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Sample records for undesirable off-target activities

  1. Kinase inhibitors can produce off-target effects and activate linked pathways by retroactivity

    Directory of Open Access Journals (Sweden)

    Wynn Michelle L

    2011-10-01

    Full Text Available Abstract Background It has been shown in experimental and theoretical work that covalently modified signaling cascades naturally exhibit bidirectional signal propagation via a phenomenon known as retroactivity. An important consequence of retroactivity, which arises due to enzyme sequestration in covalently modified signaling cascades, is that a downstream perturbation can produce a response in a component upstream of the perturbation without the need for explicit feedback connections. Retroactivity may, therefore, play an important role in the cellular response to a targeted therapy. Kinase inhibitors are a class of targeted therapies designed to interfere with a specific kinase molecule in a dysregulated signaling pathway. While extremely promising as anti-cancer agents, kinase inhibitors may produce undesirable off-target effects by non-specific interactions or pathway cross-talk. We hypothesize that targeted therapies such as kinase inhibitors can produce off-target effects as a consequence of retroactivity alone. Results We used a computational model and a series of simple signaling motifs to test the hypothesis. Our results indicate that within physiologically and therapeutically relevant ranges for all parameters, a targeted inhibitor can naturally induce an off-target effect via retroactivity. The kinetics governing covalent modification cycles in a signaling network were more important for propagating an upstream off-target effect in our models than the kinetics governing the targeted therapy itself. Our results also reveal the surprising and crucial result that kinase inhibitors have the capacity to turn "on" an otherwise "off" parallel cascade when two cascades share an upstream activator. Conclusions A proper and detailed characterization of a pathway's structure is important for identifying the optimal protein to target as well as what concentration of the targeted therapy is required to modulate the pathway in a safe and effective

  2. Potential functional and pathological side effects related to off-target pharmacological activity.

    Science.gov (United States)

    Lynch, James J; Van Vleet, Terry R; Mittelstadt, Scott W; Blomme, Eric A G

    2017-09-01

    Most pharmaceutical companies test their discovery-stage proprietary molecules in a battery of in vitro pharmacology assays to try to determine off-target interactions. During all phases of drug discovery and development, various questions arise regarding potential side effects associated with such off-target pharmacological activity. Here we present a scientific literature curation effort undertaken to determine and summarize the most likely functional and pathological outcomes associated with interactions at 70 receptors, enzymes, ion channels and transporters with established links to adverse effects. To that end, the scientific literature was reviewed using an on-line database, and the most commonly reported effects were summarized in tabular format. The resultant table should serve as a practical guide for research scientists and clinical investigators for the prediction and interpretation of adverse side effects associated with molecules interacting with components of this screening battery. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Activation Kinetics and Off-Target Effects of Thymus-Initiated Cre Transgenes

    Science.gov (United States)

    Shi, Jianjun; Petrie, Howard T.

    2012-01-01

    The bacteriophage enzyme Cre is a site-specific recombinase widely used to delete loxP-flanked DNA sequences in lineage-specific fashion. Several mouse lines that direct Cre expression to lymphoid progenitors in the thymus have been established, but a side-by-side comparison of when they first become active, and/or their relative efficiency at various developmental stages, has been lacking. In this study, we evaluated these in four common Cre transgenic strains with thymus-initiated promoters (Lck, Cd2, or Cd4). We found that while all of them eventually labeled nearly all thymocytes, their kinetics were dramatically different, and other than Cd4[Cre], did not faithfully recapitulate the expression pattern of the corresponding endogenous gene. Perhaps even more importantly, while thymuses from some strains compared favorably to thymuses from control (Cre-negative) mice, we found that Cre expression could also result in off-target effects, including moderate to severe decreases in thymic cellularity. These effects occurred in the absence of loxP-flanked DNA target genes, and were dose and copy number dependent. Loss of cellularity was attributable to a specific decrease in CD4+8+ immature cells, and corresponds to an increased rate of programmed cell death. In addition to a comprehensive analysis of activation kinetics in thymus-initiated Cre transgenes, our data show that Cre is toxic to CD4+8+ cells in a dose-dependent fashion, and emphasize that the choice of thymus-initiated Cre strain is critically important for minimizing off-target effects of Cre. PMID:23049709

  4. Minimizing off-Target Mutagenesis Risks Caused by Programmable Nucleases

    Directory of Open Access Journals (Sweden)

    Kentaro Ishida

    2015-10-01

    Full Text Available Programmable nucleases, such as zinc finger nucleases (ZFNs, transcription activator like effector nucleases (TALENs, and clustered regularly interspersed short palindromic repeats associated protein-9 (CRISPR-Cas9, hold tremendous potential for applications in the clinical setting to treat genetic diseases or prevent infectious diseases. However, because the accuracy of DNA recognition by these nucleases is not always perfect, off-target mutagenesis may result in undesirable adverse events in treated patients such as cellular toxicity or tumorigenesis. Therefore, designing nucleases and analyzing their activity must be carefully evaluated to minimize off-target mutagenesis. Furthermore, rigorous genomic testing will be important to ensure the integrity of nuclease modified cells. In this review, we provide an overview of available nuclease designing platforms, nuclease engineering approaches to minimize off-target activity, and methods to evaluate both on- and off-target cleavage of CRISPR-Cas9.

  5. Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of ?-secretase inhibitors

    OpenAIRE

    Zuhl, Andrea M.; Nolan, Charles E.; Brodney, Michael A.; Niessen, Sherry; Atchison, Kevin; Houle, Christopher; Karanian, David A.; Ambroise, Claude; Brulet, Jeffrey W.; Beck, Elizabeth M.; Doran, Shawn D.; O'Neill, Brian T.; am Ende, Christopher W.; Chang, Cheng; Geoghegan, Kieran F.

    2016-01-01

    Inhibition of ?-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked ...

  6. Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors.

    Science.gov (United States)

    Zuhl, Andrea M; Nolan, Charles E; Brodney, Michael A; Niessen, Sherry; Atchison, Kevin; Houle, Christopher; Karanian, David A; Ambroise, Claude; Brulet, Jeffrey W; Beck, Elizabeth M; Doran, Shawn D; O'Neill, Brian T; Am Ende, Christopher W; Chang, Cheng; Geoghegan, Kieran F; West, Graham M; Judkins, Joshua C; Hou, Xinjun; Riddell, David R; Johnson, Douglas S

    2016-10-11

    Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.

  7. Nbs1 ChIP-Seq Identifies Off-Target DNA Double-Strand Breaks Induced by AID in Activated Splenic B Cells.

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    Lyne Khair

    2015-08-01

    Full Text Available Activation-induced cytidine deaminase (AID is required for initiation of Ig class switch recombination (CSR and somatic hypermutation (SHM of antibody genes during immune responses. AID has also been shown to induce chromosomal translocations, mutations, and DNA double-strand breaks (DSBs involving non-Ig genes in activated B cells. To determine what makes a DNA site a target for AID-induced DSBs, we identify off-target DSBs induced by AID by performing chromatin immunoprecipitation (ChIP for Nbs1, a protein that binds DSBs, followed by deep sequencing (ChIP-Seq. We detect and characterize hundreds of off-target AID-dependent DSBs. Two types of tandem repeats are highly enriched within the Nbs1-binding sites: long CA repeats, which can form Z-DNA, and tandem pentamers containing the AID target hotspot WGCW. These tandem repeats are not nearly as enriched at AID-independent DSBs, which we also identified. Msh2, a component of the mismatch repair pathway and important for genome stability, increases off-target DSBs, similar to its effect on Ig switch region DSBs, which are required intermediates during CSR. Most of the off-target DSBs are two-ended, consistent with generation during G1 phase, similar to DSBs in Ig switch regions. However, a minority are one-ended, presumably due to conversion of single-strand breaks to DSBs during replication. One-ended DSBs are repaired by processes involving homologous recombination, including break-induced replication repair, which can lead to genome instability. Off-target DSBs, especially those present during S phase, can lead to chromosomal translocations, deletions and gene amplifications, resulting in the high frequency of B cell lymphomas derived from cells that express or have expressed AID.

  8. Harnessing off-target effects

    DEFF Research Database (Denmark)

    Saginc, Gaye; Voellmy, Franziska; Linding, Rune

    2017-01-01

    The 'off-targets' of a drug are often poorly characterized yet could be harnessed in the treatment of complex diseases. A recent study used a small-molecule screening in non-small-cell lung cancer to repurpose an FDA-approved ALK/IGF1R inhibitor and uncover its mechanism of action.......The 'off-targets' of a drug are often poorly characterized yet could be harnessed in the treatment of complex diseases. A recent study used a small-molecule screening in non-small-cell lung cancer to repurpose an FDA-approved ALK/IGF1R inhibitor and uncover its mechanism of action....

  9. Removing undesirable color and boosting biological activity in red beet extracts using gamma irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Sik; Lee, Eun Mi; Hong, Sung Hyun; Bai, Hyoung Woo; Chung, Byung Yeoup [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Lee, In Chul [Youngdong University, Youngdong (Korea, Republic of)

    2011-10-15

    Red beet (Beta vulgaris L.) is a traditional and popular vegetable distributed in many part of the world and has been used as a natural colorant in many dairy products, beverages, candies and cattle products. Red beet roots contain two groups of betalain pigments, redviolet betacyanins and yellow betaxanthins. Betalains possess several biological activities such as antioxidant, anti-inflammatory, hepatoprotective, and anticancer properities. Recent trend of using natural products in industries tends toward multifunctional, high quality, and highpriced value foods and cosmetics. To meet the needs of consumers, cosmetics, medicine, and foods should contain the proper amount of natural products. Although the color removal processes such as filtration and absorption by clay are still useful, these procedures are difficult, time-consuming and costly. To overcome this problem, the radiation technology has emerged as a new way. Radiation technology has been applied to the decomposition and decoloration of pigment and is an efficient technique for inactivating pathogens, removing undesirable color in biomaterial extracts and improving or maintaining biological activities. Gamma-irradiation and electron beamirradiation techniques in previous reports were applied in order to remove any undesirable color and to improve or maintain biological activities of various extracts such as green tea leaves, licorice root, and S. chinensis fruits. Latorre et al. reported that betacyanin concentration decreased with the irradiation dose and significantly, in 35%, after 2.0 kGy of gamma-ray, whereas betaxathin concentration increased (about 11%-ratio with respect to control) after 1 kGy but decreased (about 19%) after 2 kGy. However, they did not try to analysis for completed removal of red beet pigments. Therefore, it is necessary to find the optimum irradiation dose for entirely removing red pigments in red beet. The aim of this work was to address the effects of the color removal and

  10. Removing undesirable color and boosting biological activity in red beet extracts using gamma irradiation

    International Nuclear Information System (INIS)

    Lee, Seung Sik; Lee, Eun Mi; Hong, Sung Hyun; Bai, Hyoung Woo; Chung, Byung Yeoup; Lee, In Chul

    2011-01-01

    Red beet (Beta vulgaris L.) is a traditional and popular vegetable distributed in many part of the world and has been used as a natural colorant in many dairy products, beverages, candies and cattle products. Red beet roots contain two groups of betalain pigments, redviolet betacyanins and yellow betaxanthins. Betalains possess several biological activities such as antioxidant, anti-inflammatory, hepatoprotective, and anticancer properities. Recent trend of using natural products in industries tends toward multifunctional, high quality, and highpriced value foods and cosmetics. To meet the needs of consumers, cosmetics, medicine, and foods should contain the proper amount of natural products. Although the color removal processes such as filtration and absorption by clay are still useful, these procedures are difficult, time-consuming and costly. To overcome this problem, the radiation technology has emerged as a new way. Radiation technology has been applied to the decomposition and decoloration of pigment and is an efficient technique for inactivating pathogens, removing undesirable color in biomaterial extracts and improving or maintaining biological activities. Gamma-irradiation and electron beamirradiation techniques in previous reports were applied in order to remove any undesirable color and to improve or maintain biological activities of various extracts such as green tea leaves, licorice root, and S. chinensis fruits. Latorre et al. reported that betacyanin concentration decreased with the irradiation dose and significantly, in 35%, after 2.0 kGy of gamma-ray, whereas betaxathin concentration increased (about 11%-ratio with respect to control) after 1 kGy but decreased (about 19%) after 2 kGy. However, they did not try to analysis for completed removal of red beet pigments. Therefore, it is necessary to find the optimum irradiation dose for entirely removing red pigments in red beet. The aim of this work was to address the effects of the color removal and

  11. Off-target Effects in CRISPR/Cas9-mediated Genome Engineering

    Directory of Open Access Journals (Sweden)

    Xiao-Hui Zhang

    2015-01-01

    Full Text Available CRISPR/Cas9 is a versatile genome-editing technology that is widely used for studying the functionality of genetic elements, creating genetically modified organisms as well as preclinical research of genetic disorders. However, the high frequency of off-target activity (≥50%—RGEN (RNA-guided endonuclease-induced mutations at sites other than the intended on-target site—is one major concern, especially for therapeutic and clinical applications. Here, we review the basic mechanisms underlying off-target cutting in the CRISPR/Cas9 system, methods for detecting off-target mutations, and strategies for minimizing off-target cleavage. The improvement off-target specificity in the CRISPR/Cas9 system will provide solid genotype–phenotype correlations, and thus enable faithful interpretation of genome-editing data, which will certainly facilitate the basic and clinical application of this technology.

  12. Antimicrobial activity of Butyl acetate, Ethyl acetate and Isopropyl alcohol on undesirable microorganisms in cosmetic products.

    Science.gov (United States)

    Lens, C; Malet, G; Cupferman, S

    2016-10-01

    The microbiological contamination risk of a cosmetic product has to be assessed by the manufacturer, according to the composition, to determine whether microbiological testing is required. Certain ingredients in cosmetic formulations help to create an environment hostile towards microbial growth. In this study, the influence on microbial survival of some solvents used in nail varnishes was evaluated. The purpose of this study was two-fold. The first was to define the thresholds to be considered for the exemption of products from microbiological testing. The second was to assess the cross-contamination risk linked to the use on successive consumers of solvent-based products in beauty salons. Strains of Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Candida albicans and Trichophyton rubrum were exposed to various concentrations of ethyl acetate, butyl acetate and isopropyl alcohol in culture medium to estimate their MIC (minimum inhibitory concentration). These strains are relevant to cosmetic products as they are associated with skin and nail infections. Mixtures of the three solvents, which are characteristic of nail varnish compositions, were also tested for their cidal activity. Ethyl and butyl acetates had a stronger impact than isopropyl alcohol: the MIC of ethyl and butyl acetate is ≤5% for all of the tested strains, whereas that of isopropyl alcohol is ≤10%. Various combinations of the three solvents tested showed a significant effect on both fungal and bacterial strains (greater than 3 log reduction in 15 min for the bacterial test strains and in 30 min for T. rubrum). Products containing more than 5% ethyl or butyl acetate or more than 10% isopropyl alcohol are hostile towards microbial growth. These products can therefore be considered as microbiologically low risk during both production and use, and so do not require microbiological testing (challenge test and end-product testing). Moreover, the nine tested mixtures of these three

  13. High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

    International Nuclear Information System (INIS)

    Pan, Jian-Bo; Ji, Nan; Pan, Wen; Hong, Ru; Wang, Hao; Ji, Zhi-Liang

    2014-01-01

    Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. - Highlights: • A novel computational framework was developed for mechanistic study of SADRs. • Off-targets of drugs were identified in large scale and in a high-throughput manner. • SADRs like cardiac disorders were systematically explored in molecular networks. • A number of ADR-associated proteins were identified

  14. High-throughput identification of off-targets for the mechanistic study of severe adverse drug reactions induced by analgesics

    Energy Technology Data Exchange (ETDEWEB)

    Pan, Jian-Bo [Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005 (China); Ji, Nan; Pan, Wen; Hong, Ru [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102 (China); Wang, Hao [Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005 (China); Ji, Zhi-Liang, E-mail: appo@xmu.edu.cn [State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102 (China); Department of Chemical Biology, College of Chemistry and Chemical Engineering, The Key Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen, Fujian 361005 (China)

    2014-01-01

    Drugs may induce adverse drug reactions (ADRs) when they unexpectedly bind to proteins other than their therapeutic targets. Identification of these undesired protein binding partners, called off-targets, can facilitate toxicity assessment in the early stages of drug development. In this study, a computational framework was introduced for the exploration of idiosyncratic mechanisms underlying analgesic-induced severe adverse drug reactions (SADRs). The putative analgesic-target interactions were predicted by performing reverse docking of analgesics or their active metabolites against human/mammal protein structures in a high-throughput manner. Subsequently, bioinformatics analyses were undertaken to identify ADR-associated proteins (ADRAPs) and pathways. Using the pathways and ADRAPs that this analysis identified, the mechanisms of SADRs such as cardiac disorders were explored. For instance, 53 putative ADRAPs and 24 pathways were linked with cardiac disorders, of which 10 ADRAPs were confirmed by previous experiments. Moreover, it was inferred that pathways such as base excision repair, glycolysis/glyconeogenesis, ErbB signaling, calcium signaling, and phosphatidyl inositol signaling likely play pivotal roles in drug-induced cardiac disorders. In conclusion, our framework offers an opportunity to globally understand SADRs at the molecular level, which has been difficult to realize through experiments. It also provides some valuable clues for drug repurposing. - Highlights: • A novel computational framework was developed for mechanistic study of SADRs. • Off-targets of drugs were identified in large scale and in a high-throughput manner. • SADRs like cardiac disorders were systematically explored in molecular networks. • A number of ADR-associated proteins were identified.

  15. Whole genome analysis of CRISPR Cas9 sgRNA off-target homologies via an efficient computational algorithm.

    Science.gov (United States)

    Zhou, Hong; Zhou, Michael; Li, Daisy; Manthey, Joseph; Lioutikova, Ekaterina; Wang, Hong; Zeng, Xiao

    2017-11-17

    The beauty and power of the genome editing mechanism, CRISPR Cas9 endonuclease system, lies in the fact that it is RNA-programmable such that Cas9 can be guided to any genomic loci complementary to a 20-nt RNA, single guide RNA (sgRNA), to cleave double stranded DNA, allowing the introduction of wanted mutations. Unfortunately, it has been reported repeatedly that the sgRNA can also guide Cas9 to off-target sites where the DNA sequence is homologous to sgRNA. Using human genome and Streptococcus pyogenes Cas9 (SpCas9) as an example, this article mathematically analyzed the probabilities of off-target homologies of sgRNAs and discovered that for large genome size such as human genome, potential off-target homologies are inevitable for sgRNA selection. A highly efficient computationl algorithm was developed for whole genome sgRNA design and off-target homology searches. By means of a dynamically constructed sequence-indexed database and a simplified sequence alignment method, this algorithm achieves very high efficiency while guaranteeing the identification of all existing potential off-target homologies. Via this algorithm, 1,876,775 sgRNAs were designed for the 19,153 human mRNA genes and only two sgRNAs were found to be free of off-target homology. By means of the novel and efficient sgRNA homology search algorithm introduced in this article, genome wide sgRNA design and off-target analysis were conducted and the results confirmed the mathematical analysis that for a sgRNA sequence, it is almost impossible to escape potential off-target homologies. Future innovations on the CRISPR Cas9 gene editing technology need to focus on how to eliminate the Cas9 off-target activity.

  16. Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach

    Directory of Open Access Journals (Sweden)

    Fan Shengjun

    2012-12-01

    Full Text Available Abstract Background Torcetrapib, a cholesteryl ester transfer protein (CETP inhibitor which raises high-density lipoprotein (HDL cholesterol and reduces low-density lipoprotein (LDL cholesterol level, has been documented to increase mortality and cardiac events associated with adverse effects. However, it is still unclear the underlying mechanisms of the off-target effects of torcetrapib. Results In the present study, we developed a systems biology approach by combining a human reassembled signaling network with the publicly available microarray gene expression data to provide unique insights into the off-target adverse effects for torcetrapib. Cytoscape with three plugins including BisoGenet, NetworkAnalyzer and ClusterONE was utilized to establish a context-specific drug-gene interaction network. The DAVID functional annotation tool was applied for gene ontology (GO analysis, while pathway enrichment analysis was clustered by ToppFun. Furthermore, potential off-targets of torcetrapib were predicted by a reverse docking approach. In general, 10503 nodes were retrieved from the integrative signaling network and 47660 inter-connected relations were obtained from the BisoGenet plugin. In addition, 388 significantly up-regulated genes were detected by Significance Analysis of Microarray (SAM in adrenal carcinoma cells treated with torcetrapib. After constructing the human signaling network, the over-expressed microarray genes were mapped to illustrate the context-specific network. Subsequently, three conspicuous gene regulatory networks (GRNs modules were unearthed, which contributed to the off-target effects of torcetrapib. GO analysis reflected dramatically over-represented biological processes associated with torcetrapib including activation of cell death, apoptosis and regulation of RNA metabolic process. Enriched signaling pathways uncovered that IL-2 Receptor Beta Chain in T cell Activation, Platelet-Derived Growth Factor Receptor (PDGFR beta

  17. Gamma rays as an effective tool for removing undesirable color without adverse changes in biological activities of red beet extracts

    Science.gov (United States)

    Lee, Seung Sik; Lee, Eun Mi; Hong, Sung Hyun; Bai, Hyoung-Woo; Lee, In Chul; Chung, Byung Yeoup

    2012-08-01

    The ethanolic extracts of red beet (Beta vulgaris L.) hairy root were used to investigate the removal of color and improvement of biological activity for enhanced industrial applications. The extracts were exposed to gamma rays ranging from 2.5 to 30 kGy. The red beet hairy root is composed of two major red-colorants, betanin and isobetanin. Gamma ray radiation at 5 kGy remarkably reduced the levels of the major colorants by 94% and the reddish color was eliminated by doses greater than 10 kGy. Color removal was likely due to the gamma ray radiolysis of ethanol. Although details on the mechanism responsible for the decay of the chromophore have not been entirely determined, our results suggest that the free radicals that are produced during this process are capable of destroying the chromophore group in isobetanin, thus bleaching the substrate solution. In spite of the degradation of the major colorants, the biological activities of constituents of the extract such as DPPH radical scavenging and tyrosinase inhibition were negligibly affected by the gamma ray radiation up to 20 kGy. The antioxidant activity was 92.7% in control samples and 90.0-92.0% in irradiated samples (2.5-20 kGy), and a slight decrease to 87.5% was observed for gamma ray radiation at 30 kGy. In addition, tyrosinase inhibition activity has also the same pattern; the activity is slightly increased from 50.7% of control to 49.1-52.8% of irradiated samples (2.5-20 kGy) with a 46.8% at 30 kGy.

  18. Quantifying on- and off-target genome editing.

    Science.gov (United States)

    Hendel, Ayal; Fine, Eli J; Bao, Gang; Porteus, Matthew H

    2015-02-01

    Genome editing with engineered nucleases is a rapidly growing field thanks to transformative technologies that allow researchers to precisely alter genomes for numerous applications including basic research, biotechnology, and human gene therapy. While the ability to make precise and controlled changes at specified sites throughout the genome has grown tremendously in recent years, we still lack a comprehensive and standardized battery of assays for measuring the different genome editing outcomes created at endogenous genomic loci. Here we review the existing assays for quantifying on- and off-target genome editing and describe their utility in advancing the technology. We also highlight unmet assay needs for quantifying on- and off-target genome editing outcomes and discuss their importance for the genome editing field. Copyright © 2014 Elsevier Ltd. All rights reserved.

  19. Filtering Undesirable Flows in Networks

    NARCIS (Netherlands)

    Polevoy, G.; Trajanovski, S.; Grosso, P.; de Laat, C.; Gao, X.; Du, H.; Han, M.

    2017-01-01

    We study the problem of fully mitigating the effects of denial of service by filtering the minimum necessary set of the undesirable flows. First, we model this problem and then we concentrate on a subproblem where every good flow has a bottleneck. We prove that unless P=NP, this subproblem is

  20. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.

    Science.gov (United States)

    Janas, Maja M; Schlegel, Mark K; Harbison, Carole E; Yilmaz, Vedat O; Jiang, Yongfeng; Parmar, Rubina; Zlatev, Ivan; Castoreno, Adam; Xu, Huilei; Shulga-Morskaya, Svetlana; Rajeev, Kallanthottathil G; Manoharan, Muthiah; Keirstead, Natalie D; Maier, Martin A; Jadhav, Vasant

    2018-02-19

    Small interfering RNAs (siRNAs) conjugated to a trivalent N-acetylgalactosamine (GalNAc) ligand are being evaluated in investigational clinical studies for a variety of indications. The typical development candidate selection process includes evaluation of the most active compounds for toxicity in rats at pharmacologically exaggerated doses. The subset of GalNAc-siRNAs that show rat hepatotoxicity is not advanced to clinical development. Potential mechanisms of hepatotoxicity can be associated with the intracellular accumulation of oligonucleotides and their metabolites, RNA interference (RNAi)-mediated hybridization-based off-target effects, and/or perturbation of endogenous RNAi pathways. Here we show that rodent hepatotoxicity observed at supratherapeutic exposures can be largely attributed to RNAi-mediated off-target effects, but not chemical modifications or the perturbation of RNAi pathways. Furthermore, these off-target effects can be mitigated by modulating seed-pairing using a thermally destabilizing chemical modification, which significantly improves the safety profile of a GalNAc-siRNA in rat and may minimize the occurrence of hepatotoxic siRNAs across species.

  1. Whole-Genome Thermodynamic Analysis Reduces siRNA Off-Target Effects

    Science.gov (United States)

    Chen, Xi; Liu, Peng; Chou, Hui-Hsien

    2013-01-01

    Small interfering RNAs (siRNAs) are important tools for knocking down targeted genes, and have been widely applied to biological and biomedical research. To design siRNAs, two important aspects must be considered: the potency in knocking down target genes and the off-target effect on any nontarget genes. Although many studies have produced useful tools to design potent siRNAs, off-target prevention has mostly been delegated to sequence-level alignment tools such as BLAST. We hypothesize that whole-genome thermodynamic analysis can identify potential off-targets with higher precision and help us avoid siRNAs that may have strong off-target effects. To validate this hypothesis, two siRNA sets were designed to target three human genes IDH1, ITPR2 and TRIM28. They were selected from the output of two popular siRNA design tools, siDirect and siDesign. Both siRNA design tools have incorporated sequence-level screening to avoid off-targets, thus their output is believed to be optimal. However, one of the sets we tested has off-target genes predicted by Picky, a whole-genome thermodynamic analysis tool. Picky can identify off-target genes that may hybridize to a siRNA within a user-specified melting temperature range. Our experiments validated that some off-target genes predicted by Picky can indeed be inhibited by siRNAs. Similar experiments were performed using commercially available siRNAs and a few off-target genes were also found to be inhibited as predicted by Picky. In summary, we demonstrate that whole-genome thermodynamic analysis can identify off-target genes that are missed in sequence-level screening. Because Picky prediction is deterministic according to thermodynamics, if a siRNA candidate has no Picky predicted off-targets, it is unlikely to cause off-target effects. Therefore, we recommend including Picky as an additional screening step in siRNA design. PMID:23484018

  2. Off-target responses in the HeLa proteome subsequent to transient plasmid-mediated transfection.

    Science.gov (United States)

    Hagen, Lars; Sharma, Animesh; Aas, Per Arne; Slupphaug, Geir

    2015-01-01

    Transient transfection of mammalian cells with plasmid expression vectors and chemical transfection reagents is widely used to study protein transport and dynamics as well as phenotypic alterations mediated by the overexpressed protein. Despite the undisputed impact of this technique, surprisingly little is known about the cellular effects mediated by the transfection process per se. Conceivably, off-target effects could have implications upon proteins or processes being studied and understanding the molecular pathways affected would add value to the interpretation of experimental observations subsequent to cell transfection. Here we have used a SILAC-based proteomic approach to study differentially expressed proteins after transfection of HeLa cells with ECFP vector using a commonly employed non-liposome based transfection reagent, Fugene®HD. Whereas the transfection reagent itself mediated minimal effects upon protein expression, 11 proteins were found to be significantly upregulated after transfection, all of which were associated with an interferon type I/II response. The upregulated proteins might potentially inflict major cellular processes such as RNA splicing, chromatin remodeling, post-translational protein modification and cell cycle control. The results were validated by western analysis as well as quantitative RT-PCR and this demonstrated that an essentially identical response was induced in HeLa by transfection using an empty pUC18 vector, which does not contain a mammalian virus promoter, as well as a liposome-based transfection reagent, Lipofectamine(TM)2000. Notably, no induction of the interferon response was observed in HEK293 cells, suggesting that these cells might be preferable to HeLa to avoid undesired off-target effects in transfection studies encompassing interferon-signaling and antiviral responses. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Evaluation of the impact on food safety of a Lactobacillus coryniformis strain from pickled vegetables with degradation activity against nitrite and other undesirable compounds.

    Science.gov (United States)

    Fang, Fang; Feng, Tingting; Du, Guocheng; Chen, Jian

    2016-01-01

    Four strains of lactic acid bacteria showing antimicrobial activity against some food-spoilage microorganisms or pathogens, including both Gram-negative and -positive strains, were isolated from naturally fermented pickled vegetables and a traditional cheese product. Among these isolates, Lactobacillus coryniformis strain BBE-H3, characterised previously to be a non-biogenic amine producer, showed a high level of activity in degrading sodium nitrite and exhibited the ability to eliminate ethyl carbamate and one of its precursors, urea. The antimicrobial substance produced by L. coryniformis BBE-H3 was found to be active at an acidic pH range of 4.0-4.5. The antimicrobial activity of this strain decreased differentially after treatment with proteolytic enzymes (pepsin, papain, trypsin and proteinase K), implying this growth inhibitory compound is either a protein or a polypeptide. The results of this study show the suitability of L. coryniformis BBE-H3 as a starter in food manufacturing processes, and demonstrate its potential role in eliminating food origin carcinogens such as sodium nitrite and ethyl carbamate.

  4. Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast.

    Directory of Open Access Journals (Sweden)

    Elke Ericson

    2008-08-01

    Full Text Available To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac interfered with establishment of cell polarity, cyproheptadine (Periactin targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol and pimozide (Orap. Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes.

  5. Exploiting off-targeting in guide-RNAs for CRISPR systems for simultaneous editing of multiple genes

    DEFF Research Database (Denmark)

    Ferreira, Raphael; Gatto, Francesco; Nielsen, Jens

    2017-01-01

    Bioinformatics tools to design guide-RNAs (gRNAs) in Clustered Regularly Interspaced Short Palindromic Repeats systems mostly focused on minimizing off-targeting to enhance efficacy of genome editing. However, there are circumstances in which off-targeting might be desirable to target multiple ge...

  6. Synthesis of Superparamagnetic Core-Shell Structure Supported Pd Nanocatalysts for Catalytic Nitrite Reduction with Enhanced Activity, No Detection of Undesirable Product of Ammonium, and Easy Magnetic Separation Capability.

    Science.gov (United States)

    Sun, Wuzhu; Yang, Weiyi; Xu, Zhengchao; Li, Qi; Shang, Jian Ku

    2016-01-27

    Superparamagnetic nanocatalysts could minimize both the external and internal mass transport limitations and neutralize OH(-) produced in the reaction more effectively to enhance the catalytic nitrite reduction efficiency with the depressed product selectivity to undesirable ammonium, while possess an easy magnetic separation capability. However, commonly used qusi-monodispersed superparamagnetic Fe3O4 nanosphere is not suitable as catalyst support for nitrite reduction because it could reduce the catalytic reaction efficiency and the product selectivity to N2, and the iron leakage could bring secondary contamination to the treated water. In this study, protective shells of SiO2, polymethylacrylic acid, and carbon were introduced to synthesize Fe3O4@SiO2/Pd, Fe3O4@PMAA/Pd, and Fe3O4@C/Pd catalysts for catalytic nitrite reduction. It was found that SiO2 shell could provide the complete protection to Fe3O4 nanosphere core among these shells. Because of its good dispersion, dense structure, and complete protection to Fe3O4, the Fe3O4@SiO2/Pd catalyst demonstrated the highest catalytic nitrite reduction activity without the detection of NH4(+) produced. Due to this unique structure, the activity of Fe3O4@SiO2/Pd catalysts for nitrite reduction was found to be independent of the Pd nanoparticle size or shape, and their product selectivity was independent of the Pd nanoparticle size, shape, and content. Furthermore, their superparamagnetic nature and high saturation magnetization allowed their easy magnetic separation from treated water, and they also demonstrated a good stability during the subsequent recycling experiment.

  7. Single base mismatches in the mRNA target site allow specific seed region-mediated off-target binding of siRNA targeting human coagulation factor 7.

    Science.gov (United States)

    Ravon, Morgane; Berrera, Marco; Ebeling, Martin; Certa, Ulrich

    2012-01-01

    We have analyzed the off-target activity of two siRNAs (F7-1, F7-2) that knock-down human blood coagulation factor 7 mRNA. F7-1 modulates a significant number of non-target transcripts while F7-2 shows high selectivity for the target transcript under various experimental conditions. The 3'-UTRs of all F7-1 off-target genes show statistically significant enrichment of the reverse complement of the F7-1 siRNA seed region located in the guide strand. Seed region enrichment was confirmed in off-target transcripts modulated by siRNA targeting the glucocorticoid receptor. To investigate how these sites contribute to off-target recognition of F7-1, we employed CXCL5 transcript as model system because it contains five F7-1 seed sequence motifs with single base mismatches. We show by transient transfection of reporter gene constructs into HEK293 cells that three out of five sites located in the 3'-UTR region are required for F7-1 off-target activity. For further mechanistic dissection, the sequences of these sites were synthesized and inserted either individually or joined in dimeric or trimeric constructs. Only the fusion constructs were silenced by F7-1 while the individual sites had no off-target activity. Based on F7-1 as a model, a single mismatch between the siRNA seed region and mRNA target sites is tolerated for target recognition and the CXCL5 data suggest a requirement for binding to multiple target sites in off-target transcripts.

  8. COSMID: A Web-based Tool for Identifying and Validating CRISPR/Cas Off-target Sites

    Directory of Open Access Journals (Sweden)

    Thomas J Cradick

    2014-01-01

    Full Text Available Precise genome editing using engineered nucleases can significantly facilitate biological studies and disease treatment. In particular, clustered regularly interspaced short palindromic repeats (CRISPR with CRISPR-associated (Cas proteins are a potentially powerful tool for modifying a genome by targeted cleavage of DNA sequences complementary to designed guide strand RNAs. Although CRISPR/Cas systems can have on-target cleavage rates close to the transfection rates, they may also have relatively high off-target cleavage at similar genomic sites that contain one or more base pair mismatches, and insertions or deletions relative to the guide strand. We have developed a bioinformatics-based tool, COSMID (CRISPR Off-target Sites with Mismatches, Insertions, and Deletions that searches genomes for potential off-target sites (http://crispr.bme.gatech.edu. Based on the user-supplied guide strand and input parameters, COSMID identifies potential off-target sites with the specified number of mismatched bases and insertions or deletions when compared with the guide strand. For each site, amplification primers optimal for the chosen application are also given as output. This ranked-list of potential off-target sites assists the choice and evaluation of intended target sites, thus helping the design of CRISPR/Cas systems with minimal off-target effects, as well as the identification and quantification of CRISPR/Cas induced off-target cleavage in cells.

  9. Undesirable effects after treatment with dermal fillers.

    Science.gov (United States)

    Rodrigues-Barata, Ana Rita; Camacho-Martínez, Francisco M

    2013-04-01

    Soft tissue augmentation is one of the most frequent techniques in cosmetic dermatology. Nowadays, there are a high number of available materials. Nonanimal hyaluronic acid (HA) is one of most useful fillers for lip augmentation and for treating nasolabial folds, marionette lines, and the dynamic wrinkles of the upper face. To evaluate the type and management of undesirable effects of nonanimal reticulated or stabilized HA observed in our cosmetic unit in the past 3 years. The consecutive patients using HA attending to our clinic in the past 3 years were divided into 3 categories, according to the time of presentation of the adverse reactions: immediate, early, and late-onset complications. All patients were treated. Twenty-three patients presented to our clinic complaining of complications after soft tissue augmentation with HA. Ten patients presented immediate-onset complications, 8 showed early-onset complications, and 5 cases complaint of late-onset complications. Treatment of the first group consisted of hyaluronidase injection, massage, and topical antibiotics. Early- and late-onset complications were treated with intralesional triamcinolone acetonide. All patients improved, with the exception of a woman with recurrent granulomas. Generally, undesirable effects of HA (immediate, early, or late onset) are not frequent, and when present, they improve if treated properly. Physicians need to be aware of these possible adverse events in order to establish proper treatment and prevent scarring or other sequelae.

  10. The undesirable effects of neuromuscular blocking drugs

    DEFF Research Database (Denmark)

    Claudius, C; Garvey, L H; Viby-Mogensen, J

    2009-01-01

    Neuromuscular blocking drugs are designed to bind to the nicotinic receptor at the neuromuscular junction. However, they also interact with other acetylcholine receptors in the body. Binding to these receptors causes adverse effects that vary with the specificity for the cholinergic receptor...... in question. Moreover, all neuromuscular blocking drugs may cause hypersensitivity reactions. Often the symptoms are mild and self-limiting but massive histamine release can cause systematic reactions with circulatory and respiratory symptoms and signs. At the end of anaesthesia, no residual effect...... of a neuromuscular blocking drug should be present. However, the huge variability in response to neuromuscular blocking drugs makes it impossible to predict which patient will suffer postoperative residual curarization. This article discusses the undesirable effects of the currently available neuromuscular blocking...

  11. Off-target effects of sulforaphane include the derepression of long terminal repeats through histone acetylation events.

    Science.gov (United States)

    Baier, Scott R; Zbasnik, Richard; Schlegel, Vicki; Zempleni, Janos

    2014-06-01

    Sulforaphane is a naturally occurring isothiocyanate in cruciferous vegetables. Sulforaphane inhibits histone deacetylases, leading to the transcriptional activation of genes including tumor suppressor genes. The compound has attracted considerable attention in the chemoprevention of prostate cancer. Here we tested the hypothesis that sulforaphane is not specific for tumor suppressor genes but also activates loci such as long terminal repeats (LTRs), which might impair genome stability. Studies were conducted using chemically pure sulforaphane in primary human IMR-90 fibroblasts and in broccoli sprout feeding studies in healthy adults. Sulforaphane (2.0 μM) caused an increase in LTR transcriptional activity in cultured cells. Consumption of broccoli sprouts (34, 68 or 102 g) by human volunteers caused a dose dependent elevation in LTR mRNA in circulating leukocytes, peaking at more than a 10-fold increase. This increase in transcript levels was associated with an increase in histone H3 K9 acetylation marks in LTR 15 in peripheral blood mononuclear cells from subjects consuming sprouts. Collectively, this study suggests that sulforaphane has off-target effects that warrant further investigation when recommending high levels of sulforaphane intake, despite its promising activities in chemoprevention. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Editor's Highlight: Off-Target Effects of Neuroleptics and Antidepressants on Saccharomyces cerevisiae.

    Science.gov (United States)

    Caldara, Marina; Graziano, Sara; Gullì, Mariolina; Cadonici, Stefania; Marmiroli, Nelson

    2017-04-01

    Over the past years, the use of antidepressants and neuroleptics has steadily increased. Although incredibly useful to treat disorders like depression, schizophrenia, epilepsy, or mental retardation, these drugs display many side effects. Toxicogenomic studies aim to limit this problem by trying to identify cellular targets and off-targets of medical compounds. The baker yeast Saccharomyces cerevisiae has been shown to be a key player in this approach, as it represents an incredible toolbox for the dissection of complex biological processes. Moreover, the evolutionary conservation of many pathways allows the translation of yeast data to the human system. In this paper, a better attention was paid to chlorpromazine, as it still is one of the most widely used drug in therapy. The results of a toxicogenomic screening performed on a yeast mutants collection treated with chlorpromazine were instrumental to identify a set of genes for further analyses. For this purpose, a multidisciplinary approach was used based on growth phenotypes identification, Gene Ontology search, and network analysis. Then, the impacts of three antidepressants (imipramine, doxepin, and nortriptyline) and three neuroleptics (promazine, chlorpromazine, and promethazine) on S. cerevisiae were compared through physiological analyses, microscopy characterization, and transcriptomic studies. Data highlight key differences between neuroleptics and antidepressants, but also between the individual molecules. By performing a network analysis on the human homologous genes, it emerged that genes and proteins involved in the Notch pathway are possible off-targets of these molecules, along with key regulatory proteins. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Transient overexpression of DNA adenine methylase enables efficient and mobile genome engineering with reduced off-target effects

    DEFF Research Database (Denmark)

    Lennen, Rebecca; Nilsson Wallin, Annika; Pedersen, Margit

    2016-01-01

    Homologous recombination of single-stranded oligonucleotides is a highly efficient process for introducing precise mutations into the genome of E. coli and other organisms when mismatch repair (MMR) is disabled. This can result in the rapid accumulation of off-target mutations that can mask desired...... replacement to the use of strains with fully disabled MMR and with an approximately 12- to 33-fold lower off-target mutation rate. Furthermore, growth temperatures are not restricted and a version of the plasmid can be readily removed by sucrose counterselection. TM-MAGE was used to combinatorially...

  14. Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors.

    Science.gov (United States)

    Bertrand, Daniel; Bertrand, Sonia; Neveu, Estelle; Fernandes, Prabhavathi

    2010-12-01

    Adverse effects have limited the clinical use of telithromycin. Preferential inhibition of the nicotinic acetylcholine receptors (nAChR) at the neuromuscular junction (α3β2 and NMJ), the ciliary ganglion of the eye (α3β4 and α7), and the vagus nerve innervating the liver (α7) could account for the exacerbation of myasthenia gravis, the visual disturbance, and the liver failure seen with telithromycin use. The studies presented here enable the prediction of expected side effects of macrolides in development, such as solithromycin (CEM-101).

  15. siRNAs with decreased off-target effect facilitate the identification of essential genes in cancer cells.

    Science.gov (United States)

    Li, Chunyan; Liu, Zhenzhen; Yang, Fang; Liu, Wensheng; Wang, Di; Dong, Encheng; Wang, Yu; Wu, Chung-I; Lu, Xuemei

    2015-08-28

    Since the essential genes are crucial to the proliferation and survival of cancer cells, the interference of these genes is promising to be an option for cancer therapy to overcome heterogeneity. However, the essential genes are highly overestimated by RNA interference (RNAi) screenings, which is mainly caused by the pervasive off-target effect of small interference RNA (siRNA) and short hairpin RNA (shRNA). In the present study, we designed Match-Mismatch paired siRNAs to discriminate the on-target effect from off-target effect of siRNAs on cell viability. Only one of the 7 potential essential genes was validated as essential to cell viability, which demonstrates the high false positive rate in RNAi screenings. We modified the siRNA by introducing random nucleotides (N) into the guide strand to mitigate the off-target effect, without significantly compromising the on-target effect. The whole transcriptome profile analysis of cells transfected with siRNAs with or without Nindicates that siRNA-dN (with Ns on both the 2nd and the 18th bases of the guide strand) weakens the off-target effect by decreasing the unintended targets. The optimized siRNAs can be applied in the characterization of essential genes in cancer cells.

  16. Self-organizing molecular fingerprints: a ligand-based view on drug-like chemical space and off-target prediction.

    Science.gov (United States)

    Schneider, Gisbert; Tanrikulu, Yusuf; Schneider, Petra

    2009-04-01

    Reliable prediction of multiple ligand-receptor interactions for a given bioactive compound helps recognize and understand off-target effects, and enables drug re-purposing and scaffold-hopping in lead discovery. We developed a ligand-based computational method for drug-target prediction that is independent from protein structural analysis. The idea is to infer drug targets from the pharmacophoric feature similarity of known ligands, and define functional target similarity from a ligand perspective, which also provides access to targets with unknown structures. First, known ligands were represented by topological pharmacophoric features. Then, the self-organizing map technique was used to generate fingerprint patterns for similarity analysis, where each resulting fingerprint represents a drug target. Target fingerprints were clustered and analyzed for correlations. Well-structured dendrograms were obtained presenting interpretable and meaningful relationships between drug targets. Self-organization of fingerprints reduces noise from molecular pharmacophore descriptors, captures their essential features, and reveals potential cross-activities of ligand classes and off-target effects of bioactive compounds.

  17. Myostatin gene knockout mediated by Cas9-D10A nickase in chicken DF1 cells without off-target effect

    Directory of Open Access Journals (Sweden)

    Jeong Hyo Lee

    2017-05-01

    Full Text Available Objective Based on rapid advancement of genetic modification techniques, genomic editing is expected to become the most efficient tool for improvement of economic traits in livestock as well as poultry. In this study, we examined and verified the nickase of mutated CRISPR-associated protein 9 (Cas9 to modulate the specific target gene in chicken DF1 cells. Methods Chicken myostatin which inhibits muscle cell growth and differentiation during myogenesis was targeted to be deleted and mutated by the Cas9-D10A nickase. After co-transfection of the nickase expression vector with green fluorescent gene (GFP gene and targeted multiplex guide RNAs (gRNAs, the GFP-positive cells were sorted out by fluorescence-activated cell sorting procedure. Results Through the genotyping analysis of the knockout cells, the mutant induction efficiency was 100% in the targeted site. Number of the deleted nucleotides ranged from 2 to 39 nucleotide deletion. There was no phenotypic difference between regular cells and knockout cells. However, myostatin protein was not apparently detected in the knockout cells by Western blotting. Additionally, six off-target sites were predicted and analyzed but any non-specific mutation in the off-target sites was not observed. Conclusion The knockout technical platform with the nickase and multiplex gRNAs can be efficiently and stablely applied to functional genomics study in poultry and finally adapted to generate the knockout poultry for agribio industry.

  18. Potential high-frequency off-target mutagenesis induced by CRISPR/Cas9 in Arabidopsis and its prevention.

    Science.gov (United States)

    Zhang, Qiang; Xing, Hui-Li; Wang, Zhi-Ping; Zhang, Hai-Yan; Yang, Fang; Wang, Xue-Chen; Chen, Qi-Jun

    2018-02-23

    We present novel observations of high-specificity SpCas9 variants, sgRNA expression strategies based on mutant sgRNA scaffold and tRNA processing system, and CRISPR/Cas9-mediated T-DNA integrations. Specificity of CRISPR/Cas9 tools has been a major concern along with the reports of their successful applications. We report unexpected observations of high frequency off-target mutagenesis induced by CRISPR/Cas9 in T1 Arabidopsis mutants although the sgRNA was predicted to have a high specificity score. We also present evidence that the off-target effects were further exacerbated in the T2 progeny. To prevent the off-target effects, we tested and optimized two strategies in Arabidopsis, including introduction of a mCherry cassette for a simple and reliable isolation of Cas9-free mutants and the use of highly specific mutant SpCas9 variants. Optimization of the mCherry vectors and subsequent validation found that fusion of tRNA with the mutant rather than the original sgRNA scaffold significantly improves editing efficiency. We then examined the editing efficiency of eight high-specificity SpCas9 variants in combination with the improved tRNA-sgRNA fusion strategy. Our results suggest that highly specific SpCas9 variants require a higher level of expression than their wild-type counterpart to maintain high editing efficiency. Additionally, we demonstrate that T-DNA can be inserted into the cleavage sites of CRISPR/Cas9 targets with high frequency. Altogether, our results suggest that in plants, continuous attention should be paid to off-target effects induced by CRISPR/Cas9 in current and subsequent generations, and that the tools optimized in this report will be useful in improving genome editing efficiency and specificity in plants and other organisms.

  19. Off-Target V(DJ Recombination Drives Lymphomagenesis and Is Escalated by Loss of the Rag2 C Terminus

    Directory of Open Access Journals (Sweden)

    Martina Mijušković

    2015-09-01

    Full Text Available Genome-wide analysis of thymic lymphomas from Tp53−/− mice with wild-type or C-terminally truncated Rag2 revealed numerous off-target, RAG-mediated DNA rearrangements. A significantly higher fraction of these errors mutated known and suspected oncogenes/tumor suppressor genes than did sporadic rearrangements (p < 0.0001. This tractable mouse model recapitulates recent findings in human pre-B ALL and allows comparison of wild-type and mutant RAG2. Recurrent, RAG-mediated deletions affected Notch1, Pten, Ikzf1, Jak1, Phlda1, Trat1, and Agpat9. Rag2 truncation substantially increased the frequency of off-target V(DJ recombination. The data suggest that interactions between Rag2 and a specific chromatin modification, H3K4me3, support V(DJ recombination fidelity. Oncogenic effects of off-target rearrangements created by this highly regulated recombinase may need to be considered in design of site-specific nucleases engineered for genome modification.

