strong support for scientific research and training. In addition, the PAC will develop and study science policy and budget issues and will attempt to stimulate government and private sector interest in these issues.

  12. Stabilizing bottomless action theories

    NASA Astrophysics Data System (ADS)

    Greensite, J.; Halpern, M. B.

    1984-08-01

    We show how to construct the euclidean quantum theory corresponding to classical actions which are unbounded from below. Our method preserves the classical limit, the large- N limit, and the perturbative expansion of the unstabilized theories.

  13. Benzidine Dyes Action Plan

    EPA Pesticide Factsheets

    This Action Plan addresses the use of benzidine-based dyes and benzidine congener-based dyes, both metalized and non-metalized, in products that would result in consumer exposure, such as for use to color textiles.

  14. Oak Canyon Action Memo

    EPA Pesticide Factsheets

    This memorandum requests approval for a time-critical removal action at the 27 residential properties that compose the Oak Canyon Site located in the Village of Paguate, Pueblo of Laguna, near Cibola County, New Mexico.

  15. [Mechanism on differential gene expression and heterosis formation].

    PubMed

    Xu, Chen-Lu; Sun, Xiao-Mei; Zhang, Shou-Gong

    2013-06-01

    Despite the rediscovery of heterosis about a century ago and the suggestion of various genetic models to explain this phenomenon, little consensus has yet been reached about the genetic basis of heterosis. Following the genome organization variation and gene effects, an understanding of gene differential expression in hybrids and its parents provides a new opportunity to speculate on mechanisms that might lead to heterosis. Investigation on allele-specific gene expression in hybrid and gene differential expression between hybrids and its parents might contribute to improve our understanding of the molecular basis of heterosis and eventually guide breeding practices. In this review, we discussed the recent researches on allelic-specific expression in hybrid which was frequently observed in recent studies and analyzed its regulatory mechanism. All possible modes of gene action, including additivity, high- and low-parent dominance, underdominance, and over-dominance, were observed when investigating gene differential expression between hybrids and its parents. Data from transcriptomic studies screened several heterosis-associated genes and highlighted the importance of certain key biochemical pathways that may prove to be quintessential for the manifestation of heterosis. So far, no uniform global expression pat-terns were observed in these gene expression studies. Most heterosis-associated gene expression analyses have not revealed a predominant functional category to which differentially expressed genes belong. However, these gene expression profiling studies represent a first step towards the definition of the complex gene expression networks that might be relevant in the context of heterosis. New technique on gene expression profile and advancements in bioinformatics will facilitate our understanding of the genetic basis of heterosis at the gene-expression level.

  16. [Addictions and action systems].

    PubMed

    Loonis, E; Apter, M J

    2000-01-01

    Generalizing from some previous analyses of addiction, and introducing the concept of an action system which governs all actions which are focussed on what Brown (1988) calls "hedonic management", we argue that addictions of every kind involve an action system that displays high salience, low variety and low vicariance. Addictions also involve what Apter (1982) calls the "paratelic state". A study was carried out comparing 31 drug addicts with 29 control subjects in terms of action system variables. To measure these variables, we constructed a new instrument, the Activity-System Drawing Test, and also used the Telic Dominance Scale to measure frequency of paratelic states. Dysphoria was measured by means of the BATE (anxiety), IDA-13 (depression), SEI (self-esteem), and TAS-20 (alexithymia) instruments. Strongly significant differences were found between groups for both action system variables and dysphoria, and there were also strong correlations between both groups of variables. This supports the idea that addictions emerge from systemic properties of the action system.

  17. Antisymmetric string actions

    NASA Astrophysics Data System (ADS)

    Aragone, C.

    1986-12-01

    An action is presented for the free bosonic string on external flat space in terms of an antisymmetric second-rank string background tensor which is classically equivalent to the Nambu-Goto action. Both action and field equations are entirely described in terms of 2D world-sheet forms, without any reference to a 2D metric tensor background. The analysis of its canonical formulation shows how the quadratic Virasoro constraints are generated in this case and what their connection with the Bianchi identities are. Since in the orthonormal gauge the reduced action coincides with the standard one, it has the same critical dimension D = 26. The existence of an interaction term of a purely geometric structure stemming in the extrinsic curvature is pointed out. Its action and the new string field equations are then derived. This polynomial antisymmetric string action is uniformly generalized in order to describe d < D-dimensional extended objects in D-dimensional flat space. On leave of absence from Departamento de Física, Universidad Simon Bolívar, Apartado 80659, Caracas 1080A, Venezuela.

  18. Action-based effects on music perception.

    PubMed

    Maes, Pieter-Jan; Leman, Marc; Palmer, Caroline; Wanderley, Marcelo M

    2014-01-03

    The classical, disembodied approach to music cognition conceptualizes action and perception as separate, peripheral processes. In contrast, embodied accounts of music cognition emphasize the central role of the close coupling of action and perception. It is a commonly established fact that perception spurs action tendencies. We present a theoretical framework that captures the ways in which the human motor system and its actions can reciprocally influence the perception of music. The cornerstone of this framework is the common coding theory, postulating a representational overlap in the brain between the planning, the execution, and the perception of movement. The integration of action and perception in so-called internal models is explained as a result of associative learning processes. Characteristic of internal models is that they allow intended or perceived sensory states to be transferred into corresponding motor commands (inverse modeling), and vice versa, to predict the sensory outcomes of planned actions (forward modeling). Embodied accounts typically refer to inverse modeling to explain action effects on music perception (Leman, 2007). We extend this account by pinpointing forward modeling as an alternative mechanism by which action can modulate perception. We provide an extensive overview of recent empirical evidence in support of this idea. Additionally, we demonstrate that motor dysfunctions can cause perceptual disabilities, supporting the main idea of the paper that the human motor system plays a functional role in auditory perception. The finding that music perception is shaped by the human motor system and its actions suggests that the musical mind is highly embodied. However, we advocate for a more radical approach to embodied (music) cognition in the sense that it needs to be considered as a dynamical process, in which aspects of action, perception, introspection, and social interaction are of crucial importance.

  19. Action-based effects on music perception

    PubMed Central

    Maes, Pieter-Jan; Leman, Marc; Palmer, Caroline; Wanderley, Marcelo M.

    2013-01-01

    The classical, disembodied approach to music cognition conceptualizes action and perception as separate, peripheral processes. In contrast, embodied accounts of music cognition emphasize the central role of the close coupling of action and perception. It is a commonly established fact that perception spurs action tendencies. We present a theoretical framework that captures the ways in which the human motor system and its actions can reciprocally influence the perception of music. The cornerstone of this framework is the common coding theory, postulating a representational overlap in the brain between the planning, the execution, and the perception of movement. The integration of action and perception in so-called internal models is explained as a result of associative learning processes. Characteristic of internal models is that they allow intended or perceived sensory states to be transferred into corresponding motor commands (inverse modeling), and vice versa, to predict the sensory outcomes of planned actions (forward modeling). Embodied accounts typically refer to inverse modeling to explain action effects on music perception (Leman, 2007). We extend this account by pinpointing forward modeling as an alternative mechanism by which action can modulate perception. We provide an extensive overview of recent empirical evidence in support of this idea. Additionally, we demonstrate that motor dysfunctions can cause perceptual disabilities, supporting the main idea of the paper that the human motor system plays a functional role in auditory perception. The finding that music perception is shaped by the human motor system and its actions suggests that the musical mind is highly embodied. However, we advocate for a more radical approach to embodied (music) cognition in the sense that it needs to be considered as a dynamical process, in which aspects of action, perception, introspection, and social interaction are of crucial importance. PMID:24454299

  20. Integrated gene set analysis for microRNA studies

    PubMed Central

    Garcia-Garcia, Francisco; Panadero, Joaquin; Dopazo, Joaquin; Montaner, David

    2016-01-01

    Motivation: Functional interpretation of miRNA expression data is currently done in a three step procedure: select differentially expressed miRNAs, find their target genes, and carry out gene set overrepresentation analysis. Nevertheless, major limitations of this approach have already been described at the gene level, while some newer arise in the miRNA scenario. Here, we propose an enhanced methodology that builds on the well-established gene set analysis paradigm. Evidence for differential expression at the miRNA level is transferred to a gene differential inhibition score which is easily interpretable in terms of gene sets or pathways. Such transferred indexes account for the additive effect of several miRNAs targeting the same gene, and also incorporate cancellation effects between cases and controls. Together, these two desirable characteristics allow for more accurate modeling of regulatory processes. Results: We analyze high-throughput sequencing data from 20 different cancer types and provide exhaustive reports of gene and Gene Ontology-term deregulation by miRNA action. Availability and Implementation: The proposed methodology was implemented in the Bioconductor library mdgsa. http://bioconductor.org/packages/mdgsa. For the purpose of reproducibility all of the scripts are available at https://github.com/dmontaner-papers/gsa4mirna Contact: david.montaner@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27324197