  20. Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case.

    Science.gov (United States)

    Marquié, Marta; Verwer, Eline E; Meltzer, Avery C; Kim, Sally Ji Who; Agüero, Cinthya; Gonzalez, Jose; Makaretz, Sara J; Siao Tick Chong, Michael; Ramanan, Prianca; Amaral, Ana C; Normandin, Marc D; Vanderburg, Charles R; Gomperts, Stephen N; Johnson, Keith A; Frosch, Matthew P; Gómez-Isla, Teresa

    2017-10-19

    [F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer's disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptake has also consistently been observed in midbrain, basal ganglia and choroid plexus in elderly individuals regardless of their clinical diagnosis, including clinically normal whose brains are not expected to harbor tau pathology in those areas. We and others have shown that [F-18]-AV-1451 exhibits off-target binding to neuromelanin, melanin and blood products on postmortem material; and this is important for the correct interpretation of PET images. In the present study, we further investigated [F-18]-AV-1451 off-target binding in the first autopsy-confirmed Parkinson's disease (PD) subject who underwent antemortem PET imaging. The PET scan showed elevated [F-18]-AV-1451 retention predominantly in inferior temporal cortex, basal ganglia, midbrain and choroid plexus. Neuropathologic examination confirmed the PD diagnosis. Phosphor screen and high resolution autoradiography failed to show detectable [F-18]-AV-1451 binding in multiple brain regions examined with the exception of neuromelanin-containing neurons in the substantia nigra, leptomeningeal melanocytes adjacent to ventricles and midbrain, and microhemorrhages in the occipital cortex (all reflecting off-target binding), in addition to incidental age-related neurofibrillary tangles in the entorhinal cortex. Additional legacy postmortem brain samples containing basal ganglia, choroid plexus, and parenchymal hemorrhages from 20 subjects with various neuropathologic diagnoses were also included in the autoradiography experiments to better understand what [F-18]-AV-1451 in vivo positivity in those regions means. No detectable [F-18]-AV-1451 autoradiographic binding was

  1. TARGETED AND OFF-TARGET (BYSTANDER AND ABSCOPAL) EFFECTS OF RADIATION THERAPY: REDOX MECHANISMS AND RISK-BENEFIT ANALYSIS.

    Science.gov (United States)

    Pouget, Jean-Pierre; Georgakilas, Alexandros G; Ravanat, Jean-Luc

    2018-01-19

    Radiation therapy (from external beams to unsealed and sealed radionuclide sources) takes advantage of the detrimental effects of the clustered production of radicals and reactive oxygen species (ROS). Research has mainly focused on the interaction of radiation with water, which is the major constituent of living beings, and with nuclear DNA, which contains the genetic information. This led to the so-called "target" theory according to which cells have to be hit by ionizing particles to elicit an important biological response, including cell death. In cancer therapy, the Poisson law and linear quadratic mathematical models have been used to describe the probability of hits per cell as a function of the radiation dose. However, in the last twenty years, many studies have shown that radiation generates "danger" signals that propagate from irradiated to non-irradiated cells, leading to bystander and other off-target effects. Like for targeted effects, redox mechanisms play a key role also in off-target effects through transmission of ROS and reactive nitrogen species (RNS), but also of cytokines, ATP and extracellular DNA. Particularly, nuclear factor kappa B is essential for triggering self-sustained production of ROS and RNS, thus making the bystander response similar to inflammation. In some therapeutic situations, this phenomenon is associated with recruitment of immune cells that are involved in distant irradiation effects (called "away-from-target" i.e. abscopal effects). Determining the contribution of targeted and off-target effects in the clinic is still challenging. This has important consequences in radiotherapy, but also possibly in diagnostic procedures and in radiation protection.

  2. Accurate Local-Ancestry Inference in Exome-Sequenced Admixed Individuals via Off-Target Sequence Reads

    Science.gov (United States)

    Hu, Youna; Willer, Cristen; Zhan, Xiaowei; Kang, Hyun Min; Abecasis, Gonçalo R.

    2013-01-01

    Estimates of the ancestry of specific chromosomal regions in admixed individuals are useful for studies of human evolutionary history and for genetic association studies. Previously, this ancestry inference relied on high-quality genotypes from genome-wide association study (GWAS) arrays. These high-quality genotypes are not always available when samples are exome sequenced, and exome sequencing is the strategy of choice for many ongoing genetic studies. Here we show that off-target reads generated during exome-sequencing experiments can be combined with on-target reads to accurately estimate the ancestry of each chromosomal segment in an admixed individual. To reconstruct local ancestry, our method SEQMIX models aligned bases directly instead of relying on hard genotype calls. We evaluate the accuracy of our method through simulations and analysis of samples sequenced by the 1000 Genomes Project and the NHLBI Grand Opportunity Exome Sequencing Project. In African Americans, we show that local-ancestry estimates derived by our method are very similar to those derived with Illumina’s Omni 2.5M genotyping array and much improved in relation to estimates that use only exome genotypes and ignore off-target sequencing reads. Software implementing this method, SEQMIX, can be applied to analysis of human population history or used for genetic association studies in admixed individuals. PMID:24210252

  3. Accurate mitochondrial DNA sequencing using off-target reads provides a single test to identify pathogenic point mutations.

    Science.gov (United States)

    Griffin, Helen R; Pyle, Angela; Blakely, Emma L; Alston, Charlotte L; Duff, Jennifer; Hudson, Gavin; Horvath, Rita; Wilson, Ian J; Santibanez-Koref, Mauro; Taylor, Robert W; Chinnery, Patrick F

    2014-12-01

    Mitochondrial disorders are a common cause of inherited metabolic disease and can be due to mutations affecting mitochondrial DNA or nuclear DNA. The current diagnostic approach involves the targeted resequencing of mitochondrial DNA and candidate nuclear genes, usually proceeds step by step, and is time consuming and costly. Recent evidence suggests that variations in mitochondrial DNA sequence can be obtained from whole-exome sequence data, raising the possibility of a comprehensive single diagnostic test to detect pathogenic point mutations. We compared the mitochondrial DNA sequence derived from off-target exome reads with conventional mitochondrial DNA Sanger sequencing in 46 subjects. Mitochondrial DNA sequences can be reliably obtained using three different whole-exome sequence capture kits. Coverage correlates with the relative amount of mitochondrial DNA in the original genomic DNA sample, heteroplasmy levels can be determined using variant and total read depths, and-providing there is a minimum read depth of 20-fold-rare sequencing errors occur at a rate similar to that observed with conventional Sanger sequencing. This offers the prospect of using whole-exome sequence in a diagnostic setting to screen not only all protein coding nuclear genes but also all mitochondrial DNA genes for pathogenic mutations. Off-target mitochondrial DNA reads can also be used to assess quality control and maternal ancestry, inform on ethnic origin, and allow genetic disease association studies not previously anticipated with existing whole-exome data sets.

  4. Off-Target18F-AV-1451 Binding in the Basal Ganglia Correlates with Age-Related Iron Accumulation.

    Science.gov (United States)

    Choi, Jae Yong; Cho, Hanna; Ahn, Sung Jun; Lee, Jae Hoon; Ryu, Young Hoon; Lee, Myung Sik; Lyoo, Chul Hyoung

    2018-01-01

    Off-target binding in the basal ganglia is commonly observed in the 18 F-AV-1451 PET studies of the elderly. We sought to investigate the relationship between this phenomenon in the basal ganglia and iron accumulation using iron-sensitive R 2 * MRI. Methods: Fifty-nine healthy controls and 61 patients with Alzheimer disease and mild cognitive impairment underwent 18 F-AV-1451 PET and R 2 * MRI studies. A correlation analysis was performed for age, 18 F-AV-1451 binding, and R 2 * values. Results: There was an age-related increase in both 18 F-AV-1451 binding in the basal ganglia and R 2 * values in the putamen in both the controls and the Alzheimer disease/mild cognitive impairment patients. 18 F-AV-1451 binding in the basal ganglia increased with R 2 * values. Conclusion: Off-target 18 F-AV-1451 binding in the basal ganglia is associated with the age-related increases in iron accumulation. Postmortem studies are required to further investigate the nature of this association. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

  5. Directional R-Loop Formation by the CRISPR-Cas Surveillance Complex Cascade Provides Efficient Off-Target Site Rejection

    Directory of Open Access Journals (Sweden)

    Marius Rutkauskas

    2015-03-01

    Full Text Available CRISPR-Cas systems provide bacteria and archaea with adaptive immunity against foreign nucleic acids. In type I CRISPR-Cas systems, invading DNA is detected by a large ribonucleoprotein surveillance complex called Cascade. The crRNA component of Cascade is used to recognize target sites in foreign DNA (protospacers by formation of an R-loop driven by base-pairing complementarity. Using single-molecule supercoiling experiments with near base-pair resolution, we probe here the mechanism of R-loop formation and detect short-lived R-loop intermediates on off-target sites bearing single mismatches. We show that R-loops propagate directionally starting from the protospacer-adjacent motif (PAM. Upon reaching a mismatch, R-loop propagation stalls and collapses in a length-dependent manner. This unambiguously demonstrates that directional zipping of the R-loop accomplishes efficient target recognition by rapidly rejecting binding to off-target sites with PAM-proximal mutations. R-loops that reach the protospacer end become locked to license DNA degradation by the auxiliary Cas3 nuclease/helicase without further target verification.

  6. A two stage data envelopment analysis model with undesirable output

    Science.gov (United States)

    Shariff Adli Aminuddin, Adam; Izzati Jaini, Nur; Mat Kasim, Maznah; Nawawi, Mohd Kamal Mohd

    2017-09-01

    The dependent relationship among the decision making units (DMU) is usually assumed to be non-existent in the development of Data Envelopment Analysis (DEA) model. The dependency can be represented by the multi-stage DEA model, where the outputs from the precedent stage will be the inputs for the latter stage. The multi-stage DEA model evaluate both the efficiency score for each stages and the overall efficiency of the whole process. The existing multi stage DEA models do not focus on the integration with the undesirable output, in which the higher input will generate lower output unlike the normal desirable output. This research attempts to address the inclusion of such undesirable output and investigate the theoretical implication and potential application towards the development of multi-stage DEA model.

  7. A Case of Undesired Bleb Developed After Penetrating Injury

    Directory of Open Access Journals (Sweden)

    Cem Ozgonul

    2014-03-01

    Full Text Available Eighty-year-old male patient was admitted to our policlinic with stinging, burning and itching in both eyes. Ophthalmological examination revealed avascular undesired bleb that releated with anterior chamber at 2-3 hour quadrant nasal limbus with the surrounding corneal and conjunctival epithelium was vascularized and the dimension was 3x3x3 mm. Towards these findings, we questioned the patient again and we found that, 40 years ago, a broken part of the shaving razor had injured his eye. After penetrating injury of the eye, because of the sutured wound leakage, undesired bleb formations can be seen. We suggest that kind of patient shold be followed up to prevent late complications of penetrating injury.

  8. Cycles of undesirable substances in the food chain

    International Nuclear Information System (INIS)

    2012-01-01

    The working group ''Carry over of undesirable substances in animal feed'' at the Federal Ministry of Food, Agriculture and Forestry (BMELV) in cooperation with the Institute of Animal Nutrition of the Friedrich-Loeffler-Institute (FLI) performed on 27 and 28 October 2011 in Braunschweig a workshop on ''cycles of undesirable substances in Food Chain ''. The aim of the workshop was to present the latest findings of research and Carry over Recommendations of the Carry over - Working Group on undesirable substances in feed and production processes of the feed industry, to evaluate and discuss about this with representatives from science, business and management and to work out the further research and action need. The focus of the considerations were the pathways, the carry over and the Exposure to dioxins and other halogenated hydrocarbons, the effects of Mycotoxins in feed and starting points for preventive measures, the soil contamination and the exposure of humans and animals by cadmium and case studies on Nitrite in feed, antibiotics in plants and residues of pesticides and radionuclides in feed. Furthermore the risks associated with specified manufacturing processes of feed are considered, especially the used materials that come into contact with animal feed, and the risks from nanotechnology. [de

  9. A network model of genomic hormone interactions underlying dementia and its translational validation through serendipitous off-target effect

    Science.gov (United States)

    2013-01-01

    Background While the majority of studies have focused on the association between sex hormones and dementia, emerging evidence supports the role of other hormone signals in increasing dementia risk. However, due to the lack of an integrated view on mechanistic interactions of hormone signaling pathways associated with dementia, molecular mechanisms through which hormones contribute to the increased risk of dementia has remained unclear and capacity of translating hormone signals to potential therapeutic and diagnostic applications in relation to dementia has been undervalued. Methods Using an integrative knowledge- and data-driven approach, a global hormone interaction network in the context of dementia was constructed, which was further filtered down to a model of convergent hormone signaling pathways. This model was evaluated for its biological and clinical relevance through pathway recovery test, evidence-based analysis, and biomarker-guided analysis. Translational validation of the model was performed using the proposed novel mechanism discovery approach based on ‘serendipitous off-target effects’. Results Our results reveal the existence of a well-connected hormone interaction network underlying dementia. Seven hormone signaling pathways converge at the core of the hormone interaction network, which are shown to be mechanistically linked to the risk of dementia. Amongst these pathways, estrogen signaling pathway takes the major part in the model and insulin signaling pathway is analyzed for its association to learning and memory functions. Validation of the model through serendipitous off-target effects suggests that hormone signaling pathways substantially contribute to the pathogenesis of dementia. Conclusions The integrated network model of hormone interactions underlying dementia may serve as an initial translational platform for identifying potential therapeutic targets and candidate biomarkers for dementia-spectrum disorders such as Alzheimer

  10. The genome editing revolution: A CRISPR-Cas TALE off-target story.

    Science.gov (United States)

    Stella, Stefano; Montoya, Guillermo

    2016-07-01

    In the last 10 years, we have witnessed a blooming of targeted genome editing systems and applications. The area was revolutionized by the discovery and characterization of the transcription activator-like effector proteins, which are easier to engineer to target new DNA sequences than the previously available DNA binding templates, zinc fingers and meganucleases. Recently, the area experimented a quantum leap because of the introduction of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein (Cas) system (clustered regularly interspaced short palindromic sequence). This ribonucleoprotein complex protects bacteria from invading DNAs, and it was adapted to be used in genome editing. The CRISPR ribonucleic acid (RNA) molecule guides to the specific DNA site the Cas9 nuclease to cleave the DNA target. Two years and more than 1000 publications later, the CRISPR-Cas system has become the main tool for genome editing in many laboratories. Currently the targeted genome editing technology has been used in many fields and may be a possible approach for human gene therapy. Furthermore, it can also be used to modifying the genomes of model organisms for studying human pathways or to improve key organisms for biotechnological applications, such as plants, livestock genome as well as yeasts and bacterial strains. © 2016 The Authors. BioEssays published by WILEY Periodicals, Inc.

  11. Preferential Selectivity of Inhibitors with Human Tau Protein Kinase Gsk3 Elucidates Their Potential Roles for Off-Target Alzheimer’s Therapy

    Directory of Open Access Journals (Sweden)

    Jagadeesh Kumar Dasappa

    2013-01-01

    Full Text Available Alzheimer’s disease (AD is a neurodegenerative disorder characterized by the accumulation of amyloid beta peptides (A and neurofibrillary tangles (NFTs. The abnormal phosphorylation of tau leads to the formation of NFTs produced by the action of tau kinases, resulting in the loss of neurons and synapse, leading to dementia. Hence, tau kinases have become potential drug target candidates for small molecule inhibitors. With an aim to explore the identification of a common inhibitor, this investigation was undertaken towards analyzing all 10 tau kinases which are implicated in phosphorylation of AD. A set of 7 inhibitors with varied scaffolds were collected from the Protein Data Bank (PDB. The analysis, involving multiple sequence alignment, 3D structural alignment, catalytic active site overlap, and docking studies, has enabled elucidation of the pharmacophoric patterns for the class of 7 inhibitors. Our results divulge that tau protein kinases share a specific set of conserved structural elements for the binding of inhibitors and ATP, respectively. The scaffold of 3-aminopyrrolidine (inhibitor 6 exhibits high preferential affinity with GSK3. Surprisingly, the PDB does not contain the structural details of GSK3 with this specific inhibitor. Thus, our investigations provide vital clues towards design of novel off-target drugs for Alzheimer’s.

  12. Undesirable Effects of Media on Children: Why Limitation is Necessary?

    Science.gov (United States)

    Karaagac, Aysu Turkmen

    2015-06-01

    Pervasive media environment is a social problem shared by most of the countries around the world. Several studies have been performed to highlight the undesired effects of media on children. Some of these studies have focused on the time spent by children watching television, playing with computers or using mobile media devices while some others have tried to explain the associations between the obesity, postural abnormalities or psychological problems of children, and their media use. This article discusses the recent approaches to curb influence of media on children, and the importance of family media literacy education programs with particular relevance to developing countries.

  13. Undesirable substances in vegetable oils: anything to declare?

    Directory of Open Access Journals (Sweden)

    Lacoste Florence

    2014-01-01

    Full Text Available The presence of undesirable compounds in vegetable and animal oils and fats may have many different origins. Although the potential toxicity of most of these undesirable compounds is real, poisoning risks are rather limited due to the efficient elimination during oil-refining steps, careful conditioning, choice of efficient packaging and industrial quality control management. However the research of contaminants is part of multiple controls conducted by fat and oil industry to verify the conformity of products placed on the market in relation to regulations such as the European commission regulation EC No. 1881/2006 setting maximum levels for some contaminants in food as lead, some mycotoxins, dioxins, polychlorobiphenyls, benzo[a]pyrene. In the absence of regulation, the detection of contaminants must be addressed in partnership with authorities according to the toxicity of molecules. The controls are not confined to environmental contaminants. They also include compounds that can be formed during the production process of vegetable oils such as esters of 3-monochloropropanediol. This article focuses more particularly on heavy metals, polycyclic aromatic hydrocarbons, mineral oils, phthalates and 3-MCPD or glycidyl esters. Aspects such as methods for analysis, limits fixed by EC regulation and occurrence in vegetable oils are discussed.

  14. An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genome.

    Science.gov (United States)

    Hay, Elizabeth Anne; Khalaf, Abdulla Razak; Marini, Pietro; Brown, Andrew; Heath, Karyn; Sheppard, Darrin; MacKenzie, Alasdair

    2017-08-01

    We have successfully used comparative genomics to identify putative regulatory elements within the human genome that contribute to the tissue specific expression of neuropeptides such as galanin and receptors such as CB1. However, a previous inability to rapidly delete these elements from the mouse genome has prevented optimal assessment of their function in-vivo. This has been solved using CAS9/CRISPR genome editing technology which uses a bacterial endonuclease called CAS9 that, in combination with specifically designed guide RNA (gRNA) molecules, cuts specific regions of the mouse genome. However, reports of "off target" effects, whereby the CAS9 endonuclease is able to cut sites other than those targeted, limits the appeal of this technology. We used cytoplasmic microinjection of gRNA and CAS9 mRNA into 1-cell mouse embryos to rapidly generate enhancer knockout mouse lines. The current study describes our analysis of the genomes of these enhancer knockout lines to detect possible off-target effects. Bioinformatic analysis was used to identify the most likely putative off-target sites and to design PCR primers that would amplify these sequences from genomic DNA of founder enhancer deletion mouse lines. Amplified DNA was then sequenced and blasted against the mouse genome sequence to detect off-target effects. Using this approach we were unable to detect any evidence of off-target effects in the genomes of three founder lines using any of the four gRNAs used in the analysis. This study suggests that the problem of off-target effects in transgenic mice have been exaggerated and that CAS9/CRISPR represents a highly effective and accurate method of deleting putative neuropeptide gene enhancer sequences from the mouse genome. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD

    Directory of Open Access Journals (Sweden)

    Lindsay M. Wallace

    2018-03-01

    Full Text Available RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s. We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy.

  16. Targeting Visceral Fat by Intraperitoneal Delivery of Novel AAV Serotype Vector Restricting Off-Target Transduction in Liver

    Directory of Open Access Journals (Sweden)

    Wei Huang

    2017-09-01

    Full Text Available It is challenging to genetically manipulate fat in adults. We demonstrate that intraperitoneal (i.p. injection of an engineered adeno-associated virus (AAV serotype Rec2 leads to high transduction of multiple visceral fat depots at a dose of 1 to 2 orders lower than commonly used doses for systemic gene delivery. To target adipose tissue, we develop a single AAV vector harboring two expression cassettes: one using the CBA promoter to drive transgene expression and one using the liver-specific albumin promoter to drive a microRNA-targeting WPRE sequence that only exists in this AAV vector. This dual-cassette vector achieves highly selective transduction of visceral fat while severely restricting off-target transduction of liver. As proof of efficacy, i.p. administration of an adipose-targeting Rec2 vector harboring the leptin gene corrects leptin deficiency, obesity, and metabolic syndromes of ob/ob mice. This study provides a powerful tool to genetically manipulate fat for basic research and gene therapies of genetic and acquired diseases.

  17. Cosmetics Europe Guidelines on the Management of Undesirable Effects and Reporting of Serious Undesirable Effects from Cosmetics in the European Union

    Directory of Open Access Journals (Sweden)

    Gerald Renner

    2017-01-01

    Full Text Available The European Union (EU Cosmetics Regulation (EC No. 1223/2009 requires companies to collect and assess reports of adverse health effects from the cosmetic products (undesirable effects they market. Furthermore, undesirable effects that are considered as serious need to be reported to the national competent authorities. Cosmetics Europe, representing the European cosmetics industry, has developed these guidelines to promote a consistent practical approach for the management of undesirable effects and the notification of serious undesirable effects. Following these guidelines allows companies concerned to demonstrate due diligence and compliance with the legal requirements.

  18. CFD simulation of pesticide spray from air-assisted sprayers in an apple orchard: tree deposition and off-target losses

    Science.gov (United States)

    The ultimate goal of a pesticide spraying system is to provide adequate coverage on intended canopies with a minimum amount of spray materials and off-target waste. Better spray coverage requires an understanding of the fate and transport of spray droplets carried by turbulent airflows in orchards. ...

  19. Circular siRNAs for Reducing Off-Target Effects and Enhancing Long-Term Gene Silencing in Cells and Mice.

    Science.gov (United States)

    Zhang, Liangliang; Liang, Duanwei; Chen, Changmai; Wang, Yuan; Amu, Gubu; Yang, Jiali; Yu, Lijia; Dmochowski, Ivan J; Tang, Xinjing

    2018-03-02

    Circular non-coding RNAs are found to play important roles in biology but are still relatively unexplored as a structural motif for chemically regulating gene function. Here, we investigated whether small interfering RNA (siRNA) with a circular structure can circumvent off-target gene silencing, a problem often observed with standard linear duplex siRNA. In the present work, we, for the first time, synthesized a series of circular siRNAs by cyclizing two ends of a single-stranded RNA (sense or antisense strand) to construct circular siRNAs that were more resistant to enzymatic degradation. Gene silencing of GFP and luciferase was successfully achieved using these circular siRNAs with circular sense strand RNAs and their complementary linear antisense strand RNAs. The off-target effect of sense strand RNAs was evaluated and no cross off-target effects were observed. In addition, we successfully achieved longer gene-silencing efficiency in mice with circular siRNAs than with linear siRNAs. These results indicate the promise of circular siRNAs for overcoming off-target effects of siRNAs and enhancing the possible long-term effect of siRNA gene silencing in basic research and drug development. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Systematic analysis of off-target effects in an RNAi screen reveals microRNAs affecting sensitivity to TRAIL-induced apoptosis

    Directory of Open Access Journals (Sweden)

    Enright Anton J

    2010-03-01

    Full Text Available Abstract Background RNA inhibition by siRNAs is a frequently used approach to identify genes required for specific biological processes. However RNAi screening using siRNAs is hampered by non-specific or off target effects of the siRNAs, making it difficult to separate genuine hits from false positives. It is thought that many of the off-target effects seen in RNAi experiments are due to siRNAs acting as microRNAs (miRNAs, causing a reduction in gene expression of unintended targets via matches to the 6 or 7 nt 'seed' sequence. We have conducted a careful examination of off-target effects during an siRNA screen for novel regulators of the TRAIL apoptosis induction pathway(s. Results We identified 3 hexamers and 3 heptamer seed sequences that appeared multiple times in the top twenty siRNAs in the TRAIL apoptosis screen. Using a novel statistical enrichment approach, we systematically identified a further 17 hexamer and 13 heptamer seed sequences enriched in high scoring siRNAs. The presence of one of these seeds sequences (which could explain 6 of 8 confirmed off-target effects is sufficient to elicit a phenotype. Three of these seed sequences appear in the human miRNAs miR-26a, miR-145 and miR-384. Transfection of mimics of these miRNAs protects several cell types from TRAIL-induced cell death. Conclusions We have demonstrated a role for miR-26a, miR-145 and miR-26a in TRAIL-induced apoptosis. Further these results show that RNAi screening enriches for siRNAs with relevant off-target effects. Some of these effects can be identified by the over-representation of certain seed sequences in high-scoring siRNAs and we demonstrate the usefulness of such systematic analysis of enriched seed sequences.

  1. Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474

    NARCIS (Netherlands)

    van Esbroeck, Annelot C M; Janssen, Antonius P A; Cognetta, Armand B; Ogasawara, Daisuke; Shpak, Guy; van der Kroeg, Mark; Kantae, Vasudev; Baggelaar, Marc P; de Vrij, Femke M S; Deng, Hui; Allarà, Marco; Fezza, Filomena; Lin, Zhanmin; van der Wel, Tom; Soethoudt, Marjolein; Mock, Elliot D; den Dulk, Hans; Baak, Ilse L; Florea, Bogdan I; Hendriks, Giel; De Petrocellis, Luciano; Overkleeft, Herman S; Hankemeier, Thomas; De Zeeuw, Chris I; Di Marzo, Vincenzo; Maccarrone, Mauro; Cravatt, Benjamin F; Kushner, Steven A; van der Stelt, Mario

    2017-01-01

    A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety

  2. Off-target function of the Sonic hedgehog inhibitor cyclopamine in mediating apoptosis via nitric oxide-dependent neutral sphingomyelinase 2/ceramide induction.

    Science.gov (United States)

    Meyers-Needham, Marisa; Lewis, Jocelyn A; Gencer, Salih; Sentelle, R David; Saddoughi, Sahar A; Clarke, Christopher J; Hannun, Yusuf A; Norell, Haakan; da Palma, Telma Martins; Nishimura, Michael; Kraveka, Jacqueline M; Khavandgar, Zohreh; Murshed, Monzur; Cevik, M Ozgur; Ogretmen, Besim

    2012-05-01

    Sonic hedgehog (SHh) signaling is important in the pathogenesis of various human cancers, such as medulloblastomas, and it has been identified as a valid target for anticancer therapeutics. The SHh inhibitor cyclopamine induces apoptosis. The bioactive sphingolipid ceramide mediates cell death in response to various chemotherapeutic agents; however, ceramide's roles/mechanisms in cyclopamine-induced apoptosis are unknown. Here, we report that cyclopamine mediates ceramide generation selectively via induction of neutral sphingomyelin phosphodiesterase 3, SMPD3 (nSMase2) in Daoy human medulloblastoma cells. Importantly, short interfering RNA-mediated knockdown of nSMase2 prevented cyclopamine-induced ceramide generation and protected Daoy cells from drug-induced apoptosis. Accordingly, ectopic wild-type N-SMase2 caused cell death, compared with controls, which express the catalytically inactive N-SMase2 mutant. Interestingly, knockdown of smoothened (Smo), a target protein for cyclopamine, or Gli1, a downstream signaling transcription factor of Smo, did not affect nSMase2. Mechanistically, our data showed that cyclopamine induced nSMase2 and cell death selectively via increased nitric oxide (NO) generation by neuronal-nitric oxide synthase (n-NOS) induction, in Daoy medulloblastoma, and multiple other human cancer cell lines. Knockdown of n-NOS prevented nSMase2 induction and cell death in response to cyclopamine. Accordingly, N-SMase2 activity-deficient skin fibroblasts isolated from homozygous fro/fro (fragilitas ossium) mice exhibited resistance to NO-induced cell death. Thus, our data suggest a novel off-target function of cyclopamine in inducing apoptosis, at least in part, by n-NOS/NO-dependent induction of N-SMase2/ceramide axis, independent of Smo/Gli inhibition. ©2012 AACR

  3. Environmentally Clean Mitigation of Undesirable Plant Life Using Lasers

    Energy Technology Data Exchange (ETDEWEB)

    Rubenchik, A M; McGrann, T J; Yamamoto, R M; Parker, J M

    2009-07-01

    This concept comprises a method for environmentally clean destruction of undesirable plant life using visible or infrared radiation. We believe that during the blossom stage, plant life is very sensitive to electromagnetic radiation, with an enhanced sensitivity to specific spectral ranges. Small doses of irradiation can arrest further plant growth, cause flower destruction or promote plant death. Surrounding plants, which are not in the blossoming stage, should not be affected. Our proposed mechanism to initiate this effect is radiation produced by a laser. Tender parts of the blossom possess enhanced absorptivity in some spectral ranges. This absorption can increase the local tissue temperature by several degrees, which is sufficient to induce bio-tissue damage. In some instances, the radiation may actually stimulate plant growth, as an alternative for use in increased crop production. This would be dependent on factors such as plant type, the wavelength of the laser radiation being used and the amount of the radiation dose. Practical, economically viable realization of this concept is possible today with the advent of high efficiency, compact and powerful laser diodes. The laser diodes provide an efficient, environmentally clean source of radiation at a variety of power levels and radiation wavelengths. Figure 1 shows the overall concept, with the laser diodes mounted on a movable platform, traversing and directing the laser radiation over a field of opium poppies.

  4. Preventing Undesirable Seismic Behaviour of Infill Walls in Design Process

    Directory of Open Access Journals (Sweden)

    Azadeh Noorifard

    2017-03-01

    Full Text Available Dividing walls are usually considered as non-structural elements, but experiences of past earthquakes show that some buildings designed and constructed by engineers have been damaged during earthquakes because of disregarding the negative effects of walls. Apart from the poor quality of construction and materials, inattention in design process is the main reason for undesirable seismic behaviour of walls.The main aim of this paper is to investigate the measures taken in different stages of architectural and structural design for improving the seismic behaviour of infilled concrete structures. As a general principle, with the further progress of project from basic architectural design to detailed structural design, there is a need to reduce designer authority and increase obligation, furthermore the cost of project increases too. The conclusion of this study implies that, in order to achieve the desirable seismic behaviour of walls, close collaboration between architects and structural engineers is required from the early stages of design. The results of this study are presented in a check list for designing reinforced concrete (RC moment resisting frame and RC shear wall.

  5. A survey on the presence of undesirable botanical substances in feed in the European Union

    Directory of Open Access Journals (Sweden)

    van Raamsdonk LWD.

    2009-01-01

    Full Text Available Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on undesirable substances in animal feed lists a range of substances from botanical origin (weed seeds and additionally some chemical compounds directly originating from specific weeds. In order to examine the actual status of enforcement and of the present occurrence of these botanical substances, a survey was carried out. A questionnaire was sent to 103 laboratories, including official control labs from all member states of the European Union. The results, indicating the frequency of occurrence as far as reported, are compared to the publications of the EU Rapid Alert System for Food and Feed (RASFF. A total of 44 questionnaires was returned (42.7% from 22 member states. Ten member states predominantly from north-western Europe appeared to have an active monitoring of botanical undesirable substances. The questionnaire results did not indicate that the other member states enforce this part of Directive 2002/32/EC. Reports on the frequency of occurrence include: a few to 25-50% of the samples contain traces of ergot (8 member states, a few to 24% contain at least some traces of thorn apple (6 member states, zero to 17% contain some castor oil plant seeds (3 member states, zero to a few samples contain Crotalaria seeds (3 member states, and zero to 6% contain traces of Sareptian mustard (4 member states. One member state conducted extra surveillance since several cases of animal intoxications have been reported. In some cases a coincidence with undesirable botanical substances was found.

  6. Generalized herd effects and vaccine evaluation: impact of live influenza vaccine on off-target bacterial colonisation.

    Science.gov (United States)

    Mina, Michael J

    2017-06-01

    Interactions between pathogens and commensal microbes are major contributors to health and disease. Infectious diseases however are most often considered independent, viewed within a one-host one-pathogen paradigm and, by extension, the interventions used to treat and prevent them are measured and evaluated within this same paradigm. Vaccines, especially live vaccines, by stimulating immune responses or directly interacting with other microbes can alter the environment in which they act, with effects that span across pathogen species. Live attenuated infl uenza vaccines for example, while safe, increase upper respiratory tract bacterial carriage density of important human commensal pathogens like Streptococcus pneumoniae and Staphylococcus aureus. Further, by altering the ecological niche and dynamics of phylogenetically distinct microbes within the host, vaccines may unintentionally affect transmission of non-vaccine targeted pathogens. Thus, vaccine effects may span across species and across scales, from the individual to the population level. In keeping with traditional vaccine herd-effects that indirectly protect even unvaccinated individuals by reducing population prevalence of vaccine-targeted pathogens, we call these cross-species cross-scale effects "generalized herd-effects". As opposed to traditional herd-effects, "generalized" relaxes the assumption that the effect occurs at the level of the vaccine-target pathogen and "herd effect" implies, as usual, that the effects indirectly impact the population at large, including unvaccinated bystanders. Unlike traditional herd-effects that decrease population prevalence of the vaccine-target, generalized herd-effects may decrease or increase prevalence and disease by the off-target pathogen. LAIV, for example, by increasing pneumococcal density in the upper respiratory tract of vaccine recipients, especially children, may increase pneumococcal transmission and prevalence, leading to excess pneumococcal invasive

  7. Paralog-divergent Features May Help Reduce Off-target Effects of Drugs: Hints from Glucagon Subfamily Analysis

    Directory of Open Access Journals (Sweden)

    Zhining Sa

    2017-08-01

    Full Text Available Side effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR and glucagon-like peptide-1 receptor (GLP-1R, exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.

  8. CFD simulation of pesticide spray from air-assisted sprayers in an apple orchard: Tree deposition and off-target losses

    Science.gov (United States)

    Hong, Se-Woon; Zhao, Lingying; Zhu, Heping

    2018-02-01

    The ultimate goal of a pesticide spraying system is to provide adequate coverage on intended canopies with a minimum amount of spray materials and off-target waste. Better spray coverage requires an understanding of the fate and transport of spray droplets carried by turbulent airflows in orchards. In this study, an integrated computational fluid dynamics (CFD) model was developed to predict displacement of pesticide spray droplets discharged from an air-assisted sprayer, depositions onto tree canopies, and off-target deposition and airborne drift in an apple orchard. Pesticide droplets discharged from a moving sprayer were tracked using the Lagrangian particle transport model, and the deposition model was applied to droplets entering porous canopy zones. Measurements of the droplet deposition and drift in the same orchard were used to validate the model simulations. Good agreement was found between the measured and simulated spray concentrations inside tree canopies and off-target losses (ground deposition and airborne drifts) with the overall relative errors of 22.1% and 40.6%, respectively, under three growth stages. The CFD model was able to estimate the mass balance of pesticide droplets in the orchard, which was practically difficult to investigate by measurements in field conditions. As the foliage of trees became denser, spray deposition inside canopies increased from 8.5% to 65.8% and airborne drift and ground deposition decreased from 25.8% to 7.0% and 47.8% to 21.2%, respectively. Higher wind speed also increased the spray airborne drift downwind of the orchard. This study demonstrates that CFD model can be used to evaluate spray application performance and design and operate sprayers with increased spray efficiencies and reduced drift potentials.

  9. Teaches’ Reactions towards Undesirable Behaviors of Administrators: Whistle-blowing or Keeping Silent?

    Directory of Open Access Journals (Sweden)

    Asiye TOKER GÖKÇE

    2015-11-01

    Full Text Available This research aims to define teachers’ attitudes towards undesired behaviours at school. Therefore, in which possible undesired administrative behaviours teachers would blow a whistle was examined. Second, whether the teachers would prefer whistle-blowing or and the kind of blowing was questioned. Lastly, the reason of keeping silence was examined. This research was designed as qualitative model. The research group was 20 teachers that work at a secondary school in Darica district of Kocaeli. The results revealed that it was put forward that all teachers would react in the case of various undesired behaviours. However it was determined that teachers would mostly react in the case of serious undesired behaviours. Teachers mostly stated that they would prefer to whistle-blow internally, formally and by identifying themselves. Findings of the research are thought to contribute to the literature in terms of revealing teachers’ attitudes towards possible undesired behaviours at school.

  10. Weak Disposability in Nonparametric Production Analysis with Undesirable Outputs

    NARCIS (Netherlands)

    Kuosmanen, T.K.

    2005-01-01

    Environmental Economics and Natural Resources Group at Wageningen University in The Netherlands Weak disposability of outputs means that firms can abate harmful emissions by decreasing the activity level. Modeling weak disposability in nonparametric production analysis has caused some confusion.

  11. Enhanced DEA model with undesirable output and interval data for rice growing farmers performance assessment

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Sahubar Ali Mohd. Nadhar, E-mail: sahubar@uum.edu.my; Ramli, Razamin, E-mail: razamin@uum.edu.my; Baten, M. D. Azizul, E-mail: baten-math@yahoo.com [School of Quantitative Sciences, UUM College of Arts and Sciences, Universiti Utara Malaysia, 06010 Sintok, Kedah (Malaysia)

    2015-12-11

    Agricultural production process typically produces two types of outputs which are economic desirable as well as environmentally undesirable outputs (such as greenhouse gas emission, nitrate leaching, effects to human and organisms and water pollution). In efficiency analysis, this undesirable outputs cannot be ignored and need to be included in order to obtain the actual estimation of firms efficiency. Additionally, climatic factors as well as data uncertainty can significantly affect the efficiency analysis. There are a number of approaches that has been proposed in DEA literature to account for undesirable outputs. Many researchers has pointed that directional distance function (DDF) approach is the best as it allows for simultaneous increase in desirable outputs and reduction of undesirable outputs. Additionally, it has been found that interval data approach is the most suitable to account for data uncertainty as it is much simpler to model and need less information regarding its distribution and membership function. In this paper, an enhanced DEA model based on DDF approach that considers undesirable outputs as well as climatic factors and interval data is proposed. This model will be used to determine the efficiency of rice farmers who produces undesirable outputs and operates under uncertainty. It is hoped that the proposed model will provide a better estimate of rice farmers’ efficiency.

  12. Distinct oxytocin effects on belief updating in response to desirable and undesirable feedback

    Science.gov (United States)

    Ma, Yina; Li, Shiyi; Wang, Chenbo; Liu, Yi; Li, Wenxin; Yan, Xinyuan; Chen, Qiang; Han, Shihui

    2016-01-01

    Humans update their beliefs upon feedback and, accordingly, modify their behaviors to adapt to the complex, changing social environment. However, people tend to incorporate desirable (better than expected) feedback into their beliefs but to discount undesirable (worse than expected) feedback. Such optimistic updating has evolved as an advantageous mechanism for social adaptation. Here, we examine the role of oxytocin (OT)―an evolutionary ancient neuropeptide pivotal for social adaptation―in belief updating upon desirable and undesirable feedback in three studies (n = 320). Using a double-blind, placebo-controlled between-subjects design, we show that intranasally administered OT (IN-OT) augments optimistic belief updating by facilitating updates of desirable feedback but impairing updates of undesirable feedback. The IN-OT–induced impairment in belief updating upon undesirable feedback is more salient in individuals with high, rather than with low, depression or anxiety traits. IN-OT selectively enhances learning rate (the strength of association between estimation error and subsequent update) of desirable feedback. IN-OT also increases participants’ confidence in their estimates after receiving desirable but not undesirable feedback, and the OT effect on confidence updating upon desirable feedback mediates the effect of IN-OT on optimistic belief updating. Our findings reveal distinct functional roles of OT in updating the first-order estimation and second-order confidence judgment in response to desirable and undesirable feedback, suggesting a molecular substrate for optimistic belief updating. PMID:27482087

  13. Enhanced DEA model with undesirable output and interval data for rice growing farmers performance assessment

    Science.gov (United States)

    Khan, Sahubar Ali Mohd. Nadhar; Ramli, Razamin; Baten, M. D. Azizul

    2015-12-01

    Agricultural production process typically produces two types of outputs which are economic desirable as well as environmentally undesirable outputs (such as greenhouse gas emission, nitrate leaching, effects to human and organisms and water pollution). In efficiency analysis, this undesirable outputs cannot be ignored and need to be included in order to obtain the actual estimation of firms efficiency. Additionally, climatic factors as well as data uncertainty can significantly affect the efficiency analysis. There are a number of approaches that has been proposed in DEA literature to account for undesirable outputs. Many researchers has pointed that directional distance function (DDF) approach is the best as it allows for simultaneous increase in desirable outputs and reduction of undesirable outputs. Additionally, it has been found that interval data approach is the most suitable to account for data uncertainty as it is much simpler to model and need less information regarding its distribution and membership function. In this paper, an enhanced DEA model based on DDF approach that considers undesirable outputs as well as climatic factors and interval data is proposed. This model will be used to determine the efficiency of rice farmers who produces undesirable outputs and operates under uncertainty. It is hoped that the proposed model will provide a better estimate of rice farmers' efficiency.

  14. Distinct oxytocin effects on belief updating in response to desirable and undesirable feedback.

    Science.gov (United States)

    Ma, Yina; Li, Shiyi; Wang, Chenbo; Liu, Yi; Li, Wenxin; Yan, Xinyuan; Chen, Qiang; Han, Shihui

    2016-08-16

    Humans update their beliefs upon feedback and, accordingly, modify their behaviors to adapt to the complex, changing social environment. However, people tend to incorporate desirable (better than expected) feedback into their beliefs but to discount undesirable (worse than expected) feedback. Such optimistic updating has evolved as an advantageous mechanism for social adaptation. Here, we examine the role of oxytocin (OT)-an evolutionary ancient neuropeptide pivotal for social adaptation-in belief updating upon desirable and undesirable feedback in three studies (n = 320). Using a double-blind, placebo-controlled between-subjects design, we show that intranasally administered OT (IN-OT) augments optimistic belief updating by facilitating updates of desirable feedback but impairing updates of undesirable feedback. The IN-OT-induced impairment in belief updating upon undesirable feedback is more salient in individuals with high, rather than with low, depression or anxiety traits. IN-OT selectively enhances learning rate (the strength of association between estimation error and subsequent update) of desirable feedback. IN-OT also increases participants' confidence in their estimates after receiving desirable but not undesirable feedback, and the OT effect on confidence updating upon desirable feedback mediates the effect of IN-OT on optimistic belief updating. Our findings reveal distinct functional roles of OT in updating the first-order estimation and second-order confidence judgment in response to desirable and undesirable feedback, suggesting a molecular substrate for optimistic belief updating.

  15. The presence of undesirable mould species on the surface of dry sausages

    Directory of Open Access Journals (Sweden)

    Vesković-Moračanin Slavica M.

    2008-01-01

    Full Text Available Transition from manufacture to the industrial way of meat production and processing, as well as contemporary concept of food quality and safety, have led to the application of starter cultures. Their application leads towards the streamlining of the production process in the desired direction, quality improvement and its harmonization, and thereby to its standardization. Application of moulds in the meat industry is based on positive effects of their proteolytic and lipolytic egzoenzymes which, as a consequence, leads to the creation of characteristic sensory properties ('flavor' of fermented products. Penicillium nalgiovense is a typical representative of moulds used in the production of fermented sausages-salamis from our region. Samples of 'zimska salama' (dry sausage, produced with Penicillium nalgiovense, were evaluated as hygienically unacceptable. Their sensory properties changed due to contamination of this mould during the ripening process. Micological analysis discovered the presence of Penicillium aurantiogriseum, which is a frequent mould contaminant in the meat industry. At the same time, thin layer chromatography revealed no possibility of metabolic activity of this mould in the creation of mycotoxins. However, the presence of this mould on the surface of 'zimska salama' is considered as undesirable due to formation of 'off flavor' in products. Such product is considered as hygienically unacceptable and cannot be used for the human consumption.

  16. Critical off-target effects of the widely used Rac1 inhibitors NSC23766 and EHT1864 in mouse platelets

    DEFF Research Database (Denmark)

    Dütting, Sebastian; Heidenreich, Julius; Cherpokova, Deya

    2015-01-01

    BACKGROUND: Platelet aggregation at sites of vascular injury is essential for normal hemostasis, but may also cause pathological vessel occlusion. Rho GTPases are molecular switches that regulate essential cellular processes and they have pivotal functions in the cardiovascular system. Rac1...... is an important regulator of platelet cytoskeletal reorganizations and contributes to platelet activation. Rac1 inhibitors are thought to be beneficial in a wide range of therapeutic settings and therefore have been tested in vivo for a variety of disorders. Two small molecule inhibitors, NSC23766 and EHT1864......, have been characterized in different cell types, demonstrating high specificity for Rac1 or Rac, respectively. OBJECTIVES: We sought to analyze the specificity of NSC23766 and EHT1864. METHODS: Platelet function was assessed in mouse wild-type and Rac1-deficient platelets by using flow cytometric...

  17. Reverse translation of adverse event reports paves the way for de-risking preclinical off-targets.

    Science.gov (United States)

    Maciejewski, Mateusz; Lounkine, Eugen; Whitebread, Steven; Farmer, Pierre; DuMouchel, William; Shoichet, Brian K; Urban, Laszlo

    2017-08-08

    The Food and Drug Administration Adverse Event Reporting System (FAERS) remains the primary source for post-marketing pharmacovigilance. The system is largely un-curated, unstandardized, and lacks a method for linking drugs to the chemical structures of their active ingredients, increasing noise and artefactual trends. To address these problems, we mapped drugs to their ingredients and used natural language processing to classify and correlate drug events. Our analysis exposed key idiosyncrasies in FAERS, for example reports of thalidomide causing a deadly ADR when used against myeloma, a likely result of the disease itself; multiplications of the same report, unjustifiably increasing its importance; correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole, and risperidone, and of kinase drugs targeting the VEGF receptor, demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlying mechanisms.

  18. Modeling of human prokineticin receptors: interactions with novel small-molecule binders and potential off-target drugs.

    Directory of Open Access Journals (Sweden)

    Anat Levit

    Full Text Available The Prokineticin receptor (PKR 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs, their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity.

  19. The Differential Mortality of Undesired Infants in Sub-Saharan Africa.

    Science.gov (United States)

    Flatø, Martin

    2018-02-01

    With high rates of infant mortality in sub-Saharan Africa, investments in infant health are subject to tough prioritizations within the household, in which maternal preferences may play a part. How these preferences will affect infant mortality as African women have ever-lower fertility is still uncertain, as increased female empowerment and increased difficulty in achieving a desired gender composition within a smaller family pull in potentially different directions. I study how being born at a parity or of a gender undesired by the mother relates to infant mortality in sub-Saharan Africa and how such differential mortality varies between women at different stages of the demographic transition. Using data from 79 Demographic and Health Surveys, I find that a child being undesired according to the mother is associated with a differential mortality that is not due to constant maternal factors, family composition, or factors that are correlated with maternal preferences and vary continuously across siblings. As a share of overall infant mortality, the excess mortality of undesired children amounts to 3.3 % of male and 4 % of female infant mortality. Undesiredness can explain a larger share of infant mortality among mothers with lower fertility desires and a larger share of female than male infant mortality for children of women who desire 1-3 children. Undesired gender composition is more important for infant mortality than undesired childbearing and may also lead couples to increase family size beyond the maternal desire, in which case infants of the surplus gender are particularly vulnerable.

  20. Desirable and undesirable future thoughts call for different scene construction processes.

    Science.gov (United States)

    de Vito, S; Neroni, M A; Gamboz, N; Della Sala, S; Brandimonte, M A

    2015-01-01

    Despite the growing interest in the ability of foreseeing (episodic future thinking), it is still unclear how healthy people construct possible future scenarios. We suggest that different future thoughts require different processes of scene construction. Thirty-five participants were asked to imagine desirable and less desirable future events. Imagining desirable events increased the ease of scene construction, the frequency of life scripts, the number of internal details, and the clarity of sensorial and spatial temporal information. The initial description of general personal knowledge lasted longer in undesirable than in desirable anticipations. Finally, participants were more prone to explicitly indicate autobiographical memory as the main source of their simulations of undesirable episodes, whereas they equally related the simulations of desirable events to autobiographical events or semantic knowledge. These findings show that desirable and undesirable scenarios call for different mechanisms of scene construction. The present study emphasizes that future thinking cannot be considered as a monolithic entity.

  1. Ranking of bank branches with undesirable and fuzzy data: A DEA-based approach

    Directory of Open Access Journals (Sweden)

    Sohrab Kordrostami

    2016-07-01

    Full Text Available Banks are one of the most important financial sectors in order to the economic development of each country. Certainly, efficiency scores and ranks of banks are significant and effective aspects towards future planning. Sometimes the performance of banks must be measured in the presence of undesirable and vague factors. For these reasons in the current paper a procedure based on data envelopment analysis (DEA is introduced for evaluating the efficiency and complete ranking of decision making units (DMUs where undesirable and fuzzy measures exist. To illustrate, in the presence of undesirable and fuzzy measures, DMUs are evaluated by using a fuzzy expected value approach and DMUs with similar efficiency scores are ranked by using constraints and the Maximal Balance Index based on the optimal shadow prices. Afterwards, the efficiency scores of 25 branches of an Iranian commercial bank are evaluated using the proposed method. Also, a complete ranking of bank branches is presented to discriminate branches.

  2. Risk management of undesirable substances in feed following updated risk assessments

    International Nuclear Information System (INIS)

    Verstraete, Frans

    2013-01-01

    Directive 2002/32/EC of 7 May 2002 of the European Parliament and of the Council on undesirable substances in animal feed is the framework for the EU action on undesirable substances in feed. This framework Directive provides: ⁎that products intended for animal feed may enter for use in the Union from third countries, be put into circulation and/or used in the Union only if they are sound, genuine and of merchantable quality and therefore when correctly used do not represent any danger to human health, animal health or to the environment or could adversely affect livestock production. ⁎that in order to protect animal and public health and the environment, maximum levels for specific undesirable substances shall be established where necessary. ⁎for mandatory consultation of a scientific body (EFSA) for all provisions which may have an effect upon public health or animal health or on the environment. ⁎that products intended for animal feed containing levels of an undesirable substance that exceed the established maximum level may not be mixed for dilution purposes with the same, or other, products intended for animal feed and may not be used for the production of compound feed. Based on the provisions and principles laid down in this framework Directive, maximum levels for a whole range of undesirable substances have been established at EU level. During the discussions in view of the adoption of Directive 2002/32/EC, the European Commission made the commitment to review all existing provisions on undesirable substances on the basis of updated scientific risk assessments. Following requests of the European Commission, the Panel on Contaminants in the Food Chain (CONTAM) from the European Food Safety Authority (EFSA) has completed a series of 30 risk assessments undertaken over the last 5 years on undesirable substances in animal feed reviewing the possible risks for animal and human health due to the presence of these substances in animal feed. EU legislation

  3. Relationships between College Students' Credit Card Debt, Undesirable Academic Behaviors and Cognitions, and Academic Performance

    Science.gov (United States)

    Hogan, Eileen A.; Bryant, Sarah K.; Overymyer-Day, Leslie E.

    2013-01-01

    The acquisition of credit card debt by college students has long been a topic of concern. This study explores relationships among debt, undesirable academic behaviors and cognitions, and academic performance, through surveys of 338 students in a public university, replicating two past measures of credit card debt and creating new measures of…

  4. A survey on the presence of undesirable botanical substances in feed in the European Union

    NARCIS (Netherlands)

    Raamsdonk, van L.W.D.; Vancutsem, J.; Jorgensen, J.S.

    2009-01-01

    Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on undesirable substances in animal feed lists a range of substances from botanical origin (weed seeds) and additionally some chemical compounds directly originating from specific weeds. In order to examine the actual

  5. Array diagnostics, spatial resolution, and filtering of undesired radiation with the 3D reconstruction algorithm

    DEFF Research Database (Denmark)

    Cappellin, C.; Pivnenko, Sergey; Jørgensen, E.

    2013-01-01

    This paper focuses on three important features of the 3D reconstruction algorithm of DIATOOL: the identification of array elements improper functioning and failure, the obtainable spatial resolution of the reconstructed fields and currents, and the filtering of undesired radiation and scattering...

  6. Rice growing farmers efficiency measurement using a slack based interval DEA model with undesirable outputs

    Science.gov (United States)

    Khan, Sahubar Ali Mohd. Nadhar; Ramli, Razamin; Baten, M. D. Azizul

    2017-11-01

    In recent years eco-efficiency which considers the effect of production process on environment in determining the efficiency of firms have gained traction and a lot of attention. Rice farming is one of such production processes which typically produces two types of outputs which are economic desirable as well as environmentally undesirable. In efficiency analysis, these undesirable outputs cannot be ignored and need to be included in the model to obtain the actual estimation of firm's efficiency. There are numerous approaches that have been used in data envelopment analysis (DEA) literature to account for undesirable outputs of which directional distance function (DDF) approach is the most widely used as it allows for simultaneous increase in desirable outputs and reduction of undesirable outputs. Additionally, slack based DDF DEA approaches considers the output shortfalls and input excess in determining efficiency. In situations when data uncertainty is present, the deterministic DEA model is not suitable to be used as the effects of uncertain data will not be considered. In this case, it has been found that interval data approach is suitable to account for data uncertainty as it is much simpler to model and need less information regarding the underlying data distribution and membership function. The proposed model uses an enhanced DEA model which is based on DDF approach and incorporates slack based measure to determine efficiency in the presence of undesirable factors and data uncertainty. Interval data approach was used to estimate the values of inputs, undesirable outputs and desirable outputs. Two separate slack based interval DEA models were constructed for optimistic and pessimistic scenarios. The developed model was used to determine rice farmers efficiency from Kepala Batas, Kedah. The obtained results were later compared to the results obtained using a deterministic DDF DEA model. The study found that 15 out of 30 farmers are efficient in all cases. It

  7. Experimental investigation of undesired stable equilibria in pumpkin shape super-pressure balloon designs

    Science.gov (United States)

    Schur, W. W.

    2004-01-01

    Excess in skin material of a pneumatic envelope beyond what is required for minimum enclosure of a gas bubble is a necessary but by no means sufficient condition for the existence of multiple equilibrium configurations for that pneumatic envelope. The very design of structurally efficient super-pressure balloons of the pumpkin shape type requires such excess. Undesired stable equilibria in pumpkin shape balloons have been observed on experimental pumpkin shape balloons. These configurations contain regions with stress levels far higher than those predicted for the cyclically symmetric design configuration under maximum pressurization. Successful designs of pumpkin shape super-pressure balloons do not allow such undesired stable equilibria under full pressurization. This work documents efforts made so far and describes efforts still underway by the National Aeronautics and Space Administration's Balloon Program Office to arrive on guidance on the design of pumpkin shape super-pressure balloons that guarantee full and proper deployment.

  8. Phosphate binders affect vitamin K concentration by undesired binding, an in vitro study.

    Science.gov (United States)

    Neradova, A; Schumacher, S P; Hubeek, I; Lux, P; Schurgers, L J; Vervloet, M G

    2017-05-02

    Vascular calcification is a major contributing factor to mortality in end stage renal disease (ESRD). Despite the efficacy of phosphate binders to improve hyperphosphatemia, data on vascular calcification are less clear. There seems to be a difference in attenuation or delay in progression between different binders. In this in vitro experiment we tested whether phosphate binders could limit bioavailability of vitamin K2 by undesired binding. Vitamin K-deficiency limits activation of the vascular tissue mineralization inhibitor matrix γ-carboxyglutamate (Gla) protein (MGP) thereby exacerbating vascular calcification. In this experiment vitamin K2 (menaquinone-7; MK-7) binding was assessed by adding 1 mg of vitamin K2 to a medium with pH 6 containing 67 mg phosphate binder with either 7 mg of phosphate or no phosphate. Five different phosphate binders were tested. After five and a half hours vitamin K was analyzed by HPLC. All experiments were performed in triplicate. Sucroferric-oxyhydroxide and sevelamer carbonate did not significantly bind vitamin K2, both in solution only containing vitamin K2 or in combination with phosphate. Calcium acetate/magnesium carbonate binds vitamin K2 strongly both in absence (p = 0.001) and presence of phosphate (p = 0.003). Lanthanum carbonate significantly binds vitamin K2 in solution containing only vitamin K2 (p = 0.005) whereas no significant binding of vitamin K2 was observed in the solution containing vitamin K2 and phosphate (p = 0.462). Calcium carbonate binds vitamin K2 significantly in a solution with vitamin K2 and phosphate (p = 0.009) whereas without phosphate no significant binding of vitamin K2 was observed (p = 0.123). Sucroferric-oxyhydroxide and sevelamer carbonate were the only binders of the five binders studied that did not bind vitamin K2 in vitro. The presence or absence of phosphate significantly interferes with vitamin K2 binding so phosphate binders could potentially limit

  9. Development of Data Envelopment Analysis for the Performance Evaluation of Green Supply Chain with Undesirable Outputs

    Directory of Open Access Journals (Sweden)

    Alireza Alinezhad

    2016-08-01

    Full Text Available A fundamental problem is the use of DEA in multistep or multilevel processes such as supply chain, lack of attention to processes’ internal communications in a way that the recent studies on DEA in the context of serial processes have focused on closed systems that the outputs of one level become the inputs of the next level and none of the inputs enter the mediator process. The present study aimed to examine the general dimensions of an open multilevel process. Here, some of the data such as inputs and outputs are supposed to leave the system while other outputs turn into the inputs of the next level. The new inputs can enter the next level as well. We expand this mode for network structures. The overall performance of such a structure is considered as a weighted average of sectors’ performance or distinct steps. Therefore, this suggested model in this study, not only provides the possibility to evaluate the performance of the entire network, but creates the performance analysis for each of the sub-processes. On the other hand, considering the data with undesirable structure leads to more correct performance estimation. In the real world, all productive processes do not comprise desirable factors. Therefore, presenting a structure that is capable of taking into account the undesirable structure is of crucial importance. In this study, a new model in the DEA by network structure is offered that can analyze the performance considering undesirable factors.

  10. Assessment of undesirable dose to eye-melanoma patients after proton radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Stolarczyk, L., E-mail: liliana.stolarczyk@ifj.edu.p [Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, ul. Radzikowskiego 152, 31-342 Krakow (Poland); Olko, P.; Cywicka-Jakiel, T.; Ptaszkiewicz, M.; Swakon, J.; Dulny, B.; Horwacik, T.; Obryk, B. [Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, ul. Radzikowskiego 152, 31-342 Krakow (Poland); Waligorski, M.P.R. [Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, ul. Radzikowskiego 152, 31-342 Krakow (Poland); Maria Sklodowska-Curie Memorial Institute, Centre of Oncology, Krakow Division, ul. Garncarska 11, 31-115, Krakow (Poland)

    2010-12-15

    Radiotherapy with a proton beam of initial energy 55-80 MeV is presently the clinically recommended therapy for some cases of intraocular melanoma such as large melanomas or tumours adjacent to critical organs. Evaluation and optimization of radiation doses outside the treatment volume may contribute to reducing undesirable side-effects and decreasing the risk of occurrence of secondary cancers, particularly for paediatric patients. In this work the undesired doses to organs were assessed basing on Monte Carlo calculation of secondary radiation transport and on results of measurements of neutron and {gamma}-ray doses at the proton therapy facility of the Institute of Nuclear Physics at Krakow. Dosimetry was performed using a He-3-based FHT 762 neutron monitor (Wendi II), a FH40G proportional counter (for {gamma}-rays), and MTS-7 (LiF:Mg,Ti) thermoluminescence detectors (TLDs). Organ doses were calculated in the ADAM anthropomorphic phantom using the MCNPX Monte Carlo transport code and partly verified, for {gamma}-ray doses, with TLD measurements in the RANDO Anderson anthropomorphic phantom. The effective dose due to undesired radiation, including exposure from scattered radiation during the entire process of proton radiotherapy and patient positioning using X-rays, does not exceed 1 mSv.

  11. Undesirable Behaviors Elementary School Classroom Teachers Encounter in the Classroom and Their Reasons

    Directory of Open Access Journals (Sweden)

    E.G. Balcik

    2011-12-01

    Full Text Available The present study aims to determine how often elementary school teachers encounter undesirable behaviors in the classroom and what their thoughts regarding possible reasons of these behaviors are. The teachers’ opininon about the prevalence of these behaviors and their possible reasons were evaluated according to gender, marital status, level of class being taught, size of class being taught and it was tried to be determined if there were significant differences between variables. The measurement tool was applied to a total of 54 teachers at 5 schools in Gölcük district of the Kocaeli province. The data collection tool is composed of three sections. The first section is for establishing teachers’ personal information. In this study, as a data collection tool, a questionnaire was used. When preparing questions for the questionnaire, following the examination of resources available, the questionnaire prepared by Aksoy (1999 and used in the thesis study entitled “Classroom Management and Student Discipline in Elementary Schools of Ankara” and also used in the thesis study by Boyraz (2007 entitled “Discipline Problems that Candidate Teachers Servicing at Elementary Schools Encounter in the Classroom” was employed. Although the validity and reliability of the questionnaire was tested by Aksoy (1999 and Boyraz (2007, the reliability study for the questionnaire was retested and found to be 0,9. The questionnaire include 42 items. 19 of them are related to the reasons of undesirable behaviors observed in the classroom and 23 of them are related to undesirable behaviors observed in the classroom.

  12. Environmental efficiency evaluation of china based on a kind of congestion and undesirable output coefficient

    Directory of Open Access Journals (Sweden)

    Song Malin

    2015-01-01

    Full Text Available The production “congestion” phenomenon is widespread in reality although few models nowadays consider its influences. In this study, production congestion is introduced into an environmental efficiency evaluation model and a new data envelopment analysis model that considers both production congestion and undesirable output is established so as to measure environmental efficiency evaluation effectively. On this basis, we divide technological change into productive technological change and energy-savings emission reduction technological change to establish their influences on the congestion phenomenon. The results show that productive technological change cannot relieve the degree of congestion while green technology change that stimulates environmental efficiency improvement can greatly alleviate situations of congestion.

  13. Guidelines used in Japan to prevent the contamination of feed products with undesirable substances

    Directory of Open Access Journals (Sweden)

    Katsuaki Sugiura

    2011-01-01

    Full Text Available As Japan depends on imports for most ingredients used to manufacture feed products, close co-operation is indispensable between importers and manufacturers of feed and feed ingredients to effectively mitigate the risk associated with feed safety. Guidelines were issued by the Ministry of Agriculture, Forestry and Fisheries (MAFF in March 2008 to prevent feed products from being contaminated with undesirable substances. These guidelines identify the responsibilities of feed ingredient importers, feed manufacturers and distributors, as well as the roles of the MAFF and the Food and Agricultural Materials Inspection Centre.

  14. Distinguishing Technical Inefficiency from Desirable and Undesirable Congestion with an Application to Regional Industries in China

    Directory of Open Access Journals (Sweden)

    Jun Wang

    2014-12-01

    Full Text Available Congestion is an important issue that requires the efficiency of decision-making units (DMUs. We first classify conventional congestion into congestion (newly defined and technical inefficiency, based on prior research and real applications. Modified definitions and mathematical expression of congestion, managerial inefficiency, and technical inefficiency are proposed to better illustrate the differences between them. Several modified models are provided to identify and recognize those types of inefficiencies and congestion. We then extend the model by considering the desirable and undesirable types of congestion simultaneously. The proposed approach is applied and verified by identifying resource congestion and environmental inefficiencies in China’s economic development.

  15. A mechanism to compensate undesired stiffness in joints of prosthetic hands.

    Science.gov (United States)

    Smit, Gerwin; Plettenburg, Dick; Van der Helm, Frans

    2014-04-01

    Cosmetic gloves that cover a prosthetic hand have a parasitic positive stiffness that counteracts the flexion of a finger joint. Reducing the required input torque to move a finger of a prosthetic hand by compensating the parasitic stiffness of the cosmetic glove. Experimental, test bench. The parasitic positive stiffness and the required input torques of a polyvinyl chloride glove and a silicone glove were measured when flexing a metacarpophalangeal finger joint for 90°. To compensate this positive stiffness, an adjustable compensation mechanism with a negative stiffness was designed and built. A MATLAB model was created to predict the optimal settings of the mechanism, based on the measured stiffness, in order to minimize the required input torque of the total system. The mechanism was tested in its optimal setting with an applied glove. The mechanism reduced the required input torque by 58% for the polyvinyl chloride glove and by 52% for the silicone glove. The total energy dissipation of the joint did not change significantly. This study shows that the undesired positive stiffness in the joint can be compensated with a relatively simple negative stiffness mechanism, which fits inside a finger of a standard cosmetic glove. Clinical relevance This study presents a mechanism that compensates the undesired stiffness of cosmetic gloves on prosthetic hands. As a result, it requires less input force, torque and energy to move the fingers. Application of this mechanism in body-powered hands will reduce the control effort of the user.

  16. Cycles of undesirable substances in the food chain; Kreislaeufe unerwuenschter Stoffe in der Lebensmittelkette

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-12-15

    The working group ''Carry over of undesirable substances in animal feed'' at the Federal Ministry of Food, Agriculture and Forestry (BMELV) in cooperation with the Institute of Animal Nutrition of the Friedrich-Loeffler-Institute (FLI) performed on 27 and 28 October 2011 in Braunschweig a workshop on ''cycles of undesirable substances in Food Chain ''. The aim of the workshop was to present the latest findings of research and Carry over Recommendations of the Carry over - Working Group on undesirable substances in feed and production processes of the feed industry, to evaluate and discuss about this with representatives from science, business and management and to work out the further research and action need. The focus of the considerations were the pathways, the carry over and the Exposure to dioxins and other halogenated hydrocarbons, the effects of Mycotoxins in feed and starting points for preventive measures, the soil contamination and the exposure of humans and animals by cadmium and case studies on Nitrite in feed, antibiotics in plants and residues of pesticides and radionuclides in feed. Furthermore the risks associated with specified manufacturing processes of feed are considered, especially the used materials that come into contact with animal feed, and the risks from nanotechnology. [German] Die Arbeitsgruppe ''Carry over unerwuenschter Stoffe in Futtermitteln'' beim Bundesministerium fuer Ernaehrung, Landwirtschaft und Forsten (BMELV) hat in Zusammenarbeit mit dem Institut fuer Tierernaehrung des Friedrich-Loeffler-Instituts (FLI) am 27. und 28. Oktober 2011 in Braunschweig einen Workshop zum Thema ''Kreislaeufe unerwuenschter Stoffe in der Lebensmittelkette'' durchgefuehrt. Ziel des Workshops war es, die aktuellen Erkenntnisse der Carry over Forschung und die Empfehlungen der Carry over - Arbeitsgruppe zu unerwuenschten Stoffen in Futtermitteln und Produktionsverfahren in

  17. Operation condition for continuous anti-solvent crystallization of CBZ-SAC cocrystal considering deposition risk of undesired crystals

    Science.gov (United States)

    Nishimaru, Momoko; Nakasa, Miku; Kudo, Shoji; Takiyama, Hiroshi

    2017-07-01

    Crystallization operation of cocrystal production has deposition risk of undesired crystals. Simultaneously, continuous manufacturing processes are focused on. In this study, conditions for continuous cocrystallization considering risk reduction of undesired crystals deposition were investigated on the view point of thermodynamics and kinetics. The anti-solvent cocrystallization was carried out in four-component system of carbamazepine, saccharin, methanol and water. From the preliminary batch experiment, the relationships among undesired crystal deposition, solution composition decided by mixing ratio of solutions, and residence time for the crystals were considered, and then the conditions of continuous experiment were decided. Under these conditions, the continuous experiment was carried out. The XRD patterns of obtained crystals in the continuous experiment showed that desired cocrystals were obtained without undesired crystals. This experimental result was evaluated by using multi-component phase diagrams from the view point of the operation point's movement. From the evaluation, it was found that there is a certain operation condition which the operation point is fixed with time in the specific domain without the deposition risk of undesired single component crystals. It means the possibility of continuous production of cocrystals without deposition risk of undesired crystals was confirmed by using multi-component phase diagrams.

  18. Research on China's aquaculture efficiency evaluation and influencing factors with undesirable outputs

    Science.gov (United States)

    Ji, Jianyue; Wang, Pingping

    2015-06-01

    Taking the aquaculture area, the number of farming boats and that of aquaculturist as input variables, the aquaculture production as desirable output variable and polluted economic loss as undesirable output variable, this paper conducts SBM model to evaluate the aquaculture efficiency based on the data of 16 aquaculture-developed provinces in China from 2004 to 2011. The results show the efficiency in China has not changed much in recent years with the efficiency values mainly between 0.39 and 0.53, and the efficiency of marine-aquaculture-dominated provinces is generally higher than that of freshwater-aquaculture-dominated ones. To analyze the difference under the efficiency, the panel Tobit model is used with education level factor, training factor, technology extension factor, technical level factor, scale factor and species factor as the efficiency influencing factors. The results show that technology extension factor and technical level factor have significant positive influence.

  19. The application of game theory and cognitive economy to analyze the problem of undesired location

    International Nuclear Information System (INIS)

    Villani, S.

    2008-01-01

    The analysts of the processes of public bodies decision - taking have long been discussing on the establishment of proper strategies to manage environmental conflicts - above all the so-called problems of undesired location of public works and facilities - efficiently (i.e. on a short-period basis so as to grant decision and agreement stability) and fairly (the parties' satisfaction is itself a further guarantee of decision and agreement stability). Each strategy, anyway, is still in progress, like a universe to create and explore. Therefore, in this paper, we will focus on the analysis of the problem and provide as well some theoretical proposals to arrange a new interpreting model of public bodies decision-taking processes based on the achievements of two new subject-matters: evolutionary game theory and cognitive economy. Both sciences share their investigation field with law and economic science. [it

  20. Undesirable sulphur and carbonyl flavor compounds in UHT milk: a review.

    Science.gov (United States)

    Zabbia, Alex; Buys, Elna M; De Kock, Henriette L

    2012-01-01

    Ultra High Temperature (UHT) processing leads to the formation of "cooked" and "flat" flavors in milk. These undesirable notes occur due to the volatile formation of a variety of sulphur containing compounds, methyl ketones and aliphatic aldehydes, derived from the constituents of the milk's matrix during thermal processing and storage. The "cooked" flavor of UHT milk is associated with the presence of a variety of sulphur containing compounds while the "stale" flavor is characterized by the dissipation of these sulphur volatiles and an increase of the formation and presence of both methyl ketones and aliphatic aldehydes over time. The extent to which the individual volatiles contribute to the overall flavor of UHT milk is not clear. The proposed formation of these volatiles, that is, the methods to control the intensity of "cooked" and "stale" flavors associated with UHT milk and extraction techniques for the isolation of these volatiles from milk, have been reviewed.

  1. BETWEEN THE RIGHT AND THE COMMON. HOW GROUPS REACT TO SOCIALLY UNDESIRABLE BEHAVIOUR

    Directory of Open Access Journals (Sweden)

    Komendant-Brodowska Agata

    2017-06-01

    Full Text Available The aim of the paper is to analyse the relationship between group characteristics and the scope of reaction of the group to socially undesirable behaviour. Sometimes small groups or communities fail to react to undesirable or violent behaviour and their apathy can have devastating consequences. Such a situation can occur among co-workers witnessing workplace mobbing, or neighbours who do not react to a suspicion of domestic violence. Reasons for their inaction are diverse and can include fear, doubts concerning the necessity of such a reaction, and also conformity. In the paper I examine a seemingly favourable situation: I assume that reaction is costless and all the members of the group would like to react (internalised norm, but they also want to conform. In order to analyse the factors that can influence the scope of group reaction, a structurally embedded sequential coordination game was played for different initial conditions. Computer simulations were conducted for networks of a specific type (Erd¨os-R´enyi random graph. The main aim of the analysis was to identify non-structural and structural features of the group that can impede or even block the intervention of the group. There is a positive relationship between the scope of group reaction and the strength of the internalized norm, whereas the level of conformity affects the chances of group intervention in a negative way. Heterogeneity of the group is an important factor - the scope of reaction is higher when members of the group have different levels of norm internalisation and conformity. There is a non-linear relationship between network density and the scope of reaction. Both low and high density can make it harder for people to act.

  2. Children's disengagement from cancer care and treatment on the ward: an undesirable social tactic in the long term.

    Science.gov (United States)

    Løvschal-Nielsen, P; Clausen, N; Meinert, L

    2017-11-01

    This anthropological study explores children's non-social reactions during the active treatment period, the on-treatment, in a paediatric oncology ward in a Danish university hospital. It is argued that, although some children's non-social reactions is a tactical disengagement to manage the on-treatment situation, such non-social tactics might ultimately prove an undesirable strategy with negative long-term social consequences for social survivorship. Data were generated over 7 months of ethnographic fieldwork between May 2011 and January 2013, using qualitative methods such as participant observation and open-ended interviewing. Fifty children of both sexes between 4 and 15 years, their families and hospital staff participated in the study. These data formed the basis for the study. The findings show that children's response to care challenges, including exhaustion from care management, exposure from being in a public space, and the open-ended duration of treatment, configure in tactic forms that we term social disengagement. It is suggested that such tactical social disengagement might expand into long-term social patterns, and, as such, change from an alleviating tactic to a socially isolating and damaging tactic for survivors of cancer in childhood. © 2016 John Wiley & Sons Ltd.

  3. Undesired small RNAs originate from an artificial microRNA precursor in transgenic petunia (Petunia hybrida.

    Directory of Open Access Journals (Sweden)

    Yulong Guo

    Full Text Available Although artificial microRNA (amiRNA technology has been used frequently in gene silencing in plants, little research has been devoted to investigating the accuracy of amiRNA precursor processing. In this work, amiRNAchs1 (amiRchs1, based on the Arabidopsis miR319a precursor, was expressed in order to suppress the expression of CHS genes in petunia. The transgenic plants showed the CHS gene-silencing phenotype. A modified 5' RACE technique was used to map small-RNA-directed cleavage sites and to detect processing intermediates of the amiRchs1 precursor. The results showed that the target CHS mRNAs were cut at the expected sites and that the amiRchs1 precursor was processed from loop to base. The accumulation of small RNAs in amiRchs1 transgenic petunia petals was analyzed using the deep-sequencing technique. The results showed that, alongside the accumulation of the desired artificial microRNAs, additional small RNAs that originated from other regions of the amiRNA precursor were also accumulated at high frequency. Some of these had previously been found to be accumulated at low frequency in the products of ath-miR319a precursor processing and some of them were accompanied by 3'-tailing variant. Potential targets of the undesired small RNAs were discovered in petunia and other Solanaceae plants. The findings draw attention to the potential occurrence of undesired target silencing induced by such additional small RNAs when amiRNA technology is used. No appreciable production of secondary small RNAs occurred, despite the fact that amiRchs1 was designed to have perfect complementarity to its CHS-J target. This confirmed that perfect pairing between an amiRNA and its targets is not the trigger for secondary small RNA production. In conjunction with the observation that amiRNAs with perfect complementarity to their target genes show high efficiency and specificity in gene silencing, this finding has an important bearing on future applications of ami

  4. Study on Operator Actions during the Occurrences of Undesirable Events in PUSPATI TRIGA Reactor

    International Nuclear Information System (INIS)

    Tom, P.P.; Nurul Husna Zainal Abidin; Lanyau, T.A.; Zaredah Hashim

    2016-01-01

    Due to the recent Fukushima accident, the potential risks at one and only nuclear research reactor in the country, which is the PUSPATI TRIGA Reactor (RTP), has increasingly gain concerns and an attempt on the development of Level 1 Probabilistic Safety Assessment (PSA) for this reactor has been commenced. The preliminary scope of the PSA is to analyse the risk of core degradation during normal daily operation due to the random component failure and human error. SPAR-H and THERP method is used for quantifying human error probability (HEP). However, the scopes of this study only cover the qualitative parts that use interview/questionnaire method. The objectives of the questionnaire are to identify the main action for RTP operators when any undesired incident occurs during full power operation that might be caused by random component failures. From the questionnaires that have been conducted, the respondents consisted of 4 licensed operators and 9 trainee operators. All licensed operators have experience of operating reactor for more than 15 years while the trainee operator have been operate the reactor with experience of less than 10 years. Generally, in the event of an abnormal condition involving the reactor, an operator whether a licensed operator or the trainee does not have to ask permission in advance from the top individuals to carry out scram. This is to prevent the situation becoming increasingly severe if the reactor is still operating. With complete training and knowledge derived from the management, an operator can act efficiently in any emergency case. (author)

  5. On the undesired frequency chirping in photonic time-stretch systems

    Science.gov (United States)

    Xu, Yuxiao; Chi, Hao; Jin, Tao; Zheng, Shilie; Jin, Xiaofeng; Zhang, Xianmin

    2017-12-01

    The technique of photonic time stretch (PTS) has been intensively investigated in the past decade due to its potential in the acquisition of ultra-high speed signals. The frequency-related RF power fading in the PTS systems with double sideband (DSB) modulation has been well-known, which limits the maximum modulation frequency. Some solutions have been proposed to solve this problem. In this paper, we report another effect, i.e., undesired frequency chirping, which also relates to the performance degradation of PTS systems with DSB modulation, for the first time to our knowledge. Distinct from the nonlinearities caused by nonlinear modulation and square-law photodetection, which is common in radio frequency analog optical links, this frequency chirping originates from the addition of two beating signals with a relative delay after photodetection. A theoretical model for exactly describing the frequency chirping is presented, and is then verified by simulations. Discussion on the method to avoid the frequency chirping is also presented.

  6. Regime Shifts and Ecosystem Service Generation in Swedish Coastal Soft Bottom Habitats: When Resilience is Undesirable

    Directory of Open Access Journals (Sweden)

    Max Troell

    2005-06-01

    Full Text Available Ecosystems can undergo regime shifts where they suddenly change from one state into another.  This can have important implications for formulation of management strategies, if system characteristics develop that are undesirable from a human perspective, and that have a high resistance to restoration efforts. This paper identifies some of the ecological and economic consequences of increased abundance of filamentous algae on shallow soft bottoms along the Swedish west coast. It is suggested that a successive increase in the sediment nutrient pool has undermined the resilience of these shallow systems. After the regime shift has occurred, self-generation properties evolve keeping the system locked in a high-density algae state. The structural and functional characteristics of the new system state differ significantly from the original one, resulting in less valuable ecosystem goods and services generated for society. In Sweden, loss of value results from the reduced capacity for mitigating further coastal eutrophication, reduced habitat quality for commercial fishery species, and the loss of aesthetic and recreational values.

  7. Tracking Progress in Improving Diagnosis: A Framework for Defining Undesirable Diagnostic Events.

    Science.gov (United States)

    Olson, Andrew P J; Graber, Mark L; Singh, Hardeep

    2018-01-29

    Diagnostic error is a prevalent, harmful, and costly phenomenon. Multiple national health care and governmental organizations have recently identified the need to improve diagnostic safety as a high priority. A major barrier, however, is the lack of standardized, reliable methods for measuring diagnostic safety. Given the absence of reliable and valid measures for diagnostic errors, we need methods to help establish some type of baseline diagnostic performance across health systems, as well as to enable researchers and health systems to determine the impact of interventions for improving the diagnostic process. Multiple approaches have been suggested but none widely adopted. We propose a new framework for identifying "undesirable diagnostic events" (UDEs) that health systems, professional organizations, and researchers could further define and develop to enable standardized measurement and reporting related to diagnostic safety. We propose an outline for UDEs that identifies both conditions prone to diagnostic error and the contexts of care in which these errors are likely to occur. Refinement and adoption of this framework across health systems can facilitate standardized measurement and reporting of diagnostic safety.

  8. Role of Fault Attributions and Other Factors in Adults' Attitudes Toward Hypothetical Children With an Undesirable Characteristic.

    Science.gov (United States)

    Wadian, Taylor W; Sonnentag, Tammy L; Jones, Tucker L; Barnett, Mark A

    2018-01-01

    A total of 184 adults read descriptions of six hypothetical children with various undesirable characteristics (i.e., being extremely overweight, extremely aggressive, extremely shy, a poor student, a poor athlete, displaying symptoms of attention deficit hyperactivity disorder). Following each description, the participants were asked to rate how much they disagree or agree that the child, the child's parents, and the child's biological condition (i.e., "something wrong inside the child's body or brain") are at fault for the onset and the perpetuation of the undesirable characteristic. In addition, the participants were asked to rate their attitude toward each child using a 100-point "feeling thermometer." Analyses of the participants' various fault attribution ratings revealed that they tended to agree more strongly that a child's parents and his/her biological condition are at fault for the onset and the perpetuation of the child's undesirable characteristic than is the child him/herself. Despite the participants' reluctance to blame a hypothetical child for his/her undesirable characteristic, regression analyses revealed that, in general, the more they blamed the child for the onset of his/her undesirable characteristic, the more negative their attitude was toward the child. However, the participants' ratings of the extent to which the child's parents or biological condition are at fault for the onset and the perpetuation of the child's undesirable characteristic were not found to be associated with their attitude toward any of the children. Similarities and differences between the present findings and those reported in prior studies involving younger individuals are addressed.

  9. [Feasibility, in general practice, to give to the patients clear, loyal and appropriate information about the undesirable side effects of the medicines prescribed. EICLAT study].

    Science.gov (United States)

    Arnould, Pascale; Raineri, François; Hebbrecht, Gilles; Duhot, Didier

    2011-12-01

    Drug prescription in general practice is present in 78 to 83% of consultations; practitioners must give to their patient clear loyal and appropriate information about the undesirable side effects of the medicines prescribed. The object of the EICLAT study was to give some light on the feasibility to respect this obligation. To that effect the study evaluates, for a normal prescription activity, the average number of potential undesirable side effects (USE) in relation with the number of lines of different medicines prescribed in each doctor's prescription. A total of 8,382 doctor's prescriptions, generating 34,427 lines of prescriptions given by 175 general practitioners, were analysed. Amongst these prescriptions, 11% included only one line, 55% from 2 to 4 lines and 34% 5 lines or more. The average doctor's prescription was of 4 lines of medicines generating 407 potential USE, of which 194 were different (the same undesirable effect may be present twice or more in the same doctor's prescription), and 293 frequent or serious potential USE, of which 166 were different. The patent medicines with a major or important added medical value (AMV), present in 7,840 doctor's prescriptions for a total of 24,127 lines exposed the patient, in the average, to 151 frequent or serious USE different. The patent medicines with an insufficient AMV, present in 2,292 prescriptions for a total of 3,887 lines, exposed the patient to 37 frequent and/or serious potential USE. Supposing that the information provided by the legal authority is sufficiently adequate, precise and exhaustive, the volume of information that must be given to the patient is not compatible with the present conditions of exercise of the profession.

  10. Techniques Use by Science, Technology and Mathematics (STM) Teachers for Controlling Undesirable Classroom Behaviours in Anambra State Secondary Schools

    Science.gov (United States)

    Chinelo, Okigbo Ebele; Nwanneka, Okoli Josephine

    2016-01-01

    This study investigated the techniques used by secondary school Science Technology and Mathematics (STM) teachers in controlling undesirable behaviours in their classrooms. It adopted descriptive survey design in which 178 Anambra State teachers teaching STM subjects in senior secondary were involved in the research. Two sections of questionnaire…

  11. The Emperor’s New Clothing: National Responses to “Undesirable and Unreturnable” Aliens under Asylum and Immigration Law

    NARCIS (Netherlands)

    Cantor, David James; van Wijk, J.; Singer, Sarah; Bolhuis, M.P.

    2017-01-01

    The “scandal” of foreign criminals whom our governments cannot send back to their own countries has become something of a tabloid obsession. Yet, while suspected or convicted of serious crimes or considered to pose a danger to society, such “undesirable and unreturnable” aliens equally often

  12. Rac1 plays a role in CXCL12 but not CCL3-induced chemotaxis and Rac1 GEF inhibitor NSC23766 has off target effects on CXCR4.

    Science.gov (United States)

    Mills, Shirley C; Howell, Lesley; Beekman, Andrew; Stokes, Leanne; Mueller, Anja

    2018-01-01

    Cell migration towards a chemotactic stimulus relies on the re-arrangement of the cytoskeleton, which is triggered by activation of small G proteins RhoA, Rac1 and Cdc42, and leads to formation of lamellopodia and actin polymerisation amongst other effects. Here we show that Rac1 is important for CXCR4 induced chemotaxis but not for CCR1/CCR5 induced chemotaxis. For CXCL12-induced migration via CXCR4, breast cancer MCF-7 cells are reliant on Rac1, similarly to THP-1 monocytes and Jurkat T-cells. For CCL3-induced migration via CCR1 and/or CCR5, Rac1 signalling does not regulate cell migration in either suspension or adherent cells. We have confirmed the involvement of Rac1 with the use of a specific Rac1 blocking peptide. We also used a Rac1 inhibitor EHT 1864 and a Rac1-GEF inhibitor NSC23766 to probe the importance of Rac1 in chemotaxis. Both inhibitors did not block CCL3-induced chemotaxis, but they were able to block CXCL12-induced chemotaxis. This confirms that Rac1 activation is not essential for CCL3-induced migration, however NSC23766 might have secondary effects on CXCR4. This small molecule exhibits agonistic features in internalisation and cAMP assays, whereas it acts as an antagonist for CXCR4 in migration and calcium release assays. Our findings strongly suggest that Rac1 activation is not necessary for CCL3 signalling, and reveal that NSC23766 could be a novel CXCR4 receptor ligand. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  13. UNDESIRED REACTIONS AT THE UROGRAPHY IN THE CORRELATION OF THE IODIC AND THE NON-TODIC CONTRAST MEDIA

    Directory of Open Access Journals (Sweden)

    Rade R. Babić

    2000-07-01

    Full Text Available The paper analyzes the undesired reactions at 6053 urographies (IVU in thecorrelation of the iodic and the non-iodic contrast media (ICM.Depending on the allergological status the ICM (iodic or non-iodic is chosenfor the sake of carrying out an urographic examination as well as the necessarypremedication measures.The undesired reactions to the TCM are registered in 4,87% (1:20 TVU,namely in 5,6% (1:17 TVU to the iodic and in 2,39% (1:41 IVU to the non-iodicICM.At the intravenous application of the iodic ICM at the IVU the undesiredreactions are registered for2,4 times more often than at the application of the non-iodicICM.

  14. Order and control in the environment: Exploring the effects on undesired behaviour and the importance of locus of control

    OpenAIRE

    Jansen, A.M.; Giebels, Ellen; van Rompay, Thomas Johannes Lucas; Austrup, Sebastian; Junger, Marianne

    2017-01-01

    Purpose This study aimed at gaining more insight into the combined influence of environmental factors and personal vulnerability to environmental cues on cheating behaviour in a task-related indoor setting. We propose that a disorderly environment increases cheating as it implicitly signals that undesirable behaviours are common. Camera presence is expected to buffer these effects. We included locus of control (LOC) as a personality variable, as we expected individuals with an external LOC to...

  15. Using the incidence and impact of behavioural conditions in guide dogs to investigate patterns in undesirable behaviour in dogs

    OpenAIRE

    Caron-Lormier, Geoffrey; Harvey, Naomi D.; England, Gary C.W.; Asher, Lucy

    2016-01-01

    The domestic dog is one of our most popular companions and longest relationships, occupying different roles, from pet to working guide dog for the blind. As dogs age different behavioural issues occur and in some cases dogs may be relinquished or removed from their working service. Here we analyse a dataset on working guide dogs that were removed from their service between 1994 and 2013. We use the withdrawal reasons as a proxy for the manifestation of undesirable behaviour. More than 7,500 d...

  16. The adverse effect on innovation, of state repression, and of groups with undesirable work ethics

    Directory of Open Access Journals (Sweden)

    William R. DiPietro

    2016-07-01

    Full Text Available Innovation is crucial for economic growth, development, and progress. Using cross country regression analysis, this paper tests for two hypothesis regarding the determinants of innovation. The first is that state repression has a negative effect on innovation. The second is that lifestyles that devalue work, such as those obtaining their incomes from criminal activity or through natural resource rents, are detrimental to innovation. The findings from the empirical work of the paper provide evidence that tends to uphold both of these hypothesizes

  17. A dosimetric system for the evaluation of undesired neutron dose in radiotherapy treatments with protons: experimental method and MC simulation

    Energy Technology Data Exchange (ETDEWEB)

    Zanini, A. [INFN, Torino (Italy); Fasolo, F.; Ongaro, C.; Durisi, E. [Torino Univ., Torino (Italy). Dipartimento di Fisica Sperimentale; Nastasi, U. [Ospedale S. Giovanni, Torino (Italy); Scielzo, G.; Fabris, M. [IRCC, Candiolo (Italy); Burn, K.W. [ENEA ERGSPIEC, Bologna (Italy)

    2002-07-01

    Linear accelerator is nowadays the most used radiotherapy device to treat tumour disease. In a number of cases secondary malignancies, due to the undesired dose delivered to the patient, could arise. The optimization of radiotherapy treatment can be obtained only through an accurate evaluation of the undesired dose. A method is presented to evaluate the photoneutron dose produced by GDR during cancer radiotherapy with energetic proton beams. It consists of a computer simulation code based on MCNP4B, in which the new routine GAMMAN was implemented, for the accurate study of photoneutron production in high Z and low Z elements. An experimental technique, based on a bubble passive spectrometer, allows direct measurements of photoneutron spectra at the patient plane, also inside the treatment zone. For the evaluation of neutron contribution to the dose at clinical organs, a new anthropomorphic phantom has been designed and realized, following ICRP60 recommendations. The results are presented for medical accelerators, equipped both with traditional collimator system and with multi leaf collimators.

  18. Diminishing the Undesirable Effects of the Computer Games with the Kinect Sensors

    Directory of Open Access Journals (Sweden)

    Ömür Akdemir

    2015-04-01

    Full Text Available Abstract The popularity of the computer games are increasing every day. Spending time in front of the computers with almost no physical activity causes many health related problems. Recent technologies such as Kinect sensors may have the potential to reduce the physical side effects of the computer games. Nevertheless, the physical and emotional effects of playing computer games with the Kinect on users are still not clear. The effects of playing computer games with and without Kinect were compared in the study with 21 prospective teachers studying at the Education Faculty located in Zonguldak, Turkey in 2014. The mixed method research design was used to explore the research questions. The game playing motivation scale, self-reported muscular activity figure and structured interview questions were used to collect data. Besides t-test, descriptive analyses of the qualitative and quantitative data were conducted for analysis. Findings revealed that using the games with Kinect sensors improved users’ motivation and muscular activity. Also the Kinect has changed game players’ opinions on games. Further research should investigate the correlation between the motivation and emotional effects of the Kinect use on computer game players. Keywords: Kinect, computer games, motivation scale, physical activity   Öz Her geçen gün bilgisayar oyunlarının popülaritesi artmaktadır. Bilgisayarın önünde hiçbir fiziksel hareket yapmadan oturmak birçok sağlık problemine neden olmaktadır. Son teknolojiler örneğin Kinect sensörler bilgisayar oyunlarının yan etkilerini azaltacak potansiyele sahiptir. Ne var ki, bilgisayar oyunlarını Kinect sensör ile uygulamanın fiziksel ve duygusal etkileri hala netlik kazanmamıştır. Bu araştırmada 2014 yılında Zonguldak, Türkiye’de bulunan Ereğli Eğitim Fakültesinde okumakta olan 21 öğretmen adayının Kinect sensörü kullanarak ve Kinect sensör kullanmadan bilgisayar oyunlar

  19. A smart base restraint for wind turbines to mitigate undesired effects due to structural vibrations

    DEFF Research Database (Denmark)

    Caterino, N.; Georgakis, Christos T.; Spizzuoco, M.

    2016-01-01

    to control tower forces. The application of a semi-active (SA) control system is herein proposed and discussed. Its aim is to limit bending moment demand at the base of a wind turbine by relaxing the base restraint of the turbine's tower, without increasing the top displacement. This is done thanks...... to the sharp increase of the dissipated energy in selected intervals of time and an adaptive change in tower dynamic properties. This SA control system reproduces a variable restraint at the base that changes in real time its mechanical properties according to the instantaneous response of the turbine's tower....... This smart restraint is made of a central smooth hinge, elastic springs and SA magnetorheological dampers driven by a control algorithm properly designed for the specific application. A commercial 105 m tall wind turbine has been assumed as a case study. Several numerical simulations have been performed...

  20. The properties of chlorhexidine and undesired effects of its use in endodontics.

    Science.gov (United States)

    Bernardi, Anarela; Teixeira, Cleonice Silveira

    2015-01-01

    The purpose of this article was to review the literature on the properties of chlorhexidine (CHX) and the adverse effects that may occur from its use in endodontics. In addition, adverse effects that may result from its use, such as dark staining of teeth, chemical interaction with sodium hypochlorite and formed flocculate, biologic hazards, and interactions with the filling material were evaluated. Relevant publications on the use CHX in endodontics were thoroughly reviewed from the literature published between the years 2007 and 2014. The authors conducted an electronic search using the English language databases Medline and PubMed. According to the reviewed studies, it was concluded that CHX has proven antimicrobial activity, excellent substantivity, low surface tension, and low cytotoxicity and genotoxicity that depend on the dose and exposed area. There is scientific evidence showing the possibility of tooth staining and formation of brown precipitate when its use is associated with sodium hypochlorite. On the other hand, it is not well established that its use interferes with the quality of endodontic fillings. With respect to the biologic risks, the degradation of CHX may generate para-chloroaniline and free radicals, which are harmful to the vital tissues. There is no established consensus on the potential risk of CHX. The final considerations of this review will encourage researchers to seek scientific evidence demonstrating the safety of the use and applicability of CHX in endodontic therapy.

  1. Evaluation of input output efficiency of oil field considering undesirable output —A case study of sandstone reservoir in Xinjiang oilfield

    Science.gov (United States)

    Zhang, Shuying; Wu, Xuquan; Li, Deshan; Xu, Yadong; Song, Shulin

    2017-06-01

    Based on the input and output data of sandstone reservoir in Xinjiang oilfield, the SBM-Undesirable model is used to study the technical efficiency of each block. Results show that: the model of SBM-undesirable to evaluate its efficiency and to avoid defects caused by traditional DEA model radial angle, improve the accuracy of the efficiency evaluation. by analyzing the projection of the oil blocks, we find that each block is in the negative external effects of input redundancy and output deficiency benefit and undesirable output, and there are greater differences in the production efficiency of each block; the way to improve the input-output efficiency of oilfield is to optimize the allocation of resources, reduce the undesirable output and increase the expected output.

  2. Negative symbolic aspects in destination branding: exploring the role of the 'undesired self' on web-based vacation information search intentions among potential first-time visitors

    OpenAIRE

    Bosnjak, Michael

    2010-01-01

    Tourist destination choices depend, among other factors, on the match between the destination’s personality image and consumers’ self-concept, in line with self-image congruence theory. Motives also mediate this relationship, yet tourism research largely neglects the influence of avoidance motives. This study applies the product-based construct of undesired congruity, or consumers’ tendency to avoid undesired stereotypical images, to the context of web-based vacation destination information s...

  3. Nanofluids and chemical highly retentive hydrogels for controlled and selective removal of overpaintings and undesired graffiti from street art.

    Science.gov (United States)

    Giorgi, Rodorico; Baglioni, Michele; Baglioni, Piero

    2017-06-01

    One of the main problems connected to the conservation of street art is the selective removal of overlying undesired graffiti, i.e., drawings and tags. Unfortunately, selective and controlled removal of graffiti and overpaintings from street art is almost unachievable using traditional methodologies. Recently, the use of nanofluids confined in highly retentive pHEMA/PVP semi-interpenetrated polymer networks was proposed. Here, we report on the selective removal of acrylic overpaintings from a layer of acrylic paint on mortar mockups in laboratory tests. The results of the cleaning tests were characterized by visual and photographic observation, optical microscopy, and FT-IR microreflectance investigation. It was shown that this methodology represents a major advancement with respect to the use of nonconfined neat solvents.