  1. Temporal distortion in the perception of actions and events.

    PubMed

    Yabe, Yoshiko; Dave, Hemangi; Goodale, Melvyn A

    2017-01-01

    In everyday life, actions and sensory events occur in complex sequences, with events triggering actions that in turn give rise to additional events and so on. Earlier work has shown that a sensory event that is triggered by a voluntary action is perceived to have occurred earlier in time than an identical event that is not triggered by an action. In other words, events that are believed to be caused by our actions are drawn forward in time towards our actions. Similarly, when a sensory event triggers an action, that event is again drawn in time towards the action and is thus perceived to have occurred later than it really did. This alteration in time perception serves to bind together events and actions that are causally linked. It is not clear, however, whether or not the perceived timing of a sensory event embedded within a longer series of actions and sensory events is also temporally bound to the actions in that sequence. In the current study, we measured the temporal binding in sequences consisting of two simple dyads of event-action and action-event in a series of manual action tasks: an event-action-event triad (Experiment 1) and an action-event-action triad (Experiment 2). Auditory tones either triggered an action or were presented 250ms after an action was performed. To reduce the influence of sensory events other than the tone, such as a noise associated with pressing a key on a keyboard, we used an optical sensor to detect hand movements where no contact was made with a surface. In Experiment 1, there appeared to be no change in the perceived onset of an auditory tone when the onset of that tone followed a hand movement and then the tone triggered a second hand movement. It was as if the temporal binding between the action and the tone and then the tone and the subsequent action summed algebraically and cancelled each other out. In Experiment 2, both the perceived onset of an initial tone which triggered an action and the perceived onset of a second tone

  2. Investigating conceptions of intentional action by analyzing participant generated scenarios

    PubMed Central

    Skulmowski, Alexander; Bunge, Andreas; Cohen, Bret R.; Kreilkamp, Barbara A. K.; Troxler, Nicole

    2015-01-01

    We describe and report on results of employing a new method for analyzing lay conceptions of intentional and unintentional action. Instead of asking people for their conceptual intuitions with regard to construed scenarios, we asked our participants to come up with their own scenarios and to explain why these are examples of intentional or unintentional actions. By way of content analysis, we extracted contexts and components that people associated with these action types. Our participants associated unintentional actions predominantly with bad outcomes for all persons involved and linked intentional actions more strongly to positive outcomes, especially concerning the agent. People’s conceptions of intentional action seem to involve more aspects than commonly assumed in philosophical models of intentional action that solely stress the importance of intentions, desires, and beliefs. The additional aspects include decisions and thoughts about the action. In addition, we found that the criteria that participants generated for unintentional actions are not a mere inversion of those used in explanations for intentional actions. Associations between involuntariness and unintentional action seem to be stronger than associations between aspects of voluntariness and intentional action. PMID:26594182

  3. Additional Continuing Appropriations Amendments, 2011

    THOMAS, 112th Congress

    Rep. Rogers, Harold [R-KY-5

    2011-03-11

    03/18/2011 Became Public Law No: 112-6. (TXT | PDF) (All Actions) Notes: Continuing appropriations through 4/8/2011. Tracker: This bill has the status Became LawHere are the steps for Status of Legislation:

  4. Additional Continuing Appropriations Amendments, 2011

    THOMAS, 112th Congress

    Rep. Rogers, Harold [R-KY-5

    2011-03-11

    03/18/2011 Became Public Law No: 112-6. (PDF) (All Actions) Notes: Continuing appropriations through 4/8/2011. Tracker: This bill has the status Became LawHere are the steps for Status of Legislation:

  5. Botulinum toxin: mechanisms of action.

    PubMed

    Dressler, Dirk; Adib Saberi, Fereshte

    2005-01-01

    Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BT's therapeutic potential suddenly became apparent. We wish to give an overview over BT's mechanisms of action relevant for understanding its therapeutic use. BT's molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide.

  6. 78 FR 53733 - Procurement List Additions and Deletions

    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

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    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-12

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    Federal Register 2010, 2011, 2012, 2013, 2014

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  15. Novel aspects of hypothalamic-pituitary-adrenal axis regulation and glucocorticoid actions

    PubMed Central

    Uchoa, Ernane Torres; Aguilera, Greti; Herman, James P.; Fiedler, Jenny L.; Deak, Terrence; Cordeiro de Sousa, Maria Bernardete

    2014-01-01

    Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to rhythmic and episodic release of adrenal glucocorticoids is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, glucocorticoids regulate behavior, metabolic, cardiovascular, immune, and neuroendocrine activities. In contrast to chronic elevated levels, circadian and acute stress-induced increases in glucocorticoids are necessary for hippocampal neuronal survival and memory acquisition and consolidation, through inhibiting apoptosis, facilitating glutamate transmission and inducing immediate early genes and spine formation. In addition to its metabolic actions leading to increasing energy availability, glucocorticoids have profound effects on feeding behavior, mainly through modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that in addition to the recognized immune suppressive actions of glucocorticoids by counteracting adrenergic proinflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative feedback by glucocorticoids involves multiple mechanisms leading to limiting HPA axis activation and preventing deleterious effects of excessive glucocorticoid production. Adequate glucocorticoid secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin releasing hormone (CRH) and vasopressin secretion, the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving non-genomic actions of glucocorticoids, mediate immediate inhibition of hypothalamic CRH and ACTH secretion, while intermediate and delayed mechanisms mediated by genomic actions involve modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily

  16. Plan for early action: Recommendations

    SciTech Connect

    1998-12-31

    This report contains recommendations on the implementation of an action plan to reduce or recapture greenhouse gas (GHG) emissions in British Columbia. The report includes the consensus recommendations of the BC Greenhouse Gas Forum, as well as those items on which Forum participants have agreed to disagree, plus the reasons for those differences. The recommendations include: Umbrella actions which may affect several or all sectors of the economy, or support the success of other actions; actions to reduce vehicle kilometers travelled; actions to increase vehicle efficiency or increase the use of alternative fuels or technologies; actions to decrease GHG emissions from energy production; actions to increase end-use energy efficiency; and actions to reduce non-energy-related emissions. Appendices include work sheets on each action, with a description of the action and information on the action`s rationale, experience elsewhere, related policy initiatives, and key issues regarding feasibility and implementation.

  17. What's an Asthma Action Plan?

    MedlinePlus

    ... to 2-Year-Old What's an Asthma Action Plan? KidsHealth > For Parents > What's an Asthma Action Plan? ... normal everyday activities without having asthma symptoms. Action Plans Are Unique Each person's experience with asthma is ...

  18. National Security Technology Incubator Action Plan

    SciTech Connect

    None, None

    2008-02-28

    This report documents the action plan for developing the National Security Technology Incubator (NSTI) program for southern New Mexico. The NSTI program is being developed as part of the National Security Preparedness Project (NSPP), funded by Department of Energy (DOE)/National Nuclear Security Administration (NNSA). This action plan serves as a tool in measuring progress in the development process and delivery of services for the NSTI program. Continuous review and evaluation of the action plan is necessary in the development process of the NSTI. The action plan includes detailed steps in developing the NSTI program based on recommended best practices in incubator development by the National Business Incubation Association (NBIA). Included are tasks required to implement the NSTI, developed within a work breakdown structure. In addition, a timeline is identified for each task.

  19. 77 FR 52228 - Food Additives Permitted for Direct Addition to Food for Human Consumption; Vitamin D2

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-29

    ... HUMAN SERVICES Food and Drug Administration 21 CFR Part 172 Food Additives Permitted for Direct Addition to Food for Human Consumption; Vitamin D2 Bakers Yeast AGENCY: Food and Drug Administration, HHS. ACTION: Final rule. SUMMARY: The Food and Drug Administration (FDA) is amending the food...