  4. Rapid detection of undesired cosmetic ingredients by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

    Science.gov (United States)

    Ouyang, Jie; An, Dongli; Chen, Tengteng; Lin, Zhiwei

    2017-10-01

    In recent years, cosmetic industry profits soared due to the widespread use of cosmetics, which resulted in illicit manufacturers and products of poor quality. Therefore, the rapid and accurate detection of the composition of cosmetics has become crucial. At present, numerous methods, such as gas chromatography and liquid chromatography-mass spectrometry, were available for the analysis of cosmetic ingredients. However, these methods present several limitations, such as failure to perform comprehensive and rapid analysis of the samples. Compared with other techniques, matrix-assisted laser desorption ionization time-of-flight mass spectrometry offered the advantages of wide detection range, fast speed and high accuracy. In this article, we briefly summarized how to select a suitable matrix and adjust the appropriate laser energy. We also discussed the rapid identification of undesired ingredients, focusing on antibiotics and hormones in cosmetics.

  5. Diamagnetic composite material structure for reducing undesired electromagnetic interference and eddy currents in dielectric wall accelerators and other devices

    Science.gov (United States)

    Caporaso, George J.; Poole, Brian R.; Hawkins, Steven A.

    2015-06-30

    The devices, systems and techniques disclosed here can be used to reduce undesired effects by magnetic field induced eddy currents based on a diamagnetic composite material structure including diamagnetic composite sheets that are separated from one another to provide a high impedance composite material structure. In some implementations, each diamagnetic composite sheet includes patterned conductor layers are separated by a dielectric material and each patterned conductor layer includes voids and conductor areas. The voids in the patterned conductor layers of each diamagnetic composite sheet are arranged to be displaced in position from one patterned conductor layer to an adjacent patterned conductor layer while conductor areas of the patterned conductor layers collectively form a contiguous conductor structure in each diamagnetic composite sheet to prevent penetration by a magnetic field.

  6. undesirability , wit h relevance

    African Journals Online (AJOL)

    banzi

    disciplined environment; they were housed, fed, clothed and gainfully employed. The dissolution of the English monasteries in the late 15th century resulted in the vagrancy problem. This early example of kleptocracy had major social repercussions and led to parliament passing the Poor Laws (vide infra). The feudal system.

  7. Children's Perceptions of Hypothetical Peers With Undesirable Characteristics: Role of the Peers' Desire to Change, Source of Effort to Change, and Outcome.

    Science.gov (United States)

    Barnett, Mark A; Sonnentag, Tammy L; Wadian, Taylor W; Jones, Tucker L; Langley, Courtney A

    2015-01-01

    The present study, involving sixth- to eighth-grade students, is an extension of a prior investigation (Barnett, Livengood, Sonnentag, Barlett, & Witham, 2010) that examined children's perceptions of hypothetical peers with various undesirable characteristics. Results indicate that children's perceptions of hypothetical peers with an undesirable characteristic are influenced by the peers' desire to change, the source of effort to change, and the peers' success or failure in changing the characteristic. The children anticipated responding more favorably to peers who were successful in overcoming an undesirable characteristic than peers who were unsuccessful. Regardless of the peers' outcome, the children anticipated responding more favorably to peers who tried to change than peers who relied on the effort of adult authorities to motivate change. The children perceived successful peers as experiencing more positive affect than their unsuccessful counterparts, especially if the success was presented as a fulfillment of the peers' desire to change their undesirable characteristic. Finally, the children's ratings reflected the belief that, among peers who failed to change their undesirable characteristic, lacking the desire to change increases the relative likelihood that the characteristic will be permanent.

  8. Using the incidence and impact of behavioural conditions in guide dogs to investigate patterns in undesirable behaviour in dogs.

    Science.gov (United States)

    Caron-Lormier, Geoffrey; Harvey, Naomi D; England, Gary C W; Asher, Lucy

    2016-04-14

    The domestic dog is one of our most popular companions and longest relationships, occupying different roles, from pet to working guide dog for the blind. As dogs age different behavioural issues occur and in some cases dogs may be relinquished or removed from their working service. Here we analyse a dataset on working guide dogs that were removed from their service between 1994 and 2013. We use the withdrawal reasons as a proxy for the manifestation of undesirable behaviour. More than 7,500 dogs were in the dataset used, 83% of which were retired (due to old age) and 17% were withdrawn for behavioural issues. We found that the main reasons for behaviour withdrawal were environmental anxiety, training, and fear/aggression. Breed and sex had an effect on the odds of dogs being withdrawn under the different reasons. The age at withdrawal for the different withdrawal reasons suggested that dogs were more likely to develop fear/aggression related issues early on, whilst issues related to training could develop at almost any age. We found no evidence for heterosis effecting behaviour. We believe that this work is relevant to the pet dog population and had implications for understanding ageing and genetic influences on behaviour.

  9. Potential conflict between TRIPS and GATT concerning parallel importation of drugs and possible solution to prevent undesirable market segmentation.

    Science.gov (United States)

    Lo, Chang-Fa

    2011-01-01

    From international perspective, parallel importation, especially with respect to drugs, has to do with the exhaustion principle in Article 6 of the TRIPS Agreement and the general exception in Article XX of the GATT 1994. Issues concerning the TRIPS Agreement have been constant topics of discussion. However, parallel importation in relation to the general rules of the GATT 1994 as well as to its exceptions provided in Article XX was not seriously discussed. In the view of the paper, there is a conflict between the provisions in these two agreements. The paper explains such conflict and tries to propose a method of interpretation to resolve the conflict between GATT Article XX and TRIPS Article 6 concerning parallel importation for the purpose of reducing the possible undesirable market segmentation in pharmaceutical sector. The method suggested in the paper is a proper application of good faith principle in the Vienna Convention to interpret GATT Article XX, so that there could be some flexibility for those prohibitions of parallel importation which have positive effect on international trade.

  10. A comparative analysis of China’s regional energy and emission performance: Which is the better way to deal with undesirable outputs?

    International Nuclear Information System (INIS)

    Wang Ke; Wei Yiming; Zhang Xian

    2012-01-01

    Measuring and improving the energy performance with considering emission constraints is an important issue for China’s energy conservation, pollutant emissions reduction and environment protection. This study utilizes several data envelopment analysis (DEA) based models to evaluate the total-factor energy and emission performance of China’s 30 regions within a joint production framework of considering desirable and undesirable outputs as well as separated energy and non-energy inputs. DEA window analysis is applied in this study to deal with cross-sectional and time-varying data, so as to measure the performance during the period of 2000–2009. Two treatments for undesirable outputs are combined with DEA models and the associated indicators for simplex energy performance and unified energy and emission performance measurement are proposed and compared. The evaluation results indicate that the treatment of undesirable outputs transformation is more appropriate for China’s regional energy and emission performance evaluation because it has stronger discriminating power and can provide more reasonable evaluation results that characterize China’s regions. The empirical result shows that east China has the highest and the most balanced energy and emission performance. The energy and emission performance of China remained stable during 2000–2003, decreased slightly during 2004–2006, and has continuously increased since 2007. - Highlights: ► We evaluate China’s regional energy and emission performance using DEA based models. ► We compare two undesirable outputs treatments according to the evaluation results. ► To treat undesirable outputs as inputs has weaker discriminating power in evaluation. ► Simplex energy performance, without environmental factors, is a biased evaluation. ► China’s energy and emission performance is approximately stable during study period.

  11. Identification of new Saccharomyces cerevisiae variants of the MET2 and SKP2 genes controlling the sulfur assimilation pathway and the production of undesirable sulfur compounds during alcoholic fermentation.

    Science.gov (United States)

    Noble, Jessica; Sanchez, Isabelle; Blondin, Bruno

    2015-05-08

    Wine yeasts can produce undesirable sulfur compounds during alcoholic fermentation, such as SO2 and H2S, in variable amounts depending mostly on the yeast strain but also on the conditions. However, although sulfur metabolism has been widely studied, some of the genetic determinants of differences in sulfite and/or sulfide production between wine yeast strains remain to be identified. In this study, we used an integrated approach to decipher the genetic determinants of variation in the production of undesirable sulfur compounds. We examined the kinetics of SO2 production by two parental strains, one high and one low sulfite producer. These strains displayed similar production profiles but only the high-sulfite producer strain continued to produce SO2 in the stationary phase. Transcriptomic analysis revealed that the low-sulfite producer strain overexpressed genes of the sulfur assimilation pathway, which is the mark of a lower flux through the pathway consistent with a lower intracellular concentration in cysteine. A QTL mapping strategy then enabled us to identify MET2 and SKP2 as the genes responsible for these phenotypic differences between strains and we identified new variants of these genes in the low-sulfite producer strain. MET2 influences the availability of a metabolic intermediate, O-acetylhomoserine, whereas SKP2 affects the activity of a key enzyme of the sulfur assimilation branch of the pathway, the APS kinase, encoded by MET14. Furthermore, these genes also affected the production of propanol and acetaldehyde. These pleiotropic effects are probably linked to the influence of these genes on interconnected pathways and to the chemical reactivity of sulfite with other metabolites. This study provides new insight into the regulation of sulfur metabolism in wine yeasts and identifies variants of MET2 and SKP2 genes, that control the activity of both branches of the sulfur amino acid synthesis pathway and modulate sulfite/sulfide production and other

  12. Commercial Bank Efficiency Evaluation in Consideration of the Undesirable Output and Its Link with Stakeholders Relationship: An Application of China’s Commercial Banks

    Directory of Open Access Journals (Sweden)

    Jianyue Ji

    2014-01-01

    Full Text Available Based on the modern contract theory, expectancy theory, and stakeholder theory, this paper analyzes how stakeholders relationship influences the efficiency of commercial banks and finds that the efficiency is a function of stakeholders relationship. A DEA model with Seiford's linear transformation function is developed to evaluate the efficiency in consideration of the undesirable output. The panel Tobit model is established to conduct empirical research with data of 14 Chinese commercial banks from 2004 to 2012. The study finds that except for business customer relation, stakeholder relationship is the key variable that influences comprehensive efficiency of commercial banks.

  13. Overweight dogs are more likely to display undesirable behaviours: results of a large online survey of dog owners in the UK.

    Science.gov (United States)

    German, Alexander J; Blackwell, Emily; Evans, Mark; Westgarth, Carri

    2017-01-01

    Much of the global canine population is now overweight, and this can adversely affect health, lifespan and quality of life. Undesirable behaviours are also common in pet dogs, and these can adversely affect welfare, as well as being stressful to owners. However, links between obesity and behavioural disorders have never previously been explored. An online survey was conducted between June and August in 2014, coinciding with the broadcast of a National UK television programme, exploring dog health, welfare and behaviour. Information gathered included signalment, overweight status and the prevalence of a range of undesirable behaviours. Fisher's exact test and OR were used to determine associations between overweight status and owner-reported behaviours. A total of 17 028 responses were received. After data verification, the final dataset comprised 11 154 dogs, 1801 (16·1 %) of which were reported by owners to be overweight. Owners of overweight dogs were more likely to see them as 'a baby' ( P  dogs were also more likely to guard food ( P  dogs included barking, growling or snapping at strangers ( P  = 0·0011) and other dogs ( P  = 0·0015), being fearful of outdoors ( P  dog's health ( P  dogs. Further studies are now required to explore the reasons for these associations.

  14. 'Direct and Indirect Shadow Price Estimates of Nitrate Pollution Treated as an Undesirable Output and Input', Journal of Agricultural and Resource Economics Vol. 27, No. 2 (December 2002) pp: 420-432.

    OpenAIRE

    Saleem Shaik; Glenn A Helmers; Michael Langemeier

    2005-01-01

    The implication of treating environmental pollution as an undesirable output (weak disposability) as well as a normal input (strong disposability) on the direct and indirect shadow price and cost estimates of nitrogen pollution abatement is analyzed using Nebraska agriculture sector data. The shadow price of nitrogen pollution abatement treated as an undesirable output represents the reduced revenue from reducing nitrogen pollution. In contrast, the shadow price of nitrogen pollution abatemen...

  15. Analysis of regional total factor energy efficiency in China under environmental constraints: based on undesirable-minds and DEA window model

    Science.gov (United States)

    Zhang, Shuying; Li, Deshan; Li, Shuangqiang; Jiang, Hanyu; Shen, Yuqing

    2017-06-01

    With China’s entrance into the new economy, the improvement of energy efficiency has become an important indicator to measure the quality of ecological civilization construction and economic development. According to the panel data of Chinese regions in 1996-2014, the nearest distance to the efficient frontier of Undesirable-MinDS Xeon model and DEA window model have been used to calculate the total factor energy efficiency of China’s regions. Study found that: Under environmental constraints, China’s total factor energy efficiency has increased after the first drop in the overall 1996-2014, and then increases again. And the difference between the regions is very large, showing a characteristic of “the east is the highest, the west is lower, and lowest is in the central” finally, this paper puts forward relevant policy suggestions.

  16. Undesirable behavior in forest campgrounds

    Science.gov (United States)

    Roger N. Clark

    1971-01-01

    A 3-year study indicates that nuisance behaviors, law violations, vandalism, and littering in forest campgrounds are more extensive than is generally believed. All campers share responsibility for the problems. Violations occur because of ignorance of, lack of understanding, or a willingness to disregard rules. Control measures are discussed, including an incentive...

  17. Quantifying On and Off-Target Genome Editing

    OpenAIRE

    Hendel, Ayal; Fine, Eli J; Bao, Gang; Porteus, Matthew H

    2015-01-01

    Genome editing with engineered nucleases is a rapidly growing field, thanks to transformative technologies that allow researchers to precisely alter genomes for numerous applications, including basic research, biotechnology, and human gene therapy. While the capability to make precise and controlled changes at specified sites throughout the genome has grown tremendously in recent years, we still lack a comprehensive and standardized battery of assays for measuring the different genome editing...

  18. Diferentes métodos de controle de plantas indesejáveis em pastagem nativa Different methods for controlling undesirable plants in native pasture

    Directory of Open Access Journals (Sweden)

    Luiz Giovani de Pellegrini

    2007-10-01

    Full Text Available O experimento foi desenvolvido em área de pastagem nativa representativa da transição entre a Serra do Sudeste e a Depressão Central do Rio Grande do Sul, onde as espécies indesejáveis foram representadas especialmente por carqueja (Baccharis trimera (Less. DC., caraguatá (Eryngium horridum (Spreng. Less. e alecrim (Vernonia nudiflora Less.. Foram avaliados os efeitos iniciais de dois métodos de controle de espécies indesejáveis (até 60 dias após aplicação sobre a produção de forragem, a dinâmica da vegetação e a eficiência de controle: sem-controle; controle mecânico; e controle químico (herbicida comercial à base de Picloram [64 g/L] + 2,4-D [240 g/L], na dosagem de 5 L do produto comercial/ha. Os tratamentos foram arranjados em um delineamento em blocos ao acaso, com quatro repetições. A massa gramíneas verdes secas e a massa total de MS não diferiram entre os métodos de controle. Foram obtidos valores de 587,9; 472,0 e 0 kg de MS com o controle mecânico, o controle químico e sem-controle, respectivamente, o que comprova influência do método de controle sobre a massa de forragem de leguminosas. A eficiência de controle das espécies indesejáveis, em comparação à ausência de controle, foi de 76,2% para o controle químico e 27,9% para o controle mecânico. A eficiência de controle de espécies, sob aspectos de freqüência dos componentes da pastagem, evidenciou que o controle mecânico não foi eficiente aos 60 dias após aplicação no controle de plantas de alecrim no segundo toque (-27,7% e plantas de caraguatá no primeiro toque (-30,0%.The study was conducted in a representative native pasture area in the transition between the Serra do Sudeste and Depressão Central of RS. The main undesirable species were represented by: carqueja (Baccharis trimera (Less. DC., caraguatá (Eryngium horridum (Spreng. Less. and alecrim (Vernonia nudiflora Less. It was evaluated the initial effect (until 60 days after

  19. A Biophysical Model of CRISPR/Cas9 Activity for Rational Design of Genome Editing and Gene Regulation

    Science.gov (United States)

    Farasat, Iman; Salis, Howard M.

    2016-01-01

    The ability to precisely modify genomes and regulate specific genes will greatly accelerate several medical and engineering applications. The CRISPR/Cas9 (Type II) system binds and cuts DNA using guide RNAs, though the variables that control its on-target and off-target activity remain poorly characterized. Here, we develop and parameterize a system-wide biophysical model of Cas9-based genome editing and gene regulation to predict how changing guide RNA sequences, DNA superhelical densities, Cas9 and crRNA expression levels, organisms and growth conditions, and experimental conditions collectively control the dynamics of dCas9-based binding and Cas9-based cleavage at all DNA sites with both canonical and non-canonical PAMs. We combine statistical thermodynamics and kinetics to model Cas9:crRNA complex formation, diffusion, site selection, reversible R-loop formation, and cleavage, using large amounts of structural, biochemical, expression, and next-generation sequencing data to determine kinetic parameters and develop free energy models. Our results identify DNA supercoiling as a novel mechanism controlling Cas9 binding. Using the model, we predict Cas9 off-target binding frequencies across the lambdaphage and human genomes, and explain why Cas9’s off-target activity can be so high. With this improved understanding, we propose several rules for designing experiments for minimizing off-target activity. We also discuss the implications for engineering dCas9-based genetic circuits. PMID:26824432

  20. Purifying Sufism: Observations on the Marginalization and Exclusion of Undesirable and Rejected Elements in the Earlier Middle Period (late fourth/tenth to mid-seventh/thirteenth centuries

    Directory of Open Access Journals (Sweden)

    Ephrat, Daphna

    2014-06-01

    Full Text Available This article offers observations on the process of differentiation and purification within premodern Sufism during a seminal period in the institutionalization of the Sufi ṭarīqa as a Path to God and as a community of followers. Drawing on manuals and narratives by prominent articulators and representatives of the emerging mainstream Sufi tradition, the article highlights the discursive and actual mechanisms they employed to delineate the borderlines of affiliation with the communities of the genuine Sufis, disentangle the solid-core from lay affiliates, and exclude undesirable elements wrongly associated with Sufism. The construction of higher barriers between mainstream Sufism and its margins is closely tied to the spread of popular forms of Sufism and a new kind of antinomianism that gained popularity in the public sphere, beginning in the late sixth/twelfth century. The final part of the article considers the involvement of the political rulers of the time in the inner dynamics of Sufism. My main conclusion is that by patronizing mainstream Sufis and supporting arbiters of true religion in the public sphere, the ruling elite of military lords in the Arab Near East played a significant role in marginalizing the undesirable and rejected elements and in strengthening the mainstream Sunni camp against its rivals.Este artículo ofrece una serie de observaciones sobre el proceso de diferenciación y purificación dentro del sufismo pre-moderno durante un periodo crucial para la institucionalización de las ṭarīqa-s sufíes como una Vía hacia Dios y como una comunidad de seguidores. Basándose en manuales y en narraciones de autores prominentes y representantes de la tradición sufí mainstream emergente, este artículo pone de relieve los mecanismos discursivos que emplearon para marcar los bordes de la afiliación con comunidades de sufíes genuinos, separar el núcleo central de los afiliados externos, y excluir a los elementos

  1. Capturing structure-activity relationships from chemogenomic spaces.

    Science.gov (United States)

    Wendt, Bernd; Uhrig, Ulrike; Bös, Fabian

    2011-04-25

    Modeling off-target effects is one major goal of chemical biology, particularly in its applications to drug discovery. Here, we describe a new approach that allows the extraction of structure-activity relationships from large chemogenomic spaces starting from a single chemical structure. Several public source databases, offering a vast amount of data on structure and activity for a large number of different targets, have been investigated for their usefulness in automated structure-activity relationships (SAR) extraction. SAR tables were constructed by assembling similar structures around each query structure that have an activity record for a particular target. Quantitative series enrichment analysis (QSEA) was applied to these SAR tables to identify trends and to transform these trends into topomer CoMFA models. Overall more than 1700 SAR tables with topomer CoMFA models have been obtained from the ChEMBL, PubChem, and ChemBank databases. These models were able to highlight the structural trends associated with various off-target effects of marketed drugs, including cases where other structural similarity metrics would not have detected an off-target effect. These results indicate the usefulness of the QSEA approach, particularly whenever applicable with public databases, in providing a new means, beyond a simple similarity between ligand structures, to capture SAR trends and thereby contribute to success in drug discovery.

  2. A critical assessment for the value of markers to gate-out undesired events in HLA-peptide multimer staining protocols

    Directory of Open Access Journals (Sweden)

    Odunsi Kunle

    2011-07-01

    Full Text Available Abstract Background The introduction of antibody markers to identify undesired cell populations in flow-cytometry based assays, so called DUMP channel markers, has become a practice in an increasing number of labs performing HLA-peptide multimer assays. However, the impact of the introduction of a DUMP channel in multimer assays has so far not been systematically investigated across a broad variety of protocols. Methods The Cancer Research Institute's Cancer Immunotherapy Consortium (CRI-CIC conducted a multimer proficiency panel with a specific focus on the impact of DUMP channel use. The panel design allowed individual laboratories to use their own protocol for thawing, staining, gating, and data analysis. Each experiment was performed twice and in parallel, with and without the application of a dump channel strategy. Results The introduction of a DUMP channel is an effective measure to reduce the amount of non-specific MULTIMER binding to T cells. Beneficial effects for the use of a DUMP channel were observed across a wide range of individual laboratories and for all tested donor-antigen combinations. In 48% of experiments we observed a reduction of the background MULTIMER-binding. In this subgroup of experiments the median background reduction observed after introduction of a DUMP channel was 0.053%. Conclusions We conclude that appropriate use of a DUMP channel can significantly reduce background staining across a large fraction of protocols and improve the ability to accurately detect and quantify the frequency of antigen-specific T cells by multimer reagents. Thus, use of a DUMP channel may become crucial for detecting low frequency antigen-specific immune responses. Further recommendations on assay performance and data presentation guidelines for publication of MULTIMER experimental data are provided.

  3. The Undesirable Behaviors of Students in Academic Classrooms, and the Discipline Strategies Used by Faculty Members to Control Such Behaviors from the Perspective of the College of Education Students in King Saud University

    Science.gov (United States)

    Al Qahtani, Norah Saad Sultan

    2016-01-01

    This study aimed to identify the undesirable students' behaviors in academic classrooms, and the disciplinary, preventive and therapeutic strategies that will be used by faculty members to control those behaviors from the perspective of the College of Education's students in King Saud University. The results of the study has shown that the…

  4. Mães avaliam comportamentos socialmente "desejados" e "indesejados" de pré-escolares Mothers assess socially "desirable" and "undesirable" behavior of kindergarteners

    Directory of Open Access Journals (Sweden)

    Alessandra Turini Bolsoni-Silva

    2005-08-01

    Full Text Available Comportamentos socialmente habilidosos promovem o desenvolvimento, ao passo que problemas de comportamento dificultam o acesso a novas contingências de reforçamento, facilitadoras da aquisição de repertórios de aprendizagem. Esta pesquisa investiga avaliações maternas de repertórios socialmente "desejados" e "indesejados" de crianças que, segundo o professor, apresentam problemas de comportamento. Participaram mães de 24 crianças indicadas pelo professor como tendo problemas de comportamento e mães de 24 crianças indicadas como tendo comportamentos socialmente "desejados". O Questionário de Comportamentos Socialmente Desejados e a Escala Comportamental Infantil de Rutter foram aplicados nas residências das participantes. Os resultados indicaram mais problemas de comportamento externalizante no grupo previamente indicado como tendo problemas; os grupos não diferiram quanto a comportamentos "desejados". Em ambos os grupos, as crianças obtiveram altos escores de comportamentos socialmente desejados, apontando reservas comportamentais. Também em ambos foram identificadas crianças que poderiam ser beneficiadas com programas para a promoção de interações sociais mais equilibradas, prevenindo problemas de comportamento.Socially desirable behaviors promote development but behavior problems prevent the access to new reinforcement contingencies that could facilitate the acquisition of relevant learning repertoires. This work investigated assessments of mothers concerning socially "desirable" and "undesirable" behaviors in children whose teachers identified as having behavior problems. The sample consisted of 24 mothers of children indicated as having behavioral problems, and 24 mothers of children indicated as presenting socially desirable behaviors. Data about children's behaviors were collected during a home interview, when the Socially Desired Behavior Questionnaire and the Rutter Scale for Parents were filled out. Results

  5. Aberrant glomerular filtration of urokinase-plasminogen activator in nephrotic syndrome leads to amiloride-sensitive plasminogen activation in urine

    DEFF Research Database (Denmark)

    Stæhr, Mette; Buhl, Kristian Bergholt; Andersen, René F

    2015-01-01

    In nephrotic syndrome, aberrant glomerular filtration of plasminogen and conversion to active plasmin in pre-urine is thought to activate proteolytically ENaC and contribute to sodium retention and edema. The ENaC blocker amiloride is an off-target inhibitor of urokinase-type plasminogen activator...... with aberrant filtration of uPA across the injured glomerular barrier. Amiloride inhibits urine uPA activity which attenuates plasminogen activation and urine protease activity in vivo. Urine uPA is a relevant target for amiloride in vivo....

  6. Towards Stabilizing Parametric Active Contours

    DEFF Research Database (Denmark)

    Liu, Jinchao; Fan, Zhun; Olsen, Søren Ingvor

    2014-01-01

    to a parametrization that is proportional to the natural parametrization which implies that the control points of the contour are uniformly distributed. We theoretically prove that this tangential diffusion term is bounded and therefore numerically stable. Several experiments were conducted and verified......Numerical instability often occurs in evolving of parametric active contours. This is mainly due to the undesired change of parametrization during evolution. In this paper, we propose a new tangential diffusion term to compensate this undesired change. As a result, the parametrization will converge...

  7. The Value of Physical Activity.

    Science.gov (United States)

    Seefeldt, Vern; Vogel, Paul

    This booklet summarizes results of research and literature reviews that had been collected in a source book titled "Physical Activity & Well-Being" and published in 1986 by the National Association for Sport and Physical Education. The evidence presented suggests that exercise can reduce or delay the undesirable effects of many degenerative…

  8. Lewis Acid Assisted Nickel-Catalyzed Cross-Coupling of Aryl Methyl Ethers by C−O Bond-Cleaving Alkylation: Prevention of Undesired β-Hydride Elimination

    KAUST Repository

    Liu, Xiangqian

    2016-04-10

    In the presence of trialkylaluminum reagents, diverse aryl methyl ethers can be transformed into valuable products by C-O bond-cleaving alkylation, for the first time without the limiting β-hydride elimination. This new nickel-catalyzed dealkoxylative alkylation method enables powerful orthogonal synthetic strategies for the transformation of a variety of naturally occurring and easily accessible anisole derivatives. The directing and/or activating properties of aromatic methoxy groups are utilized first, before they are replaced by alkyl chains in a subsequent coupling process.

  9. Intermittent hypoxia and cancer: Undesirable bed partners?

    Science.gov (United States)

    Almendros, Isaac; Gozal, David

    2017-08-14

    The deleterious effects of intermittent hypoxia (IH) on cancer biology have been primarily evaluated in the context of the aberrant circulation observed in solid tumors which results in recurrent intra-tumoral episodic hypoxia. From those studies, IH has been linked to an accelerated tumor progression, metastasis and resistance to therapies. More recently, the role of IH in cancer has also been studied in the context of obstructive sleep apnea (OSA), since IH is a hallmark characteristic of this condition. Such recent studies are undoubtedly adding more information regarding the role of IH on tumor malignancy. In terms of the IH patterns associated with OSA, this altered oxygenation paradigm has been recently proposed as a determinant factor in fostering cancer incidence and progression from both in vitro and in vivo experimental models. Here, we summarize all the available evidence to date linking IH effects on several types of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Anphibole, an undesirable presence in cosmetic talc

    International Nuclear Information System (INIS)

    Amaral, M.A.M.

    1980-01-01

    A semi-quantitative X-ray diffractometric study, compared to CaO analysis, for the evaluation of the percentage of amphibole present in cosmetic talcs is presented. Scanning electron images show these needle-like minerals togheter with talc; these minerals can cause from simple allergies to serious health problems to the human being. (Author) [pt

  11. Undesired Plant-Derived Components in Food

    NARCIS (Netherlands)

    Dusemund, Birgit; Rietjens, Ivonne M.C.M.; Abraham, Klaus; Cartus, Alexander; Schrenk, Dieter

    2017-01-01

    Among the various chemical compounds, the class of natural plant-derived substances in the modern food chain is generating increasing concern. Adverse effects encountered may be various and pose risks of acute, subchronic, or chronic toxicity. The underlying mechanisms of toxicity may be

  12. Antioxidative, anticholinesterase and antityrosinase activities of the ...

    African Journals Online (AJOL)

    user

    2012-05-15

    May 15, 2012 ... In addition to undesirable color and flavor, the quinine compounds produced in the browning ... necessary to search and develop novel tyrosinase inhibitors with potent activities and fewer side effects. Dementia is a chronic progressive mental disorder, which adversely affects memory, thinking, compre-.

  13. Returns to damage under undesirable congestion and damages to return under desirable congestion measured by DEA environmental assessment with multiplier restriction: Economic and energy planning for social sustainability in China

    International Nuclear Information System (INIS)

    Sueyoshi, Toshiyuki; Yuan, Yan

    2016-01-01

    This study discusses the concept of natural and managerial disposability from their economic and methodological implications on social sustainability development. Then, it explores their analytical linkages to a concept on “congestion.” The concept is classified into Undesirable Congestion (UC) under natural disposability and Desirable Congestion (DC) under managerial disposability. Considering the two disposability concepts, this study compares between Returns to Damage (RTD) under UC and Damages to Return (DTR) under DC. Conceptually, UC and DC are conceptually different from RTD and DTR although they are closely related to each other group. An occurrence of the former measures is identified by a single negative multiplier (i.e. dual variable). In contrast, the latter measures are associated with multiple negative multipliers and an intercept of a supporting hyperplane on a production and pollution possibility set. Thus, an occurrence of UC and DC is a necessary condition, but not a sufficient condition on RTD and DTR, respectively, in terms of the number of negative multipliers on production factors. To document the practicality of the proposed approach, this study applies it to Chinese economic and environmental assessment for its economic and energy planning for social sustainability development. This study identifies four important findings: First, the Chinese government has historically paid attention to the economic prosperity, but not paying serious attention on the environmental pollution (e.g., air pollution). Second, there was an increasing trend in improving the two components (i.e., economic and environmental performance measures) regarding social sustainability. Third, China's economic and energy policy concerns have been focused upon well-developed municipalities (e.g., Beijing and Shanghai) and large provinces. Therefore, it is an important strategy for the government to allocate economic and energy resources to other provinces so that

  14. Why Gupta et al.'s critique of niche construction theory is off target

    Indian Academy of Sciences (India)

    MARCUS W. FELDMAN

    2017-07-20

    Jul 20, 2017 ... 2003), the cor- rect reading of which is that, whereas niche construction has been widely studied as a phenomenon, it has not been widely recognized as an evolutionary process. Clearly,. Gupta et al. dispute that niche construction should be rec- ognized as an evolutionary process; however, that it is not.

  15. An analysis of health promotion materials for Dutch truck drivers: Off target and too complex?

    Science.gov (United States)

    Boeijinga, Anniek; Hoeken, Hans; Sanders, José

    2017-01-01

    Despite various health promotion initiatives, unfavorable figures regarding Dutch truck drivers' eating behaviors, exercise behaviors, and absenteeism have not improved. The aim was to obtain a better understanding of the low level of effectiveness of current health interventions for Dutch truck drivers by examining to what extent these are tailored to the target group's particular mindset (focus of content) and health literacy skills (presentation of content). The article analyzes 21 health promotion materials for Dutch truck drivers using a two-step approach: (a) an analysis of the materials' focus, guided by the Health Action Process Approach; and (b) an argumentation analysis, guided by pragma-dialectics. The corpus analysis revealed: (a) a predominant focus on the motivation phase; and (b) in line with the aim of motivating the target group, a consistent use of pragmatic arguments, which were typically presented in an implicit way. The results indicate that existing health promotion materials for Dutch truck drivers are not sufficiently tailored to the target group's mindset and health literacy skills. Recommendations are offered to develop more tailored/effective health interventions targeting this high-risk, underserved occupational group.

  16. Why Gupta et al.'s critique of niche construction theory is off target

    Indian Academy of Sciences (India)

    2017-07-20

    Jul 20, 2017 ... Journal of Genetics. Current Issue : Vol. 96, Issue 6 · Current Issue Volume 96 | Issue 6. December 2017. Home · Volumes & Issues · Online Resources · Special Issues · Forthcoming Articles · Search · Editorial Board · Information for Authors · Subscription ...

  17. Why Gupta et al.'s critique of niche construction theory is off target

    Indian Academy of Sciences (India)

    MARCUS W. FELDMAN

    2017-07-20

    : the construction of an academic niche? ... their poor scholarship has done a disservice to the evolutionary biology community through propagating misinformation. ... while the third is a perfectly legitimate scientific posi-.

  18. rich extract on total polyphenols and antioxidant activity obtained by ...

    African Journals Online (AJOL)

    Z. Ghouila

    USTHB, Organic Functional Analysis Laboratory, 16111 Bab Ezzouar, Algiers, Algeria. 3. Department of General ... Keywords: Ahmeur Bouamer, extraction, grape seeds, total polyphenols, antioxidant activity. ... in food and pharmaceutical industry like BHA and BHT, which their undesirable effect on health was often ...

  19. Produção animal em pastagem nativa submetida ao controle de plantas indesejáveis e a intensidades de pastejo Animal production on native pasture submitted to the control of undesirable plants and grazing intensity

    Directory of Open Access Journals (Sweden)

    José Acélio Silveira da Fontoura Júnior

    2007-02-01

    Full Text Available O objetivo deste trabalho, realizado no município de Cachoeira do Sul, região Fisiográfica da Serra do Sudeste do Rio Grande do Sul, foi estudar diferentes métodos de controle de espécies indesejáveis em pastagem nativa, associados a dois níveis de oferta de forragem, medindo suas eficiências em termos de resposta animal. Os tratamentos foram: testemunha (T, roçada de primavera (P, roçada de primavera + outono (P+O e roçada de primavera + controle químico (P+Q, todos submetidos a dois níveis de oferta de forragem (8 e 14kg de matéria seca 100kg-1 de peso vivo por dia. O delineamento experimental utilizado foi o de fatorial em blocos completos casualizados (4 x 2, com duas repetições. Não houve efeito significativo de blocos nem interação dos fatores métodos de controle e níveis de oferta de forragem. O maior nível de oferta proporcionou maior ganho de peso vivo por área (P0,05. Os resultados mostram que é possível manter o peso vivo de bovinos em pastagens nativas da Serra do Sudeste/RS, durante o período de inverno, utilizando práticas de manejo que assegurem nível mínimo de oferta de forragem e, ainda, que o manejo da pastagem nativa com roçada de primavera, com ou sem o uso de herbicida, proporciona melhor desempenho individual e menores perdas de peso no período hibernal.The aim of this experiment was to study different methods of controlling undesirable plants in native pastures, associated with two levels of herbage allowance, and their effects on animal production. The treatments were no control (T, spring slashing (P, spring+autumn slashing (P+O and spring slashing +chemical control (P+Q, under two levels of herbage allowance (8 and 14kg of dry matter 100kg-1 of liveweight per day. The experimental design was a randomized complete block with two replicates. Not have block effects neither interaction between methods of control and herbage allowances (P>0.05. The higher herbage allowance resulted in more

  20. Activity and specificity of TRV-mediated gene editing in plants

    KAUST Repository

    Ali, Zahir

    2015-06-03

    © 2015 Taylor and Francis Group, LLC. Plant trait engineering requires efficient targeted genome-editing technologies. Clustered regularly interspaced palindromic repeats (CRISPRs)/ CRISPR associated (Cas) type II system is used for targeted genome-editing applications across eukaryotic species including plants. Delivery of genome engineering reagents and recovery of mutants remain challenging tasks for in planta applications. Recently, we reported the development of Tobacco rattle virus (TRV)-mediated genome editing in Nicotiana benthamiana. TRV infects the growing points and possesses small genome size; which facilitate cloning, multiplexing, and agroinfections. Here, we report on the persistent activity and specificity of the TRV-mediated CRISPR/Cas9 system for targeted modification of the Nicotiana benthamiana genome. Our data reveal the persistence of the TRVmediated Cas9 activity for up to 30 d post-agroinefection. Further, our data indicate that TRV-mediated genome editing exhibited no off-target activities at potential off-targets indicating the precision of the system for plant genome engineering. Taken together, our data establish the feasibility and exciting possibilities of using virus-mediated CRISPR/Cas9 for targeted engineering of plant genomes.

  1. Actively controlled vibration welding system and method

    Science.gov (United States)

    Cai, Wayne W.; Kang, Bongsu; Tan, Chin-An

    2013-04-02

    A vibration welding system includes a controller, welding horn, an active material element, and anvil assembly. The assembly may include an anvil body connected to a back plate and support member. The element, e.g., a piezoelectric stack or shape memory alloy, is positioned with respect to the assembly. The horn vibrates in a desirable first direction to form a weld on a work piece. The element controls any vibrations in a second direction by applying calibrated response to the anvil body in the second direction. A method for controlling undesirable vibrations in the system includes positioning the element with respect to the anvil assembly, connecting the anvil body to the support member through the back plate, vibrating the horn in a desirable first direction, and transmitting an input signal to the element to control vibration in an undesirable second direction.

  2. Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators.

    Science.gov (United States)

    Guigas, Bruno; Sakamoto, Kei; Taleux, Nellie; Reyna, Sara M; Musi, Nicolas; Viollet, Benoit; Hue, Louis

    2009-01-01

    5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICA riboside) has been extensively used in vitro and in vivo to activate the AMP-activated protein kinase (AMPK), a metabolic sensor involved in both cellular and whole body energy homeostasis. However, it has been recently highlighted that AICA riboside also exerts AMPK-independent effects, mainly on AMP-regulated enzymes and mitochondrial oxidative phosphorylation (OXPHOS), leading to the conclusion that new compounds with reduced off target effects are needed to specifically activate AMPK. Here, we review recent findings on newly discovered AMPK activators, notably on A-769662, a nonnucleoside compound from the thienopyridone family. We also report that A-769662 is able to activate AMPK and stimulate glucose uptake in both L6 cells and primary myotubes derived from human satellite cells. In addition, A-769662 increases AMPK activity and phosphorylation of its main downstream targets in primary cultured rat hepatocytes but, by contrast with AICA riboside, does neither affect mitochondrial OXPHOS nor change cellular AMP:ATP ratio. We conclude that A-769662 could be one of the new promising chemical agents to activate AMPK with limited AMPK-independent side effects.

  3. Design, Synthesis, Structure-Activity Relationship Studies, and Three-Dimensional Quantitative Structure-Activity Relationship (3D-QSAR) Modeling of a Series of O-Biphenyl Carbamates as Dual Modulators of Dopamine D3 Receptor and Fatty Acid Amide Hydrolase.

    Science.gov (United States)

    De Simone, Alessio; Russo, Debora; Ruda, Gian Filippo; Micoli, Alessandra; Ferraro, Mariarosaria; Di Martino, Rita Maria Concetta; Ottonello, Giuliana; Summa, Maria; Armirotti, Andrea; Bandiera, Tiziano; Cavalli, Andrea; Bottegoni, Giovanni

    2017-03-23

    We recently reported molecules designed according to the multitarget-directed ligand paradigm to exert combined activity at human fatty acid amide hydrolase (FAAH) and dopamine receptor subtype D3 (D3R). Both targets are relevant for tackling several types of addiction (most notably nicotine addiction) and other compulsive behaviors. Here, we report an SAR exploration of a series of biphenyl-N-[4-[4-(2,3-substituted-phenyl)piperazine-1-yl]alkyl]carbamates, a novel class of molecules that had shown promising activities at the FAAH-D3R target combination in preliminary studies. We have rationalized the structural features conducive to activities at the main targets and investigated activities at two off-targets: dopamine receptor subtype D2 and endocannabinoid receptor CB 1. To understand the unexpected affinity for the CB 1 receptor, we devised a 3D-QSAR model, which we then prospectively validated. Compound 33 was selected for PK studies because it displayed balanced affinities for the main targets and clear selectivity over the two off-targets. 33 has good stability and oral bioavailability and can cross the blood-brain barrier.

  4. Pharmacological promiscuity: dependence on compound properties and target specificity in a set of recent Roche compounds.

    Science.gov (United States)

    Peters, Jens-Uwe; Schnider, Patrick; Mattei, Patrizio; Kansy, Manfred

    2009-04-01

    The term "pharmacological promiscuity" describes a compound's pharmacological activity at multiple targets. Pharmacological promiscuity is undesired in typical drug discovery projects, which focus on the "one drug-one target" paradigm. Off-target activity can lead to adverse drug reactions, or can obscure pharmacodynamic effects in animal models. Therefore, advanced lead compounds, pharmacological tool compounds, and drug candidates are usually screened against panels of safety-relevant targets to detect unwanted pharmacological activities. To identify determinants of pharmacological promiscuity, we compared the panel screening outcomes of 213 recent Roche compounds with their molecular properties. Pronounced promiscuity was not observed below a threshold Clog P value of 2. For basic compounds, the propensity for weak off-target activity was found to increase with calculated basicities, whereas the potential for strong off-target activity depends more qualitatively on the presence of a positive charge at physiological pH. Compounds originating from projects with an aminergic receptor or transporter as a therapeutic target are particularly prone to promiscuity; the promiscuity of such compounds is mainly caused by their activity at other aminergic targets in the screening panel.

  5. Exploiting the Undesired: Beam-Gas Interactions in the LHC

    CERN Document Server

    Versaci, R; Baglin, V; Mereghetti, A

    2012-01-01

    The vacuum inside the LHC pipes has a key role in correct operation of the accelerator. The interaction of the beam with residual gas in the pipes can lead to the loss of the beam itself and damage accelerator components. Nevertheless, beam-gas interactions can be exploited to indirectly measure the gas pressure inside the beam pipe, detecting the secondaries produced. The showers generated are detected by Beam Loss Monitors, whose signals depend on the gas pressure. This technique would also allow to punctually measure the gas pressure in sections of the accelerator where vacuum gauges are not frequent, such as the arcs. The problem has been addressed by means of FLUKA simulations and the results have been benchmarked with direct measurements performed in the LHC in 2011.

  6. Pig herd monitoring and undesirable tripping and stepping prevention

    DEFF Research Database (Denmark)

    Gronskyte, Ruta; Clemmensen, Line Katrine Harder; Hviid, Marchen Sonja

    2015-01-01

    Humane handling and slaughter of livestock are of major concern in modern societies. Monitoring animal wellbeing in slaughterhouses is critical in preventing unnecessary stress and physical damage to livestock, which can also affect the meat quality. The goal of this study is to monitor pig herds...

  7. FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-β autoinduction.

    Science.gov (United States)

    Smith, Edward R; Holt, Stephen G; Hewitson, Tim D

    2017-11-01

    Bone-derived fibroblast growth factor 23 (FGF23) is an important endocrine regulator of mineral homeostasis with effects transduced by cognate FGF receptor (FGFR)1-α-Klotho complexes. Circulating FGF23 levels rise precipitously in patients with kidney disease and portend worse renal and cardiovascular outcomes. De novo expression of FGF23 has been found in the heart and kidney following injury but its significance remains unclear. Studies showing that exposure to chronically high FGF23 concentrations activates hypertrophic gene programs in the cardiomyocyte has spawned intense interest in other pathological off-target effects of FGF23 excess. In the kidney, observational evidence points to a concordance of ectopic renal FGF23 expression and the activation of local transforming growth factor (TGF)-β signalling. Although we have previously shown that FGF23 activates injury-primed renal fibroblasts in vitro, our understanding of the mechanism underpinning these effects was incomplete. Here we show that in the absence of α-Klotho, FGF23 augments pro-fibrotic signalling cascades in injury-primed renal fibroblasts via activation of FGFR4 and upregulation of the calcium transporter, transient receptor potential cation channel 6. The resultant rise in intracellular calcium and production of mitochondrial reactive oxygen species induced expression of NFAT responsive-genes and enhanced TGF-β1 autoinduction through non-canonical JNK-dependent pathways. Reconstitution with transmembrane α-Klotho, or its soluble ectodomain, restored classical Egr signalling and antagonised FGF23-driven myofibroblast differentiation. Thus, renal FGF23 may amplify local myofibroblast activation in injury and perpetuate pro-fibrotic signalling. These findings strengthen the rationale for exploring therapeutic inhibition of FGFR4 or restoration of α-Klotho as upstream regulators of off-target FGF23 effects. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  8. Therapeutic drug monitoring of voriconazole helps to decrease the percentage of patients with off-target trough serum levels.

    Science.gov (United States)

    Guinea, Jesús; Escribano, Pilar; Marcos-Zambrano, Laura Judith; Peláez, Teresa; Kestler, Marta; Muñoz, Patricia; Vena, Antonio; López-Fabal, Fátima; Bouza, Emilio

    2016-05-01

    We monitored trough voriconazole serum concentrations from 107 patients (n = 258 samples) at 6 hospitals in Madrid. Most of the patients were male (67%) and had the following underlying conditions: hematological cancer (42%), solid organ transplantation (15%), chronic obstructive pulmonary disease (14%), human immunodeficiency virus infection (8.4%), solid cancer (5.6%), and other (29%). The indication for voriconazole administration was aspergillosis treatment (74.6%) and prophylaxis (14%). The main reasons for voriconazole trough drug monitoring were initiation of treatment/prophylaxis (33%), patient monitoring (47%), and suspected toxicity (3.5%). Levels (μg/ml) were subtherapeutic (5.5; 10.5%). The samples percentage with on-target levels was significantly lower for the first sample than for subsequent samples (62.6% vs. 77.5%). "Subsequent samples," "admission in nonpediatric wards," "voriconazole used for treatment of invasive aspergillosis," and "use of proton pump inhibitors" were predictors of voriconazole therapeutic levels (≥1 μg/ml). © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  9. Gene expression profile of coronary artery cells treated with nonsteroidal anti-inflammatory drugs reveals off-target effects.

    Science.gov (United States)

    Palayoor, Sanjeewani T; J-Aryankalayil, Molykutty; Makinde, Adeola Y; Cerna, David; Falduto, Michael T; Magnuson, Scott R; Coleman, C Norman

    2012-06-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal, and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in the clinic. Coronary artery smooth muscle cells and endothelial cells were treated with low (clinically achievable) and high (typically used in preclinical studies) concentrations of celecoxib, NS398, and ibuprofen for 24 hours. NSAIDs-induced gene expression changes were evaluated by microarray analysis and validated by real-time reverse-transcription polymerase chain reaction and western blotting. The functional significance of differentially expressed genes was evaluated by Ingenuity Pathway Analysis. At high concentrations, NSAIDs altered the expression of genes regulating cell proliferation and cell death. NSAIDs also altered genes associated with cardiovascular functions including inflammation, thrombosis, fibrinolysis, coronary artery disease, and hypertension. The gene expression was most impacted by ibuprofen, celecoxib, and NS398, in that order. This study revealed that NSAIDs altered expression of an array of genes associated with cardiovascular events and emphasizes the potential for fingerprinting drugs in preclinical studies to assess the potential drug toxicity and to optimize the drug efficacy in clinical settings.