  20. Classifying Facial Actions

    PubMed Central

    Donato, Gianluca; Bartlett, Marian Stewart; Hager, Joseph C.; Ekman, Paul; Sejnowski, Terrence J.

    2010-01-01

    The Facial Action Coding System (FACS) [23] is an objective method for quantifying facial movement in terms of component actions. This system is widely used in behavioral investigations of emotion, cognitive processes, and social interaction. The coding is presently performed by highly trained human experts. This paper explores and compares techniques for automatically recognizing facial actions in sequences of images. These techniques include analysis of facial motion through estimation of optical flow; holistic spatial analysis, such as principal component analysis, independent component analysis, local feature analysis, and linear discriminant analysis; and methods based on the outputs of local filters, such as Gabor wavelet representations and local principal components. Performance of these systems is compared to naive and expert human subjects. Best performances were obtained using the Gabor wavelet representation and the independent component representation, both of which achieved 96 percent accuracy for classifying 12 facial actions of the upper and lower face. The results provide converging evidence for the importance of using local filters, high spatial frequencies, and statistical independence for classifying facial actions. PMID:21188284

  1. Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications.

    PubMed

    Kopchick, John J; List, Edward O; Kelder, Bruce; Gosney, Elahu S; Berryman, Darlene E

    2014-04-05

    The discovery of a growth hormone receptor antagonist (GHA) was initially established via expression of mutated GH genes in transgenic mice. Following this discovery, development of the compound resulted in a drug termed pegvisomant, which has been approved for use in patients with acromegaly. Pegvisomant treatment in a dose dependent manner results in normalization of IGF-1 levels in most patients. Thus, it is a very efficacious and safe drug. Since the GH/IGF-1 axis has been implicated in the progression of several types of cancers, many have suggested the use of pegvisomant as an anti-cancer therapeutic. In this manuscript, we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions. Additionally, we will describe experiments in which the GHA was discovered, review results of pegvisomant's preclinical and clinical trials, and provide data suggesting pegvisomant's therapeutic value in selected types of cancer.

  2. Gene Overexpression Resources in Cereals for Functional Genomics and Discovery of Useful Genes

    PubMed Central

    Abe, Kiyomi; Ichikawa, Hiroaki

    2016-01-01

    Identification and elucidation of functions of plant genes is valuable for both basic and applied research. In addition to natural variation in model plants, numerous loss-of-function resources have been produced by mutagenesis with chemicals, irradiation, or insertions of transposable elements or T-DNA. However, we may be unable to observe loss-of-function phenotypes for genes with functionally redundant homologs and for those essential for growth and development. To offset such disadvantages, gain-of-function transgenic resources have been exploited. Activation-tagged lines have been generated using obligatory overexpression of endogenous genes by random insertion of an enhancer. Recent progress in DNA sequencing technology and bioinformatics has enabled the preparation of genomewide collections of full-length cDNAs (fl-cDNAs) in some model species. Using the fl-cDNA clones, a novel gain-of-function strategy, Fl-cDNA OvereXpressor gene (FOX)-hunting system, has been developed. A mutant phenotype in a FOX line can be directly attributed to the overexpressed fl-cDNA. Investigating a large population of FOX lines could reveal important genes conferring favorable phenotypes for crop breeding. Alternatively, a unique loss-of-function approach Chimeric REpressor gene Silencing Technology (CRES-T) has been developed. In CRES-T, overexpression of a chimeric repressor, composed of the coding sequence of a transcription factor (TF) and short peptide designated as the repression domain, could interfere with the action of endogenous TF in plants. Although plant TFs usually consist of gene families, CRES-T is effective, in principle, even for the TFs with functional redundancy. In this review, we focus on the current status of the gene-overexpression strategies and resources for identifying and elucidating novel functions of cereal genes. We discuss the potential of these research tools for identifying useful genes and phenotypes for application in crop breeding. PMID

  3. Action languages: Dimensions, effects

    NASA Technical Reports Server (NTRS)

    Hayes, Daniel G.; Streeter, Gordon

    1989-01-01

    Dimensions of action languages are discussed for communication between humans and machines, and the message handling capabilities of object oriented programming systems are examined. Design of action languages is seen to be very contextual. Economical and effective design will depend on features of situations, the tasks intended to be accomplished, and the nature of the devices themselves. Current object oriented systems turn out to have fairly simple and straightforward message handling facilities, which in themselves do little to buffer action or even in some cases to handle competing messages. Even so, it is possible to program a certain amount of discretion about how they react to messages. Such thoughtfulness and perhaps relative autonomy of program modules seems prerequisite to future systems to handle complex interactions in changing situations.

  4. Mitigation Action Plan

    SciTech Connect

    Not Available

    1994-02-01

    This Mitigation Action Plan (MAP) focuses on mitigation commitments stated in the Supplemental Environmental Impact Statement (SEIS) and the Record of Decision (ROD) for the Naval Petroleum Reserve No. 1 (NPR-1). Specific commitments and mitigation implementation actions are listed in Appendix A-Mitigation Actions, and form the central focus of this MAP. They will be updated as needed to allow for organizational, regulatory, or policy changes. It is the intent of DOE to comply with all applicable federal, state, and local environmental, safety, and health laws and regulations. Eighty-six specific commitments were identified in the SEIS and associated ROD which pertain to continued operation of NPR-1 with petroleum production at the Maximum Efficient Rate (MER). The mitigation measures proposed are expected to reduce impacts as much as feasible, however, as experience is gained in actual implementation of these measures, some changes may be warranted.

  5. Regulation of UDP glucuronosyltransferase genes.

    PubMed

    Mackenzie, P I; Gregory, P A; Gardner-Stephen, D A; Lewinsky, R H; Jorgensen, B R; Nishiyama, T; Xie, Wen; Radominska-Pandya, A

    2003-06-01

    The UDP glucuronosyltransferase (UGT) content of cells and tissues is a major determinant of our response to those chemicals that are primarily eliminated by conjugation with glucuronic acid. There are marked interindividual differences in the content of UGTs in the liver and other organs. The mechanisms that lead to these differences are unknown but are most likely the result of differential UGT gene expression. Several transcription factors involved in the regulation of UGT genes have been identified. These include factors such as Hepatocyte Nuclear Factor 1, CAAT-Enhancer Binding Protein, Octamer transcription Factor 1 and Pbx2, which appear to control the constitutive levels of UGTs in tissues and organs. In addition, UGT gene expression is also modulated by hormones, drugs and other foreign chemicals through the action of proteins that bind and/or sense the presence of these chemicals. These proteins include the Ah receptor, members of the nuclear receptor superfamily, such as CAR and PXR and transcription factors that respond to stress.

  6. Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

    PubMed Central

    2013-01-01

    Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, “direct” action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus “indirect” action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits. PMID:24147833

  7. Microbial functional gene diversity with a shift of subsurface redox conditions during In Situ uranium reduction.

    PubMed

    Liang, Yuting; Van Nostrand, Joy D; N'guessan, Lucie A; Peacock, Aaron D; Deng, Ye; Long, Philip E; Resch, C Tom; Wu, Liyou; He, Zhili; Li, Guanghe; Hazen, Terry C; Lovley, Derek R; Zhou, Jizhong

    2012-04-01

    To better understand the microbial functional diversity changes with subsurface redox conditions during in situ uranium bioremediation, key functional genes were studied with GeoChip, a comprehensive functional gene microarray, in field experiments at a uranium mill tailings remedial action (UMTRA) site (Rifle, CO). The results indicated that functional microbial communities altered with a shift in the dominant metabolic process, as documented by hierarchical cluster and ordination analyses of all detected functional genes. The abundance of dsrAB genes (dissimilatory sulfite reductase genes) and methane generation-related mcr genes (methyl coenzyme M reductase coding genes) increased when redox conditions shifted from Fe-reducing to sulfate-reducing conditions. The cytochrome genes detected were primarily from Geobacter sp. and decreased with lower subsurface redox conditions. Statistical analysis of environmental parameters and functional genes indicated that acetate, U(VI), and redox potential (E(h)) were the most significant geochemical variables linked to microbial functional gene structures, and changes in microbial functional diversity were strongly related to the dominant terminal electron-accepting process following acetate addition. The study indicates that the microbial functional genes clearly reflect the in situ redox conditions and the dominant microbial processes, which in turn influence uranium bioreduction. Microbial functional genes thus could be very useful for tracking microbial community structure and dynamics during bioremediation.

  8. Microbial Functional Gene Diversity with a Shift of Subsurface Redox Conditions during In Situ Uranium Reduction

    PubMed Central

    Liang, Yuting; Van Nostrand, Joy D.; N′Guessan, Lucie A.; Peacock, Aaron D.; Deng, Ye; Long, Philip E.; Resch, C. Tom; Wu, Liyou; He, Zhili; Li, Guanghe; Hazen, Terry C.; Lovley, Derek R.

    2012-01-01

    To better understand the microbial functional diversity changes with subsurface redox conditions during in situ uranium bioremediation, key functional genes were studied with GeoChip, a comprehensive functional gene microarray, in field experiments at a uranium mill tailings remedial action (UMTRA) site (Rifle, CO). The results indicated that functional microbial communities altered with a shift in the dominant metabolic process, as documented by hierarchical cluster and ordination analyses of all detected functional genes. The abundance of dsrAB genes (dissimilatory sulfite reductase genes) and methane generation-related mcr genes (methyl coenzyme M reductase coding genes) increased when redox conditions shifted from Fe-reducing to sulfate-reducing conditions. The cytochrome genes detected were primarily from Geobacter sp. and decreased with lower subsurface redox conditions. Statistical analysis of environmental parameters and functional genes indicated that acetate, U(VI), and redox potential (Eh) were the most significant geochemical variables linked to microbial functional gene structures, and changes in microbial functional diversity were strongly related to the dominant terminal electron-accepting process following acetate addition. The study indicates that the microbial functional genes clearly reflect the in situ redox conditions and the dominant microbial processes, which in turn influence uranium bioreduction. Microbial functional genes thus could be very useful for tracking microbial community structure and dynamics during bioremediation. PMID:22327592

  9. Characterizations of proper actions

    NASA Astrophysics Data System (ADS)

    Biller, Harald

    2004-03-01

    Three kinds of proper actions of increasing strength are defined. We prove that the three definitions specialize to the definitions by Bourbaki, by Palais and by Baum, Connes and Higson in their respective settings. The third of these, which thus turns out to be the strongest, originally only concerns actions of second countable locally compact groups on metrizable spaces. In this situation, it is shown to coincide with the other two definitions if the total space locally has the Lindelöf property and the orbit space is regular.

  10. 50 CFR 660.409 - Inseason actions.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... the management objectives for the affected species and the additional open period is no less than 24... Wildlife and Fisheries FISHERY CONSERVATION AND MANAGEMENT, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION... Inseason actions. (a) Fixed inseason management provisions. NMFS is authorized to take the...

  11. Insights into the Mode of Action of Chitosan as an Antibacterial Compound▿ †

    PubMed Central

    Raafat, Dina; von Bargen, Kristine; Haas, Albert; Sahl, Hans-Georg

    2008-01-01

    Chitosan is a polysaccharide biopolymer that combines a unique set of versatile physicochemical and biological characteristics which allow for a wide range of applications. Although its antimicrobial activity is well documented, its mode of action has hitherto remained only vaguely defined. In this work we investigated the antimicrobial mode of action of chitosan using a combination of approaches, including in vitro assays, killing kinetics, cellular leakage measurements, membrane potential estimations, and electron microscopy, in addition to transcriptional response analysis. Chitosan, whose antimicrobial activity was influenced by several factors, exhibited a dose-dependent growth-inhibitory effect. A simultaneous permeabilization of the cell membrane to small cellular components, coupled to a significant membrane depolarization, was detected. A concomitant interference with cell wall biosynthesis was not observed. Chitosan treatment of Staphylococcus simulans 22 cells did not give rise to cell wall lysis; the cell membrane also remained intact. Analysis of transcriptional response data revealed that chitosan treatment leads to multiple changes in the expression profiles of Staphylococcus aureus SG511 genes involved in the regulation of stress and autolysis, as well as genes associated with energy metabolism. Finally, a possible mechanism for chitosan's activity is postulated. Although we contend that there might not be a single classical target that would explain chitosan's antimicrobial action, we speculate that binding of chitosan to teichoic acids, coupled with a potential extraction of membrane lipids (predominantly lipoteichoic acid) results in a sequence of events, ultimately leading to bacterial death. PMID:18456858

  12. Investigations to the Antibacterial Mechanism of Action of Kendomycin

    PubMed Central

    A. Elnakady, Yasser; Chatterjee, Indranil; Bischoff, Markus; Rohde, Manfred; Josten, Michaele; Sahl, Hans-Georg; Herrmann, Mathias; Müller, Rolf

    2016-01-01

    Purpose The emergence of bacteria that are resistant to many currently used drugs emphasizes the need to discover and develop new antibiotics that are effective against such multi-resistant strains. Kendomycin is a novel polyketide that has a unique quinone methide ansa structure and various biological properties. This compound exhibits strong antibacterial activity against Gram-negative and Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Despite the promise of kendomycinin in several therapeutic areas, its mode of action has yet to be identified. Methods In this study, we used a multidisciplinary approach to gain insight into the antibacterial mechanism of this compound. Results The antibacterial activity of kendomycin appears to be bacteriostatic rather than bactericidal. Kendomycin inhibited the growth of the MRSA strain COL at a low concentration (MIC of 5 μg/mL). Proteomic analysis and gene transcription profiling of kendomycin-treated cells indicated that this compound affected the regulation of numerous proteins and genes involved in central metabolic pathways, such as the tricarboxylic acid (TCA) cycle (SdhA) and gluconeogenesis (PckA and GapB), cell wall biosynthesis and cell division (FtsA, FtsZ, and MurAA), capsule production (Cap5A and Cap5C), bacterial programmed cell death (LrgA and CidA), the cellular stress response (ClpB, ClpC, ClpP, GroEL, DnaK, and GrpE), and oxidative stress (AhpC and KatA). Electron microscopy revealed that kendomycin strongly affected septum formation during cell division. Most kendomycin-treated cells displayed incomplete septa with abnormal morphology. Conclusions Kendomycin might directly or indirectly affect the cell division machinery, protein stability, and programmed cell death in S. aureus. Additional studies are still needed to obtain deeper insight into the mode of action of kendomycin. PMID:26795276

  13. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

    PubMed Central

    Christakos, Sylvia; Dhawan, Puneet; Verstuyf, Annemieke; Verlinden, Lieve; Carmeliet, Geert

    2016-01-01

    1,25-Dihydroxvitamin D3 [1,25(OH)2D3] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH)2D3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH)2D3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease. PMID:26681795

  14. Angels in Action

    ERIC Educational Resources Information Center

    Stylianou, Xanthippi Cynthia

    2009-01-01

    In this article, the author discusses the importance of the placement of action lines to show the direction of movement. The author shows some visuals of angels and discusses in details the texture of the wings, the hair and the clothing.

  15. Executive Mind, Timely Action.

    ERIC Educational Resources Information Center

    Torbert, William R.

    1983-01-01

    The idea of "Executive Mind" carries with it the notion of purposeful and effective action. Part I of this paper characterizes three complements to "Executive Mind"--"Observing Mind,""Theorizing Mind," and "Passionate Mind"--and offers historical figures exemplifying all four types. The concluding…

  16. College Comedy and Action

    ERIC Educational Resources Information Center

    Moore, Rosanna

    1977-01-01

    A few materials such as yarn and scraps of paper and cloth can provide the media for recording limitless ideas from the imaginations of students. With a little encouragement and a few suggestions of actions, emotions, exaggerations and activities students will produce a vast array of amusing characters. (Author)

  17. Affirmative Action Plan.

    ERIC Educational Resources Information Center

    Triton Coll., River Grove, IL.

    In order to develop an affirmative action plan at Triton College, the college President appointed a committee made up of nine representatives from the various college constituencies, the majority of which were women and minorities, to determine the objectives to be achieved and how to implement them, and to establish appropriate review procedures.…

  18. Youth Engaged for Action

    ERIC Educational Resources Information Center

    Post, Margaret; Little, Priscilla

    2005-01-01

    This article examines how out-of-school time programs can promote youth involvement in civic action by focusing on four interrelated programmatic strategies: establishing organizational readiness that fosters engagement; promoting youth-adult partnerships; engaging youth as leaders and decision makers; and involving youth in research and…

  19. Expert Teacher Action Program.

    ERIC Educational Resources Information Center

    Washington, Eva

    The expert teacher action program is to improve classroom teaching performance. The program has been tested in workshop sessions involving more than 1,200 educators representing 50 school districts. A set of standards, consisting of 25 variables, lead to the definition of expert teaching. Each variable deals with a major aspect of the duties of…

  20. Court Action for Migrants.

    ERIC Educational Resources Information Center

    Ewald, Thomas R.