  10. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

    NARCIS (Netherlands)

    Sofat, Reecha; Hingorani, Aroon D.; Smeeth, Liam; Humphries, Steve E.; Talmud, Philippa J.; Cooper, Jackie; Shah, Tina; Sandhu, Manjinder S.; Ricketts, Sally L.; Boekholdt, S. Matthijs; Wareham, Nicholas; Khaw, Kay Tee; Kumari, Meena; Kivimaki, Mika; Marmot, Michael; Asselbergs, Folkert W.; van der Harst, Pim; Dullaart, Robin P. F.; Navis, Gerjan; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; Thompson, John F.; McCaskie, Pamela; Palmer, Lyle J.; Arca, Marcello; Quagliarini, Fabiana; Gaudio, Carlo; Cambien, François; Nicaud, Viviane; Poirer, Odette; Gudnason, Vilmundur; Isaacs, Aaron; Witteman, Jacqueline C. M.; van Duijn, Cornelia M.; Pencina, Michael; Vasan, Ramachandran S.; D'Agostino, Ralph B.; Ordovas, Jose; Li, Tricia Y.; Kakko, Sakari; Kauma, Heikki; Savolainen, Markku J.; Kesäniemi, Y. Antero; Sandhofer, Anton; Paulweber, Bernhard; Sorli, Jose V.; Goto, Akimoto; Yokoyama, Shinji; Okumura, Kenji; Horne, Benjamin D.; Packard, Chris; Freeman, Dilys; Ford, Ian; Sattar, Naveed; McCormack, Valerie; Lawlor, Debbie A.; Ebrahim, Shah; Smith, George Davey; Kastelein, John J. P.; Deanfield, John; Casas, Juan P.

    2010-01-01

    BACKGROUND: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the

  11. Separating the Mechanism-Based and Off-Target Actions of Cholesteryl Ester Transfer Protein Inhibitors With CETP Gene Polymorphisms

    NARCIS (Netherlands)

    Sofat, Reecha; Hingorani, Aroon D.; Smeeth, Liam; Humphries, Steve E.; Talmud, Philippa J.; Cooper, Jackie; Shah, Tina; Sandhu, Manjinder S.; Ricketts, Sally L.; Boekholdt, S. Matthijs; Wareham, Nicholas; Khaw, Kay Tee; Kumari, Meena; Kivimaki, Mika; Marmot, Michael; Asselbergs, Folkert W.; van der Harst, Pim; Dullaart, Robin P. F.; Navis, Gerjan; van Veldhuisen, Dirk J.; Van Gilst, Wiek H.; Thompson, John F.; McCaskie, Pamela; Palmer, Lyle J.; Arca, Marcello; Quagliarini, Fabiana; Gaudio, Carlo; Cambien, Francois; Nicaud, Viviane; Poirer, Odette; Gudnason, Vilmundur; Isaacs, Aaron; Witteman, Jacqueline C. M.; van Duijn, Cornelia M.; Pencina, Michael; Vasan, Ramachandran S.; D'Agostino, Ralph B.; Ordovas, Jose; Li, Tricia Y.; Kakko, Sakari; Kauma, Heikki; Savolainen, Markku J.; Kesaniemi, Y. Antero; Sandhofer, Anton; Paulweber, Bernhard; Sorli, Jose V.; Goto, Akimoto; Yokoyama, Shinji; Okumura, Kenji; Horne, Benjamin D.; Packard, Chris; Freeman, Dilys; Ford, Ian; Sattar, Naveed; McCormack, Valerie; Lawlor, Debbie A.; Ebrahim, Shah; Smith, George Davey; Kastelein, John J. P.; Deanfield, John; Casas, Juan P.

    2010-01-01

    Background-Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive

  12. Terpene metabolic engineering via nuclear or chloroplast genomes profoundly and globally impacts off-target pathways through metabolite signalling.

    Science.gov (United States)

    Pasoreck, Elise K; Su, Jin; Silverman, Ian M; Gosai, Sager J; Gregory, Brian D; Yuan, Joshua S; Daniell, Henry

    2016-09-01

    The impact of metabolic engineering on nontarget pathways and outcomes of metabolic engineering from different genomes are poorly understood questions. Therefore, squalene biosynthesis genes FARNESYL DIPHOSPHATE SYNTHASE (FPS) and SQUALENE SYNTHASE (SQS) were engineered via the Nicotiana tabacum chloroplast (C), nuclear (N) or both (CN) genomes to promote squalene biosynthesis. SQS levels were ~4300-fold higher in C and CN lines than in N, but all accumulated ~150-fold higher squalene due to substrate or storage limitations. Abnormal leaf and flower phenotypes, including lower pollen production and reduced fertility, were observed regardless of the compartment or level of transgene expression. Substantial changes in metabolomes of all lines were observed: levels of 65-120 unrelated metabolites, including the toxic alkaloid nicotine, changed by as much as 32-fold. Profound effects of transgenesis on nontarget gene expression included changes in the abundance of 19 076 transcripts by up to 2000-fold in CN; 7784 transcripts by up to 1400-fold in N; and 5224 transcripts by as much as 2200-fold in C. Transporter-related transcripts were induced, and cell cycle-associated transcripts were disproportionally repressed in all three lines. Transcriptome changes were validated by qRT-PCR. The mechanism underlying these large changes likely involves metabolite-mediated anterograde and/or retrograde signalling irrespective of the level of transgene expression or end product, due to imbalance of metabolic pools, offering new insight into both anticipated and unanticipated consequences of metabolic engineering. © 2016 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  13. Ex Vivo Dual Perfusion of the Human Placenta: Disease Simulation, Therapeutic Pharmacokinetics and Analysis of Off-Target Effects.

    Science.gov (United States)

    Brownbill, Paul; Sebire, Neil; McGillick, Erin V; Ellery, Stacey; Murthi, Padma

    2018-01-01

    In recent years ex vivo dual perfusion of the human placental lobule is seeing an international renaissance in its application to understanding fetal health and development. Here, we discuss the methods and uses of this technique in the evaluation of (1) vascular function, (2) transplacental clearance, (3) hemodynamic and oxygenation changes associated with pregnancy complications on placental structure and function, and (4) placental toxicology and post-perfusion evaluation of tissue architecture.

  14. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms

    NARCIS (Netherlands)

    R. Sofat (Reecha); A. Hingorani (Aroon); L. Smeeth (Liam); S.E. Humphries (Steve); P.J. Talmud; J. Cooper (Jim); T. Shah (Tina); M.S. Sandhu (Manjinder); S.L. Ricketts (Sally); S.M. Boekholdt (Matthijs); N.J. Wareham (Nick); K-T. Khaw (Kay-Tee); M. Kumari (Meena); M. Kivimaki (Mika); M. Marmot (Michael); F.W. Asselbergs (Folkert); P. van der Harst (Pim); R.P.F. Dullaart (Robin); G. Navis (Gerjan); D.J. van Veldhuisen (Dirk); W.H. van Gilst (Wiek); J.F. Thompson (John); P. McCaskie (Pamela); C. Palmer (Cameron); M. Arca (Marcello); F. Quagliarini (Fabiana); C. Gaudio (Carlo); F. Cambien (François); V. Nicaud; O. Poirer (Odette); V. Gudnason (Vilmundur); A.J. Isaacs (Aaron); J.C.M. Witteman (Jacqueline); P. Tikka-Kleemola (Päivi); M. Pencina (Michael); R.S. Vasan (Ramachandran Srini); R.B. D'Agostino (Ralph); J.M. Ordovas (Jose); T.Y. Li (Tricia); S. Kakko (Sakari); H. Kauma (Heikki); M.J. Savolainen (Markku); Y.A. Kesäniemi (Antero); A. Sandhofer (Anton); B. Paulweber (Bernhard); J.V. Sorli (Jose); A. Goto (Akimoto); S. Yokoyama (Shinji); K. Okumura (Kenji); B.D. Horne (Benjamin); C. Packard (Chris); D. Freeman (Dilys); I. Ford (Ian); N. Sattar (Naveed); V. McCormack (Valerie); D.A. Lawlor (Debbie); S. Ebrahim (Shanil); G.D. Smith; J.J.P. Kastelein (John); J. Deanfield (John); J.P. Casas (Juan)

    2010-01-01

    textabstractBackground: Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the

  15. UNDESIRABLE STUDENT BEHAVIORS FACED BY CLASSROOM TEACHERS AND WAYS OF COPING WITH THIS BEHAVIORS SINIF ÖĞRETMENLERİNİN KARŞILAŞTIKLARI İSTENMEYEN ÖĞRENCİ DAVRANIŞLARI VE BU DAVRANIŞLARLA BAŞA ÇIKMA YOLLARI

    Directory of Open Access Journals (Sweden)

    İbrahim ÇANKAYA

    2011-06-01

    Full Text Available The aim of this research is to determine the undesirable student behaviors faced by the classroom teachers and the solutions they apply to these behaviors. The population of the research comprises of the class teachers who worked in the Elazığ Province Central Elementary Schools during the 2010-2011 fall semester. The sample of the research was carried out on the 60 class teachers who were selected randomly among the population and who were interviewed face to face. The data written in the interview forms which were answered by the 38 teachers among the teachers who were interviewed face to face was evaluated with the “Nvivo 7” qualitative data analysis program. “Being irrelevant to the course”, “cheating”, “physical or verbal violence”, “being disrespectful to the teacher”, refusing responsibility”, “disturbing the order in the class” and “grouping” are among the undesirable student behaviors frequently faced by the teachers. The short or long run solution suggestions such as “guidance-counseling”, “confrontation”, “responsibility training”, “punishing”, “rewarding” and “providing social support” are among the solutions to which the teachers appeal against the undesirable behaviors Bu çalışmanın amacı sınıf öğretmenlerinin karşılaştıkları istenmeyen öğrenci davranışları ve bu davranışlara karşı uyguladıkları çözüm yollarını tespit etmektir. Araştırmanın çalışma evrenini 2010-2011 yılı eğitim-öğretim yılı güz döneminde Elazığ İli Merkez İlköğretim okullarında görev yapan sınıf öğretmenleri oluşturmaktadır. Araştırmanın örneklemi, çalışma evreni içerisinden tesadüfî olarak belirlenen ve yüz yüze görüşülen 60 sınıf öğretmeni üzerinden yürütülmüştür. Yüz yüze görüşülen öğretmenlerden 38 öğretmenin cevapladığı görüşme formlarındaki yazılı veriler “Nvivo 7” nitel veri analizi program

  16. Loss of the interferon-γ-inducible regulatory immunity-related GTPase (IRG), Irgm1, causes activation of effector IRG proteins on lysosomes, damaging lysosomal function and predicting the dramatic susceptibility of Irgm1-deficient mice to infection.

    Science.gov (United States)

    Maric-Biresev, Jelena; Hunn, Julia P; Krut, Oleg; Helms, J Bernd; Martens, Sascha; Howard, Jonathan C

    2016-04-20

    The interferon-γ (IFN-γ)-inducible immunity-related GTPase (IRG), Irgm1, plays an essential role in restraining activation of the IRG pathogen resistance system. However, the loss of Irgm1 in mice also causes a dramatic but unexplained susceptibility phenotype upon infection with a variety of pathogens, including many not normally controlled by the IRG system. This phenotype is associated with lymphopenia, hemopoietic collapse, and death of the mouse. We show that the three regulatory IRG proteins (GMS sub-family), including Irgm1, each of which localizes to distinct sets of endocellular membranes, play an important role during the cellular response to IFN-γ, each protecting specific membranes from off-target activation of effector IRG proteins (GKS sub-family). In the absence of Irgm1, which is localized mainly at lysosomal and Golgi membranes, activated GKS proteins load onto lysosomes, and are associated with reduced lysosomal acidity and failure to process autophagosomes. Another GMS protein, Irgm3, is localized to endoplasmic reticulum (ER) membranes; in the Irgm3-deficient mouse, activated GKS proteins are found at the ER. The Irgm3-deficient mouse does not show the drastic phenotype of the Irgm1 mouse. In the Irgm1/Irgm3 double knock-out mouse, activated GKS proteins associate with lipid droplets, but not with lysosomes, and the Irgm1/Irgm3(-/-) does not have the generalized immunodeficiency phenotype expected from its Irgm1 deficiency. The membrane targeting properties of the three GMS proteins to specific endocellular membranes prevent accumulation of activated GKS protein effectors on the corresponding membranes and thus enable GKS proteins to distinguish organellar cellular membranes from the membranes of pathogen vacuoles. Our data suggest that the generalized lymphomyeloid collapse that occurs in Irgm1(-/-) mice upon infection with a variety of pathogens may be due to lysosomal damage caused by off-target activation of GKS proteins on lysosomal

  17. [Colombian plants with spermicidal activity, new options in anticonception: brief review].

    Science.gov (United States)

    Alvarez-Gómez, A M; Cardona-Maya, W D; Castro-Alvarez, J F; Jiménez, Silvia; Cadavid, A

    2007-04-01

    Currently there exists increasing preoccupation concerning sexual and reproductive health among teenagers; in spite of the availability of different contraceptive methods, the number of undesired pregnancies is steadily increasing. Among the products presently available for birth control, spermicides are a means that can be totally controlled by the woman and are very reliable compared to other contraceptives in common use. However, they cause irritation in the vaginal epithelium due to their tensoactive effect on cellular membranes which might enhance the risk of acquiring sexually transmissible diseases. In searching for new alternatives, it was observed that a wide variety of plants have spermicidal activity. Hence it is interesting to consider potential contraceptives of vegetable origin, as they may constitute a key tool to prevent undesired pregnancies in general, and in particular in vulnerable groups such as teenagers and young women.

  18. Ganho de peso de novilhas em pastagem nativa da Serra do Sudeste do RS submetida ao controle de plantas indesejáveis e intensidades de pastejo Heifers weight gain on Serra do Sudeste native pasture in RS, submitted to undesirable plants control and grazing intensities

    Directory of Open Access Journals (Sweden)

    Leonardo Araripe Crancio

    2006-08-01

    Full Text Available Este trabalho teve como objetivo avaliar o efeito de métodos de controle de espécies indesejáveis e de intensidades de pastejo sobre o desempenho animal em pastagem nativa da Serra do Sudeste do Rio Grande do Sul. Foram utilizados os métodos de controle: roçada de primavera (RP, roçada de outono (RO, controle químico (Q e um tratamento testemunha (T, todos submetidos a dois níveis de oferta de forragem, médio (8% e alto (14%, expressos em kg de matéria seca diariamente ofertada para cada 100kg de peso vivo animal. O delineamento experimental empregado foi o de blocos completamente casualizados, num arranjo fatorial com duas repetições. A análise estatística não demonstrou interação entre os fatores estudados, bem como existência de diferença entre os métodos de controle de espécies indesejáveis para as variáveis de produção primária e secundária (P>0,1. Não houve diferença de ganho médio diário entre os níveis de oferta de forragem estudados (P>0,1. Animais submetidos à alta oferta de forragem apresentaram menor perda de peso por unidade de área (PThis work aimed to evaluate the effect of different undesirable plants controlling methods and grazing intensities on animal production in native pastures. The treatments were no control (T, spring clipping (P, autumn clipping (O and chemical control (Q, under two levels of forage allowance, medium (8% and high (14%, expressed in kg of dry matter offered daily per each 100kg of liveweight. The experimental design was a completely randomized block arranged in a factorial with two repetitions. Statistical analysis showed no interaction among treatments nor differences among control methods for variables concerning primary and secondary production (P>0.1. Animal performance in both forage allowances was not different (P>0.1. High forage allowances increased animal performance per unit area (P<0.1.

  19. Active Disturbance Rejection Control of a Heat Integrated Distillation Column

    DEFF Research Database (Denmark)

    Al-Kalbani, Fahad; Zhang, Jie; Bisgaard, Thomas

    2016-01-01

    -toluene mixture. The efficiency of the ADRC technique is demonstrated by comparing with the conventional PI controller in terms of set-point trackingand external disturbance rejection capability. The results show that the ADRC gives much improved control performance than the PID control....... pressure. However, the control of some HiDC processesis generally difficult due to the strong control loop interaction, high purity of the components and undesired disturbances. Active disturbance rejection control (ADRC) is used in this paperto control a simulated HiDC for separating benzene...

  20. Negotiations between the private life and public activism: Ethnographic case study of LGBTQI rights movement in Saint Petersburg, Russia

    OpenAIRE

    Lukinmaa, Pauliina

    2015-01-01

    In the past three years (2012-2015), several repressive law amendments have been introduced in Russia, focusing on controlling the civil activism. "Foreign Agent Law" (2012) on Russian NGOs (Non-Governmental Organizations), the adoption of a federal “Homopropaganda” law (2013) and, most recently, a law on “Undesired NGOs” (2015), have contributed the most to the hostile attitudes towards civil society, namely LGBTQI (lesbian, gay, trans-gender, queer and intersex) movement. These law amendmen...

  1. Negotiations between the private life and public activism: Ethnographic case study of LGBTQI rights movement in Saint Petersburg, Russia

    OpenAIRE

    Lukinmaa, Pauliina

    2016-01-01

    ABSTRACT In the past three years (2012-2015), several repressive law amendments have been introduced in Russia, focusing on controlling the civil activism. "Foreign Agent Law" (2012) on Russian NGOs (Non-Governmental Organizations), the adoption of a federal "Homopropaganda" law (2013) and, most recently, a law on "Undesired NGOs" (2015), have contributed the most to the hostile attitudes towards civil society, namely LGBTQI (lesbian, gay, trans-gender, queer and intersex) movement. The...

  2. Protein hydrophobic dressing on seeds aiming at the delay of undesirable germination Cobertura hidrofóbica a base de proteínas sobre sementes visando a redução de germinações indesejáveis

    Directory of Open Access Journals (Sweden)

    Odilio Benedito Garrido Assis

    2009-02-01

    Full Text Available Polymer seed-coatings have been largely tested as an alternative method for preventing diseases and have the potential to be used to control undesirable germination and thereby increasing seed storage. Amongst these, the protein-based coatings can be applied with advantage of forming stable biodegradable and hydrophobic films. Due to their chemical structure, protein dressings act as efficient barriers for water uptake, even when seeds are unavoidable exposed to a moist environment. In this work, the effect of hydrophobic dressings was tested on the germination rate of sugar beet (Beta vulgaris L. and broccolis (Brassica oleraceae var italic L. seeds under laboratorial condition. Zein, natural maize (Zea mays L. proteins extracted from gluten meal, was used as precursor polymers to form the coatings. Seeds were dressed by direct submersion into a zein/ethanol formulation of zein concentration of 3.0 g L-1, followed by natural air drying. The resultant coating has elevated the hydrophobic feature due to the high content amino acids present in the structure of the zein. For both types of seeds an overall delay in sprouting and germination was observed, with a more accentuated reduction on sugar beet germination percentage after eleven days of measurements. The effect on germination rates is understood as the efficiency of the zein coating to form a physical barrier preventing water permeation into the seeds.Filmes com características hidrofóbicas baseados em proteínas foram avaliados como revestimento em sementes de beterraba e brócolis, com o objetivo de prevenir germinações prematuras pela redução na absorção de água. Zeínas, proteínas naturais extraídas do glúten de milho, foram empregados como polímeros precursores na elaboração das soluções de cobertura. Os revestimentos se deram pela completa imersão das sementes em formulação zeínas/etanol na concentração de 3,0 g L-1, seguidos de secagem ao ar. Os filmes

  3. Chemical modifications on siRNAs avoid Toll-like-receptor-mediated activation of the hepatic immune system in vivo and in vitro.

    Science.gov (United States)

    Broering, Ruth; Real, Catherine I; John, Matthias J; Jahn-Hofmann, Kerstin; Ickenstein, Ludger M; Kleinehr, Kathrin; Paul, Andreas; Gibbert, Kathrin; Dittmer, Ulf; Gerken, Guido; Schlaak, Joerg F

    2014-01-01

    The therapeutic application of small interfering RNAs (siRNAs) is limited by the induction of severe off-target effects, especially in the liver. Therefore, we assessed the potential of differently modified siRNAs to induce the hepatic innate immune system in vitro and in vivo. Primary isolated liver cells were transfected with siRNAs against apolipoprotein B1 (APOB1), luciferase (LUC) or galactosidase (GAL). For in vivo use, siRNAs were formulated in lipid nanoparticles (LNPs) and administered intravenously to C57BL/6 mice. Liver tissue was collected 6-48 h after injection and knock-down efficiency or immune responses were determined by quantitative reverse-transcription-linked PCR. Unmodified GAL siRNA transiently induced the expression of TNF-α, IL-6, IL-10, IFN-β and IFN-sensitive gene 15 in vivo, whereas a formulation of 2'-O-methylated-LUC siRNA had no such effects. Formulation of unmodified APOB1-specific siRNA suppressed APOB1 mRNA levels by ~80% in the liver 48h after application. The results were paralleled in vitro, where transfection of liver cells with unmodified siRNAs, but not with chemically modified siRNAs, led to cell-type-specific induction of immune genes. These immune responses were not observed in MYD88-deficient mice or in chloroquine-treated cells in vitro. Our data indicate that siRNAs activate endosomal Toll-like receptors in different liver-derived cell types to various degrees, in vitro. LNP-formulated siRNA selectively leads to hepatic knock-down of target genes in vivo. Here, off-target immune responses are restricted to non-parenchymal liver cells. However, 2'-O-methyl modifications of siRNA largely avoid immune-stimulatory effects, which is a crucial prerequisite for the development of safe and efficient RNA-interference-based therapeutics.

  4. Peroxisome Proliferators-Activated Receptor (PPAR Modulators and Metabolic Disorders

    Directory of Open Access Journals (Sweden)

    Min-Chul Cho

    2008-01-01

    Full Text Available Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR, which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α,γ, and σ are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.

  5. Studies on the Simultaneous Formation of Aroma-Active and Toxicologically Relevant Vinyl Aromatics from Free Phenolic Acids during Wheat Beer Brewing.

    Science.gov (United States)

    Langos, Daniel; Granvogl, Michael

    2016-03-23

    During the brewing process of wheat beer, the desired aroma-active vinyl aromatics 2-methoxy-4-vinylphenol and 4-vinylphenol as well as the undesired and toxicologically relevant styrene are formed from their respective precursors, free ferulic acid, p-coumaric acid, and cinnamic acid, deriving from the malts. Analysis of eight commercial wheat beers revealed high concentrations of 2-methoxy-4-vinylphenol and 4-vinylphenol always in parallel with high concentrations of styrene or low concentrations of the odorants in parallel with low styrene concentrations, suggesting a similar pathway. To better understand the formation of these vinyl aromatics, each process step of wheat beer brewing and the use of different strains of Saccharomyces cerevisiae were evaluated. During wort boiling, only a moderate decarboxylation of free phenolic acids and formation of desired and undesired vinyl aromatics were monitored due to the thermal treatment. In contrast, this reaction mainly occurred enzymatically catalyzed during fermentation with S. cerevisiae strain W68 with normal Pof(+) activity (phenolic off-flavor) resulting in a wheat beer eliciting the typical aroma requested by consumers due to high concentrations of 2-methoxy-4-vinylphenol (1790 μg/L) and 4-vinylphenol (937 μg/L). Unfortunately, also a high concentration of undesired styrene (28.3 μg/L) was observed. Using a special S. cerevisiae strain without Pof(+) activity resulted in a significant styrene reduction (beer aroma.

  6. Mechanisms of peroxisome proliferator activated receptor γ regulation by non-steroidal anti-inflammatory drugs

    Science.gov (United States)

    Puhl, Ana C.; Milton, Flora A.; Cvoro, Aleksandra; Sieglaff, Douglas H.; Campos, Jéssica C.L.; Bernardes, Amanda; Filgueira, Carly S.; Lindemann, Jan Lammel; Deng, Tuo; Neves, Francisco A.R.; Polikarpov, Igor; Webb, Paul

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation. PMID:26445566

  7. Local and Sustained Activity of Doxycycline Delivered with Layer-by-Layer Microcapsules.

    Science.gov (United States)

    Luo, Dong; Gould, David J; Sukhorukov, Gleb B

    2016-04-11

    Achieving localized delivery of small molecule drugs has the potential to increase efficacy and reduce off target and side effects associated with systemic distribution. Herein, we explore the potential use of layer-by-layer (LbL) assembled microcapsules for the delivery of doxycycline. Absorbance of doxycycline onto core dextran sulfate of preassembled microcapsules provides an efficient method to load both synthetic and biodegradable microcapsules with the drug. Application of an outer layer lipid coat enhances the sustained in vitro release of doxycycline from both microcapsule types. To monitor doxycycline delivery in a biological system, C2C12 mouse myoblasts are engineered to express EGFP under the control of the optimized components of the tetracycline regulated gene expression system. Microcapsules are not toxic to these cells, and upon delivery to the cells, EGFP is more efficiently induced in those cells that contain engulfed microcapsules and monitored EGFP expression clearly demonstrates that synthetic microcapsules with a DPPC coat are the most efficient for sustain intracellular delivery. Doxycycline released from microcapsules also displayed sustained activity in an antimicrobial growth inhibition assay compared with doxycycline solution. This study reveals the potential for LbL microcapsules in small molecule drug delivery and their feasible use for achieving prolonged doxycycline activity.

  8. Research resource: modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay.

    Science.gov (United States)

    Blackford, John A; Brimacombe, Kyle R; Dougherty, Edward J; Pradhan, Madhumita; Shen, Min; Li, Zhuyin; Auld, Douglas S; Chow, Carson C; Austin, Christopher P; Simons, S Stoney

    2014-07-01

    Glucocorticoid steroids affect almost every type of tissue and thus are widely used to treat a variety of human pathological conditions. However, the severity of numerous side effects limits the frequency and duration of glucocorticoid treatments. Of the numerous approaches to control off-target responses to glucocorticoids, small molecules and pharmaceuticals offer several advantages. Here we describe a new, extended high-throughput screen in intact cells to identify small molecule modulators of dexamethasone-induced glucocorticoid receptor (GR) transcriptional activity. The novelty of this assay is that it monitors changes in both GR maximal activity (A(max)) and EC(50) (the position of the dexamethasone dose-response curve). Upon screening 1280 chemicals, 10 with the greatest changes in the absolute value of A(max) or EC(50) were selected for further examination. Qualitatively identical behaviors for 60% to 90% of the chemicals were observed in a completely different system, suggesting that other systems will be similarly affected by these chemicals. Additional analysis of the 10 chemicals in a recently described competition assay determined their kinetically defined mechanism and site of action. Some chemicals had similar mechanisms of action despite divergent effects on the level of the GR-induced product. These combined assays offer a straightforward method of identifying numerous new pharmaceuticals that can alter GR transactivation in ways that could be clinically useful.

  9. The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation

    Energy Technology Data Exchange (ETDEWEB)

    Du, Kuo; Williams, C. David; McGill, Mitchell R.; Xie, Yuchao [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Farhood, Anwar [Department of Pathology, St. David' s North Austin Medical Center, Austin, TX 78756 (United States); Vinken, Mathieu [Department of Toxicology, Center for Pharmaceutical Sciences, Vrije Universiteit Brussels, 1090 Brussels (Belgium); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2013-12-15

    Acetaminophen (APAP) hepatotoxicity is the leading cause of acute liver failure in the US. Although many aspects of the mechanism are known, recent publications suggest that gap junctions composed of connexin32 function as critical intercellular communication channels which transfer cytotoxic mediators into neighboring hepatocytes and aggravate liver injury. However, these studies did not consider off-target effects of reagents used in these experiments, especially the gap junction inhibitor 2-aminoethoxy-diphenyl-borate (2-APB). In order to assess the mechanisms of protection of 2-APB in vivo, male C56Bl/6 mice were treated with 400 mg/kg APAP to cause extensive liver injury. This injury was prevented when animals were co-treated with 20 mg/kg 2-APB and was attenuated when 2-APB was administered 1.5 h after APAP. However, the protection was completely lost when 2-APB was given 4–6 h after APAP. Measurement of protein adducts and c-jun-N-terminal kinase (JNK) activation indicated that 2-APB reduced both protein binding and JNK activation, which correlated with hepatoprotection. Although some of the protection was due to the solvent dimethyl sulfoxide (DMSO), in vitro experiments clearly demonstrated that 2-APB directly inhibits cytochrome P450 activities. In addition, JNK activation induced by phorone and tert-butylhydroperoxide in vivo was inhibited by 2-APB. The effects against APAP toxicity in vivo were reproduced in primary cultured hepatocytes without use of DMSO and in the absence of functional gap junctions. We conclude that the protective effect of 2-APB was caused by inhibition of metabolic activation of APAP and inhibition of the JNK signaling pathway and not by blocking connexin32-based gap junctions. - Highlights: • 2-APB protected against APAP-induced liver injury in mice in vivo and in vitro • 2-APB protected by inhibiting APAP metabolic activation and JNK signaling pathway • DMSO inhibited APAP metabolic activation as the solvent of 2-APB

  10. Sequence Design for a Test Tube of Interacting Nucleic Acid Strands.

    Science.gov (United States)

    Wolfe, Brian R; Pierce, Niles A

    2015-10-16

    We describe an algorithm for designing the equilibrium base-pairing properties of a test tube of interacting nucleic acid strands. A target test tube is specified as a set of desired "on-target" complexes, each with a target secondary structure and target concentration, and a set of undesired "off-target" complexes, each with vanishing target concentration. Sequence design is performed by optimizing the test tube ensemble defect, corresponding to the concentration of incorrectly paired nucleotides at equilibrium evaluated over the ensemble of the test tube. To reduce the computational cost of accepting or rejecting mutations to a random initial sequence, the structural ensemble of each on-target complex is hierarchically decomposed into a tree of conditional subensembles, yielding a forest of decomposition trees. Candidate sequences are evaluated efficiently at the leaf level of the decomposition forest by estimating the test tube ensemble defect from conditional physical properties calculated over the leaf subensembles. As optimized subsequences are merged toward the root level of the forest, any emergent defects are eliminated via ensemble redecomposition and sequence reoptimization. After successfully merging subsequences to the root level, the exact test tube ensemble defect is calculated for the first time, explicitly checking for the effect of the previously neglected off-target complexes. Any off-target complexes that form at appreciable concentration are hierarchically decomposed, added to the decomposition forest, and actively destabilized during subsequent forest reoptimization. For target test tubes representative of design challenges in the molecular programming and synthetic biology communities, our test tube design algorithm typically succeeds in achieving a normalized test tube ensemble defect ≤1% at a design cost within an order of magnitude of the cost of test tube analysis.

  11. Determination of elemental impurities in polymer materials of electrical cables for use in safety systems of nuclear power plants and for data transfer in the Large Hadron Collider by instrumental neutron activation analysis

    Czech Academy of Sciences Publication Activity Database

    Kučera, Jan; Cabalka, M.; Ferencei, Jozef; Kubešová, Marie; Strunga, Vladimír

    2016-01-01

    Roč. 309, č. 3 (2016), s. 1341-1348 ISSN 0236-5731 R&D Projects: GA TA ČR TA02010218; GA MŠk(CZ) LM2011019 Institutional support: RVO:61389005 Keywords : instrumental neutron activation analysis * polymer materials * undesired elements * nuclear power plant * Large Hadron Collider Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 1.282, year: 2016

  12. Optimal functional levels of activation-induced deaminase specifically require the Hsp40 DnaJa1

    Science.gov (United States)

    Orthwein, Alexandre; Zahn, Astrid; Methot, Stephen P; Godin, David; Conticello, Silvestro G; Terada, Kazutoyo; Di Noia, Javier M

    2012-01-01

    The enzyme activation-induced deaminase (AID) deaminates deoxycytidine at the immunoglobulin genes, thereby initiating antibody affinity maturation and isotype class switching during immune responses. In contrast, off-target DNA damage caused by AID is oncogenic. Central to balancing immunity and cancer is AID regulation, including the mechanisms determining AID protein levels. We describe a specific functional interaction between AID and the Hsp40 DnaJa1, which provides insight into the function of both proteins. Although both major cytoplasmic type I Hsp40s, DnaJa1 and DnaJa2, are induced upon B-cell activation and interact with AID in vitro, only DnaJa1 overexpression increases AID levels and biological activity in cell lines. Conversely, DnaJa1, but not DnaJa2, depletion reduces AID levels, stability and isotype switching. In vivo, DnaJa1-deficient mice display compromised response to immunization, AID protein and isotype switching levels being reduced by half. Moreover, DnaJa1 farnesylation is required to maintain, and farnesyltransferase inhibition reduces, AID protein levels in B cells. Thus, DnaJa1 is a limiting factor that plays a non-redundant role in the functional stabilization of AID. PMID:22085931

  13. Targeted editing of goat genome with modular-assembly zinc finger nucleases based on activity prediction by computational molecular modeling.

    Science.gov (United States)

    Xiong, Kai; Li, Shanshan; Zhang, Hongxiao; Cui, Ye; Yu, Debing; Li, Yan; Sun, Wenxing; Fu, Yingying; Teng, Yun; Liu, Zhi; Zhou, Xiaolong; Xiao, Peng; Li, Juan; Liu, Honglin; Chen, Jie

    2013-07-01

    Zinc finger nuclease (ZFN) technology can mediate targeted genome modification to produce transgenic animals in a high-efficient and biological-safe way. Modular assembly is a rapid, convenient and open-source method for the synthesis of ZFNs. However, this biotechnology is hampered by multistep construction, low-efficiency editing and off-target cleavage. Here we synthesized and tested six pairs of three- or four-finger ZFNs to target one site in goat beta-lactoglobulin (BLG, a dominant allergen in goat milk) gene. Homology modeling was applied to build the structure model of ZFNs to predict their editing activities targeting at goat BLG gene. Goat fibroblast cells were transfected with plasmids that encoded ZFN pairs, and genomic DNA was isolated 72 h later for genome editing efficiency assay. The results of editing efficiency assay demonstrated that ZFNs with optimal interaction modes can edit goat BLG gene more efficiently, whereas ZFNs with unexpected interaction modes showed lower activities in editing BLG gene. We concluded that modular-assembly ZFNs can provide a rapid, public-available, and easy-to-practice platform for transgenic animal research and molecular modeling would help as a useful tool for ZFNs activity prediction.

  14. The dynamics of estrogen receptor activity.

    Science.gov (United States)

    Ciana, P; Scarlatti, F; Biserni, A; Ottobrini, L; Brena, A; Lana, A; Zagari, F; Lucignani, G; Maggi, A

    2006-07-20

    In the latest few years, the merging of imaging and animal engineering technologies has led to the generation of innovative tools that provide the opportunity to look into the dynamics of specific molecular events in living animals during their entire life under a completely renewed perspective. These tools will have a profound impact not only on basic research, but also on drug discovery and development allowing to depict the activity of any therapeutic agents in all their designed targets as well as in the organs where they may cause undesired effects. Along this research line, our laboratory has recently described the first animal model reporting the state of activity of estrogen receptors (ERs) in real time: the ERE-luc reporter mouse. The application of optical imaging to the ERE-luc has allowed an unprecedented in depth view of estrogen signaling in all of its target tissues. For example, the analysis of the state of activity of ERs in the physiological setting of the estrous cycle has provided compelling evidence that hormone-independent mechanisms are responsible for activating ERs in non-reproductive organs. This discovery may pave the way to a rational basis for the development of novel, more selective and effective treatments for menopause.

  15. Active Teachers - Active Students

    DEFF Research Database (Denmark)

    Learning is active in nature. It is something you do, not something that is done to you. Engineering educators around the world recognize this basic truth and implement one or another form of active learning to enhance their teaching. Active learning in Engineering (ALE) was started as an initiat...

  16. Non-specific activities of the major herbicide-resistance gene BAR.

    Science.gov (United States)

    Christ, Bastien; Hochstrasser, Ramon; Guyer, Luzia; Francisco, Rita; Aubry, Sylvain; Hörtensteiner, Stefan; Weng, Jing-Ke

    2017-12-01

    Bialaphos resistance (BAR) and phosphinothricin acetyltransferase (PAT) genes, which convey resistance to the broad-spectrum herbicide phosphinothricin (also known as glufosinate) via N-acetylation, have been globally used in basic plant research and genetically engineered crops 1-4 . Although early in vitro enzyme assays showed that recombinant BAR and PAT exhibit substrate preference toward phosphinothricin over the 20 proteinogenic amino acids 1 , indirect effects of BAR-containing transgenes in planta, including modified amino acid levels, have been seen but without the identification of their direct causes 5,6 . Combining metabolomics, plant genetics and biochemical approaches, we show that transgenic BAR indeed converts two plant endogenous amino acids, aminoadipate and tryptophan, to their respective N-acetylated products in several plant species. We report the crystal structures of BAR, and further delineate structural basis for its substrate selectivity and catalytic mechanism. Through structure-guided protein engineering, we generated several BAR variants that display significantly reduced non-specific activities compared with its wild-type counterpart in vivo. The transgenic expression of enzymes can result in unintended off-target metabolism arising from enzyme promiscuity. Understanding such phenomena at the mechanistic level can facilitate the design of maximally insulated systems featuring heterologously expressed enzymes.

  17. Direct observation of transcription activator-like effector (TALE) protein dynamics

    Science.gov (United States)

    Cuculis, Luke; Abil, Zhanar; Zhao, Huimin; Schroeder, Charles M.

    2014-03-01

    In this work, we describe a single molecule assay to probe the site-search dynamics of transcription activator-like effector (TALE) proteins along DNA. In modern genetics, the ability to selectively edit the human genome is an unprecedented development, driven by recent advances in targeted nuclease proteins. Specific gene editing can be accomplished using TALE proteins, which are programmable DNA-binding proteins that can be fused to a nuclease domain. In this way, TALENs are a leading technology that has shown great success in the genomic editing of pluripotent stem cells. A major hurdle facing clinical implementation, however, is the potential for deleterious off-target binding events. For these reasons, a molecular-level understanding of TALE binding and target sequence search on DNA is essential. To this end, we developed a single-molecule fluorescence imaging assay that provides a first-of-its-kind view of the 1-D diffusion of TALE proteins along stretched DNA. Taken together with co-crystal structures of DNA-bound TALEs, our results suggest a rotationally-coupled, major groove tracking model for diffusion. We further report diffusion constants for TALE proteins as a function of salt concentration, consistent with previously described models of 1-D protein diffusion.

  18. Why not procrastinate? Development and validation of a new active procrastination scale.

    Science.gov (United States)

    Choi, Jin Nam; Moran, Sarah V

    2009-04-01

    Procrastination has been studied as a dysfunctional, self-effacing behavior that ultimately results in undesirable outcomes. However, A. H. C. Chu and J. N. Choi (2005) found a different form of procrastination (i.e., active procrastination) that leads to desirable outcomes. The construct of active procrastination has a high potential to expand the time management literature and is likely to be adopted by researchers in multiple areas of psychology. To facilitate the research on this new construct and its further integration into the literature, the authors developed and validated a new, expanded measure of active procrastination that reliably assesses its four dimensions. Using this new measure of active procrastination, they further examined its nomological network. The new 16-item measure is a critical step toward further empirical investigation of active procrastination.

  19. Off-Target Function of the Sonic-Hedgehog Inhibitor Cyclopamine in Mediating Apoptosis via Nitric Oxide-Dependent Neutral Sphingomyelinase 2/Ceramide Induction

    OpenAIRE

    Meyers-Needham, Marisa; Lewis, Jocelyn A.; Gencer, Salih; Sentelle, R. David; Saddoughi, Sahar A.; Clarke, Christopher J.; Hannun, Yusuf A.; Norell, Haakan; da Palma, Telma Martins; Nishimura, Michael; Kraveka, Jacqueline M.; Khavandgar, Zohreh; Murshed, Monzur; Cevik, M. Ozgur; Ogretmen, Besim

    2012-01-01

    Sonic hedgehog (SHh) signaling is important in the pathogenesis of various human cancers, such as medulloblastomas, and it has been identified as a valid target for anti-cancer therapeutics. The SHh inhibitor cyclopamine induces apoptosis. The bioactive sphingolipid ceramide mediates cell death in response to various chemotherapeutic agents; however, ceramide’s roles/mechanisms in cyclopamine-induced apoptosis are unknown. Here, we report that cyclopamine mediates ceramide generation selectiv...

  20. The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers

    DEFF Research Database (Denmark)

    Smink, P A; Miao, Y; Eijkemans, M J C

    2014-01-01

    Angiotensin receptor blockers (ARBs) have multiple effects that may contribute to their efficacy on renal/cardiovascular outcomes. We developed and validated a risk score that incorporated short-term changes in multiple risk markers to predict the ARB effect on renal/cardiovascular outcomes.......98), in addition to being markedly more accurate than predicted RRRs based on changes in single markers. The score was validated in an independent ARB trial. Predictions of long-term renal/cardiovascular ARB effects are more accurate when considering short-term changes in multiple risk markers, challenging the use...

  1. Gene Expression Profile of Coronary Artery cells Treated with Non-steroidal Anti-inflammatory Drugs Reveals Off-target Effects

    Science.gov (United States)

    Palayoor, Sanjeewani T.; J-Aryankalayil, Molykutty; Makinde, Adeola. Y.; Cerna, David; Falduto, Michael T.; Magnuson, Scott. R.; Coleman, C. Norman

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in clinic. Coronary artery smooth muscle cells (CASMC) and endothelial cells (HCAEC) were treated with low (clinically achievable) and high (typically used in preclinical studies) concentrations of celecoxib (CXB), NS398 (NS) and ibuprofen (IBU) for 24h. NSAIDs-induced gene expression changes were evaluated by microarray analysis and validated by real-time RT-PCR and western blotting. The functional significance of differentially expressed genes was evaluated by Ingenuity Pathway Analysis (IPA). At high concentrations, NSAIDs altered the expression of genes regulating cell proliferation and cell death. NSAIDs also altered genes associated with cardiovascular functions including inflammation, thrombosis, fibrinolysis, coronary artery disease and hypertension. The gene expression was most impacted by IBU, CXB and NS, in that order. This study revealed that NSAIDs altered expression of an array of genes associated with cardiovascular events and emphasizes the potential for fingerprinting drugs in preclinical studies to assess the potential drug toxicity and to optimize the drug efficacy in clinical settings. PMID:22668799

  2. Gene Expression Profile of Coronary Artery cells Treated with Non-steroidal Anti-inflammatory Drugs Reveals Off-target Effects

    OpenAIRE

    Palayoor, Sanjeewani T.; J-Aryankalayil, Molykutty; Makinde, Adeola. Y.; Cerna, David; Falduto, Michael T.; Magnuson, Scott. R.; Coleman, C. Norman

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) have come under scrutiny because of the gastrointestinal, renal and cardiovascular toxicity associated with prolonged use of these drugs. The purpose of this study was to identify molecular targets for NSAIDs related to cellular toxicity with a view to optimize drug efficacy in clinic. Coronary artery smooth muscle cells (CASMC) and endothelial cells (HCAEC) were treated with low (clinically achievable) and high (typically used in preclinical stu...

  3. Allogeneic HLA-A*02-Restricted WT1-Specific T Cells from Mismatched Donors Are Highly Reactive but Show Off-Target Promiscuity

    NARCIS (Netherlands)

    Falkenburg, Willem J. J.; Melenhorst, J. Joseph; van de Meent, Marian; Kester, Michel G. D.; Hombrink, Pleun; Heemskerk, Mirjam H. M.; Hagedoorn, Renate S.; Gostick, Emma; Price, David A.; Falkenburg, J. H. Frederik; Barrett, A. John; Jedema, Inge

    2011-01-01

    T cells recognizing tumor-associated Ags such as Wilms tumor protein (WT1) are thought to exert potent antitumor reactivity. However, no consistent high-avidity T cell responses have been demonstrated in vaccination studies with WT1 as target in cancer immunotherapy. The aim of this study was to

  4. The therapeutic potential of LNA-modified siRNAs: reduction of off-target effects by chemical modification of the siRNA sequence

    NARCIS (Netherlands)

    Fluiter, Kees; Mook, Olaf R. F.; Baas, Frank

    2009-01-01

    Post-transcriptional gene silencing mediated by double-stranded RNA represents an evolutionarily conserved cellular mechanism. Small dsRNAs, such as microRNAs (miRNAs), are part of the main regulatory mechanisms of gene expression in cells. The possibilities of harnessing this intrinsic natural

  5. Differential cathepsin responses to inhibitor-induced feedback: E-64 and cystatin C elevate active cathepsin S and suppress active cathepsin L in breast cancer cells.

    Science.gov (United States)

    Wilder, Catera L; Walton, Charlene; Watson, Valencia; Stewart, Fermin A A; Johnson, Jade; Peyton, Shelly R; Payne, Christine K; Odero-Marah, Valerie; Platt, Manu O

    2016-10-01

    Cathepsins are powerful proteases, once referred to as the lysosomal cysteine proteases, that have been implicated in breast cancer invasion and metastasis, but pharmaceutical inhibitors have suffered failures in clinical trials due to adverse side effects. Scientific advancement from lysosomotropic to cell impermeable cathepsin inhibitors have improved efficacy in treating disease, but off-target effects have still been problematic, motivating a need to better understand cellular feedback and responses to treatment with cathepsin inhibitors. To address this need, we investigated effects of E-64 and cystatin C, two broad spectrum cathepsin inhibitors, on cathepsin levels intra- and extracellularly in MDA-MB-231 breast cancer cells. Cathepsins S and L had opposing responses to both E-64 and cystatin C inhibitor treatments with paradoxically elevated amounts of active cathepsin S, but decreased amounts of active cathepsin L, as determined by multiplex cathepsin zymography. This indicated cellular feedback to selectively sustain the amounts of active cathepsin S even in the presence of inhibitors with subnanomolar inhibitory constant values. These differences were identified in cellular locations of cathepsins L and S, trafficking for secretion, co-localization with endocytosed inhibitors, and longer protein turnover time for cathepsin S compared to cathepsin L. Together, this work demonstrates that previously underappreciated cellular compensation and compartmentalization mechanisms may sustain elevated amounts of some active cathepsins while diminishing others after inhibitor treatment. This can confound predictions based solely on inhibitor kinetics, and must be better understood to effectively deploy therapies and dosing strategies that target cathepsins to prevent cancer progression. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Site-Specific Modification Using the 2′-Methoxyethyl Group Improves the Specificity and Activity of siRNAs

    Directory of Open Access Journals (Sweden)

    Xinyun Song

    2017-12-01

    Full Text Available Rapid progress has been made toward small interfering RNA (siRNA-based therapy for human disorders, but rationally optimizing siRNAs for high specificity and potent silencing remains a challenge. In this study, we explored the effect of chemical modification at the cleavage site of siRNAs. We found that modifications at positions 9 and 10 markedly reduced the silencing potency of the unmodified strand of siRNAs but were well tolerated by the modified strand. Intriguingly, addition of the 2′-methoxyethyl (MOE group at the cleavage site improved both the specificity and silencing activity of siRNAs by facilitating the oriented RNA-induced silencing complex (RISC loading of the modified strand. Furthermore, we combined MOE modifications at positions 9 and 10 of one strand together with 2′-O-methylation (OMe at position 14 of the other strand and found a synergistic effect that improved the specificity of siRNAs. The surprisingly beneficial effect of the combined modification was validated using siRNA-targeting endogenous gene intercellular adhesion molecule 1 (ICAM1. We found that the combined modifications eliminated its off-target effects. In conclusion, we established effective strategies to optimize siRNAs using site-specific MOE modifications. The findings may allow the creation of superior siRNAs for therapy in terms of activity and specificity.