    Aiding attorneys who represent migrant farmworkers and their families when affirmative civil action is required, this book helps to raise the level of migrants' legal protection to a minimum standard of adequacy. The text is based on the Federal Rules of Civil Procedure, a national set of rules. The book is divided into 3 sections: the…

  1. Action for Children's Television.

    ERIC Educational Resources Information Center

    Ranly, Donald P.

    The origins, development, and effectiveness of Action for Children's Television (ACT) are examined in this pamphlet. The strategies used by ACT to obtain change at the congressional level and within television stations and networks include the following: a "tuneout" day when people are urged to turn off their television sets, a boycott…

  2. School Reform in Action.

    ERIC Educational Resources Information Center

    Miller, A. Christine

    This study describes and analyzes the impact on student learning and the learning environment of 55 schools in Broward, Palm Beach, and Miami-Dade school districts as they implemented the schoolwide action-research framework for school improvement. Interviews, observations, document review during site visits, school framework reports, surveys,…

  3. Cognitive framing in action.

    PubMed

    Huhn, John M; Potts, Cory Adam; Rosenbaum, David A

    2016-06-01

    Cognitive framing effects have been widely reported in higher-level decision-making and have been ascribed to rules of thumb for quick thinking. No such demonstrations have been reported for physical action, as far as we know, but they would be expected if cognition for physical action is fundamentally similar to cognition for higher-level decision-making. To test for such effects, we asked participants to reach for a horizontally-oriented pipe to move it from one height to another while turning the pipe 180° to bring one end (the "business end") to a target on the left or right. From a physical perspective, participants could have always rotated the pipe in the same angular direction no matter which end was the business end; a given participant could have always turned the pipe clockwise or counter-clockwise. Instead, our participants turned the business end counter-clockwise for left targets and clockwise for right targets. Thus, the way the identical physical task was framed altered the way it was performed. This finding is consistent with the hypothesis that cognition for physical action is fundamentally similar to cognition for higher-level decision-making. A tantalizing possibility is that higher-level decision heuristics have roots in the control of physical action, a hypothesis that accords with embodied views of cognition.

  4. Nutrition Action Pack.

    ERIC Educational Resources Information Center

    Sockut, Joanne; Stumpe, Stephanie

    One of five McDonald's Action Packs, these instructional materials integrate elementary school-level nutrition education into other disciplines--biology, sociology, physiology, mathematics, and art. Contents include four units consisting of twelve activities. Unit 1, Why You Need Food, is a self-examination of what is needed for growth, health,…

  5. Sustainability as Moral Action

    ERIC Educational Resources Information Center

    Dunn, Merrily S.; Hart-Steffes, Jeanne S.

    2012-01-01

    When one considers sustainability as a moral action, there are equally complex realities at hand--climate change, resource depletion, water and land rights. One author describes this broad sense of sustainability as "the connection of specific social and environmental problems to the functioning of human and ecological systems" (Jenkins, 2011).…

  6. Conjugate flow action functionals

    NASA Astrophysics Data System (ADS)

    Venturi, Daniele

    2013-11-01

    We present a new general framework to construct an action functional for a non-potential field theory. The key idea relies on representing the governing equations relative to a diffeomorphic flow of curvilinear coordinates which is assumed to be functionally dependent on the solution field. Such flow, which will be called the conjugate flow, evolves in space and time similarly to a physical fluid flow of classical mechanics and it can be selected in order to symmetrize the Gâteaux derivative of the field equations with respect to suitable local bilinear forms. This is equivalent to requiring that the governing equations of the field theory can be derived from a principle of stationary action on a Lie group manifold. By using a general operator framework, we obtain the determining equations of such manifold and the corresponding conjugate flow action functional. In particular, we study scalar and vector field theories governed by second-order nonlinear partial differential equations. The identification of transformation groups leaving the conjugate flow action functional invariant could lead to the discovery of new conservation laws in fluid dynamics and other disciplines.

  7. Economics Action Pack.

    ERIC Educational Resources Information Center

    McDonald's Corp., Oak Brook, IL.

    One of five McDonald's Action Packs, this learning package introduces intermediate grade students to basic economic concepts. The fourteen activities include the topics of consumption (4 activities), production (5), the market system (3), a pretest, and a posttest. Specific titles under consumption include The Wonderful Treasure Tree (introduction…

  8. From Awareness to Action

    ERIC Educational Resources Information Center

    Micklos, John, Jr.

    2012-01-01

    What inspires young people to become activists? Events such as wars or regime changes obviously raise high emotions. But some choose to get involved because they saw a need and felt compelled to take action. Young Americans have a long track record as activists. Among other things, they played a key role in the civil rights movement of the 1950s…

  9. Affirmative Action Fallout

    ERIC Educational Resources Information Center

    Roach, Ronald

    2005-01-01

    Race-conscious affirmative action in higher education survived a close challenge in 2003 when the U.S. Supreme Court ruled that race was a valid academic admission criteria in the "Grutter v. Bollinger" case. Two years later, a number of "pipeline" programs to help under-represented minorities gain admission to and complete graduate school have…

  10. Conjugate flow action functionals

    SciTech Connect

    Venturi, Daniele

    2013-11-15

    We present a new general framework to construct an action functional for a non-potential field theory. The key idea relies on representing the governing equations relative to a diffeomorphic flow of curvilinear coordinates which is assumed to be functionally dependent on the solution field. Such flow, which will be called the conjugate flow, evolves in space and time similarly to a physical fluid flow of classical mechanics and it can be selected in order to symmetrize the Gâteaux derivative of the field equations with respect to suitable local bilinear forms. This is equivalent to requiring that the governing equations of the field theory can be derived from a principle of stationary action on a Lie group manifold. By using a general operator framework, we obtain the determining equations of such manifold and the corresponding conjugate flow action functional. In particular, we study scalar and vector field theories governed by second-order nonlinear partial differential equations. The identification of transformation groups leaving the conjugate flow action functional invariant could lead to the discovery of new conservation laws in fluid dynamics and other disciplines.

  11. The Constitution in Action

    ERIC Educational Resources Information Center

    Potter, Lee Ann

    2007-01-01

    In this article, the author describes the experiences middle school students on a field trip to the new Constitution in Action Learning Lab in the Boeing Learning Center at the National Archives can expect. There, middle school students take on the roles of archivists and researchers collecting and analyzing primary sources from the holdings of…

  12. Jump into Action

    ERIC Educational Resources Information Center

    Ball, Stephen; Cohen, Ann; Meyer, Margaret

    2012-01-01

    Jump Into Action (JIA) is a school-based team-taught program to help fifth-grade students make healthy food choices and be more active. The JIA team (physical education teacher, classroom teacher, school nurse, and parent) work together to provide a supportive environment as students set goals to improve food choices and increase activity.…

  13. Hope for Environmental Action

    ERIC Educational Resources Information Center

    Fleischer, Barbara J.; DeMoor, Emily

    2015-01-01

    Environmental consciousness-raising programs tend to emphasize the magnitude of imminent ecological disasters, if humans continue on their current trajectory. While these environmental literacy programs also call for action to avoid cataclysmic ecological changes, psychological research on "learned helplessness" suggests that information…

  14. Action Learning Issues.

    ERIC Educational Resources Information Center

    1998

    This document contains four papers from a symposium on adult learning issues and human resource development (HRD). "Creating a Systemic Framework for the Transfer of Learning from an Action Learning Experience" (Suzanne D. Butterfield, Kitty Gold, Verna J. Willis) discusses a study of the organizational elements that affect learning and…

  15. Target: Development Action.

    ERIC Educational Resources Information Center

    American Freedom from Hunger Foundation, Washington, DC. Young World Development.

    This handbook, suggestive rather than prescriptive, is written for Young World Development and/or similar groups committed to active involvement in community, national, and world improvement. Emphasis is upon organizing high school, college, and adult courses and action programs in the community which will help sensitize participants and make them…

  16. Justifying Action Research

    ERIC Educational Resources Information Center

    Helskog, Guro Hansen

    2014-01-01

    In this paper I use a general philosophy of science perspective in looking at the problem of justifying action research. First I try to clarify the concept of justification, by contrasting it with the concept of validity, which seems to be used almost as a synonym in some parts of the literature. I discuss the need for taking a stand in relation…

  17. Classroom Assessment in Action

    ERIC Educational Resources Information Center

    Shermis, Mark D.; DiVesta, Francis J.