  7. Site-Specific Modification Using the 2'-Methoxyethyl Group Improves the Specificity and Activity of siRNAs.

    Science.gov (United States)

    Song, Xinyun; Wang, Xiaoxia; Ma, Yuan; Liang, Zicai; Yang, Zhenjun; Cao, Huiqing

    2017-12-15

    Rapid progress has been made toward small interfering RNA (siRNA)-based therapy for human disorders, but rationally optimizing siRNAs for high specificity and potent silencing remains a challenge. In this study, we explored the effect of chemical modification at the cleavage site of siRNAs. We found that modifications at positions 9 and 10 markedly reduced the silencing potency of the unmodified strand of siRNAs but were well tolerated by the modified strand. Intriguingly, addition of the 2'-methoxyethyl (MOE) group at the cleavage site improved both the specificity and silencing activity of siRNAs by facilitating the oriented RNA-induced silencing complex (RISC) loading of the modified strand. Furthermore, we combined MOE modifications at positions 9 and 10 of one strand together with 2'-O-methylation (OMe) at position 14 of the other strand and found a synergistic effect that improved the specificity of siRNAs. The surprisingly beneficial effect of the combined modification was validated using siRNA-targeting endogenous gene intercellular adhesion molecule 1 (ICAM1). We found that the combined modifications eliminated its off-target effects. In conclusion, we established effective strategies to optimize siRNAs using site-specific MOE modifications. The findings may allow the creation of superior siRNAs for therapy in terms of activity and specificity. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  8. MODELO DE LOCALIZACIÓN ÓPTIMA DE ACTIVIDADES NO DESEADAS APLICADO A LOS RESIDUOS SÓLIDOS EN LA REGIÓN METROPOLITANA AN OPTIMAL LOCATION MODEL OF UNDESIRABLE FACILITIES APPLIED TO THE SOLID WASTES IN THE METROPOLITAN REGION

    Directory of Open Access Journals (Sweden)

    Marcos Medina Tapia

    2008-06-01

    Full Text Available El trabajo analiza los principios y estructuras de modelación de localización óptima de actividades indeseables (obnoxious location models, revisando criterios de "eficiencia espacial" en la localización, y "justicia espacial" en la distribución de externalidades. La eficiencia se logra con modelos de localización-asignación optimizando el costo total (plant location. Para la justicia se calibran curvas de rechazo con métodos econométricos. Finalmente todo se optimiza en una estructura multiobjetivo ponderada. Este modelo mixto se aplica a la localización de estaciones de transferencia y rellenos sanitarios en la Región Metropolitana, obteniendo localizaciones óptimas (económica y socialmente, y asignaciones óptimas de residuos sólidos comunales.This work analyses the principles and structures of optimal location models of obnoxious activities, by studying criterion of spatial efficiency in the location, and spatial justice in the distribution of externalities. The efficiency is obtained through the Plant Location model (a location-allocation model. For the justice, opposition curves are fitted using econometrics models. Finally, everything is optimised in a weighted multi-objective structure. This mixed model is applied to the location of transfer stations and landfill operations in the Metropolitan Area in Santiago-Chile. The results give optimal locations (economic and social, and optimal allocation of municipal solid waste.

  9. EFFECT OF AERO-/ANAEROBIOSIS ON DECARBOXYLASE ACTIVITY OF SELECTED LACTIC ACID BACTERIA

    Directory of Open Access Journals (Sweden)

    Stanislav Kráčmar

    2010-05-01

    Full Text Available Biogenic amines are undesirable compounds produced in foods mainly through bacterial decarboxylase activity. The aim of this study was to investigate some environmental conditions (particularly aero/anaerobiosis, sodium chloride concentration (0–2% w/w, and amount of lactose (0–1% w/w on the activity of tyrosine decarboxylase enzymes of selected six technological important Lactococcus lactis strains. The levels of parameters tested were chosen according to real situation in fermented dairy products technology (especially cheese-making. Tyramine was determined by the ion-exchange chromatography with post-column ninhydrine derivatization and spectrophotometric detection. Tyrosine decarboxylation occurred during the active growth phase. Under the model conditions used, oxygen availability had influence on tyramine production, anaerobiosis seemed to favour the enzyme activity because all L. lactis strains produced higher tyramine amount. doi:10.5219/43

  10. A Compressed Sensing Based Decomposition of Electrodermal Activity Signals.

    Science.gov (United States)

    Jain, Swayambhoo; Oswal, Urvashi; Xu, Kevin Shuai; Eriksson, Brian; Haupt, Jarvis

    2017-09-01

    The measurement and analysis of electrodermal activity (EDA) offers applications in diverse areas ranging from market research to seizure detection and to human stress analysis. Unfortunately, the analysis of EDA signals is made difficult by the superposition of numerous components that can obscure the signal information related to a user's response to a stimulus. We show how simple preprocessing followed by a novel compressed sensing based decomposition can mitigate the effects of the undesired noise components and help reveal the underlying physiological signal. The proposed framework allows for decomposition of EDA signals with provable bounds on the recovery of user responses. We test our procedure on both synthetic and real-world EDA signals from wearable sensors and demonstrate that our approach allows for more accurate recovery of user responses as compared with the existing techniques.

  11. Design, synthesis and biological activity evaluation of novel 4-subtituted 2-naphthamide derivatives as AcrB inhibitors.

    Science.gov (United States)

    Wang, Yinhu; Mowla, Rumana; Ji, Shengli; Guo, Liwei; De Barros Lopes, Miguel A; Jin, Chaobin; Song, Di; Ma, Shutao; Venter, Henrietta

    2018-01-01

    A novel series of 4-substituted 2-naphthamide derivatives were designed, synthesized and evaluated for their biological activity. In particular, the ability of the compounds to potentiate the action of antibiotics, to inhibit Nile Red efflux and to target AcrB specifically was investigated. The results indicated that most of the 4-substituted 2-naphthamide derivatives were able to synergize with the antibiotics tested, and inhibit Nile Red efflux by AcrB in the resistant phenotype. Subsequent exclusion of compounds with off target effects such as outer- or inner membrane permeabilization identified compounds 7c, 7g, 12c, 12i and 13g as efflux pump inhibitors (EPIs). Particularly, compounds 7c, 7g and 12i were found to be the most potent EPIs, which synergized with the two substrates tested at lower concentrations than that of parent A3, demonstrating an improvement in potency as compared to A3. Additionally, when the outer membrane of E. coli was permeabilized, compound 12c displayed a huge increase in efficacy and was able to synergize with erythromycin at a concentration that was 16 times lower than that of the parent A3. Hence we were able to design and synthesize compounds that displayed significant increase in efficacy as EPIs against AcrB. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Surface-Bound Ligands Modulate Chemoselectivity and Activity of a Bimetallic Nanoparticle Catalyst

    KAUST Repository

    Vu, Khanh B.

    2015-04-03

    "Naked" metal nanoparticles (NPs) are thermodynamically and kinetically unstable in solution. Ligands, surfactants, or polymers, which adsorb at a particle\\'s surface, can be used to stabilize NPs; however, such a mode of stabilization is undesirable for catalytic applications because the adsorbates block the surface active sites. The catalytic activity and the stability of NPs are usually inversely correlated. Here, we describe an example of a bimetallic (PtFe) NP catalyst stabilized by carboxylate surface ligands that bind preferentially to one of the metals (Fe). NPs stabilized by fluorous ligands were found to be remarkably competent in catalyzing the hydrogenation of cinnamaldehyde; NPs stabilized by hydrocarbon ligands were significantly less active. The chain length of the fluorous ligands played a key role in determining the chemoselectivity of the FePt NP catalysts. (Chemical Presented). © 2015 American Chemical Society.

  13. "That's Kind of One of Our Jobs": Sexual Activity as a Form of Care Work Among Women with Sexual Difficulties.

    Science.gov (United States)

    Braksmajer, Amy

    2017-10-01

    Willing engagement in unwanted or undesired sexual activity, often associated with fulfilling a partner's needs or sustaining intimate relationships, is common. Acquiescence with undesired sexual activity can be conceptualized as sexual care work, that is, domestic "labor" that women undertake with the goal of caring for their partners' well-being. Drawing on interviews with 53 women with dyspareunia (pain experienced during intercourse) and low desire, the aim of this study was to examine how women with sexual difficulties engage in sexual care work, the implications of the inability to perform such work for gender identity, and the ways in which sexual care work may blur the lines between women's perceptions of coercion and consent. The women in this study engaged in sexual activity for a number of reasons, including the pursuit of intimacy, to care for their partner, and to fulfill their perceived sexual obligations. Sexual compliance was conceptualized as a form of work, similar to other forms of unpaid care work such as housework or childcare, which negatively affected women's gender identities when it could not be performed. For many women, sex was simultaneously wanted and unwanted, contributing to women's ambivalence regarding the meaning of consent. Further exploration of these issues may lead to a better understanding of how gender is achieved through normative sexuality.

  14. Preparation and characterization of intelligent starch/PVA films for simultaneous colorimetric indication and antimicrobial activity for food packaging applications.

    Science.gov (United States)

    Liu, Bin; Xu, Han; Zhao, Huiying; Liu, Wei; Zhao, Liyun; Li, Yuan

    2017-02-10

    We have developed an intelligent starch/poly-vinyl alcohol (PVA) film that is capable of monitoring pH changes and inhibiting undesired microbial growth in foods. Starch and PVA polymers in the film were doubly cross-linked by sodium trimetaphosphate and boric acid to improve their water-resistance and mechanical strength. Anthocyanins (ANT) and limonene (LIM) were used to achieve simultaneous colorimetric indication and antimicrobial activity. Firstly, the characterization of surface morphology using SEM confirmed that the starch-PVA-ANT-LIM film possessed a smooth surface. Secondly, the results of the mechanical strength test showed that starch-PVA-ANT-LIM possesses the highest mechanical strength. Additionally, there was a distinguishable change of colors as the film was immersed in solutions of pH ranging from 1.0 to 14.0. Moreover, the film showed excellent antimicrobial activity for three typical undesired microorganisms in foods, Bacillus subtilis, Aspergillus niger, and Staphylococcus aureus. Finally, the film exhibited good color indication and antimicrobial activity on pasteurized milk. The results suggest that the intelligent film reported here shows good capability for both alerting and inhibiting food spoilage. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Antidiabetic and anticancer activities of Mangifera indica cv. Okrong leaves

    Science.gov (United States)

    Ganogpichayagrai, Aunyachulee; Palanuvej, Chanida; Ruangrungsi, Nijsiri

    2017-01-01

    Diabetes and cancer are a major global public health problem. Plant-derived agents with undesirable side-effects were required. This study aimed to evaluate antidiabetic and anticancer activities of the ethanolic leaf extract of Mangifera indica cv. Okrong and its active phytochemical compound, mangiferin. Antidiabetic activities against yeast α-glucosidase and rat intestinal α-glucosidase were determined using 1 mM of p-nitro phenyl-α-D-glucopyranoside as substrate. Inhibitory activity against porcine pancreatic α-amylase was performed using 1 mM of 2-chloro-4 nitrophenol-α-D-maltotroside-3 as substrate. Nitrophenol product was spectrophotometrically measured at 405 nm. Anticancer activity was evaluated against five human cancer cell lines compared to two human normal cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Mango leaf extract and mangiferin exhibited dose-dependent inhibition against yeast α-glucosidase with the IC50 of 0.0503 and 0.5813 mg/ml, respectively, against rat α-glucosidase with the IC50 of 1.4528 and 0.4333 mg/ml, respectively, compared to acarbose with the IC50 of 11.9285 and 0.4493 mg/ml, respectively. For anticancer activity, mango leaf extract, at ≥200 μg/ml showed cytotoxic potential against all tested cancer cell lines. In conclusion, mango leaf possessed antidiabetic and anticancer potential in vitro. PMID:28217550

  16. Undesirable financial effects of head and neck cancer radiotherapy during the initial treatment period.

    Science.gov (United States)

    Egestad, Helen; Nieder, Carsten

    2015-01-01

    Healthcare cost and reforms are at the forefront of international debates. One of the current discussion themes in oncology is whether and how patients' life changes due to costs of cancer care. In Norway, the main part of the treatment costs is supported by general taxpayer revenues. The objective of this study was to clarify whether head and neck cancer patients (n=67) in northern Norway experienced financial health-related quality of life (HRQOL) deterioration due to costs associated with treatment. HRQOL was examined by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 in the beginning and in the end of radiation treatment in patients treated at the University Hospital in Northern Norway. Changes in financial HRQOL were calculated and compared by paired sample T-tests. Multiple regression analyses were used to examine correlations among gender, marital status, age and treatment with or without additional chemotherapy and changes in the HRQOL domain of financial difficulties. The majority of score results at both time points were in the lower range (mean 15-25), indicating limited financial difficulties. We observed no statistically significant differences by gender, marital status and age. Increasing financial difficulties during treatment were reported by male patients and those younger than 65, that is, patients who were younger than retirement age. The largest effect was seen in singles. However, differences were not statistically significant. During the initial phase of the disease trajectory, no significant increase in financial difficulties was found. This is in line with the aims of the Norwegian public healthcare model. However, long-term longitudinal studies should be performed, especially with regard to the trends we observed in single, male and younger patients.

  17. Cardiotoxicity as undesired side effect in the treatment of breast cancer

    Directory of Open Access Journals (Sweden)

    Michalina Gramatyka

    2014-05-01

    Full Text Available Improvement of methods used in breast cancer therapy resulted in increased treatment effectiveness and prolonged survival of patients. However, this is accompanied by increased frequency of adverse side effects, including cardiac toxicity, which is becoming a serious problem affecting the quality of life and overall survival of cancer patients. The risk of developing cardiovascular complications depends on the type and dose of therapeutic agent used. The highest risk of cardiotoxicity is associated with anthracyclines. They are used frequently in cancer therapy due to their high efficiency but show a dose-dependent toxicity to the cardiovascular system. Cardiotoxicity can also occur with other substances used in breast cancer chemotherapy, as well as with radiotherapy. Combining potentially cardiotoxic therapeutic agents, commonly used in combination therapy, may result in escalation of toxic side effects. Mechanisms of heart damage are different for various cardiotoxic agents, but symptoms usually involve heart failure, ischemic heart disease, arrhythmias, hypertension, valvular diseases or pericarditis and myocarditis. The practices used to reduce the risk of cardiotoxic effects of cancer therapy include evaluation of cardiac functions before treatment and constant monitoring during and after treatment. Furthermore, limited doses and modifications of anticancer agent administration patterns are employed, as well as simultaneous application of cardioprotective agents. Understanding of cardiotoxic mechanisms of agents used in breast cancer treatment can help to develop efficient cardioprotective substances. Because oxidative stress plays an important role in the toxicity of cancer therapy, compounds with antioxidant properties are a very promising target of research.

  18. Identification of undesirable white-colony-forming yeasts appeared on the surface of Japanese kimchi.

    Science.gov (United States)

    Suzuki, Ayaka; Muraoka, Naomi; Nakamura, Mariko; Yanagisawa, Yasuhira; Amachi, Seigo

    2018-02-01

    To identify yeasts involved in white-colony formation on Japanese commercial kimchi products, three types of kimchi were prepared and fermented at four different temperatures. At 4 °C, yeast colonies did not appear until 35 days, while more rapid white-colony formation occurred at higher temperatures (10, 15, and 25 °C). Combination of PCR-DGGE and direct isolation of yeasts from white colonies revealed that Kazachstania exigua and K. pseudohumilis were responsible for the white-colony formation. Inoculation of the isolated Kazachstania strains into fresh kimchi successfully reproduced white-colony formation at 15 °C but not at 4 °C. Growth experiments in liquid medium revealed that Kazachstania spp. grew fast at 15 °C even in the presence of acidulants, which are commonly added to Japanese kimchi products for prevention of yeast growth. These results suggest that white-colony formation on Japanese kimchi is caused by the genus Kazachstania, and that one of important factors determining white-colony formation is its fermentation temperature.

  19. Catalyst Influence on Undesired Side Reactions in the Polycondensation of Fully Bio-Based Polyester Itaconates

    Directory of Open Access Journals (Sweden)

    Ina Schoon

    2017-12-01

    Full Text Available Bio-based unsaturated polyester resins derived from itaconic acid can be an alternative to established resins of this type in the field of radical-curing resins. However, one of the challenges of these polyester itaconates is the somewhat more elaborate synthetic process, especially under polycondensation conditions used on an industrial scale. The α,β-unsaturated double bond of the itaconic acid is prone to side reactions that can lead to the gelation of the polyester resin under standard conditions. This is especially true when bio-based diols such as 1,3-propanediol or 1,4-butanediol are used to obtain resins that are 100% derived from renewable resources. It was observed in earlier studies that high amounts of these aliphatic diols in the polyester lead to low conversion and gelation of the resins. In this work, a catalytic study using different diols was performed in order to elucidate the reasons for this behavior. It was shown that the choice of catalyst has a crucial influence on the side reactions occurring during the polycondensation reactions. In addition, the side reactions taking place were identified and suppressed. These results will allow for the synthesis of polyester itaconates on a larger scale, setting the stage for their industrial application.

  20. Functional Analysis and Treatment of Human-Directed Undesirable Behavior Exhibited by a Captive Chimpanzee

    Science.gov (United States)

    Martin, Allison L.; Bloomsmith, Mollie A.; Kelley, Michael E.; Marr, M. Jackson; Maple, Terry L.

    2011-01-01

    A functional analysis identified the reinforcer maintaining feces throwing and spitting exhibited by a captive adult chimpanzee ("Pan troglodytes"). The implementation of a function-based treatment combining extinction with differential reinforcement of an alternate behavior decreased levels of inappropriate behavior. These findings further…

  1. Quantifying undesired parallel components in Thévenin-equivalent acoustic source parameters

    DEFF Research Database (Denmark)

    Nørgaard, Kren Rahbek; Neely, Stephen T.; Rasetshwane, Daniel M.

    2018-01-01

    in the source parameters. Such parallel components can result from, e.g., a leak in the ear tip or improperly accounting for evanescent modes, and introduce errors into subsequent measurements of impedance and reflectance. This paper proposes a set of additional error metrics that are capable of detecting...

  2. Prediction of fracture toughness and durability of adhesively bonded composite joints with undesirable bonding conditions

    Science.gov (United States)

    Musaramthota, Vishal

    Advanced composite materials have enabled the conventional aircraft structures to reduce weight, improve fuel efficiency and offer superior mechanical properties. In the past, materials such as aluminum, steel or titanium have been used to manufacture aircraft structures for support of heavy loads. Within the last decade or so, demand for advanced composite materials have been emerging that offer significant advantages over the traditional metallic materials. Of particular interest in the recent years, there has been an upsurge in scientific significance in the usage of adhesively bonded composite joints (ABCJ's). ABCJ's negate the introduction of stress risers that are associated with riveting or other classical techniques. In today's aircraft transportation market, there is a push to increase structural efficiency by promoting adhesive bonding to primary joining of aircraft structures. This research is focused on the issues associated with the durability and related failures in bonded composite joints that continue to be a critical hindrance to the universal acceptance of ABCJ's. Of particular interest are the short term strength, contamination and long term durability of ABCJ's. One of the factors that influence bond performance is contamination and in this study the influence of contamination on composite-adhesive bond quality was investigated through the development of a repeatable and scalable surface contamination procedure. Results showed an increase in the contaminant coverage area decreases the overall bond strength significantly. A direct correlation between the contaminant coverage area and the fracture toughness of the bonded joint was established. Another factor that influences bond performance during an aircraft's service life is its long term strength upon exposure to harsh environmental conditions or when subjected to severe mechanical loading. A test procedure was successfully developed in order to evaluate durability of ABCJ's comprising severe environmental conditioning, fatiguing in ambient air and a combination of both. The bonds produced were durable enough to sustain the tests cases mentioned above when conditioned for 8 weeks and did not experience any loss in strength. Specimens that were aged for 80 weeks showed a degradation of 10% in their fracture toughness when compared to their baseline datasets. The effect of various exposure times needs to be further evaluated to establish the relationship of durability that is associated with the fracture toughness of ABCJ's.

  3. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    International Nuclear Information System (INIS)

    Kim, Eun-Hee; Hong, Kyung-Sook; Hong, Hua; Hahm, Ki Baik

    2011-01-01

    Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis

  4. Undesirable financial effects of head and neck cancer radiotherapy during the initial treatment period

    Directory of Open Access Journals (Sweden)

    Helen Egestad

    2015-01-01

    Full Text Available Background: Healthcare cost and reforms are at the forefront of international debates. One of the current discussion themes in oncology is whether and how patients’ life changes due to costs of cancer care. In Norway, the main part of the treatment costs is supported by general taxpayer revenues. Objectives: The objective of this study was to clarify whether head and neck cancer patients (n=67 in northern Norway experienced financial health-related quality of life (HRQOL deterioration due to costs associated with treatment. Design: HRQOL was examined by the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30 in the beginning and in the end of radiation treatment in patients treated at the University Hospital in Northern Norway. Changes in financial HRQOL were calculated and compared by paired sample T-tests. Multiple regression analyses were used to examine correlations among gender, marital status, age and treatment with or without additional chemotherapy and changes in the HRQOL domain of financial difficulties. Results: The majority of score results at both time points were in the lower range (mean 15–25, indicating limited financial difficulties. We observed no statistically significant differences by gender, marital status and age. Increasing financial difficulties during treatment were reported by male patients and those younger than 65, that is, patients who were younger than retirement age. The largest effect was seen in singles. However, differences were not statistically significant. Conclusions: During the initial phase of the disease trajectory, no significant increase in financial difficulties was found. This is in line with the aims of the Norwegian public healthcare model. However, long-term longitudinal studies should be performed, especially with regard to the trends we observed in single, male and younger patients.

  5. Pretreatment and prophylaxis against nerve agent poisoning: Are undesirable behavioral side effects unavoidable?

    Science.gov (United States)

    Myhrer, Trond; Aas, Pål

    2016-12-01

    The threat of chemical warfare agents like nerve agents requires life saving measures of medical pretreatment combined with treatment after exposure. Pretreatment (pyridostigmine) may cause some side effects in a small number of individuals. A comprehensive research on animals has been performed to clarify effects on behavior. The results from these studies are far from unambiguous, since pyridostigmine may produce adverse effects on behavior in animals in relatively high doses, but not in a consistent way. Other animal studies have examined the potential of drugs like physostigmine, galantamine, benactyzine, trihexyphenidyl, and procyclidine, but they all produce marked behavioral impairment at doses sufficient to contribute to protection against a convulsant dose of soman. Attempts have also been made to develop a combination of drugs capable of assuring full protection (prophylaxis) against nerve agents. However, common to all combinations is that they at anticonvulsant doses cause behavioral deficits. Therefore, the use of limited pretreatment doses may be performed without marked side effects followed by post-exposure therapy with a combination of drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Designing nanomaterials to maximize performance and minimize undesirable implications guided by the Principles of Green Chemistry.

    Science.gov (United States)

    Gilbertson, Leanne M; Zimmerman, Julie B; Plata, Desiree L; Hutchison, James E; Anastas, Paul T

    2015-08-21

    The Twelve Principles of Green Chemistry were first published in 1998 and provide a framework that has been adopted not only by chemists, but also by design practitioners and decision-makers (e.g., materials scientists and regulators). The development of the Principles was initially motivated by the need to address decades of unintended environmental pollution and human health impacts from the production and use of hazardous chemicals. Yet, for over a decade now, the Principles have been applied to the synthesis and production of engineered nanomaterials (ENMs) and the products they enable. While the combined efforts of the global scientific community have led to promising advances in the field of nanotechnology, there remain significant research gaps and the opportunity to leverage the potential global economic, societal and environmental benefits of ENMs safely and sustainably. As such, this tutorial review benchmarks the successes to date and identifies critical research gaps to be considered as future opportunities for the community to address. A sustainable material design framework is proposed that emphasizes the importance of establishing structure-property-function (SPF) and structure-property-hazard (SPH) relationships to guide the rational design of ENMs. The goal is to achieve or exceed the functional performance of current materials and the technologies they enable, while minimizing inherent hazard to avoid risk to human health and the environment at all stages of the life cycle.

  7. Life-as-Lived Today: Perpetual (Undesired Liminality of the Half-widows of Kashmir

    Directory of Open Access Journals (Sweden)

    Paul DSouza

    2016-04-01

    Full Text Available According to Victor Turner, all liminality must eventually dissolve, for it is a state of great intensity that cannot exist very long without some sort of structure to sta-bilize it. This paper takes his lead and attempts to describe the liminal status of those women, the whereabouts of whose husbands are not known (they are locally re-ferred to as 'half-widows' in the conflict zone of Kashmir, India. The article ex-amines the concept of liminality based on life as lived today by these half-widows and shows how the effects of liminality operate in their day to day life, making them extremely vulnerable victims. In this, it is an attempt to expand upon the concept of liminality, originally linked almost exclusively to rites of passage. Furthermore, this paper reflects on the idea of permanent liminality that has been elaborated by soci-ologist Arpad Szakolczai. The narratives of the half-widows of Kashmir provide an example of how they are trapped in a form of 1permanent liminality1 far beyond what was initially defined as a 'temporal state'.

  8. Unexpected and undesired conservation outcomes of wildlife trade bans—An emerging problem for stakeholders?

    Directory of Open Access Journals (Sweden)

    Diana S. Weber

    2015-01-01

    Full Text Available CITES regulates international trade with the goal of preventing over-exploitation, thus the survival of species are not jeopardized from trade practices; however it has been used recently in nontrade conservation measures. As an example, the US proposed to up-list polar bears under CITES Appendix I, despite that the species did not conform to the biological criteria. Polar bears were listed as ‘threatened’ under US ESA in 2008, in response to loss of sea-ice and warming temperatures. In Nunavut, where most of Canada’s polar bears are harvested, the resulting trade ban did not decrease total harvest after the ESA listing but reduced US hunter participation and the proportion of quotas taken by sport hunters from specific populations. Consequently, the import ban impacted livelihoods of Arctic indigenous communities with negative conservation — reduced tolerance for dangerous fauna and affected local participation in shared management initiatives. The polar bear may be the exemplar of an emerging problem: the use of trade bans in place of action for non-trade threats, e.g., climate change. Conservation prospects for this species and other climate-sensitive wildlife will likely diminish if the increasing use of trade bans to combat non-trade issues cause stakeholders to lose faith in participatory management.

  9. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    Directory of Open Access Journals (Sweden)

    Ki Baik Hahm

    2011-07-01

    Full Text Available Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis.

  10. Undesirable charge-enhancement of isobaric tagged phosphopeptides leads to reduced identification efficiency

    DEFF Research Database (Denmark)

    Thingholm, Tine E; Palmisano, Giuseppe; Kjeldsen, Frank

    2010-01-01

    labeling of proteins and peptides for in vitro cell culture systems (stable isotope labeling using amino acids in cell culture, SILAC) or isobaric peptide labels such as isobaric tags for relative and absolute quantitation (iTRAQ) and tandem mass tags (TMT) for both in vitro and in vivo systems...... identifications observed for large cell- or tissue-based data sets from labeled and nonlabeled peptide mixtures. Ammonia vapor sprayed perpendicular to the electrospray needle during ionization resulted in an overall decrease in the average charge states and a concomitant increase in phosphopeptide...

  11. Detouring the Undesired Route of Helicobacter pylori-Induced Gastric Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun-Hee; Hong, Kyung-Sook; Hong, Hua [Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Hahm, Ki Baik, E-mail: hahmkb@gachon.ac.kr [Lab of Translational Medicine, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, 7-45 Songdo-dong, Yeonsu-gu, Incheon 406-840 (Korea, Republic of); Department of Gastroenterology, Gachon Graduate School of Medicine, Gil Hospital, Incheon 406-840 (Korea, Republic of)

    2011-07-25

    Epidemiological and experimental evidence has emerged that a dysregulated inflammation is associated with most of the tumors, and many studies have begun to unravel the molecular pathways linking inflammation and cancer. As a typical example linking these associations, Helicobacter pylori (H. pylori) infection-associated atrophic gastritis has been recognized as precursor lesion of gastric cancer. The identification of transcription factors such as NF-κB and STAT3, and their gene products such as IL-8, COX-2, iNOS, cytokines, chemokines and their receptors, etc have laid the molecular foundation for our understanding of the decisive role of inflammation in carcinogenesis. In addition to the role as the initiator of cancer, inflammation contributes to survival and proliferation of malignant cells, tumor angiogenesis, and even metastasis. In this review, the fundamental mechanisms of H. pylori-induced carcinogenesis as well as the possibility of cancer prevention through suppressing H. pylori-induced inflammation are introduced. We infer that targeting inflammatory pathways have a potential role to detour the unpleasant journey to H. pylori-associated gastric carcinogenesis.

  12. Overview of undesirable effects of using diatomaceous earths for direct mixing with grains

    Directory of Open Access Journals (Sweden)

    Korunić Zlatko

    2016-01-01

    Full Text Available Despite numerous advantages of diatomaceous earth (DE, its use for direct mixing with grains to control stored-product insects remains limited because of some very serious obstacles and disadvantages. The main obstacles preventing a wider use of DEs for mixing with grain, such as health concerns, the reduction in bulk density, differences in insect species tolerance to the same DE formulation, the effects of grain moisture and temperature on the effectiveness against insects, the influence of various commodities on DE efficacy, the use of DEs in some other fields, and possible solutions for overcoming DE limitations during direct mixing with grains are described in this manuscript. The same attempts have been made to discover new ways of increasing significantly the effectiveness against insects when much lower concentrations are used for direct mixing with grains. If these newer enhanced formulations can respond to the existing limitations of diatomaceous earth, a wider utilization of diatomaceous earth may be expected to control stored-product insect pests.

  13. Undesired reinforcement of harmful ‘self-evident truths’ concerning the implementation of wind power

    International Nuclear Information System (INIS)

    Wolsink, Maarten

    2012-01-01

    This ‘viewpoint’ draws attention to a lingering, simplistic and faulty interpretation of the complex phenomenon of acceptance of renewables and their implementation in concrete projects by all relevant actors—namely the ‘backyard theory’. During the last decade, research that investigated NIMBY has provided support to disprove the two prime hypotheses (proximity and decreasing property-value). The current mainstream trend in academic circles is clearly towards abandoning NIMBY explanations. However, in practice among developers and policymakers NIMBY thinking still prevails. Unfortunately there is also some academic writing that persists in recycling the ‘backyard theory’—despite ample research to the contrary—thus feeding this faulty interpretation of implementation problems. A recent review of the state of the art of wind power implementation is taken as an example; it presents NIMBY as a common-sense, self-evident truth, while to support this explanation it cites publications that actually refute this view and instead support the mainstream move towards abandoning NIMBY thinking. This shift is important, because further academic support for this concept would serve to hinder rapid deployment of wind power and also other renewables.

  14. MEDUSA: Mining Events to Detect Undesirable uSer Actions in SCADA

    NARCIS (Netherlands)

    Hadziosmanovic, D.; Bolzoni, D.; Hartel, Pieter H.; Jha, Somesh; Sommer, Robin; Kreibich, Christian

    2010-01-01

    Standard approaches for detecting malicious behaviors, e.g. monitoring network traffic, cannot address process-related threats in SCADA(Supervisory Control And Data Acquisition) systems. These threats take place when an attacker gains user access rights and performs actions which look legitimate,

  15. In vivo imaging of cell proliferation for a dynamic, whole body, analysis of undesired drug effects.

    Science.gov (United States)

    Rizzi, Nicoletta; Manni, Isabella; Vantaggiato, Cristina; Delledonne, Giacomo Andrea; Gentileschi, Maria Pia; Maggi, Adriana; Piaggio, Giulia; Ciana, Paolo

    2015-06-01

    Noninvasive in vivo imaging offers a novel approach to preclinical studies opening the possibility of investigating biological events in the spatiotemporal dimension (eg, in any district of the body in time). Toxicological analysis may benefit from this novel approach through precise identification of the time and the target organs of toxicity manifestations, and assessment of the reversibility of toxic insults. The current limitation for routine application of this technology is the lack of appropriate surrogate markers for imaging toxicological events. Here, we demonstrate that in vivo imaging of a proliferation marker is capable of measuring the reduction of cell proliferation due to genotoxic/apoptotic agents, γ rays or antineoplastic drugs, or the increased proliferation associated with the inflammatory and regenerative reactions occurring after a toxic insult. A number of tools are currently available for imaging proliferation in preclinical and clinical settings, however our data provide a novel way to translate the evidence of toxic effects obtained in preclinical animal studies, by the direct, noninvasive measure of dividing cells in humans. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Student Perceptions regarding Vocational High School Teachers' Problem Solving Methods against Undesired Behaviors in Classroom Management

    Science.gov (United States)

    Gulcan, Murat Gurkan

    2010-01-01

    Teachers' classroom management approach varies depending on several factors such as the social, psychological, cultural and educational status of the student, classroom level, the physical conditions of the school, organization structure. There are different approaches in classroom management. These approaches are gathered under three headings in…

  17. Regulation of Nanorefrigerant Use: A Proactive Measure Against Possible Undesirable Health and Environmental Implications

    Directory of Open Access Journals (Sweden)

    Nnamdi V. Ogueke

    2017-06-01

    Full Text Available Recent research studies have shown the very high potentials nanotechnology application has in the refrigeration and air conditioning industry for improving the thermophysical properties of refrigerants and lubricants hence leading to systems with higher COP and much reduced size. The successes achieved with nanorefrigerants are connected to the improved technology for the preparation of nanofluids that has led to achieving more homogeneous and stable mixture of the base fluid and nanoparticle. However, available literatures point to the fact that nanoparticles can find its way into the human cells and as such is a potential health risk for humans and animals. At present, emphasis appears to concentrate more on the technological successes achieved with nanorefrigerants, like improved thermal conductivity, nucleate boiling and boiling heat transfer coefficient without factoring in much the potential health implications of adopting it. This paper therefore looked at the potential health consequences of adopting nanotechnology and called for an early regulatory framework to guard against any unforeseen health issues. Areas of future research were also suggested.

  18. Spatially and Temporally Regulated NRF2 Gene Therapy Using Mcp-1 Promoter in Retinal Ganglion Cell Injury

    Directory of Open Access Journals (Sweden)

    Kosuke Fujita

    2017-06-01

    Full Text Available Retinal ganglion cell degeneration triggered by axonal injury is believed to underlie many ocular diseases, including glaucoma and optic neuritis. In these diseases, retinal ganglion cells are affected unevenly, both spatially and temporally, such that healthy and unhealthy cells coexist in different patterns at different time points. Herein, we describe a temporally and spatially regulated adeno-associated virus gene therapy aiming to reduce undesired off-target effects on healthy retinal neurons. The Mcp-1 promoter previously shown to be activated in stressed retinal ganglion cells following murine optic nerve injury was combined with the neuroprotective intracellular transcription factor Nrf2. In this model, Mcp-1 promoter-driven NRF2 expression targeting only stressed retinal ganglion cells showed efficacy equivalent to non-selective cytomegalovirus promoter-driven therapy for preventing cell death. However, cytomegalovirus promoter-mediated NRF2 transcription induced cellular stress responses and death of Brn3A-positive uninjured retinal ganglion cells. Such undesired effects were reduced substantially by adopting the Mcp-1 promoter. Combining a stress-responsive promoter and intracellular therapeutic gene is a versatile approach for specifically targeting cells at risk of degeneration. This strategy may be applicable to numerous chronic ocular and non-ocular conditions.

  19. Constitutive activation of Nrf2 induces a stable reductive state in the mouse myocardium

    Directory of Open Access Journals (Sweden)

    Gobinath Shanmugam

    2017-08-01

    Full Text Available Redox homeostasis regulates key cellular signaling pathways in both physiology and pathology. The cell's antioxidant response provides a defense against oxidative stress and establishes a redox tone permissive for cell signaling. The molecular regulation of the well-known Keap1/Nrf2 system acts as sensor responding to changes in redox homeostasis and is poorly studied in the heart. Importantly, it is not yet known whether Nrf2 alone can serve as a master regulator of cellular redox homeostasis without compensation of the transcriptional regulation of antioxidant response element (ARE genes through alternate mechanisms. Here, we addressed this question using cardiac-specific transgenic expression at two different levels of constitutively active nuclear erythroid related factor 2 (caNrf2 functioning independently of Keap1. The caNrf2 mice showed augmentation of glutathione (GSH, the key regulator of the cellular thiol redox state. The Trans-AM assay for Nrf2-binding to the antioxidant response element (ARE showed a dose-dependent increase associated with upregulation of several major antioxidant genes and proteins. This was accompanied by a significant decrease in dihydroethidium staining and malondialdehyde (MDA in the caNrf2-TG mice myocardium. Interestingly, caNrf2 gene-dosage dependent redox changes were noted resulting in generation of a multi-stage model of pro-reductive and reductive conditions in the myocardium of TG-low and TG-high mice, respectively. These data clearly show that Nrf2 levels alone are capable of serving as the master regulator of the ARE. These models provide an important platform to investigate the impact of the Nrf2 system independent of the need to regulate the activity of Keap1 and the consequent exposure to pro-oxidants or electrophiles, which have numerous off-target effects.

  20. Reporting sodium channel activity using calcium flux: pharmacological promiscuity of cardiac Nav1.5.

    Science.gov (United States)

    Zhang, Hongkang; Zou, Beiyan; Du, Fang; Xu, Kaiping; Li, Min

    2015-02-01

    Voltage-gated sodium (Nav) channels are essential for membrane excitability and represent therapeutic targets for treating human diseases. Recent reports suggest that these channels, e.g., Nav1.3 and Nav1.5, are inhibited by multiple structurally distinctive small molecule drugs. These studies give reason to wonder whether these drugs collectively target a single site or multiple sites in manifesting such pharmacological promiscuity. We thus investigate the pharmacological profile of Nav1.5 through systemic analysis of its sensitivity to diverse compound collections. Here, we report a dual-color fluorescent method that exploits a customized Nav1.5 [calcium permeable Nav channel, subtype 5 (SoCal5)] with engineered-enhanced calcium permeability. SoCal5 retains wild-type (WT) Nav1.5 pharmacological profiles. WT SoCal5 and SoCal5 with the local anesthetics binding site mutated (F1760A) could be expressed in separate cells, each with a different-colored genetically encoded calcium sensor, which allows a simultaneous report of compound activity and site dependence. The pharmacological profile of SoCal5 reveals a hit rate (>50% inhibition) of around 13% at 10 μM, comparable to that of hERG. The channel activity is susceptible to blockage by known drugs and structurally diverse compounds. The broad inhibition profile is highly dependent on the F1760 residue in the inner cavity, which is a residue conserved among all nine subtypes of Nav channels. Both promiscuity and dependence on F1760 seen in Nav1.5 were replicated in Nav1.4. Our evidence of a broad inhibition profile of Nav channels suggests a need to consider off-target effects on Nav channels. The site-dependent promiscuity forms a foundation to better understand Nav channels and compound interactions. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  1. Is activation analysis still active?

    International Nuclear Information System (INIS)

    Chai Zhifang

    2001-01-01

    This paper reviews some aspects of neutron activation analysis (NAA), covering instrumental neutron activation analysis (INAA), k 0 method, prompt gamma-ray neutron activation analysis (PGNAA), radiochemical neutron activation analysis (RNAA) and molecular activation analysis (MAA). The comparison of neutron activation analysis with other analytical techniques are also made. (author)

  2. Neural predictive control for active buffet alleviation

    Science.gov (United States)

    Pado, Lawrence E.; Lichtenwalner, Peter F.; Liguore, Salvatore L.; Drouin, Donald

    1998-06-01

    The adaptive neural control of aeroelastic response (ANCAR) and the affordable loads and dynamics independent research and development (IRAD) programs at the Boeing Company jointly examined using neural network based active control technology for alleviating undesirable vibration and aeroelastic response in a scale model aircraft vertical tail. The potential benefits of adaptive control includes reducing aeroelastic response associated with buffet and atmospheric turbulence, increasing flutter margins, and reducing response associated with nonlinear phenomenon like limit cycle oscillations. By reducing vibration levels and thus loads, aircraft structures can have lower acquisition cost, reduced maintenance, and extended lifetimes. Wind tunnel tests were undertaken on a rigid 15% scale aircraft in Boeing's mini-speed wind tunnel, which is used for testing at very low air speeds up to 80 mph. The model included a dynamically scaled flexible fail consisting of an aluminum spar with balsa wood cross sections with a hydraulically powered rudder. Neural predictive control was used to actuate the vertical tail rudder in response to strain gauge feedback to alleviate buffeting effects. First mode RMS strain reduction of 50% was achieved. The neural predictive control system was developed and implemented by the Boeing Company to provide an intelligent, adaptive control architecture for smart structures applications with automated synthesis, self-optimization, real-time adaptation, nonlinear control, and fault tolerance capabilities. It is designed to solve complex control problems though a process of automated synthesis, eliminating costly control design and surpassing it in many instances by accounting for real world non-linearities.

  3. Get Active

    Science.gov (United States)

    ... activity are best for you. Get tips on physical activity and diabetes Learn how physical activity helps high blood pressure What if I have ... benefits by stepping up your routine. Getting more physical activity can further lower your risk for: ... cancer Colorectal cancer Do more vigorous activities. ...

  4. Contrasting activity patterns of sympatric and allopatric black and grizzly bears

    Science.gov (United States)

    Schwartz, C.C.; Cain, S.L.; Podruzny, S.; Cherry, S.; Frattaroli, L.

    2010-01-01

    The distribution of grizzly (Ursus arctos) and American black bears (U. americanus) overlaps in western North America. Few studies have detailed activity patterns where the species are sympatric and no studies contrasted patterns where populations are both sympatric and allopatric. We contrasted activity patterns for sympatric black and grizzly bears and for black bears allopatric to grizzly bears, how human influences altered patterns, and rates of grizzlyblack bear predation. Activity patterns differed between black bear populations, with those sympatric to grizzly bears more day-active. Activity patterns of black bears allopatric with grizzly bears were similar to those of female grizzly bears; both were crepuscular and day-active. Male grizzly bears were crepuscular and night-active. Both species were more night-active and less day-active when ???1 km from roads or developments. In our sympatric study area, 2 of 4 black bear mortalities were due to grizzly bear predation. Our results suggested patterns of activity that allowed for intra- and inter-species avoidance. National park management often results in convergence of locally high human densities in quality bear habitat. Our data provide additional understanding into how bears alter their activity patterns in response to other bears and humans and should help park managers minimize undesirable bearhuman encounters when considering needs for temporal and spatial management of humans and human developments in bear habitats. ?? 2010 The Wildlife Society.

  5. Active Damping of LLCL-Filter Resonance Based on LC-Trap Voltage or Current Feedback

    DEFF Research Database (Denmark)

    Huang, Min; Wang, Xiongfei; Loh, Poh Chiang

    2016-01-01

    LLCL-filter is an emerging fourth-order filter proposed after the third-order LCL-filter. It uses smaller passive components than the LCL-filter, but is still burdened by resonance complications when used with a grid converter. An LLCL-filtered converter must hence be passively or actively damped....... Active damping is presently more efficient, and can easily be realized by feeding back a state variable. For the LCL-filter, the variable is usually its middle capacitor current. However, with computational delays considered, a simple proportional damper cannot be used with the capacitor current. Instead......, a high-pass damper must be used, which as commonly known, may cause undesired noise complications depending on operating conditions. In this paper, the same capacitor current damper has been investigated for LLCL-filter with its limitations clarified. Both cases of with and without delays have been...

  6. Physicochemical properties and oxidative stability of bleached pomace-olive oil on Tunisian activated clays

    International Nuclear Information System (INIS)

    Jahouach, Wafa

    2002-01-01

    This work is a contribution to studying bleaching process, which is an important stage in refining of vegetable oils. This process permitted to reduce or convert undesired constituents to harmless ones from oils and fats. Virgin olive oil, considered as reference, and pomace-olive oil were bleached in optimal conditions using Tunisian activated clays ( collected from the South of Tunisia) which were prepared in our laboratory and compared with commercial bleaching earths. It was shown that activated Tunisian clays are characterized by a very important adsorptive capacity, which is similar to that of commercial ones. In addition, the study of physicochemical properties of bleached oils was considered. The fatty acid composition (GC), the triacylglycerol composition (HPLC), and oxidative stability (UV spectrometry) allowed to conclude that treated oils do not undergo considerable physicochemical alterations and their caracteristics remain in concordance with international standards relative to edible refined oils. (Author)

  7. Controlling activation site density by low-energy far-field stimulation in cardiac tissue

    Science.gov (United States)

    Hörning, Marcel; Takagi, Seiji; Yoshikawa, Kenichi

    2012-06-01

    Tachycardia and fibrillation are potentially fatal arrhythmias associated with the formation of rotating spiral waves in the heart. Presently, the termination of these types of arrhythmia is achieved by use of antitachycardia pacing or cardioversion. However, these techniques have serious drawbacks, in that they either have limited application or produce undesirable side effects. Low-energy far-field stimulation has recently been proposed as a superior therapy. This proposed therapeutic method would exploit the phenomenon in which the application of low-energy far-field shocks induces a large number of activation sites (“virtual electrodes”) in tissue. It has been found that the formation of such sites can lead to the termination of undesired states in the heart and the restoration of normal beating. In this study we investigate a particular aspect of this method. Here we seek to determine how the activation site density depends on the applied electric field through in vitro experiments carried out on neonatal rat cardiac tissue cultures. The results indicate that the activation site density increases exponentially as a function of the intracellular conductivity and the level of cell isotropy. Additionally, we report numerical results obtained from bidomain simulations of the Beeler-Reuter model that are quantitatively consistent with our experimental results. Also, we derive an intuitive analytical framework that describes the activation site density and provides useful information for determining the ratio of longitudinal to transverse conductivity in a cardiac tissue culture. The results obtained here should be useful in the development of an actual therapeutic method based on low-energy far-field pacing. In addition, they provide a deeper understanding of the intrinsic properties of cardiac cells.

  8. Quantification of low-expressed mRNA using 5' LNA-containing real-time PCR primers

    International Nuclear Information System (INIS)

    Malgoyre, A.; Banzet, S.; Mouret, C.; Bigard, A.X.; Peinnequin, A.

    2007-01-01

    Real-time RT-PCR is the most sensitive and accurate method for mRNA quantification. Using specific recombinant DNA as a template, real-time PCR allows accurate quantification within a 7-log range and increased sensitivity below 10 copies. However, when using RT-PCR to quantify mRNA in biological samples, a stochastic off-targeted amplification can occur. Classical adjustments of assay parameters have minimal effects on such amplification. This undesirable amplification appears mostly to be dependent on specific to non-specific target ratio rather than on the absolute quantity of the specific target. This drawback, which decreases assay reliability, mostly appears when quantifying low-expressed transcript in a whole organ. An original primer design using properties of LNA allows to block off-target amplification. 5'-LNA substitution strengthens 5'-hybridization. Consequently on-target hybridization is stabilized and the probability for the off-target to lead to amplification is decreased

  9. Valproic acid induces hair regeneration in murine model and activates alkaline phosphatase activity in human dermal papilla cells.

    Directory of Open Access Journals (Sweden)

    Soung-Hoon Lee

    Full Text Available Alopecia is the common hair loss problem that can affect many people. However, current therapies for treatment of alopecia are limited by low efficacy and potentially undesirable side effects. We have identified a new function for valproic acid (VPA, a GSK3β inhibitor that activates the Wnt/β-catenin pathway, to promote hair re-growth in vitro and in vivo.Topical application of VPA to male C3H mice critically stimulated hair re-growth and induced terminally differentiated epidermal markers such as filaggrin and loricrin, and the dermal papilla marker alkaline phosphatase (ALP. VPA induced ALP in human dermal papilla cells by up-regulating the Wnt/β-catenin pathway, whereas minoxidil (MNX, a drug commonly used to treat alopecia, did not significantly affect the Wnt/β-catenin pathway. VPA analogs and other GSK3β inhibitors that activate the Wnt/β-catenin pathway such as 4-phenyl butyric acid, LiCl, and BeCl(2 also exhibited hair growth-promoting activities in vivo. Importantly, VPA, but not MNX, successfully stimulate hair growth in the wounds of C3H mice.Our findings indicate that small molecules that activate the Wnt/β-catenin pathway, such as VPA, can potentially be developed as drugs to stimulate hair re-growth.

  10. Alteration of chemical composition and the oxidative stability of bleached pomace-olive oil on activated clays.

    Science.gov (United States)

    Jahouach, W; Essid, K; Trabelsi, M; Frikha, M H

    2006-09-20

    This work is a contribution to the study of the bleaching process, which is a very important stage in the refining process of vegetable oils and used to reduce or convert undesired constituents to harmless ones from fats and oils. The virgin olive oil, taken as reference, and the pomace-olive oil were bleached in the optimal conditions using Tunisian bleaching earths (South of Tunisia) which were activated in our laboratory and compared with commercial clays. It was shown that activated Tunisian clays are characterized by a very important adsorptive capacity, comparable to that of commercial clays. Also, the physicochemical stability of bleached oils was studied. The fatty acid composition (GC), the triacylglycerol composition (HPLC), and the oxidative stability (UV spectrometry) allowed us to conclude that oils, bleached with the Tunisian activated clays, do not undergo considerable physicochemical alterations and remain corresponding to the international standards for refined oils for human consumption.

  11. Active turbulence in active nematics

    Science.gov (United States)

    Thampi, S. P.; Yeomans, J. M.

    2016-07-01

    Dense, active systems show active turbulence, a state characterised by flow fields that are chaotic, with continually changing velocity jets and swirls. Here we review our current understanding of active turbulence. The development is primarily based on the theory and simulations of active liquid crystals, but with accompanying summaries of related literature.

  12. Synergistic antioxidant activity of green tea with some herbs

    Directory of Open Access Journals (Sweden)

    Dheeraj P Jain

    2011-01-01

    Full Text Available Cardiovascular diseases, cancer, arthritis, etc. are caused by free radicals that are byproducts of metabolic pathways. Selected plants namely Vitis vinifera, Phyllanthus emblica L., Punica granatum, Cinnamomum cassia, Ginkgo biloba L., and Camellia sinensis Linn. are reported to produce antioxidant property. This study is undertaken to support the hypothesis that formulation of a polyherbal combination of these plants shows a synergistic effect with green tea. The extracts of each drug were characterized by phytochemical studies and tests for phenolics and flavonoids. In vitro antioxidant activity for individual drug and its combination was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH, superoxide, and nitric oxide free radical scavenging methods. Our results suggest that a combination of all these herbs with green tea can synergistically enhance antioxidant activity and thus lower doses of each herb with green tea may be used. Antioxidant potential of polyherbal combination was also comparable to that of standard ascorbic acid. Studies showed that selected individual plants contained abundant quantity of phenolics and flavonoids and their polyherbal combination with green tea was found to produce best antioxidant activity among all individual extracts. This will help in avoiding undesirable side effects due to higher doses of single herb.

  13. Active control of multi-input hydraulic journal bearing system

    Science.gov (United States)

    Chuang, Jen-Chen; Chen, Chi-Yin; Tu, Jia-Ying

    2016-09-01

    Because of the advantages of high accuracy, high capacity, and low friction, the development of hydrostatic bearing for machine tool receives significant attention in the last decades. The mechanics and mechanical design of hydrostatic journal bearing with capillary restrictors has been discussed in literature. However, pragmatically, the undesired loading effects of cutting force tend to result in resonance and instability of the rotor and damage the shaft during operation. Therefore, multi-input, active flow control using state feedback design is proposed in this paper. To this purpose, the proportional pressure valves are added to the hydraulic system as active control devices, and the linearised models of the bearing and valve are discussed and identified. Simulation and experimental work is conducted to verify the proposed active control and parameter identification techniques. The results show that the unbalance responses of the rotor are reduced by the proposed state feedback controller, which is able to regulate the flow pressure effectively, thus enhancing the stability and accuracy of the hydraulic journal bearing.

  14. Association between parenting practices and children's dietary intake, activity behavior and development of body mass index: the KOALA Birth Cohort Study

    Directory of Open Access Journals (Sweden)

    de Vries Nanne K

    2011-03-01

    Full Text Available Abstract Background Insights into the effects of energy balance-related parenting practices on children's diet and activity behavior at an early age is warranted to determine which practices should be recommended and to whom. The purpose of this study was to examine child and parent background correlates of energy balance-related parenting practices at age 5, as well as the associations of these practices with children's diet, activity behavior, and body mass index (BMI development. Methods Questionnaire data originated from the KOALA Birth Cohort Study for ages 5 (N = 2026 and 7 (N = 1819. Linear regression analyses were used to examine the association of child and parent background characteristics with parenting practices (i.e., diet- and activity-related restriction, monitoring and stimulation, and to examine the associations between these parenting practices and children's diet (in terms of energy intake, dietary fiber intake, and added sugar intake and activity behavior (i.e., physical activity and sedentary time at age 5, as well as BMI development from age 5 to age 7. Moderation analyses were used to examine whether the associations between the parenting practices and child behavior depended on child characteristics. Results Several child and parent background characteristics were associated with the parenting practices. Dietary monitoring, stimulation of healthy intake and stimulation of physical activity were associated with desirable energy balance-related behaviors (i.e., dietary intake and/or activity behavior and desirable BMI development, whereas restriction of sedentary time showed associations with undesirable behaviors and BMI development. Child eating style and weight status, but not child gender or activity style, moderated the associations between parenting practices and behavior. Dietary restriction and monitoring showed weaker, or even undesirable associations for children with a deviant eating style, whereas these

  15. Association between parenting practices and children's dietary intake, activity behavior and development of body mass index: the KOALA Birth Cohort Study.

    Science.gov (United States)

    Gubbels, Jessica S; Kremers, Stef P J; Stafleu, Annette; de Vries, Sanne I; Goldbohm, R Alexandra; Dagnelie, Pieter C; de Vries, Nanne K; van Buuren, Stef; Thijs, Carel

    2011-03-14

    Insights into the effects of energy balance-related parenting practices on children's diet and activity behavior at an early age is warranted to determine which practices should be recommended and to whom. The purpose of this study was to examine child and parent background correlates of energy balance-related parenting practices at age 5, as well as the associations of these practices with children's diet, activity behavior, and body mass index (BMI) development. Questionnaire data originated from the KOALA Birth Cohort Study for ages 5 (N = 2026) and 7 (N = 1819). Linear regression analyses were used to examine the association of child and parent background characteristics with parenting practices (i.e., diet- and activity-related restriction, monitoring and stimulation), and to examine the associations between these parenting practices and children's diet (in terms of energy intake, dietary fiber intake, and added sugar intake) and activity behavior (i.e., physical activity and sedentary time) at age 5, as well as BMI development from age 5 to age 7. Moderation analyses were used to examine whether the associations between the parenting practices and child behavior depended on child characteristics. Several child and parent background characteristics were associated with the parenting practices. Dietary monitoring, stimulation of healthy intake and stimulation of physical activity were associated with desirable energy balance-related behaviors (i.e., dietary intake and/or activity behavior) and desirable BMI development, whereas restriction of sedentary time showed associations with undesirable behaviors and BMI development. Child eating style and weight status, but not child gender or activity style, moderated the associations between parenting practices and behavior. Dietary restriction and monitoring showed weaker, or even undesirable associations for children with a deviant eating style, whereas these practices showed associations with desirable behavior for

  16. Efficacy, safety and anticancer activity of protein nanoparticle-based delivery of doxorubicin through intravenous administration in rats.

    Directory of Open Access Journals (Sweden)

    Kishore Golla

    Full Text Available Doxorubicin is a potent anticancer drug and a major limiting factor that hinders therapeutic use as its high levels of systemic circulation often associated with various off-target effects, particularly cardiotoxicity. The present study focuses on evaluation of the efficacy of doxorubicin when it is loaded into the protein nanoparticles and delivered intravenously in rats bearing Hepatocellular carcinoma (HCC. The proteins selected as carrier were Apotransferrin and Lactoferrin, since the receptors for these two proteins are known to be over expressed on cancer cells due to their iron transport capacity.Doxorubicin loaded apotransferrin (Apodoxonano and lactoferrin nanoparticles (Lactodoxonano were prepared by sol-oil chemistry. HCC in the rats was induced by 100 mg/l of diethylnitrosamine (DENA in drinking water for 8 weeks. Rats received 5 doses of 2 mg/kg drug equivalent nanoparticles through intravenous administration. Pharmacokinetics and toxicity of nanoformulations was evaluated in healthy rats and anticancer activity was studied in DENA treated rats. The anticancer activity was evaluated through counting of the liver nodules, H & E analysis and by estimating the expression levels of angiogenic and antitumor markers.In rats treated with nanoformulations, the numbers of liver nodules were found to be significantly reduced. They showed highest drug accumulation in liver (22.4 and 19.5 µg/g. Both nanoformulations showed higher localization compared to doxorubicin (Doxo when delivered in the absence of a carrier. Higher amounts of Doxo (195 µg/g were removed through kidney, while Apodoxonano and Lactodoxonano showed only a minimal amount of removal (<40 µg/g, suggesting the extended bioavailability of Doxo when delivered through nanoformulation. Safety analysis shows minimal cardiotoxicity due to lower drug accumulation in heart in the case of nanoformulation.Drug delivery through nanoformulations not only minimizes the cardiotoxicity of

  17. Selectivity Profiling and Biological Activity of Novel β-Carbolines as Potent and Selective DYRK1 Kinase Inhibitors.

    Directory of Open Access Journals (Sweden)

    Katharina Rüben

    Full Text Available DYRK1A is a pleiotropic protein kinase with diverse functions in cellular regulation, including cell cycle control, neuronal differentiation, and synaptic transmission. Enhanced activity and overexpression of DYRK1A have been linked to altered brain development and function in Down syndrome and neurodegenerative diseases such as Alzheimer's disease. The β-carboline alkaloid harmine is a high affinity inhibitor of DYRK1A but suffers from the drawback of inhibiting monoamine oxidase A (MAO-A with even higher potency. Here we characterized a series of novel harmine analogs with minimal or absent MAO-A inhibitory activity. We identified several inhibitors with submicromolar potencies for DYRK1A and selectivity for DYRK1A and DYRK1B over the related kinases DYRK2 and HIPK2. An optimized inhibitor, AnnH75, inhibited CLK1, CLK4, and haspin/GSG2 as the only off-targets in a panel of 300 protein kinases. In cellular assays, AnnH75 dose-dependently reduced the phosphorylation of three known DYRK1A substrates (SF3B1, SEPT4, and tau without negative effects on cell viability. AnnH75 inhibited the cotranslational tyrosine autophosphorylation of DYRK1A and threonine phosphorylation of an exogenous substrate protein with similar potency. In conclusion, we have characterized an optimized β-carboline inhibitor as a highly selective chemical probe that complies with desirable properties of drug-like molecules and is suitable to interrogate the function of DYRK1A in biological studies.

  18. Validation of spectrophotometric microplate methods for polyphenol oxidase and peroxidase activities analysis in fruits and vegetables

    Directory of Open Access Journals (Sweden)

    Érica Sayuri SIGUEMOTO

    Full Text Available Abstract Enzymes polyphenol oxidase (PPO and peroxidase (POD play important roles in the processing of fruits and vegetables, since they can produce undesirable changes in color, texture and flavor. Classical methods of activity assessment are based on cuvette spectrophotometric readings. This work aims to propose, to validate and to test microplate spectrophotometric methods. Samples of apple juice and lyophilized enzymes from mushroom and horseradish were analyzed by the cuvette and microplate methods and it was possible to validate the microplate assays with satisfactory results regarding linearity, repeatability, accuracy along with quantitation and detection limits. The proposed microplate methods proved to be reliable and reproducible as the classical methods besides having the advantages of allowing simultaneous analysis and requiring a reduced amount of samples and reactants, which can beneficial to the study of enzyme inactivation in the processing of fruits and vegetables.

  19. A Linear Active Disturbance Rejection Control for a Ball and Rigid Triangle System

    Directory of Open Access Journals (Sweden)

    Carlos Aguilar-Ibanez

    2016-01-01

    Full Text Available This paper proposes an application of linear flatness control along with active disturbance rejection control (ADRC for the local stabilization and trajectory tracking problems in the underactuated ball and rigid triangle system. To this end, an observer-based linear controller of the ADRC type is designed based on the flat tangent linearization of the system around its corresponding unstable equilibrium rest position. It was accomplished through two decoupled linear extended observers and a single linear output feedback controller, with disturbance cancelation features. The controller guarantees locally exponentially asymptotic stability for the stabilization problem and practical local stability in the solution of the tracking error. An advantage of combining the flatness and the ADRC methods is that it possible to perform online estimates and cancels the undesirable effects of the higher-order nonlinearities discarded by the linearization approximation. Simulation indicates that the proposed controller behaves remarkably well, having an acceptable domain of attraction.

  20. Multisensor fusion for atrial and ventricular activity detection in coronary care monitoring.

    Science.gov (United States)

    Hernández, A I; Carrault, G; Mora, F; Thoraval, L; Passariello, G; Schleich, J M

    1999-10-01

    Information management for critical care monitoring is still a very difficult task. Medical staff is often overwhelmed by the amount of data provided by the increased number of specific monitoring devices and instrumentation, and the lack of an effective automated system. Specifically, a basic task such as arrhythmia detection still produce an important amount of undesirable alarms, due in part to the mechanistic approach of current monitoring systems. In this work, multisensor and multisource data fusion schemes to improve atrial and ventricular activity detection in critical care environments are presented. Applications of these schemes are quantitatively evaluated and compared with current methods, showing the potential advantages of data fusion techniques for event detection in noise corrupted signals.

  1. Study on Active Suppression Control of Drivetrain Oscillations in an Electric Vehicle

    Science.gov (United States)

    Huang, Lei; Cui, Ying

    2017-07-01

    Due to the low damping in a central driven electric vehicle and lack of passive damping mechanisms as compared with a conventional vehicle, the vehicle may endure torsional vibrations which may deteriorates the vehicle’s drivability. Thus active damping control strategy is required to reduce the undesirable oscillations in an EV. In this paper, the origin of the vibration and the design of a damping control method to suppress such oscillations to improve the drivability of an EV are studied. The traction motor torque that is given by the vehicle controller is adjusted according to the acceleration rate of the motor speed to attenuate the resonant frequency. Simulations and experiments are performed to validate the system. The results show that the proposed control system can effectively suppress oscillations and hence improve drivability.

  2. Proteolytic activity of protease produced by Pseudomonas fluorescens IB 2312 in skimmed milk subject to the process of high pressure homogenization

    Directory of Open Access Journals (Sweden)

    Claudia Regina Gonçalves Pinho

    2014-08-01

    Full Text Available The presence of thermoresistant proteases produced by psychrotrophic microorganisms have been identified as a limiting factor of the UHT milk shelflife, causing undesirable changes in milk products. High pressure homogenization (HPH processing is a non-thermal method of food preservation, able to promotes the microbiological safety and inactivation of some enzymes. Thus, this work assessed the proteolytic activity of protease produced by Pseudomonas fluorescens in skim milk subjected to high pressure homogenization process. The milk samples were added by the protease enzymatic extract (10% v/v and subjected to pressures up to 300 MPa. The assays showed that pressures on the order of 300 MPa caused a 72.5% reduction in proteolytic activity. Therefore, the process at high pressures resulted in significant inactivation of this thermoresistent enzyme, which possibly favors the shelf-life extension of the UHT milk and also limits the yield and quality loss of cheeses due to undesirable sensory changes in flavor and texture caused by this enzyme.

  3. Antioxidant and antibacterial activities of Piliostigma reticulatum (DC ...

    African Journals Online (AJOL)

    USER

    2010-08-16

    , high concentration polyphenols and phenolic compounds in methanolic solution often cause undesirable gastric disorders. The solution of this problem is found by the traditional healers who used to prescribe decoctions to ...

  4. Electronically Active Impurities in Colloidal Quantum Dot Solids

    KAUST Repository

    Carey, Graham H.

    2014-11-25

    © 2014 American Chemical Society. Colloidal quantum dot films have seen rapid progress as active materials in photodetection, light emission, and photovoltaics. Their processing from the solution phase makes them an attractive option for these applications due to the expected cost reductions associated with liquid-phase material deposition. Colloidally stable nanoparticles capped using long, insulating aliphatic ligands are used to form semiconducting, insoluble films via a solid-state ligand exchange in which the original ligands are replaced with short bifunctional ligands. Here we show that this ligand exchange can have unintended and undesired side effects: a high molecular weight complex can form, containing both lead oleate and the shorter conductive ligand, and this poorly soluble complex can end up embedded within the colloidal quantum dot (CQD) active layer. We further show that, by adding an acidic treatment during film processing, we can break up and wash away these complexes, producing a higher quality CQD solid. The improved material leads to photovoltaic devices with reduced series resistance and enhanced fill factor relative to controls employing previously reported CQD solids. (Figure Presented).

  5. Active packaging using ethylene absorber to extend shelf-life

    International Nuclear Information System (INIS)

    Ponce, Patricia; Carbonari, Guilherme L.R.; Lugao, Ademar B.

    2009-01-01

    Ethylene gas is a plant hormone which is produced by fruits and vegetables during ripening and it is also found in the environment. It plays an essential role in normal ripening, but excessive exposure can radically reduce the shelf-life of the product, in some cases inducing undesirable reactions such as development of bitter flavors and loss of chlorophyll (yellowing of greens). The objectives of our work were: to test an active packaging of polyvinyl alcohol (PVA) for apple stored; to test the effect of ethylene absorber agent, impregnated in plastic film, to reduce decay of fresh apple; to study the influence of radiation on the barrier properties, mechanical properties and biodegradability of PVA films. This study evaluated the effect of coating produced from PVA and polyol (glycerol and sorbitol) as plasticizer on apple conservation (75 deg F (24 deg C); 70%RH). The coated product was analyzed for mass loss, color alterations and fungi. The PVA films were produced by casting process (dehydration of a filmogenic solution on Petriplastic dishes) and were irradiated at low doses of 2, 5 and 10 kGy, commonly used in food irradiation. The resulting films were transparent and homogeneous. The active packaged fruits presented higher acceptance, lower microbiological growth, less alterations in acidity, lower weight loss rate during the storage time and an extended shelf-life as compared to the control fruits (without plastic films). (author)

  6. Identity Activities

    Science.gov (United States)

    2016-08-03

    various types of accommodations (including dwellings, shelters and institutions for the homeless or other living quarters). Appendix D D-4 JDN X-XX...activity capabilities can be severely impacted by a lack of forethought and planning related to these factors. Assessing Identity Activities Threat...complement and reinforce many of the activities making up civil-military counterinsurgency (COIN) operations. (c) Criminal Networks. Areas that lack

  7. Physical Activity

    DEFF Research Database (Denmark)

    Andersen, Lars Bo; Anderssen, Sigmund Alfred; Wisløff, Ulrik

    2014-01-01

    Andersen LB, Anderssen SA, Wisløff U, Hellénius M-L, Fogelholm M, Ekelund U. (Expert Group) Nordic Nutrition Recommendations 2012. Integrating nutrition and physical activity. Chapter: Physical Activity p. 195-217.Nordic Counsil of Ministers.......Andersen LB, Anderssen SA, Wisløff U, Hellénius M-L, Fogelholm M, Ekelund U. (Expert Group) Nordic Nutrition Recommendations 2012. Integrating nutrition and physical activity. Chapter: Physical Activity p. 195-217.Nordic Counsil of Ministers....

  8. Nelfinavir and other protease inhibitors in cancer: mechanisms involved in anticancer activity [v2; ref status: indexed, http://f1000r.es/536

    Directory of Open Access Journals (Sweden)

    Tomas Koltai

    2015-03-01

    Full Text Available Objective: To review the mechanisms of anti-cancer activity of nelfinavir and other protease inhibitors (PIs based on evidences reported in the published literature. Methods: We extensively reviewed the literature concerning nelfinavir (NFV as an off target anti-cancer drug and other PIs. A classification of PIs based on anti-cancer mode of action was proposed. Controversies regarding nelfinavir mode of action were also addressed. Conclusions: The two main mechanisms involved in anti-cancer activity are endoplasmic reticulum stress-unfolded protein response pathway and Akt inhibition. However there are many other effects, partially dependent and independent of those mentioned, that may be useful in cancer treatment, including MMP-9 and MMP-2 inhibition, down-regulation of CDK-2, VEGF, bFGF, NF-kB, STAT-3, HIF-1 alfa, IGF, EGFR, survivin, BCRP, androgen receptor, proteasome, fatty acid synthase (FAS, decrease in cellular ATP concentration and upregulation of TRAIL receptor DR5, Bax, increased radiosensitivity, and autophagy. The end result of all these effects is slower growth, decreased angiogenesis, decreased invasion and increased apoptosis, which means reduced proliferation and increased cancer cells death. PIs may be classified according to their anticancer activity at clinically achievable doses, in AKT inhibitors, ER stressors and Akt inhibitors/ER stressors. Beyond the phase I trials that have been recently completed, adequately powered and well-designed clinical trials are needed in the various cancer type settings, and specific trials where NFV is tested in association with other known anti-cancer pharmaceuticals should be sought, in order to find an appropriate place for NFV in cancer treatment. The analysis of controversies on the molecular mechanisms of NFV hints to the possibility that NFV works in a different way in tumor cells and in hepatocytes and adipocytes.

  9. Activity report

    International Nuclear Information System (INIS)

    1990-11-01

    The Department of Physics and Measurement Technology, Biology and Chemistry (IFM) presents every year a progress report containing a brief description of activities in research and education within the department. The report is intended as an information for colleagues and institutions. The present report contains activities for the academic year July 1989 to June 1990

  10. Nano-engineered mesenchymal stem cells increase therapeutic efficacy of anticancer drug through true active tumor targeting.

    Science.gov (United States)

    Layek, Buddhadev; Sadhukha, Tanmoy; Panyam, Jayanth; Prabha, Swayam

    2018-03-28

    Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor targeting strategy that relies on engineering mesenchymal stem cells (MSCs) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Further, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUClung of PTX (1.5 µg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 µg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Copyright ©2018, American Association for Cancer Research.

  11. Catalytic activity control of restriction endonuclease--triplex forming oligonucleotide conjugates.

    Science.gov (United States)

    Silanskas, Arunas; Zaremba, Mindaugas; Sasnauskas, Giedrius; Siksnys, Virginijus

    2012-02-15

    Targeting of individual genes in complex genomes requires endonucleases of extremely high specificity. To direct cleavage at the unique site(s) in the genome, both naturally occurring and artificial enzymes have been developed. These include homing endonucleases, zinc-finger nucleases, transcription activator-like effector nucleases, and restriction or chemical nucleases coupled to a triple-helix forming oligonucleotide (TFO). The desired cleavage has been demonstrated both in vivo and in vitro for several model systems. However, to limit cleavage strictly to unique sites and avoid undesired reactions, endonucleases with controlled activity are highly desirable. In this study we present a proof-of-concept demonstration of two strategies to generate restriction endonuclease-TFO conjugates with controllable activity. First, we combined the restriction endonuclease caging and TFO coupling procedures to produce a caged MunI-TFO conjugate, which can be activated by UV-light upon formation of a triple helix. Second, we coupled TFO to a subunit interface mutant of restriction endonuclease Bse634I which shows no activity due to impaired dimerization but is assembled into an active dimer when two Bse634I monomers are brought into close proximity by triple helix formation at the targeted site. Our results push the restriction endonuclease-TFO conjugate technology one step closer to potential in vivo applications.

  12. Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Hanisak, Jennifer; Seganish, W. Michael; McElroy, William T.; Tang, Haiquin; Zhang, Rui; Tsui, Hon-Chung; Fischmann, Theirry; Tulshian, Deen; Tata, James; Sondey, Christopher; Devito, Kristine; Fossetta, James; Garlisi, Charles G.; Lundell, Daniel; Niu, Xiaoda (Merck)

    2016-09-01

    IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.

  13. Biological characterization of SN32976, a selective inhibitor of PI3K and mTOR with preferential activity to PI3Kα, in comparison to established pan PI3K inhibitors.

    Science.gov (United States)

    Rewcastle, Gordon W; Kolekar, Sharada; Buchanan, Christina M; Gamage, Swarna A; Giddens, Anna C; Tsang, Kit Y; Kendall, Jackie D; Singh, Ripudaman; Lee, Woo-Jeong; Smith, Greg C; Han, Weiping; Matthews, David J; Denny, William A; Shepherd, Peter R; Jamieson, Stephen M F

    2017-07-18

    Multiple therapeutic agents have been developed to target the phosphatidylinositol 3-kinase (PI3K) signaling pathway, which is frequently dysregulated in cancer promoting tumor growth and survival. These include pan PI3K inhibitors, which target class Ia PI3K isoforms and have largely shown limited single agent activity with narrow therapeutic windows in clinical trials. Here, we characterize SN32976, a novel pan PI3K inhibitor, for its biochemical potency against PI3K isoforms and mTOR, kinase selectivity, cellular activity, pharmacokinetics, pharmacodynamics and antitumor efficacy relative to five clinically-evaluated pan PI3K inhibitors: buparlisib, dactolisib, pictilisib, omipalisib and ZSTK474. SN32976 potently inhibited PI3K isoforms and mTOR, displaying preferential activity for PI3Kα and sparing of PI3Kδ relative to the other inhibitors, while showing less off-target activity than the clinical inhibitors in a panel of 442 kinases. The major metabolites of SN32976 were also potent PI3K inhibitors with similar selectivity for PI3Kα as the parent compound. SN32976 compared favorably with the clinically-evaluated PI3K inhibitors in cellular assays, inhibiting pAKT expression and cell proliferation at nM concentrations, and in animal models, inducing a greater extent and duration of pAKT inhibition in tumors than pictilisib, dactolisib and omipalisib at similarly tolerated dose levels and inhibiting tumor growth to a greater extent than dactolisib and ZSTK474 and with similar efficacy to pictilisib and omipalisib. These results suggest that SN32976 is a promising clinical candidate for cancer therapy with enhanced kinase selectivity and preferential inhibition of PI3Kα compared to first generation pan PI3K inhibitors, while retaining comparable anticancer activity.

  14. Active Galaxies

    DEFF Research Database (Denmark)

    Kilerci Eser, Ece

    Galaxy formation and evolution is one of the main research themes of modern astronomy. Active galaxies such as Active Galactic Nuclei (AGN) and Ultraluminous Infrared Galaxies (ULIRGs) are important evolutionary stages of galaxies. The ULIRG stage is mostly associated with galaxy mergers...... and interactions. During the interactions of gas-rich galaxies, the gas inflows towards the centers of the galaxies and can trigger both star formation and AGN activity. The ULIRG stage includes rapid star formation activity and fast black hole growth that is enshrouded by dust. Once the AGN emission...... one is related to the mass estimates of supermassive black holes (SMBHs). Mass estimates of SMBHs are important to understand the formation and evolution of SMBHs and their host galaxies. Black hole masses in Type 1 AGN are measured with the reverberation mapping (RM) technique. Reverberation mapping...

  15. In vitro antidiabetic activity of various crude extracts of Boletus variipes

    Science.gov (United States)

    Muniandy, Sutha; Fazry, Shazrul; Daud, Fauzi; Senafi, Sahidan

    2015-09-01

    Diabetes mellitus is a complex metabolic disease that progressively spread worldwide and difficult to treat due to various physical and metabolic complications. Current treatment using synthetic drugs has lead to various undesirable side effects. Here we determined the effect of Boletus variipes extracts on diabetes related enzymes. In this study, hot water, cold water and methanol extracts of B. variipes were utilized in order to assess their in vitro antidiabetic activity by measuring the effect on α-amylase and α-glucosidase enzyme. Hot water extract possessed the highest inhibition activity of α-amylase and α-glucosidase in a concentration dependent manner with the IC50 value 87 mg/mL and 89 mg/mL respectively. The methanol extract also showed inhibition activity of α-amylase and α-glucosidase but significantly lower than the hot water extract. Whereas cold water extract did not show any inhibition activity towards both the enzymes. Therefore, it is hypothesized that the hot water extract of Boletus variipes contains bioactive compound that can inhibit alpha-amylase and alpha-glucosidase enzyme activity. At the request of all authors of the paper an updated version was published on 11 May 2016. The original version identified the species of mushroom as Boletus variipes, but new findings have proved the species of mushroom to be Boletus qriseipurpureus. The species name has been updated throughout the revised version of this paper.

  16. Application of an Integrated GPCR SAR-Modeling Platform To Explain the Activation Selectivity of Human 5-HT2C over 5-HT2B.

    Science.gov (United States)

    Heifetz, Alexander; Storer, R Ian; McMurray, Gordon; James, Tim; Morao, Inaki; Aldeghi, Matteo; Bodkin, Mike J; Biggin, Philip C

    2016-05-20

    Agonism of the 5-HT2C serotonin receptor has been associated with the treatment of a number of diseases including obesity, psychiatric disorders, sexual health, and urology. However, the development of effective 5-HT2C agonists has been hampered by the difficulty in obtaining selectivity over the closely related 5-HT2B receptor, agonism of which is associated with irreversible cardiac valvulopathy. Understanding how to design selective agonists requires exploration of the structural features governing the functional uniqueness of the target receptor relative to related off targets. X-ray crystallography, the major experimental source of structural information, is a slow and challenging process for integral membrane proteins, and so is currently not feasible for every GPCR or GPCR-ligand complex. Therefore, the integration of existing ligand SAR data with GPCR modeling can be a practical alternative to provide this essential structural insight. To demonstrate this, we integrated SAR data from 39 azepine series 5-HT2C agonists, comprising both selective and unselective examples, with our hierarchical GPCR modeling protocol (HGMP). Through this work we have been able to demonstrate how relatively small differences in the amino acid sequences of GPCRs can lead to significant differences in secondary structure and function, as supported by experimental data. In particular, this study suggests that conformational differences in the tilt of TM7 between 5-HT2B and 5-HT2C, which result from differences in interhelical interactions, may be the major source of selectivity in G-protein activation between these two receptors. Our approach also demonstrates how the use of GPCR models in conjunction with SAR data can be used to explain activity cliffs.

  17. Researchers use Modified CRISPR Systems to Modulate Gene Expression on a Genomic Scale

    Science.gov (United States)

    Cancer Target Discovery and Development Network (CTD2) researchers at the University of California, San Francisco, developed a CRISPR system that can regulate both gene repression and activation with fewer off-target effects.

  18. Switching off H2O2 Decomposition during TS-1 Catalysed Epoxidation via Post-Synthetic Active Site Modification

    Directory of Open Access Journals (Sweden)

    Ceri Hammond

    2015-12-01

    Full Text Available Despite its widespread use, the Lewis acidic zeolite, TS-1, still exhibits several unfavourable properties, such as excessive H2O2 decomposition, which decrease its overall performance. In this manuscript, we demonstrate that post-synthetic modification of TS-1 with aqueous NH4HF2 leads to modifications in epoxidation catalysis, which both improves the levels of epoxide selectivity obtained, and drastically minimises undesirable H2O2 decomposition. Through in situ spectroscopic study with UV-resonance enhanced Raman spectroscopy, we also observe a change in Ti site speciation, which occurs via the extraction of mononuclear [Ti(OSi4] atoms, and which may be responsible for the changes in observed activity.

  19. Physics activities

    International Nuclear Information System (INIS)

    1997-09-01

    As we move into the 21st Century, nuclear technology is on the verge of rejuvenation in advanced Member States and of expansion in developing Member States. The principal responsibilities of the IAEA are transferring technologies, co-ordinating scientific research, managing specialized projects and maintaining analytical quality control. The IAEA physics activities provide assistance with nuclear instrumentation, promote more effective utilization of research reactors and accelerators, and facilitate global co-operation in nuclear fusion research. These activities will help Member States improve their standards of living through the benefits of nuclear technology. This booklet presents a brief profile on the physics activities and involvement in these fields of the Physics Section, IAEA

  20. Integrative Analysis of CRISPR/Cas9 Target Sites in the Human HBB Gene

    Directory of Open Access Journals (Sweden)

    Yumei Luo

    2015-01-01

    Full Text Available Recently, the clustered regularly interspaced short palindromic repeats (CRISPR system has emerged as a powerful customizable artificial nuclease to facilitate precise genetic correction for tissue regeneration and isogenic disease modeling. However, previous studies reported substantial off-target activities of CRISPR system in human cells, and the enormous putative off-target sites are labor-intensive to be validated experimentally, thus motivating bioinformatics methods for rational design of CRISPR system and prediction of its potential off-target effects. Here, we describe an integrative analytical process to identify specific CRISPR target sites in the human β-globin gene (HBB and predict their off-target effects. Our method includes off-target analysis in both coding and noncoding regions, which was neglected by previous studies. It was found that the CRISPR target sites in the introns have fewer off-target sites in the coding regions than those in the exons. Remarkably, target sites containing certain transcriptional factor motif have enriched binding sites of relevant transcriptional factor in their off-target sets. We also found that the intron sites have fewer SNPs, which leads to less variation of CRISPR efficiency in different individuals during clinical applications. Our studies provide a standard analytical procedure to select specific CRISPR targets for genetic correction.

  1. Active handling

    International Nuclear Information System (INIS)

    Wheelton, I.S.

    1988-01-01

    The paper describes the work carried out by the National Nuclear Corporation on radioactive handling projects. The categories of these active handling projects include: irradiated reactor fuel and components handling for AGR fuel and fast reactor fuel, nuclear facilities for laboratory facilities and tritium handling, and nuclear waste from power station arisings and repository design. A description is given of the design work and responsibility for the facilities in each of the above active handling categories. The work requires a consistent approach to compliance with design codes and radiological protection criteria. (U.K.)

  2. Activating schoolyards

    DEFF Research Database (Denmark)

    Andersen, Henriette Bondo; Pawlowski, Charlotte Skau; Scheller, Hanne Bebendorf

    2015-01-01

    BACKGROUND: The aim of the Activating Schoolyards Study is to develop, implement, document and assess a comprehensive schoolyard intervention to promote physical activity (PA) during school recess for primary school children (grade 4-8). The intervention is designed to implement organizational...... project schools (cases) were selected by means of an open competition and the interventions were developed using a participatory bottom-up approach. DISCUSSION: The participatory approach and case selection strategy make the study design novel. The use of a mixed methods design including qualitative...... in the schoolyard will lead to recommendations for schools undergoing schoolyard renovations at some point in the future....

  3. Regulatory activities

    International Nuclear Information System (INIS)

    2001-01-01

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information

  4. The NDUFB6 subunit of the mitochondrial respiratory chain complex I is required for electron transfer activity: A proof of principle study on stable and controlled RNA interference in human cell lines

    International Nuclear Information System (INIS)

    Loublier, Sandrine; Bayot, Aurelien; Rak, Malgorzata; El-Khoury, Riyad; Benit, Paule; Rustin, Pierre

    2011-01-01

    Highlights: → NDUFB6 is required for activity of mitochondrial complex I in human cell lines. → Lentivirus based RNA interference results in frequent off target insertions. → Flp-In recombinase mediated miRNA insertion allows gene-specific extinction. -- Abstract: Molecular bases of inherited deficiencies of mitochondrial respiratory chain complex I are still unknown in a high proportion of patients. Among 45 subunits making up this large complex, more than half has unknown function(s). Understanding the function of these subunits would contribute to our knowledge on mitochondrial physiology but might also reveal that some of these subunits are not required for the catalytic activity of the complex. A direct consequence of this finding would be the reduction of the number of candidate genes to be sequenced in patients with decreased complex I activity. In this study, we tested two different methods to stably extinct complex I subunits in cultured cells. We first found that lentivirus-mediated shRNA expression frequently resulted in the unpredicted extinction of additional gene(s) beside targeted ones. This can be ascribed to uncontrolled genetic material insertions in the genome of the host cell. This approach thus appeared inappropriate to study unknown functions of a gene. Next, we found it possible to specifically extinct a CI subunit gene by direct insertion of a miR targeting CI subunits in a Flp site (HEK293 Flp-In cells). By using this strategy we unambiguously demonstrated that the NDUFB6 subunit is required for complex I activity, and defined conditions suitable to undertake a systematic and stable extinction of the different supernumerary subunits in human cells.

  5. The NDUFB6 subunit of the mitochondrial respiratory chain complex I is required for electron transfer activity: A proof of principle study on stable and controlled RNA interference in human cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Loublier, Sandrine; Bayot, Aurelien; Rak, Malgorzata; El-Khoury, Riyad; Benit, Paule [Inserm U676, Hopital Robert Debre, F-75019 Paris (France); Universite Paris 7, Faculte de medecine Denis Diderot, IFR02 Paris (France); Rustin, Pierre, E-mail: pierre.rustin@inserm.fr [Inserm U676, Hopital Robert Debre, F-75019 Paris (France); Universite Paris 7, Faculte de medecine Denis Diderot, IFR02 Paris (France)

    2011-10-22

    Highlights: {yields} NDUFB6 is required for activity of mitochondrial complex I in human cell lines. {yields} Lentivirus based RNA interference results in frequent off target insertions. {yields} Flp-In recombinase mediated miRNA insertion allows gene-specific extinction. -- Abstract: Molecular bases of inherited deficiencies of mitochondrial respiratory chain complex I are still unknown in a high proportion of patients. Among 45 subunits making up this large complex, more than half has unknown function(s). Understanding the function of these subunits would contribute to our knowledge on mitochondrial physiology but might also reveal that some of these subunits are not required for the catalytic activity of the complex. A direct consequence of this finding would be the reduction of the number of candidate genes to be sequenced in patients with decreased complex I activity. In this study, we tested two different methods to stably extinct complex I subunits in cultured cells. We first found that lentivirus-mediated shRNA expression frequently resulted in the unpredicted extinction of additional gene(s) beside targeted ones. This can be ascribed to uncontrolled genetic material insertions in the genome of the host cell. This approach thus appeared inappropriate to study unknown functions of a gene. Next, we found it possible to specifically extinct a CI subunit gene by direct insertion of a miR targeting CI subunits in a Flp site (HEK293 Flp-In cells). By using this strategy we unambiguously demonstrated that the NDUFB6 subunit is required for complex I activity, and defined conditions suitable to undertake a systematic and stable extinction of the different supernumerary subunits in human cells.

  6. Protein Kinase C-Independent Inhibition of Organic Cation Transporter 1 Activity by the Bisindolylmaleimide Ro 31-8220.

    Science.gov (United States)

    Mayati, Abdullah; Bruyere, Arnaud; Moreau, Amélie; Jouan, Elodie; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

    2015-01-01

    Ro 31-8220 is a potent protein kinase C (PKC) inhibitor belonging to the chemical class of bisindolylmaleimides (BIMs). Various PKC-independent effects of Ro 31-8220 have however been demonstrated, including inhibition of the ATP-binding cassette drug transporter breast cancer resistance protein. In the present study, we reported that the BIM also blocks activity of the solute carrier organic cation transporter (OCT) 1, involved in uptake of marketed drugs in the liver, in a PKC-independent manner. Ro 31-8220, in contrast to other pan-PKC inhibitors such as staurosporine and chelerythrine, was thus shown to cis-inhibit uptake of the reference OCT1 substrate tetraethylammonium in OCT1-transfected HEK293 cells in a concentration-dependent manner (IC50 = 0.18 μM) and without altering membrane expression of OCT1. This blockage of OCT1 was also observed in human hepatic HepaRG cells that constitutionally express OCT1. It likely occurred through a mixed mechanism of inhibition. Ro 31-8220 additionally trans-inhibited TEA uptake in OCT1-transfected HEK293 cells, which likely discards a transport of Ro 31-8220 by OCT1. Besides Ro 31-8220, 7 additional BIMs, including the PKC inhibitor LY 333531, inhibited OCT1 activity, whereas 4 other BIMs were without effect. In silico analysis of structure-activity relationships next revealed that various molecular descriptors, especially 3D-WHIM descriptors related to total size, correspond to key physico-chemical parameters for inhibition of OCT1 activity by BIMs. In addition to activity of OCT1, Ro 31-8220 inhibited those of other organic cation transporters such as multidrug and toxin extrusion protein (MATE) 1 and MATE2-K, whereas, by contrast, it stimulated that of OCT2. Taken together, these data extend the nature of cellular off-targets of the BIM Ro 31-8220 to OCT1 and other organic cation transporters, which has likely to be kept in mind when using Ro 31-8220 and other BIMs as PKC inhibitors in experimental or clinical

  7. Activated Charcoal

    Science.gov (United States)

    ... if you are pregnant. Gastrointestinal (GI) blockage or slow movement of food through the intestine: Don’t use activated charcoal ... obstruction. Also, if you have a condition that slows the passage of food through your intestine (reduced peristalsis), don’t use ...

  8. Activated Sludge.

    Science.gov (United States)

    Saunders, F. Michael

    1978-01-01

    Presents the 1978 literature review of wastewater treatment. This review covers: (1) activated sludge process; (2) process control; (3) oxygen uptake and transfer; (4) phosphorus removal; (5) nitrification; (6) industrial wastewater; and (7) aerobic digestion. A list of 136 references is also presented. (HM)

  9. Staying Active: Physical Activity and Exercise

    Science.gov (United States)

    ... Patients About ACOG Staying Active: Physical Activity and Exercise Home For Patients Search FAQs Staying Active: Physical ... 2016 PDF Format Staying Active: Physical Activity and Exercise Women's Health What are the benefits of physical ...

  10. Physical activity behavior change in persons with neurologic disorders: overview and examples from Parkinson disease and multiple sclerosis.

    Science.gov (United States)

    Ellis, Terry; Motl, Robert W

    2013-06-01

    Persons with chronic progressive neurologic diseases such as Parkinson disease (PD) and multiple sclerosis (MS) face significant declines in mobility and activities of daily living, resulting in a loss of independence and compromised health-related quality of life over the course of the disease. Such undesirable outcomes can be attenuated through participation in exercise and physical activity, yet there is profound and prevalent physical inactivity in persons with PD and MS that may initiate a cycle of deconditioning and worsening of disease consequences, independent of latent disease processes. This Special Interest article highlights the accruing evidence revealing the largely sedentary behaviors common among persons living with physically disabling conditions and summarizes the evidence on the benefits of physical activity in persons with PD and MS. We then examine the social cognitive theory as an approach to identifying the primary active ingredients for behavioral change and, hence, the targets of interventions for increasing physical activity levels. The design and efficacies of interventions based on the social cognitive theory for increasing physical activity in persons with PD and MS are discussed. Finally, a rationale for adopting a secondary prevention approach to delivering physical therapy services is presented, with an emphasis on the integration of physical activity behavior change interventions into the care of persons with chronic, progressive disabilities over the course of the disease.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A42) for more insights from the authors.

  11. Posidonia oceanica (L. Delile Ethanolic Extract Modulates Cell Activities with Skin Health Applications

    Directory of Open Access Journals (Sweden)

    Laura Cornara

    2018-01-01

    Full Text Available Seagrasses are high plants sharing adaptive metabolic features with both terrestrial plants and marine algae, resulting in a phytocomplex possibly endowed with interesting biological properties. The aim of this study is to evaluate the in vitro activities on skin cells of an ethanolic extract obtained from the leaves of Posidonia oceanica (L. Delile, family Potamogetonaceae, herein named Posidonia ethanolic extract (PEE. PEE showed high radical scavenging activity, high phenolic content, and resulted rich in chicoric acid, as determined through HPLC-MS analysis. The use of MTT assay on fibroblasts showed a PEE cytotoxicity threshold (IC05 of 50 µg/mL at 48 h, while a sub-toxic dose of 20 µg/mL induced a significant increase of fibroblast growth rate after 10 days. In addition, an ELISA assay revealed that PEE doses of 5 and 10 µg/mL induced collagen production in fibroblasts. PEE induced dose-dependent mushroom tyrosinase inhibition, up to about 45% inhibition at 1000 µg/mL, while 50% reduction of melanin was observed in melanoma cells exposed to 50 µg/mL PEE. Finally, PEE lipolytic activity was assessed by measuring glycerol release from adipocytes following triglyceride degradation. In conclusion, we have collected new data about the biological activities of the phytocomplex of P. oceanica seagrass on skin cells. Our findings indicate that PEE could be profitably used in the development of products for skin aging, undesired hyperpigmentation, and cellulite.

  12. Depolymerized glycosaminoglycan and its anticoagulant activities from sea cucumber Apostichopus japonicus.

    Science.gov (United States)

    Yang, Jie; Wang, Yuanhong; Jiang, Tingfu; Lv, Lv; Zhang, Boyuan; Lv, Zhihua

    2015-01-01

    A controlled Cu(2+) catalytic free-radical depolymerization process of fucosylated chondroitin sulfate from sea cucumber Apostichopus japonicus was established. The results showed a good linear relationship between 1/Mw and time during the depolymerization. A series of fractions with different molecular weight were obtained, and the physicochemical properties of them were investigated and compared utilizing the chemical method, IR spectra and NMR spectra. The results showed no significant variations of the backbone and branches structures during the depolymerization. Furthermore, the anticoagulant activities of the depolymerized fractions were evaluated by the activated partial thromboplastin time (APTT). The APTT decreases in proportion to the molecular weight following a linear relationship and the prolongation of APTT activity requires at least oligosaccharide of 4 trisaccharide units (about 4000 Da). Their anticoagulant activity of low molecular weight fraction (Mw = 24,755 Da) is similar to LMWH with significantly less bleeding risk. The results suggest that the low molecular weight fraction could be used as a novel anticoagulant with less undesired side effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Effects of electron acceptors on sulphate reduction activity in activated sludge processes

    NARCIS (Netherlands)

    Rubio-Rincón, Francisco; Lopez-Vazquez, Carlos; Welles, L.; van den Brand, Tessa; Abbas, B.A.; van Loosdrecht, Mark C.M.; Brdanovic, Damir

    2017-01-01

    The concentration of sulphate present in wastewater can vary from 10 to 500 mg SO4 2−/L. During anaerobic conditions, sulphate is reduced to sulphide by sulphate-reducing bacteria (SRB). Sulphide generation is undesired in wastewater treatment plants (WWTPs). Previous

  14. Active particles

    CERN Document Server

    Degond, Pierre; Tadmor, Eitan

    2017-01-01

    This volume collects ten surveys on the modeling, simulation, and applications of active particles using methods ranging from mathematical kinetic theory to nonequilibrium statistical mechanics. The contributing authors are leading experts working in this challenging field, and each of their chapters provides a review of the most recent results in their areas and looks ahead to future research directions. The approaches to studying active matter are presented here from many different perspectives, such as individual-based models, evolutionary games, Brownian motion, and continuum theories, as well as various combinations of these. Applications covered include biological network formation and network theory; opinion formation and social systems; control theory of sparse systems; theory and applications of mean field games; population learning; dynamics of flocking systems; vehicular traffic flow; and stochastic particles and mean field approximation. Mathematicians and other members of the scientific commu...

  15. Regulatory Forum Review*: Utility of in Vitro Secondary Pharmacology Data to Assess Risk of Drug-induced Valvular Heart Disease in Humans: Regulatory Considerations.

    Science.gov (United States)

    Papoian, Thomas; Jagadeesh, Gowraganahalli; Saulnier, Muriel; Simpson, Natalie; Ravindran, Arippa; Yang, Baichun; Laniyonu, Adebayo A; Khan, Imran; Szarfman, Ana

    2017-04-01

    Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT 2B ) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT 2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC 50 , K i ) or cellular functional activity (EC 50 ) are often compared to maximum therapeutic free plasma drug levels ( fC max ) from which safety margins (SMs) can be derived. However, there is no clear consensus on what constitutes an appropriate SM under various therapeutic conditions of use. The strengths and limitations of SM determinations and current risk assessment methodology are reviewed and evaluated. It is concluded that the use of SMs based on K i values, or those relative to serotonin (5-HT), appears to be a better predictor than the use of EC 50 or EC 50 /human fC max values for determining whether known 5-HT 2B agonists have resulted in VHD. It is hoped that such a discussion will improve efforts to reduce this preventable serious drug-induced toxicity from occurring and lead to more informed risk assessment strategies.

  16. Identification of potential small molecule binding pockets on Rho family GTPases.

    Directory of Open Access Journals (Sweden)

    Juan Manuel Ortiz-Sanchez

    Full Text Available Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (>100 and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism.

  17. Role of cysteine residues in the structure, stability, and alkane producing activity of cyanobacterial aldehyde deformylating oxygenase.

    Directory of Open Access Journals (Sweden)

    Yuuki Hayashi

    Full Text Available Aldehyde deformylating oxygenase (AD is a key enzyme for alkane biosynthesis in cyanobacteria, and it can be used as a catalyst for alkane production in vitro and in vivo. However, three free Cys residues in AD may impair its catalytic activity by undesired disulfide bond formation and oxidation. To develop Cys-deficient mutants of AD, we examined the roles of the Cys residues in the structure, stability, and alkane producing activity of AD from Nostoc punctiforme PCC 73102 by systematic Cys-to-Ala/Ser mutagenesis. The C71A/S mutations reduced the hydrocarbon producing activity of AD and facilitated the formation of a dimer, indicating that the conserved Cys71, which is located in close proximity to the substrate-binding site, plays crucial roles in maintaining the activity, structure, and stability of AD. On the other hand, mutations at Cys107 and Cys117 did not affect the hydrocarbon producing activity of AD. Therefore, we propose that the C107A/C117A double mutant is preferable to wild type AD for alkane production and that the double mutant may be used as a pseudo-wild type protein for further improvement of the alkane producing activity of AD.