    2011-01-01

    "Classroom Assessment in Action" clarifies the multi-faceted roles of measurement and assessment and their applications in a classroom setting. Comprehensive in scope, Shermis and Di Vesta explain basic measurement concepts and show students how to interpret the results of standardized tests. From these basic concepts, the authors then…

  18. Quick action clamp

    NASA Technical Reports Server (NTRS)

    Calco, Frank S. (Inventor)

    1991-01-01

    A quick release toggle clamp that utilizes a spring that requires a deliberate positive action for disengagement is presented. The clamp has a sliding bolt that provides a latching mechanism. The bolt is moved by a handle that tends to remain in an engaged position while under tension.

  19. SYRACUSE ACTION FOR YOUTH.

    ERIC Educational Resources Information Center

    ADDINGTON, HAROLD E.; AND OTHERS

    A PROPOSAL WAS MADE TO PREVENT AND CONTROL JUVENILE DELINQUENCY BY OPENING OPPORTUNITIES AND DEVELOPING COMPETENCE AMONG DISADVANTAGED YOUTH. THE TOTAL COMMUNITY WAS MOBILIZED TO DEVELOP A PROGRAM TO ATTACK THE PROBLEM AT ALL LEVELS THEY WORKED FOR 18 MONTHS TO PLAN A SERIES OF CREATIVE ACTION PROGRAMS IN EDUCATION, EMPLOYMENT, AND COMMUNITY…

  20. Affirmative Action Plan.

    ERIC Educational Resources Information Center

    North Carolina State Dept. of Public Instruction, Raleigh.

    This affirmative action (AA) guide is intended to identify and remove discriminatory employment practices that may still exist in the North Carolina State Department of Public Instruction (DPI). DPI extends equal employment opportunity (EEO) to all applicants and employees without regard to race, color, religion, sex, age, handicap, political…

  1. The Shape of Action

    ERIC Educational Resources Information Center

    Hard, Bridgette Martin; Recchia, Gabriel; Tversky, Barbara

    2011-01-01

    How do people understand the everyday, yet intricate, behaviors that unfold around them? In the present research, we explored this by presenting viewers with self-paced slideshows of everyday activities and recording looking times, subjective segmentation (breakpoints) into action units, and slide-to-slide physical change. A detailed comparison of…

  2. Epilepsy-associated genes.

    PubMed

    Wang, Jie; Lin, Zhi-Jian; Liu, Liu; Xu, Hai-Qing; Shi, Yi-Wu; Yi, Yong-Hong; He, Na; Liao, Wei-Ping

    2017-01-01

    Development in genetic technology has led to the identification of an increasing number of genes associated with epilepsy. These discoveries will both provide the basis for including genetic tests in clinical practice and improve diagnosis and treatment of epilepsy. By searching through several databases (OMIM, HGMD, and EpilepsyGene) and recent publications on PubMed, we found 977 genes that are associated with epilepsy. We classified these genes into 4 categories according to the manifestation of epilepsy in phenotypes. We found 84 genes that are considered as epilepsy genes: genes that cause epilepsies or syndromes with epilepsy as the core symptom. 73 genes were listed as neurodevelopment-associated genes: genes associated with both brain-development malformations and epilepsy. Several genes (536) were epilepsy-related: genes associated with both physical or other systemic abnormalities and epilepsy or seizures. We found 284 additional genes putatively associated with epilepsy; this requires further verification. These integrated data will provide new insights useful for both including genetic tests in the clinical practice and evaluating the results of genetic tests. We also summarized the epilepsy-associated genes according to their function, with the goal to better characterize the association between genes and epilepsies and to further understand the mechanisms underlying epilepsy.

  3. Biosynthetic Genes for the Tetrodecamycin Antibiotics

    PubMed Central

    Gverzdys, Tomas

    2016-01-01

    ABSTRACT We recently described 13-deoxytetrodecamycin, a new member of the tetrodecamycin family of antibiotics. A defining feature of these molecules is the presence of a five-membered lactone called a tetronate ring. By sequencing the genome of a producer strain, Streptomyces sp. strain WAC04657, and searching for a gene previously implicated in tetronate ring formation, we identified the biosynthetic genes responsible for producing 13-deoxytetrodecamycin (the ted genes). Using the ted cluster in WAC04657 as a reference, we found related clusters in three other organisms: Streptomyces atroolivaceus ATCC 19725, Streptomyces globisporus NRRL B-2293, and Streptomyces sp. strain LaPpAH-202. Comparing the four clusters allowed us to identify the cluster boundaries. Genetic manipulation of the cluster confirmed the involvement of the ted genes in 13-deoxytetrodecamycin biosynthesis and revealed several additional molecules produced through the ted biosynthetic pathway, including tetrodecamycin, dihydrotetrodecamycin, and another, W5.9, a novel molecule. Comparison of the bioactivities of these four molecules suggests that they may act through the covalent modification of their target(s). IMPORTANCE The tetrodecamycins are a distinct subgroup of the tetronate family of secondary metabolites. Little is known about their biosynthesis or mechanisms of action, making them an attractive subject for investigation. In this paper we present the biosynthetic gene cluster for 13-deoxytetrodecamycin in Streptomyces sp. strain WAC04657. We identify related clusters in several other organisms and show that they produce related molecules. PMID:27137499

  4. Expression of bvg-repressed genes in Bordetella pertussis is controlled by RisA through a novel c-di-GMP signaling pathway

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The BvgAS two component system of Bordetella pertussis controls virulence factor expression. In addition, BvgAS controls expression of the bvg-repressed genes through the action of the repressor, BvgR. The transcription factor RisA is inhibited by BvgR, and when BvgR is not expressed RisA induces th...

  5. Gastric cytoprotection beyond prostaglandins: cellular and molecular mechanisms of gastroprotective and ulcer healing actions of antacids.

    PubMed

    Tarnawski, Andrzej; Ahluwalia, Amrita; Jones, Michael K

    2013-01-01

    This article updates current views on gastric mucosal defense, injury, protection and ulcer healing with a focus on mucosal protective and ulcer healing actions of antacids. The gastric mucosa is continuously exposed to a variety of noxious factors, both endogenous such as: 0.1N hydrochloric acid, pepsin, bile acids, lysolecithin, H. pylori toxins and exogenous such as NSAIDs, ethanol and others. Gastric mucosal integrity is maintained by pre-epithelial, epithelial and post-epithelial defense mechanisms permitting the mucosa to withstand exposure to the above damaging factors. When mucosal defense is weakened or overwhelmed by injurious factors, injury develops in the form of erosions or ulcers. In the late 1970s Andre Robert and coworkers discovered that microgram amounts of a prostaglandin E2 analog protects the gastric mucosa against a variety of ulcerogenic and necrotizing agents - even such strong inducers of injury as 100% ethanol and boiling water. They proposed a new concept of cytoprotection. Subsequently, other compounds, such as sulfhydryls, sucralfate and epidermal growth factor were shown to exert protective action on gastric mucosa. Additionally, some antacids have been shown to exert a potent mucosal protective action against a variety of injurious factors and accelerate healing of erosions and gastric ulcers. These actions of antacids, especially hydrotalcite - the newest and the most extensively studied antacid - are due to activation of prostaglandin synthesis; binding to and inactivation of pepsin, bile acids and H. pylori toxins; induction of heat shock proteins; and, activation of genes encoding growth factors and their receptors.

  6. Animal models to study thyroid hormone action in cerebellum.

    PubMed

    Koibuchi, Noriyuki

    2009-06-01

    Thyroid hormone plays a crucial role in the development and functional maintenance of the central nervous system including the cerebellum. To study the molecular mechanisms of thyroid hormone action, various animal models have been used. These are classified: (1) congenital hypothyroid animals due to thyroid gland dysgenesis or thyroid dyshormonogenesis, (2) thyroid hormone receptor (TR) gene-mutated animals, and (3) thyroid hormone transport or metabolism-modified animals. TR is a ligand-activated transcription factor. In the presence of ligand, it activates transcription of target gene, whereas it represses the transcription without ligand. Thus, phenotype of TR-knockout mouse is different from that of hypothyroid animal (low thyroid hormone level), in which unliganded TR actively represses the transcription. On the other hand, human patient harboring mutant TR expresses different phenotypes depending on the function of mutated TR. To mimic this phenotype, other animal models are generated. In addition, recent human studies have shown that thyroid hormone transporters such as monocarboxylate transporter (MCT) 8 may play an important role in thyroid hormone-mediated brain development. However, MCT8 knockout mouse show different phenotypes from a human patient. This article introduces representative animal models currently used to study various aspects of thyroid hormone, particularly to study the involvement of the thyroid hormone system on the development and functional maintenance of the cerebellum.

  7. Transport and transformation of genetic information in the critical zone: The case of antibiotic resistance genes

    NASA Astrophysics Data System (ADS)

    Zhu, Y. G.

    2015-12-01

    In addition to material and energy flows, the dynamics and functions of the Earth's critical zone are intensively mediated by biological actions performed by diverse organisms. These biological actions are modulated by the expression of functional genes and their translation into enzymes that catalyze geochemical reactions, such as nutrient turnover and pollutant biodegradation. Although geobiology, as an interdisciplinary research area, is playing and vital role in linking biological and geochemical processes at different temporal and spatial scales, the distribution and transport of functional genes have rarely been investigated from the Earth's critical zone perspectives. To illustrate the framework of studies on the transport and transformation of genetic information in the critical zone, antibiotic resistance is taken as an example. Antibiotic resistance genes are considered as a group of emerging contaminants, and their emergence and spread within the critical zone on one hand are induced by anthropogenic activities, and on other hand are threatening human health worldwide. The transport and transformation of antibiotic resistance genes are controlled by both horizontal gene transfer between bacterial cells and the movement of bacteria harboring antibiotic resistance genes. In this paper, the fate and behavior of antibiotic resistance genes will be discussed in the following aspects: 1) general overview of environmental antibiotic resistance; 2) high through quantification of the resistome in various environmental media; 3) pathways of resistance gene flow within the critical zone; and 4) potential strategies in mitigating antibiotic resistance, particularly from the critical zone perspectives.

  8. Membrane-initiated Actions of Estradiol that Regulate Reproduction, Energy Balance and Body Temperature

    PubMed Central

    Kelly, Martin J.; Rønnekleiv, Oline K.

    2012-01-01

    It is well known that many of the actions of estrogens in the central nervous system are mediated via intracellular receptor/transcription factors that interact with steroid response elements on target genes. However, there now exists compelling evidence for membrane estrogen receptors in hypothalamic and other brain neurons. But, it is not well understood how estrogens signal via membrane receptors, and how these signals impact not only membrane excitability but also gene transcription in neurons. Indeed, it has been known for sometime that estrogens can rapidly alter neuronal activity within seconds, indicating that some cellular effects can occur via membrane delimited events. In addition, estrogens can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell signaling. Therefore, this review will consider our current knowledge of rapid membrane-initiated and intracellular signaling by estrogens in the hypothalamus, the nature of receptors involved and how they contribute to homeostatic functions. PMID:22871514

  9. Supersymmetric component actions via coset approach

    NASA Astrophysics Data System (ADS)

    Bellucci, S.; Krivonos, S.; Sutulin, A.

    2013-10-01

    We propose a method to construct the on-shell component actions for the theories with 1/2 partial breaking of global supersymmetry within the nonlinear realization (coset) approach. In contrast with the standard superfield approach in which unbroken supersymmetry plays the leading role, we have shifted the attention to the spontaneously broken supersymmetry. It turns out that in the theories in which half of supersymmetries is spontaneously broken, all physical fermions are just the fermions of the nonlinear realization. Moreover, the transformation properties of these fermions with respect to the broken supersymmetry are the same as in the famous Volkov-Akulov model. Just this fact completely fixed all possible appearances of the fermions in the component action: they can enter the action through the determinant of the vielbein (to compensate the transformation of the volume form) and the covariant derivatives, only. It is very important that in our parametrization of the coset the rest of physical components, i.e. all bosonic components, transform as “matter fields” with respect to the broken supersymmetry. Clearly, in such a situation the component action acquires the form of the Volkov-Akulov action for these “matter fields”. The complete form of the action can be further fixed by two additional requirements: (a) to reproduce the bosonic limit, which is explicitly known in many interesting cases, and (b) to have a proper linearized form, which has to be invariant with respect to the linearized unbroken supersymmetry. We supply the general consideration by a detailed example of the component action of N=1 supermembrane in D=4 constructed within our procedure. In this case we provide the exact proof of the invariance of the constructed component action with respect to both, broken and unbroken supersymmetries.

  10. Final Action Plan to Tiger Team

    SciTech Connect

    Not Available

    1992-02-28

    This document presents planned actions, and their associated costs, for addressing the findings in the Environmental, Safety and Health Tiger Team Assessment of the Sandia National Laboratories, Albuquerque, May 1991, hereafter called the Assessment. This Final Action Plan should be read in conjunction with the Assessment to ensure full understanding of the findings addressed herein. The Assessment presented 353 findings in four general categories: (1)Environmental (82 findings); (2) Safety and Health (243 findings); (3) Management and Organization (18 findings); and (4) Self-Assessment (10 findings). Additionally, 436 noncompliance items with Occupational Safety and Health Administration (OSHA) standards were addressed during and immediately after the Tiger Team visit.

  11. Evaluation of certain food additives and contaminants.

    PubMed

    2004-01-01

    This report represents the conclusions of a Joint FAO/WHO Expert Committee convened to evaluate the safety of various food additives, with a view to recommending acceptable daily intakes (ADIs) and to prepare specifications for the identity and purity of food additives. The first part of the report contains a general discussion of the principles governing the toxicological evaluation of food additives (including flavouring agents) and contaminants, assessments of intake, and the establishment and revision of specifications for food additives. A summary follows of the Committee's evaluations of toxicological and intake data on various specific food additives (alpha-amylase from Bacillus lichenformis containing a genetically engineered alpha-amylase gene from B. licheniformis, annatto extracts, curcumin, diacetyl and fatty acid esters of glycerol, D-tagatose, laccase from Myceliophthora thermophila expressed in Aspergillus oryzae, mixed xylanase, beta-glucanase enzyme preparation produced by a strain of Humicola insolens, neotame, polyvinyl alcohol, quillaia extracts and xylanase from Thermomyces lanuginosus expressed in Fusarium venenatum), flavouring agents, a nutritional source of iron (ferrous glycinate, processed with citric acid), a disinfectant for drinking-water (sodium dichloroisocyanurate) and contaminants (cadmium and methylmercury). Annexed to the report are tables summarizing the Committee's recommendations for ADIs of the food additives, recommendations on the flavouring agents considered, and tolerable intakes of the contaminants considered, changes in the status of specifications and further information requested or desired.

  12. Action of methyl-, propyl- and butylparaben on GPR30 gene and protein expression, cAMP levels and activation of ERK1/2 and PI3K/Akt signaling pathways in MCF-7 breast cancer cells and MCF-10A non-transformed breast epithelial cells.

    PubMed

    Wróbel, Anna Maria; Gregoraszczuk, Ewa Łucja

    2015-10-14

    In the present study, we examined cAMP levels and activation of the MAPK/ERK1/2 and PI3K/Akt signaling pathways in response to the actions of parabens on GPR30 in MCF-7 and MCF-10A cells. Cells were exposed to methyl-, propyl- or butylparaben at a concentration of 20nM; 17-β-estradiol (10nM) was used as a positive control. 17β-estradiol and all tested parabens increased GPR30 gene and protein expression in MCF-7 and MCF-10A cells. No parabens affected cAMP levels in either cell line, with the exception of propylparaben in MCF-10A cells. 17β-estradiol, propylparaben, and butylparaben increased phosphorylation of ERK1/2 in MCF-7 cells, whereas 17β-estradiol, methyl- and butylparaben, but not propylparaben, increased phosphorylation of ERK1/2 in MCF-10A cells. Akt activation was noted only in MCF-7 cells and only with propylparaben treatment. Collectively, the data presented here point to a nongenomic mechanism of action of parabens in activation GPR30 in both cancer and non-cancer breast cell lines through βγ dimer-mediated activation of the ERK1/2 pathway, but not the cAMP/PKA pathway. Moreover, among investigated parabens, propylparaben appears to inhibit apoptosis in cancer cells through activation of Akt kinases, confirming conclusions suggested by our previously published data. Nevertheless, continuing research on the carcinogenic action of parabens is warranted.

  13. GS-5759, a Bifunctional β2-Adrenoceptor Agonist and Phosphodiesterase 4 Inhibitor for Chronic Obstructive Pulmonary Disease with a Unique Mode of Action: Effects on Gene Expression in Human Airway Epithelial Cells.

    PubMed

    Joshi, Taruna; Yan, Dong; Hamed, Omar; Tannheimer, Stacey L; Phillips, Gary B; Wright, Clifford D; Kim, Musong; Salmon, Michael; Newton, Robert; Giembycz, Mark A

    2017-02-01

    (R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl] carbamoyl}phenyl)sulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide trifluoroacetic acid (GS-5759) is a bifunctional ligand composed of a quinolinone-containing pharmacophore [β2-adrenoceptor agonist orthostere (β2A)] found in several β2-adrenoceptor agonists, including indacaterol, linked covalently to a phosphodiesterase 4 (PDE4) inhibitor related to 6-[3-(dimethylcarbamoyl)benzenesulphonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GSK 256066) by a pent-1-yn-1-ylbenzene spacer. GS-5759 had a similar affinity for PDE4B1 and the native β2-adrenoceptor expressed on BEAS-2B human airway epithelial cells. However, compared with the monofunctional parent compound, β2A, the KA of GS-5759 for the β2-adrenoceptor was 35-fold lower. Schild analysis determined that the affinities of the β-adrenoceptor antagonists, (2R,3R)-1-[(2,3-dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol (ICI 118551) and propranolol, were agonist-dependent, being significantly lower for GS-5759 than β2A. Collectively, these data can be explained by "forced proximity," bivalent binding where the pharmacophore in GS-5759 responsible for PDE4 inhibition also interacts with a nonallosteric domain within the β2-adrenoceptor that enhances the affinity of β2A for the orthosteric site. Microarray analyses revealed that, after 2-hour exposure, GS-5759 increased the expression of >3500 genes in BEAS-2B cells that were highly rank-order correlated with gene expression changes produced by indacaterol and GSK 256066 in combination (Ind/GSK). Moreover, the line of regression began close to the origin with a slope of 0.88, indicating that the magnitude of most gene expression changes produced by Ind/GSK was quantitatively replicated by GS-5759. Thus, GS-5759 is a novel compound exhibiting dual β2-adrenoceptor agonism and PDE4 inhibition

  14. How Safe Are Color Additives?

    MedlinePlus

    ... Home For Consumers Consumer Updates How Safe are Color Additives? Share Tweet Linkedin Pin it More sharing ... Consumer Updates RSS Feed Download PDF (380 K) Color additives give the red tint to your fruit ...

  15. Bitumen fume-induced gene expression profile in rat lung

    SciTech Connect

    Gate, Laurent . E-mail: laurent.gate@inrs.fr; Langlais, Cristina; Micillino, Jean-Claude; Nunge, Herve; Bottin, Marie-Claire; Wrobel, Richard; Binet, Stephane

    2006-08-15

    Exposure to bitumen fumes during paving and roofing activities may represent an occupational health risk. To date, most of the studies performed on the biological effect of asphalt fumes have been done with regard to their content in carcinogenic polycyclic aromatic hydrocarbons (PAH). In order to gain an additional insight into the mechanisms of action of bitumen fumes, we studied their pulmonary effects in rodents following inhalation using the microarray technology. Fisher 344 rats were exposed for 5 days, 6 h/day to bitumen fumes generated at road paving temperature (170 {sup o}C) using a nose-only exposition device. With the intention of studying the early transcriptional events induced by asphalt fumes, lung tissues were collected immediately following exposure and gene expression profiles in control and exposed rats were determined by using oligonucleotide microarrays. Data analysis revealed that genes involved in lung inflammatory response as well as genes associated with PAH metabolization and detoxification were highly expressed in bitumen-exposed animals. In addition, the expression of genes related to elastase activity and its inhibition which are associated with emphysema was also modulated. More interestingly genes coding for monoamine oxidases A and B involved in the metabolism of neurotransmitters and xenobiotics were downregulated in exposed rats. Altogether, these data give additional information concerning the bitumen fumes biological effects and would allow to better review the health effects of occupational asphalt fumes exposure.

  16. Bitumen fume-induced gene expression profile in rat lung.

    PubMed

    Gate, Laurent; Langlais, Cristina; Micillino, Jean-Claude; Nunge, Hervé; Bottin, Marie-Claire; Wrobel, Richard; Binet, Stéphane

    2006-08-15

    Exposure to bitumen fumes during paving and roofing activities may represent an occupational health risk. To date, most of the studies performed on the biological effect of asphalt fumes have been done with regard to their content in carcinogenic polycyclic aromatic hydrocarbons (PAH). In order to gain an additional insight into the mechanisms of action of bitumen fumes, we studied their pulmonary effects in rodents following inhalation using the microarray technology. Fisher 344 rats were exposed for 5 days, 6 h/day to bitumen fumes generated at road paving temperature (170 degrees C) using a nose-only exposition device. With the intention of studying the early transcriptional events induced by asphalt fumes, lung tissues were collected immediately following exposure and gene expression profiles in control and exposed rats were determined by using oligonucleotide microarrays. Data analysis revealed that genes involved in lung inflammatory response as well as genes associated with PAH metabolization and detoxification were highly expressed in bitumen-exposed animals. In addition, the expression of genes related to elastase activity and its inhibition which are associated with emphysema was also modulated. More interestingly genes coding for monoamine oxidases A and B involved in the metabolism of neurotransmitters and xenobiotics were downregulated in exposed rats. Altogether, these data give additional information concerning the bitumen fumes biological effects and would allow to better review the health effects of occupational asphalt fumes exposure.

  17. A Metadata Action Language

    NASA Technical Reports Server (NTRS)

    Golden, Keith; Clancy, Dan (Technical Monitor)

    2001-01-01

    The data management problem comprises data processing and data tracking. Data processing is the creation of new data based on existing data sources. Data tracking consists of storing metadata descriptions of available data. This paper addresses the data management problem by casting it as an AI planning problem. Actions are data-processing commands, plans are dataflow programs and goals are metadata descriptions of desired data products. Data manipulation is simply plan generation and execution, and a key component of data tracking is inferring the effects of an observed plan. We introduce a new action language for data management domains, called ADILM. We discuss the connection between data processing and information integration and show how a language for the latter must be modified to support the former. The paper also discusses information gathering within a data-processing framework, and show how ADILM metadata expressions are a generalization of Local Completeness.

  18. Adipokines and insulin action

    PubMed Central

    Knights, Alexander J; Funnell, Alister PW; Pearson, Richard CM; Crossley, Merlin; Bell-Anderson, Kim S

    2014-01-01

    Obesity is a major public health concern and a strong risk factor for insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease. The last two decades have seen a reconsideration of the role of white adipose tissue (WAT) in whole body metabolism and insulin action. Adipose tissue-derived cytokines and hormones, or adipokines, are likely mediators of metabolic function and dysfunction. While several adipokines have been associated with obese and insulin-resistant phenotypes, a select group has been linked with insulin sensitivity, namely leptin, adiponectin, and more recently, adipolin. What is known about these insulin-sensitizing molecules and their effects in healthy and insulin resistant states is the subject of this review. There remains a significant amount of research to do to fully elucidate the mechanisms of action of these adipokines for development of therapeutics in metabolic disease. PMID:24719781

  19. 77 FR 40402 - Actions Taken at June 7, 2012 Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-09

    ... Commission took the following actions: (1) Rescinded approval for one water resources project; (2) approved or tabled the applications of certain water resources projects; and (3) took additional actions as... Protection Policy from May 16, 2012, to July 16, 2012; (3) adoption of a Water Resources Program for FY...

  20. 12 CFR 615.5361 - Relation to other administrative actions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 12 Banks and Banking 6 2010-01-01 2010-01-01 false Relation to other administrative actions. 615.5361 Section 615.5361 Banks and Banking FARM CREDIT ADMINISTRATION FARM CREDIT SYSTEM FUNDING AND... § 615.5361 Relation to other administrative actions. A capital directive may be issued in addition...