  18. Activation analysis

    International Nuclear Information System (INIS)

    Beeck, J. OP de

    1977-01-01

    It is shown that activation analysis is especially suited to serve as a basis for determining the chemical similarity between samples defined by their trace-element concentration patterns. The general problem of classification and identification is discussed. The nature of possible classification structures and their appropriate clustering strategies is considered. A practical computer method is suggested and its application as well as the graphical representation of classification results are given. The possibility for classification using information theory is mentioned. Classification of chemical elements is discussed and practically realized after Hadamard transformation of the concentration variation patterns in a series of samples. (Sz.N.Z.)

  19. Chocolate active

    International Nuclear Information System (INIS)

    Anon.

    1987-01-01

    There is a table of current radioactivity values for various foods and mushrooms. A special accent is on milk and chocolate. Chocolate sorts with more powdered milk are more active. Finally there is a chapter on radionucleides contained in the Chernobyl fallout, other than cesium 137, cesium 134 and strontium 90. The amounts of ruthenium 106, antimony 125, cerium 144, silver 110 m, cesium 134, strontium 90 and plutonium 239 relative to cesium 137 in soil samples in autumn 1987 are given. Special emphasis is on ruthenium 'hot particles' and on plutonium. (qui)

  20. Analysis of Low-Carbon Economy Efficiency of Chinese Industrial Sectors Based on a RAM Model with Undesirable Outputs

    Directory of Open Access Journals (Sweden)

    Ming Meng

    2017-03-01

    Full Text Available Industrial energy and environment efficiency evaluation become especially crucial as industrial sectors play a key role in CO2 emission reduction and energy consumption. This study adopts the additive range-adjusted measure data envelope analysis (RAM-DEA model to estimate the low-carbon economy efficiency of Chinese industrial sectors in 2001–2013. In addition, the CO2 emission intensity mitigation target for each industrial sector is assigned. Results show that, first, most sectors are not completely efficient, but they have experienced and have improved greatly during the period. These sectors can be divided into four categories, namely, mining, light, heavy, and electricity, gas, and water supply industries. The efficiency is diverse among the four industrial categories. The average efficiency of the light industry is the highest among the industries, followed by those of the mining and the electricity, gas, and water supply industries, and that of the heavy industry is the lowest. Second, the electricity, gas, and water supply industry shows the biggest potential for CO2 emission reduction, thus containing most of the sectors with large CO2 emission intensity mitigation targets (more than 45%, followed by the mining and the light industries. Therefore, the Chinese government should formulate diverse and flexible policy implementations according to the actual situation of the different sectors. Specifically, the sectors with low efficiency should be provided with additional policy support (such as technology and finance aids to improve their industrial efficiency, whereas the electricity, gas, and water supply industry should maximize CO2 emission reduction.

  1. Is It Desirable to Be Able to Do the Undesirable? Moral Bioenhancement and the Little Alex Problem.

    Science.gov (United States)

    Hauskeller, Michael

    2017-07-01

    It has been argued that moral bioenhancement is desirable even if it would make it impossible for us to do what is morally required. Others find this apparent loss of freedom deplorable. However, it is difficult to see how a world in which there is no moral evil can plausibly be regarded as worse than a world in which people are not only free to do evil, but also where they actually do it, which would commit us to the seemingly paradoxical view that, under certain circumstances, the bad can be better than the good. Notwithstanding, this view is defended here.

  2. Penalising Presence in Public Space: Control through Exclusion of the ‘Difficult’ and ‘Undesirable

    Directory of Open Access Journals (Sweden)

    Craig Johnstone

    2017-05-01

    Full Text Available Over the last two decades and across a number of jurisdictions, new measures enshrined in criminal law and administrative codes have empowered authorities to exclude unwelcome groups and individuals from public spaces. Focusing particular attention on recent reform in Britain, this paper traces the evolution of contemporary exclusionary practices, from their initial concern with proscribed behaviour to the penalisation of mere presence. The latter part of the paper offers a critical assessment of what has driven these innovations in control of the public realm. Here consideration is given to two possibilities. First, such policy is the outcome of punitive and revanchist logics. Second, their intentions are essentially benign, reflecting concerns about risk, liveability and failures of traditional order-maintenance mechanisms. While acknowledging concerns about the over-eagerness of scholars to brand new policy as punitive, the paper concludes that any benign intentions are overshadowed by the regressive and marginalising consequences of preferred solutions.

  3. Efficient CRISPR-Cas9-Mediated Generation of Knockin Human Pluripotent Stem Cells Lacking Undesired Mutations at the Targeted Locus

    Directory of Open Access Journals (Sweden)

    Florian T. Merkle

    2015-05-01

    Full Text Available The CRISPR-Cas9 system has the potential to revolutionize genome editing in human pluripotent stem cells (hPSCs, but its advantages and pitfalls are still poorly understood. We systematically tested the ability of CRISPR-Cas9 to mediate reporter gene knockin at 16 distinct genomic sites in hPSCs. We observed efficient gene targeting but found that targeted clones carried an unexpectedly high frequency of insertion and deletion (indel mutations at both alleles of the targeted gene. These indels were induced by Cas9 nuclease, as well as Cas9-D10A single or dual nickases, and often disrupted gene function. To overcome this problem, we designed strategies to physically destroy or separate CRISPR target sites at the targeted allele and developed a bioinformatic pipeline to identify and eliminate clones harboring deleterious indels at the other allele. This two-pronged approach enables the reliable generation of knockin hPSC reporter cell lines free of unwanted mutations at the targeted locus.

  4. Body image distortion in fifth and sixth grade students may lead to stress, depression, and undesirable dieting behavior.

    Science.gov (United States)

    Cho, Jin Hee; Han, Sung Nim; Kim, Jung Hee; Lee, Hong Mie

    2012-04-01

    The widespread pursuit of a thin physique may have a detrimental impact on the wellbeing of preadolescents. The influence of body image distortions on the lifestyles, dieting behaviors, and psychological factors was investigated in 631 fifth and sixth grade children in Kyeonggi-do, Korea. Children were classified into three weight groups (underweight, normal, and overweight) and three perception groups (underestimation, normal, and overestimation). Necessary information was obtained by questionnaire, and each subject's weight status was determined by the Röhrer index calculated from the annual measurement records, which were obtained from the school. According to their current weights, 57.4% of children were normal and 32.2% were overweight or obese, 16.6% of the children overestimated their body weight, and 55.2% had an undistorted body image. Overweight children had desirable lifestyles and dietary habits and presented reasonable weight control behaviors. Compared to those without distortion, the overestimated group had greater interest in weight control (P = 0.003) and dissatisfaction with their body weights (P = 0.011), presented unhealthy reasons to lose weight (P = 0.026), and had higher scores for "feeling sad when comparing own body with others" (P = 0.000) and for "easily getting annoyed and tired" (P = 0.037), even though they had similar obesity indices. More subjects from the overestimation group (P = 0.006) chose drama/movies as their favorite TV programs, suggesting a possible role for the media in body image distortion. These findings suggest that body image distortion can lead preadolescents to develop stress about obesity and unhealthy dieting practices, despite similar obesity indices to those without distorted body images. These results emphasize the importance of having an undistorted body image.

  5. Order and control in the environment : Exploring the effects on undesired behaviour and the importance of locus of control

    NARCIS (Netherlands)

    Jansen, A.M.; Giebels, Ellen; van Rompay, Thomas Johannes Lucas; Austrup, Sebastian; Junger, Marianne

    Purpose This study aimed at gaining more insight into the combined influence of environmental factors and personal vulnerability to environmental cues on cheating behaviour in a task-related indoor setting. We propose that a disorderly environment increases cheating as it implicitly signals that

  6. Body image distortion in fifth and sixth grade students may lead to stress, depression, and undesirable dieting behavior

    OpenAIRE

    Cho, Jin Hee; Han, Sung Nim; Kim, Jung Hee; Lee, Hong Mie

    2012-01-01

    The widespread pursuit of a thin physique may have a detrimental impact on the wellbeing of preadolescents. The influence of body image distortions on the lifestyles, dieting behaviors, and psychological factors was investigated in 631 fifth and sixth grade children in Kyeonggi-do, Korea. Children were classified into three weight groups (underweight, normal, and overweight) and three perception groups (underestimation, normal, and overestimation). Necessary information was obtained by questi...

  7. [Undesirable effects of medicine in the Internal Medicine Service of the University Hospital Center du Point G].

    Science.gov (United States)

    Soukho-Kaya, A; Minta, D K; Diarra, M T; Konaté, A; Diallo, B; Sidibé, A T; Dembélé, M; Bah, M; Doumbia, A A; Dao, K; Tolo, N; Camara, B D; Sy, D; Maiga, M Y; Traoré, H A

    2010-01-01

    The aim of this study was to determine the frequency of adverse reactions to drugs, the WHO grade, describe the clinical features and identify the drug responsible. This was a descriptive cross-sectional study which took place from February 2005 to January 2006 in the Internal Medicine Department at the hospital point G. Were included in this study, all patients hospitalized during the study period, which presented adverse drug reactions (ADRs) that the relation of cause and effect was certain or likely. Thus, 47 ADRs were identified in 39 patients of 426 admitted during the same period a frequency of 9.2%. The average age of our patients was 48.5 ± 16.5 years. The sex-ratio was 1.6 for women. Eighty-two percent of our patients had an ADR and 18% more than one. The WHO grade 1 was the most met or 36.2%, followed by grades 4 and 2 respectively 27.7% and 25.5%. Antidiabetics were responsible for adverse reactions in 46.8% and 21.3% in TB. Adverse events were neurological in 53.2% and type of manifestations of hypoglycemia 46.8% (22/47 cases), polyneuritis 6.4% (3 / 47 cases) and 29.8% in digestive cases dominated by vomiting 12.8% (6 / 47 cases), the epigastria pain 6.4% (3 / 47 cases). The outcome was favorable in 87.2% of cases, however, 3 cases of death among those over 60 years all grade 4 WHO. ADRs deserve special attention to this high death rate (6.4% 3/47 cases) where the interest to search systematically for all patients under medical treatment with a good clinical examination and questioning some thoroughly.

  8. Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis

    Directory of Open Access Journals (Sweden)

    Yuan Tian

    2016-08-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD, characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC. The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.

  9. Conformation-induced remote meta-C-H activation of amines

    Science.gov (United States)

    Tang, Ri-Yuan; Li, Gang; Yu, Jin-Quan

    2014-03-01

    Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C-H bonds in any given organic molecule can lead to the activation of undesired C-H bonds by a non-selective catalyst. One solution to this problem is to distinguish C-H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C-H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied. However, the directed activation of C-H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C-H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C-H bonds--as far as 11 bonds away--of anilines and benzylic amines. This template is able to direct the meta-selective C-H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.

  10. Enhanced oxidation of naphthalene using plasma activation of TiO2/diatomite catalyst.

    Science.gov (United States)

    Wu, Zuliang; Zhu, Zhoubin; Hao, Xiaodong; Zhou, Weili; Han, Jingyi; Tang, Xiujuan; Yao, Shuiliang; Zhang, Xuming

    2018-04-05

    Non-thermal plasma technology has great potential in reducing polycyclic aromatic hydrocarbons (PAHs) emission. But in plasma-alone process, various undesired by-products are produced, which causes secondary pollutions. Here, a dielectric barrier discharge (DBD) reactor has been developed for the oxidation of naphthalene over a TiO 2 /diatomite catalyst at low temperature. In comparison to plasma-alone process, the combination of plasma and TiO 2 /diatomite catalyst significantly enhanced naphthalene conversion (up to 40%) and CO x selectivity (up to 92%), and substantially reduced the formation of aerosol (up to 90%) and secondary volatile organic compounds (up to near 100%). The mechanistic study suggested that the presence of the TiO 2 /diatomite catalyst intensified the electron energy in the DBD. Meantime, the energized electrons generated in the discharge activated TiO 2 , while the presence of ozone enhanced the activity of the TiO 2 /diatomite catalyst. This plasma-catalyst interaction led to the synergetic effect resulting from the combination of plasma and TiO 2 /diatomite catalyst, consequently enhanced the oxidation of naphthalene. Importantly, we have demonstrated the effectiveness of plasma to activate the photocatalyst for the deep oxidation of PAH without external heating, which is potentially valuable in the development of cost-effective gas cleaning process for the removal of PAHs in vehicle applications during cold start conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing-Part 2.

    Science.gov (United States)

    Brufani, Mario; Rizzi, Nicoletta; Meda, Clara; Filocamo, Luigi; Ceccacci, Francesca; D'Aiuto, Virginia; Bartoli, Gabriele; Bella, Angela La; Migneco, Luisa M; Bettolo, Rinaldo Marini; Leonelli, Francesca; Ciana, Paolo; Maggi, Adriana

    2017-05-31

    Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17β-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17β-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing.

  12. Halal Activism

    DEFF Research Database (Denmark)

    Fischer, Johan

    2016-01-01

    zones between new forms of Islamic revivalism, the ethnicised state and Muslim consumer culture. Organisations such as the Muslim Consumers Association of Malaysia play an important role in pushing and protecting halal in Malaysia, that is, halal activists constantly call on the state to tighten halal......The purpose of this article is to further our understanding of contemporary Muslim consumer activism in Malaysia with a particular focus on halal (in Arabic, literally “permissible” or “lawful”) products and services. Muslim activists and organisations promote halal on a big scale in the interface...... in particular historical/national settings and that these issues should be explored in the interfaces between Islam, the state and market. More specifically, this article examines the above issues building on ethnography from fieldwork with three Muslim organisations in Malaysia....

  13. Selective killing of human immunodeficiency virus infected cells by non-nucleoside reverse transcriptase inhibitor-induced activation of HIV protease

    Directory of Open Access Journals (Sweden)

    Smeulders Liesbeth

    2010-10-01

    Full Text Available Abstract Background Current antiretroviral therapy against human immunodeficiency virus (HIV-1 reduces viral load and thereby prevents viral spread, but it cannot eradicate proviral genomes from infected cells. Cells in immunological sanctuaries as well as cells producing low levels of virus apparently contribute to a reservoir that maintains HIV persistence in the presence of highly active antiretroviral therapy. Thus, accelerated elimination of virus producing cells may represent a complementary strategy to control HIV infection. Here we sought to exploit HIV protease (PR related cytotoxicity in order to develop a strategy for drug induced killing of HIV producing cells. PR processes the viral Gag and Gag-Pol polyproteins during virus maturation, but is also implicated in killing of virus producing cells through off-target cleavage of host proteins. It has been observed previously that micromolar concentrations of certain non-nucleoside reverse transcriptase inhibitors (NNRTIs can stimulate intracellular PR activity, presumably by enhancing Gag-Pol dimerization. Results Using a newly developed cell-based assay we compared the degree of PR activation displayed by various NNRTIs. We identified inhibitors showing higher potency with respect to PR activation than previously described for NNRTIs, with the most potent compounds resulting in ~2-fold increase of the Gag processing signal at 250 nM. The degree of enhancement of intracellular Gag processing correlated with the compound's ability to enhance RT dimerization in a mammalian two-hybrid assay. Compounds were analyzed for their potential to mediate specific killing of chronically infected MT-4 cells. Levels of cytotoxicity on HIV infected cells determined for the different NNRTIs corresponded to the relative degree of drug induced intracellular PR activation, with CC50 values ranging from ~0.3 μM to above the tested concentration range (10 μM. Specific cytotoxicity was reverted by addition

  14. Pinecone of Pinus koraiensis Inducing Apoptosis in Human Lung Cancer Cells by Activating Caspase-3 and its Chemical Constituents.

    Science.gov (United States)

    Lee, Tae Kyoung; Roh, Hyun-Soo; Yu, Jae Sik; Baek, Jiwon; Lee, Seul; Ra, Moonjin; Kim, Sun Young; Baek, Kwan-Hyuck; Kim, Ki Hyun

    2017-04-01

    Pinecones from Pinus koraiensisSiebold & Zucc. (Pinaceae), which have historically been treated as an undesired waste by-product in the processing of seeds, have recently been shown to contain ingredients with potent biological activities, such as polyphenols exhibiting antitumor activity. With this study, we seek to broaden our understanding of antitumor compounds contained in these pinecones beyond just polyphenols. We found that the water extract of P. koraiensis pinecones exhibits significant cytotoxic activity, with IC 50 values ranging from 0.62 to 1.73 mg/ml in four human lung cancer cell lines, A549, H1264, H1299, and Calu-6, irrespective of their p53 status. We also demonstrate that pinecone water extract induces apoptosis associated with caspase-3 activation in the same cancer cell lines. Chemical investigation of the pinecone water extract revealed eight main components (1 - 8), and their structures were identified as dehydroabietic acid (1), 15-hydroxy-7-oxodehydroabietic acid (2), 7β,15-dihydroxydehydroabietic acid (3), β-d-glucopyranosyl labda-8(17,13)-diene-(15,16)-lactone-19-oate (4), 7α,15-dihydroxydehydroabietic acid (5), (+)-(1S,2S,4R)-limonene-1,2-diol (6), sobrerol (7), and 4-hydroxybenzoic acid (8). These findings suggest a novel biological application of P. koraiensis pinecones in combatting human lung cancer, and further identify the major compounds that could contribute to this anticancer activity. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

  15. Suppression of HBV replication by the expression of nickase- and nuclease dead-Cas9.

    Science.gov (United States)

    Kurihara, Takeshi; Fukuhara, Takasuke; Ono, Chikako; Yamamoto, Satomi; Uemura, Kentaro; Okamoto, Toru; Sugiyama, Masaya; Motooka, Daisuke; Nakamura, Shota; Ikawa, Masato; Mizokami, Masashi; Maehara, Yoshihiko; Matsuura, Yoshiharu

    2017-07-21

    Complete removal of hepatitis B virus (HBV) DNA from nuclei is difficult by the current therapies. Recent reports have shown that a novel genome-editing tool using Cas9 with a single-guide RNA (sgRNA) system can cleave the HBV genome in vitro and in vivo. However, induction of a double-strand break (DSB) on the targeted genome by Cas9 risks undesirable off-target cleavage on the host genome. Nickase-Cas9 cleaves a single strand of DNA, and thereby two sgRNAs are required for inducing DSBs. To avoid Cas9-induced off-target mutagenesis, we examined the effects of the expressions of nickase-Cas9 and nuclease dead Cas9 (d-Cas9) with sgRNAs on HBV replication. The expression of nickase-Cas9 with a pair of sgRNAs cleaved the target HBV genome and suppressed the viral-protein expression and HBV replication in vitro. Moreover, nickase-Cas9 with the sgRNA pair cleaved the targeted HBV genome in mouse liver. Interestingly, d-Cas9 expression with the sgRNAs also suppressed HBV replication in vitro without cleaving the HBV genome. These results suggest the possible use of nickase-Cas9 and d-Cas9 with a pair of sgRNAs for eliminating HBV DNA from the livers of chronic hepatitis B patients with low risk of undesirable off-target mutation on the host genome.

  16. A Qualitative Study to Examine Feasibility and Design of an Online Social Networking Intervention to Increase Physical Activity in Teenage Girls.

    Science.gov (United States)

    Van Kessel, Gisela; Kavanagh, Madeleine; Maher, Carol

    2016-01-01

    Online social networks present wide-reaching and flexible platforms through which to deliver health interventions to targeted populations. This study used a social marketing approach to explore teenage girls' perceptions of physical activity and the potential use of online social networks to receive a physical activity intervention. Six focus groups were conducted with 19 Australian teenage girls (ages 13 to 18 years) with varying levels of physical activity and socioeconomic status. A semi-structured format was used, with groups discussion transcribed verbatim. Content analysis identified emergent themes, with triangulation and memos used to ensure accuracy. Physical activity was most appealing when it emphasised sport, exercise and fitness, along with opportunities for socialisation with friends and self-improvement. Participants were receptive to delivery of a physical activity intervention via online social networks, with Facebook the most widely reported site. Participants commonly accessed online social networks via mobile devices and particularly smartphones. Undesirable features included promotion of physical activity in terms of walking; use of cartoon imagery; use of humour; and promotion of the intervention via schools, each of which were considered "uncool". Participants noted that their parents were likely to be supportive of them using an online social networking physical activity intervention, particularly if not promoted as a weight loss intervention. This study identified key features likely to increase the feasibility and retention of an online social networking physical activity intervention for teenage girls. Guidelines for the design of interventions for teenage girls are provided for future applications.

  17. A Qualitative Study to Examine Feasibility and Design of an Online Social Networking Intervention to Increase Physical Activity in Teenage Girls.

    Directory of Open Access Journals (Sweden)

    Gisela Van Kessel

    Full Text Available Online social networks present wide-reaching and flexible platforms through which to deliver health interventions to targeted populations. This study used a social marketing approach to explore teenage girls' perceptions of physical activity and the potential use of online social networks to receive a physical activity intervention.Six focus groups were conducted with 19 Australian teenage girls (ages 13 to 18 years with varying levels of physical activity and socioeconomic status. A semi-structured format was used, with groups discussion transcribed verbatim. Content analysis identified emergent themes, with triangulation and memos used to ensure accuracy.Physical activity was most appealing when it emphasised sport, exercise and fitness, along with opportunities for socialisation with friends and self-improvement. Participants were receptive to delivery of a physical activity intervention via online social networks, with Facebook the most widely reported site. Participants commonly accessed online social networks via mobile devices and particularly smartphones. Undesirable features included promotion of physical activity in terms of walking; use of cartoon imagery; use of humour; and promotion of the intervention via schools, each of which were considered "uncool". Participants noted that their parents were likely to be supportive of them using an online social networking physical activity intervention, particularly if not promoted as a weight loss intervention.This study identified key features likely to increase the feasibility and retention of an online social networking physical activity intervention for teenage girls. Guidelines for the design of interventions for teenage girls are provided for future applications.

  18. Active sharing

    CERN Multimedia

    2012-01-01

    The big news this week is, of course, the conclusions from the LHC performance workshop held in Chamonix from 6 to 10 February . The main recommendation, endorsed by CERN’s Machine Advisory Committee and adopted by the Management, is that the LHC will run at 4 TeV per beam this year. You can find all the details from Chamonix in the slides presented on Wednesday at the summary session, which leaves me free to talk about another important development coming up soon.   In ten days time, a new kind of gathering will be taking place in Geneva, bringing together two previously separate conferences, one driven by physics, the other by the medical community, but both looking to apply physics to the advancement of health. The merger of the International Conference for Translational Research in Radio-Oncology and CERN’s workshop on Physics for Health in Europe (ICTR-PHE) makes for a very eclectic mix. Presentations range from active shielding for interplanetary flight to the rather...

  19. Study of carbonitriding thermochemical treatment by plasma screen in active with pressures main austenitic stainless steels AISI 409 and AISI 316L

    International Nuclear Information System (INIS)

    Melo, M.S.; Oliveira, A.M.; Leal, V.S.; Sousa, R.R.M. de; Alves Junior, C.; Centro Federal de Educacao Tecnologica do Piaui; Universidade Federal do Rio Grande do Norte

    2010-01-01

    The technique called Active Screen Plasma Nitriding (ASPN) is being used as an alternative once it offers several advantages with respect to conventional DC plasma. In this method, the plasma does not form directly in the sample's surface but on a screen, in such a way that undesired effects such as the edge effect is minimized. Stainless steels present not very satisfactory wearing characteristics. However, plasma carbonitriding has been used as to improve its resistance to wearing due to the formation of a fine surface layer with good properties. In this work, samples of stainless steel AISI 316L and AISI 409 were treated at pressures of 2.5 and 5 mbar. After the treatments they were characterized by microhardness, microscopy and Xray diffraction. Microscopy and hardness analysis showed satisfactory layers and toughness in those steels. (author)

  20. 3 D localization system for inspection activities in metallic plates; Sistema de localizacao em tres dimensoes para auxilio na atividade de inspecao em chapas metalicas

    Energy Technology Data Exchange (ETDEWEB)

    Bonacin, Mario Vicente; Polli, Helton Luis; Czaikowski, Daniel Irineu; Arruda, Lucia Valeria Ramos de; Neves Junior, Flavio; Oliveira, Daniel Rossato de [Universidade Tecnologica Federal do Parana (UTFPR), Curitiba, Parana (Brazil)

    2008-07-01

    This work presents the development of a 3D localization system based on inertial sensors. The prototype aims for its application in the oil and gas industry, which presents deficiencies on automation of inspection procedures. Recent advances on the field of Nondestructive Testing (NDT) have contributed to automation of these inspections, but installation and removal of NDT equipment, as well as location measurements and data acquired processing, are still highly dependent on labour-human. However, only the double integration of data from the inertial sensors - position determination - does not reach the precision level required by inspection activity. It requires the use of techniques and methods to minimize errors. Different models and techniques can be applied to minimize these undesired effects in addition with filters as the Kalman filter, widely used on problems of estimation of trajectories and fusion of sensors. This paper presents the modeling and implementation of some of these techniques, obtaining interesting results. (author)

  1. Epigenome engineering in cancer: fairytale or a realistic path to the clinic?

    Directory of Open Access Journals (Sweden)

    Fahimeh eFalahi

    2015-02-01

    Full Text Available Epigenetic modifications such as histone post-transcriptional modifications and DNA methylation organize the DNA in the nucleus of eukaryotic cells and are critical for the spatio-temporal regulation of gene expression. These epigenetic modifications are reversible and precisely regulated by epigenetic enzymes. In addition to genetic mutations, epigenetic modifications are highly disrupted in cancer relative to normal tissues. Many epigenetic alterations (epi-mutations are associated with aberrations in the expression and/or activity of epigenetic enzymes. Thus, epigenetic regulators have emerged as prime targets for cancer therapy. Currently, several inhibitors of epigenetic enzymes (epi-drugs have been approved for use in the clinic to treat cancer patients with hematological malignancies. However, one potential disadvantage of epi-drugs is their lack of locus-selective specificity, which may result in the over-expression of undesirable parts of the genome. The emerging and rapidly growing field of epigenome engineering has opened new grounds for improving epigenetic therapy in view of reducing the genome-wide off-target effects of the treatment. In the current review, we will first describe the language of epigenetic modifications and their involvement in cancer. Next, we will overview the current strategies for engineering of artificial DNA binding domains in order to manipulate and ultimately normalize the aberrant landscape of the cancer epigenome (epigenome engineering. Lastly, the potential clinical applications of these emerging genome-engineering approaches will be discussed.

  2. Glass Durability Modeling, Activated Complex Theory (ACT)

    International Nuclear Information System (INIS)

    CAROL, JANTZEN

    2005-01-01

    The most important requirement for high-level waste glass acceptance for disposal in a geological repository is the chemical durability, expressed as a glass dissolution rate. During the early stages of glass dissolution in near static conditions that represent a repository disposal environment, a gel layer resembling a membrane forms on the glass surface through which ions exchange between the glass and the leachant. The hydrated gel layer exhibits acid/base properties which are manifested as the pH dependence of the thickness and nature of the gel layer. The gel layer has been found to age into either clay mineral assemblages or zeolite mineral assemblages. The formation of one phase preferentially over the other has been experimentally related to changes in the pH of the leachant and related to the relative amounts of Al +3 and Fe +3 in a glass. The formation of clay mineral assemblages on the leached glass surface layers ,lower pH and Fe +3 rich glasses, causes the dissolution rate to slow to a long-term steady state rate. The formation of zeolite mineral assemblages ,higher pH and Al +3 rich glasses, on leached glass surface layers causes the dissolution rate to increase and return to the initial high forward rate. The return to the forward dissolution rate is undesirable for long-term performance of glass in a disposal environment. An investigation into the role of glass stoichiometry, in terms of the quasi-crystalline mineral species in a glass, has shown that the chemistry and structure in the parent glass appear to control the activated surface complexes that form in the leached layers, and these mineral complexes ,some Fe +3 rich and some Al +3 rich, play a role in whether or not clays or zeolites are the dominant species formed on the leached glass surface. The chemistry and structure, in terms of Q distributions of the parent glass, are well represented by the atomic ratios of the glass forming components. Thus, glass dissolution modeling using simple

  3. Activation Energy

    Science.gov (United States)

    Gadeken, Owen

    2002-01-01

    Teaming is so common in today's project management environment that most of us assume it comes naturally. We further assume that when presented with meaningful and challenging work, project teams will naturally engage in productive activity to complete their tasks. This assumption is expressed in the simple (but false) equation: Team + Work = Teamwork. Although this equation appears simple and straightforward, it is far from true for most project organizations whose reality is a complex web of institutional norms based on individual achievement and rewards. This is illustrated by the very first successful team experience from my early Air Force career. As a young lieutenant, I was sent to Squadron Officer School, which was the first in the series of Air Force professional military education courses I was required to complete during my career. We were immediately formed into teams of twelve officers. Much of the course featured competition between these teams. As the most junior member of my team, I quickly observed the tremendous pressure to show individual leadership capability. At one point early in the course, almost everyone in our group was vying to become the team leader. This conflict was so intense that it caused us to fail miserably in our first outdoor team building exercise. We spent so much time fighting over leadership that we were unable to complete any of the events on the outdoor obstacle course. This complete lack of success was so disheartening to me that I gave our team little hope for future success. What followed was a very intense period of bickering, conflict, and even shouting matches as our dysfunctional team tried to cope with our early failures and find some way to succeed. British physician and researcher Wilfred Bion (Experiences in Groups, 1961) discovered that there are powerful psychological forces inherent in all groups that divert from accomplishing their primary tasks. To overcome these restraining forces and use the potential

  4. Size and surface modification of amorphous silica particles determine their effects on the activity of human CYP3A4 in vitro

    Science.gov (United States)

    Imai, Shunji; Yoshioka, Yasuo; Morishita, Yuki; Yoshida, Tokuyuki; Uji, Miyuki; Nagano, Kazuya; Mukai, Yohei; Kamada, Haruhiko; Tsunoda, Shin-ichi; Higashisaka, Kazuma; Tsutsumi, Yasuo

    2014-12-01

    Because of their useful chemical and physical properties, nanomaterials are widely used around the world - for example, as additives in food and medicines - and such uses are expected to become more prevalent in the future. Therefore, collecting information about the effects of nanomaterials on metabolic enzymes is important. Here, we examined the effects of amorphous silica particles with various sizes and surface modifications on cytochrome P450 3A4 (CYP3A4) activity by means of two different in vitro assays. Silica nanoparticles with diameters of 30 and 70 nm (nSP30 and nSP70, respectively) tended to inhibit CYP3A4 activity in human liver microsomes (HLMs), but the inhibitory activity of both types of nanoparticles was decreased by carboxyl modification. In contrast, amine-modified nSP70 activated CYP3A4 activity. In HepG2 cells, nSP30 inhibited CYP3A4 activity more strongly than the larger silica particles did. Taken together, these results suggest that the size and surface characteristics of the silica particles determined their effects on CYP3A4 activity and that it may be possible to develop silica particles that do not have undesirable effects on metabolic enzymes by altering their size and surface characteristics.

  5. Retaining Oxidative Stability of Emulsified Foods by Novel Nonmigratory Polyphenol Coated Active Packaging.

    Science.gov (United States)

    Roman, Maxine J; Decker, Eric A; Goddard, Julie M

    2016-07-13

    Oxidation causes lipid rancidity, discoloration, and nutrient degradation that decrease shelf life of packaged foods. Synthetic additives are effective oxidation inhibitors, but are undesirable to consumers who prefer "clean" label products. The aim of this study was to improve oxidative stability of emulsified foods by a novel nonmigratory polyphenol coated active packaging. Polyphenol coatings were applied to chitosan functionalized polypropylene (PP) by laccase assisted polymerization of catechol and catechin. Polyphenol coated PP exhibited both metal chelating (39.3 ± 2.5 nmol Fe(3+) cm(-2), pH 4.0) and radical scavenging (up to 52.9 ± 1.8 nmol Trolox eq cm(-2)) capacity, resulting in dual antioxidant functionality to inhibit lipid oxidation and lycopene degradation in emulsions. Nonmigratory polyphenol coated PP inhibited ferric iron promoted degradation better than soluble chelators, potentially by partitioning iron from the emulsion droplet interface. This work demonstrates that polyphenol coatings can be designed for advanced material chemistry solutions in active food packaging.

  6. ACE-I Inhibitory Activity from Phaseolus lunatus and Phaseolus vulgaris Peptide Fractions Obtained by Ultrafiltration.

    Science.gov (United States)

    Betancur-Ancona, David; Dávila-Ortiz, Gloria; Chel-Guerrero, Luis Antonio; Torruco-Uco, Juan Gabriel

    2015-11-01

    The involvement of angiotensin-I-converting enzyme (ACE-I) as one of the mechanisms controlling blood pressure is being studied to find alternative means of control of hypertension on human beings. On the market there are synthetic drugs that can control it, but these can cause undesirable health side effects. In this work was assessed the fractionation by ultrafiltration of the Lima bean (Phaseolus lunatus) and Jamapa bean (Phaseolus vulgaris), protein hydrolysates obtained with Alcalase(®) and Flavourzyme(®) on ACE-I inhibitory activity. Four membranes of different molecular cutoffs (10, 5, 3, and 1 kDa) were used. Fractions that had a higher inhibitory activity in both legumes were denominated as E (Phaseolus vulgaris with Alcalase and Flavourzyme with about 63.8 and 65.8 μg/mL values, respectively. The amino acid composition of these fractions showed residues in essential amino acids, which make a good source of energy and amino acids. On the other hand, the presence of hydrophobic amino acids such as V and P is a determining factor in the ACE-I inhibitor effect. The results suggest the possibility of obtaining and utilizing these peptide fractions in the development and innovation of a functional product that helps with treatment and/or prevention of hypertension.

  7. Split2 Protein-Ligation Generates Active IL-6-Type Hyper-Cytokines from Inactive Precursors.

    Science.gov (United States)

    Moll, Jens M; Wehmöller, Melanie; Frank, Nils C; Homey, Lisa; Baran, Paul; Garbers, Christoph; Lamertz, Larissa; Axelrod, Jonathan H; Galun, Eithan; Mootz, Henning D; Scheller, Jürgen

    2017-12-15

    Trans-signaling of the major pro- and anti-inflammatory cytokines Interleukin (IL)-6 and IL-11 has the unique feature to virtually activate all cells of the body and is critically involved in chronic inflammation and regeneration. Hyper-IL-6 and Hyper-IL-11 are single chain designer trans-signaling cytokines, in which the cytokine and soluble receptor units are trapped in one complex via a flexible peptide linker. Albeit, Hyper-cytokines are essential tools to study trans-signaling in vitro and in vivo, the superior potency of these designer cytokines are accompanied by undesirable stress responses. To enable tailor-made generation of Hyper-cytokines, we developed inactive split-cytokine-precursors adapted for posttranslational reassembly by split-intein mediated protein trans-splicing (PTS). We identified cutting sites within IL-6 (E 134 /S 135 ) and IL-11 (G 116 /S 117 ) and obtained inactive split-Hyper-IL-6 and split-Hyper-IL-11 cytokine precursors. After fusion with split-inteins, PTS resulted in reconstitution of active Hyper-cytokines, which were efficiently secreted from transfected cells. Our strategy comprises the development of a background-free cytokine signaling system from reversibly inactivated precursor cytokines.

  8. Efficient enzymatic degradation used as pre-stage treatment for norfloxacin removal by activated sludge.

    Science.gov (United States)

    Zhao, Ruinan; Li, Xiaohong; Hu, Mancheng; Li, Shuni; Zhai, Quanguo; Jiang, Yucheng

    2017-08-01

    Norfloxacin is often found in wastewater treatment plants, groundwater, and even drinking water causing environmental concerns because of its potential undesirable effects on human health or aquatic ecosystems. However, conventional treatments cannot deal with norfloxacin efficiently. This work proposes an efficiently enzymatic degradation of norfloxacin by chloroperoxidase (CPO). 82.18% degradation efficiency of norfloxacin was achieved after 25 min reaction time at pH 5.0 with an enzyme concentration of 1.5 × 10 -9  mol L -1 . HPLC-MS was used to determine the intermediates or final products. The product analysis and determination of the chemical oxygen demand indicated if the enzymatic degradation by CPO was carried out before the usually existing bioremediation techniques (usually activated sludge) in sewage treatment plant, the effluent containing norfloxacin can be decontaminated more efficiently and thoroughly than that only by activated sludge treatment. The eco-toxicity tests using a green algae, Chlorella pyrenoidosa, indicated that the toxicity of degraded products of norfloxacin was lower than the parent norfloxacin molecule. CPO-catalyzed degradation of norfloxacin is a promising alternative for treating effluent containing norfloxacin.

  9. Antioxidant activity of ethanolic and aqueous extracts of Uncaria tomentosa (Willd.) DC.

    Science.gov (United States)

    Pilarski, Radosław; Zieliński, Henryk; Ciesiołka, Danuta; Gulewicz, Krzysztof

    2006-03-08

    The antioxidant properties of aqueous and ethanolic extracts of the Uncaria tomentosa bark were evaluated. The analysis included trolox equivalent antioxidant capacity (TEAC), peroxyl radical-trapping capacity (PRTC), superoxide radical scavenging activity (SOD) and quantitation of total tannins (TT) and total phenolic compounds (TPC). The obtained results indicate high antioxidant capacity of the studied materials in comparison to the other extracts of fruits, vegetables, cereals and medicinal plants. Higher antioxidant activity and total phenolic compounds of the alcoholic preparations -- TEAC=0.57 mmol of Trolox/g, PRTC=0.52 mmol of Trolox/g and SOD=0.39 U/mg than of the aqueous preparation -- TEAC=0.34 mmol of Trolox/g, PRTC=0.19 mmol of Trolox/g and SOD=0.10 U/mg were observed. These results might suggest higher medical suitability of alcoholic extracts. However, the highly elevated level of tannins in alcoholic extracts may cause undesirable gastric effects.

  10. Antiviral Activity of Crude Hydroethanolic Extract from Schinus terebinthifolia against Herpes simplex Virus Type 1.

    Science.gov (United States)

    Nocchi, Samara Requena; Companhoni, Mychelle Vianna Pereira; de Mello, João Carlos Palazzo; Dias Filho, Benedito Prado; Nakamura, Celso Vataru; Carollo, Carlos Alexandre; Silva, Denise Brentan; Ueda-Nakamura, Tânia

    2017-04-01

    Herpes simplex virus infections persist throughout the lifetime of the host and affect more than 80 % of the humans worldwide. The intensive use of available therapeutic drugs has led to undesirable effects, such as drug-resistant strains, prompting the search for new antiherpetic agents. Although diverse bioactivities have been identified in Schinus terebinthifolia , its antiviral activity has not attracted much attention. The present study evaluated the antiherpetic effects of a crude hydroethanolic extract from the stem bark of S. terebinthifolia against Herpes simplex virus type 1 in vitro and in vivo as well as its genotoxicity in bone marrow in mammals and established the chemical composition of the crude hydroethanolic extract based on liquid chromatography-diode array detector-mass spectrometry and MS/MS. The crude hydroethanolic extract inhibited all of the tested Herpes simplex virus type 1 strains in vitro and was effective in the attachment and penetration stages, and showed virucidal activity, which was confirmed by transmission electron microscopy. The micronucleus test showed that the crude hydroethanolic extract had no genotoxic effect at the concentrations tested. The crude hydroethanolic extract afforded protection against lesions that were caused by Herpes simplex virus type 1 in vivo . Liquid chromatography-diode array detector-mass spectrometry and MS/MS identified 25 substances, which are condensed tannins mainly produced by a B-type linkage and prodelphinidin and procyanidin units. Georg Thieme Verlag KG Stuttgart · New York.

  11. Antioxidant activity of various solvent extracts from Allomyrina dichotoma (Arthropoda: Insecta) larvae.

    Science.gov (United States)

    Suh, Hwa-Jin; Kim, Seong-Ryul; Lee, Kyung-Seok; Park, Shin; Kang, Sun Chul

    2010-05-03

    This study was under taken to evaluate the antioxidant properties of larvae extracts of Allomyrina dichotoma. The antioxidant activities of various larvae extracts of water, methanol, ethyl-acetate, chloroform, and hexane were measured by 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide anion radical and singlet oxygen ((1)O(2)). The methanolic larvae extracts displayed the greatest effect in DPPH radical scavenging assay, but the reducing activity of larvae extracts was weaker in the superoxide anion radical assay. However, methanol (ME) and chloroform extracts (CE) could be compared to ascorbic acid in (1)O(2) quenching ability. ME (the concentration of 50% (1)O(2) quenching, QC(50)=0.080mg/ml) and CE (QC(50)=0.051mg/ml) extracts had 1.7, 2.7 times better efficiency than ascorbic acid (QC(50)=0.138mg/ml), respectively. Also the extracts were found to protect biological systems in Escherichia coli and lactate dehydrogenase against detrimental effects of (1)O(2) of type II photosensitization in vitro. The ability of larvae extracts to scavenge free radicals could significantly change contents of GA equivalent, an important factor for the potency of antioxidant capacity. The results suggest that our study may contribute to the development of new bioactive products with potential applications to reduce oxidative stress in living organisms involving reactive oxygen species as well as play a vital role in insect organisms against oxidative damage of undesirable conditions. Copyright 2010 Elsevier B.V. All rights reserved.

  12. Discovery of PI-1840, a novel noncovalent and rapidly reversible proteasome inhibitor with anti-tumor activity.

    Science.gov (United States)

    Kazi, Aslamuzzaman; Ozcan, Sevil; Tecleab, Awet; Sun, Ying; Lawrence, Harshani R; Sebti, Saïd M

    2014-04-25

    The proteasome inhibitor bortezomib is effective in hematologic malignancies such as multiple myeloma but has little activity against solid tumors, acts covalently, and is associated with undesired side effects. Therefore, noncovalent inhibitors that are less toxic and more effective against solid tumors are desirable. Structure activity relationship studies led to the discovery of PI-1840, a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC50 value = 27 ± 0.14 nm) over trypsin-like and peptidylglutamyl peptide hydrolyzing (IC50 values >100 μm) activities of the proteasome. Furthermore, PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Mass spectrometry and dialysis studies demonstrate that PI-1840 is a noncovalent and rapidly reversible CT-L inhibitor. In intact cancer cells, PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax, and IκB-α, inhibits survival pathways and viability, and induces apoptosis. Furthermore, PI-1840 sensitizes human cancer cells to the mdm2/p53 disruptor, nutlin, and to the pan-Bcl-2 antagonist BH3-M6. Finally, in vivo, PI-1840 but not bortezomib suppresses the growth in nude mice of human breast tumor xenografts. These results warrant further evaluation of a noncovalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors.

  13. Treatment of Aqueous Film-Forming Foam by Heat-Activated Persulfate Under Conditions Representative of In Situ Chemical Oxidation

    Science.gov (United States)

    2017-01-01

    Poly- and perfluoroalkyl substances (PFASs) have been detected in an increasing number of water supplies. In many instances, the contamination is associated with the use of PFAS-containing aqueous film-forming foams (AFFF) in firefighting activities. To investigate the potential for remediating AFFF contamination in groundwater with heat-activated persulfate, PFAS oxidation and the generation of transformation products was evaluated under well-controlled conditions. Fluorotelomer- and perfluoroalkyl sulfonamide-based polyfluorinated compounds were transformed to perfluorinated carboxylic acids, which underwent further degradation under acidic conditions produced after persulfate decomposed. The presence of aquifer sediments decreased the efficiency of the remedial process but did not alter the transformation pathways. At high concentrations, the presence of organic solvents, such as those present in AFFF formulations, inhibited transformation of a representative perfluorinated compound, perfluorooctanoic acid. Heat-activated persulfate did not transform perfluorooctanesulfonic acid or perfluorohexanesulfonic acid under any conditions. Despite challenges associated with the creation of acidic conditions in the subsurface, the potential for generation of undesirable transformation products, and the release of toxic metals, heat-activated persulfate may be a useful in situ treatment for sites contaminated with polyfluoroalkyl substances and perfluorocarboxylic acids. PMID:29164864

  14. Differential growth inhibition of cancer cell lines and antioxidant activity of extracts of red, brown, and green marine algae.

    Science.gov (United States)

    Murugan, Kavitha; Iyer, Vidhya V

    2013-05-01

    As the use of various anticancer drugs is associated with many undesirable side effects, there is an urgent need for the discovery of new, better, and specific anticancer compounds. Antioxidant and antiproliferative activities as well as effects on cell morphology were investigated for methanol (M), chloroform (C), ethyl acetate (E), and aqueous (A) extracts of Caulerpa peltata, Gelidiella acerosa, Padina gymnospora, and Sargassum wightii using 2,2-diphenyl-1-picrylhydrazyl radical-scavenging, ferrous ion chelation, and resazurin-based growth inhibition (in A549, HCT-15, MG-63, and PC-3 cell lines) assays. A general trend was the greater extraction of phenols and flavonoids by chloroform and ethyl acetate, which showed higher activity in many assays. These non-polar C and E extracts showed higher DPPH radical-scavenging and growth inhibitory activities in A549, HCT-15, and PC-3 cells. However, higher ferrous ion chelation (A extracts) and growth inhibition in MG-63 cells (M and A extracts) were seen for the polar extracts. Furthermore, P. gymnospora and C. peltata emerged as promising sources for antiproliferative agents that could be explored for their own activity and as leads for the development of other compounds.

  15. Inhibitory effects of spirulina platensis on carcinogen-activating cytochrome P450 isozymes and potential for drug interactions.

    Science.gov (United States)

    Savranoglu, Seda; Tumer, Tugba Boyunegmez

    2013-01-01

    Spirulina platensis (SP) has been considered as potential food source of 21st century due to its remarkable nutrient profile and therapeutic benefits. However, the cytochrome P450 (CYP)-mediated drug/chemical interaction potential of SP has not yet been pursued. We investigated the effects of SP on the expressions and enzymatic activities of main CYP isozymes. After the rats were orally administered with SP daily for 5 consecutive weeks, there were significant downregulations in hepatic expression levels and inhibition in enzymatic activities of CYP1A2 and CYP2E1 compared to controls. In addition, a significant decrease was observed in CYP2C6-associated enzyme activity with no remarkable changes in messenger RNA (mRNA)/protein levels. The SP application resulted in significant increases in mRNA/protein levels of both CYP2B1 and CYP3A1 without a significant change in enzyme activities. These findings partly explain the chemopreventive properties of SP toward various organ toxicities, mutagenesis, and carcinogenesis; however, its coadministration with some CYP substrates may lead to undesirable drug interactions.

  16. Adsorption of Arsenate by Nano Scaled Activated Carbon Modified by Iron and Manganese Oxides

    Directory of Open Access Journals (Sweden)

    George P. Gallios

    2017-09-01

    Full Text Available The presence of arsenic in water supplies is a major problem for public health and still concerns large parts of population in Southeast Asia, Latin America and Europe. Removal of arsenic is usually accomplished either by coagulation with iron salts or by adsorption with iron oxides or activated alumina. However, these materials, although very efficient for arsenic, normally do not remove other undesirable constituents from waters, such as chlorine and organo-chlorine compounds, which are the results of water chlorination. Activated carbon has this affinity for organic compounds, but does not remove arsenic efficiently. Therefore, in the present study, iron modified activated carbons are investigated as alternative sorbents for the removal of arsenic(V from aqueous solutions. In addition, modified activated carbons with magnetic properties can easily be separated from the solutions. In the present study, a simple and efficient method was used for the preparation of magnetic Fe3(Mn2+O4 (M:Fe and/or Mn activated carbons. Activated carbons were impregnated with magnetic precursor solutions and then calcinated at 400 °C. The obtained carbons were characterized by X-ray diffraction (XRD, nitrogen adsorption isotherms, scanning electron microscopy (SEM, vibrating sample magnetometer (VSM, Fourier Transform Infrared Spectrometry (FTIR and X-ray photoelectron spectroscopy (XPS measurements. Their adsorption performance for As(V was evaluated. The iron impregnation presented an increase in As(V maximum adsorption capacity (Qmax from about 4 mg g−1 for the raw carbon to 11.05 mg g−1, while Mn incorporation further increased the adsorption capacity at 19.35 mg g−1.

  17. Data-mining of potential antitubercular activities from molecular ingredients of traditional Chinese medicines.

    Science.gov (United States)

    Jamal, Salma; Scaria, Vinod

    2014-01-01

    Background. Traditional Chinese medicine encompasses a well established alternate system of medicine based on a broad range of herbal formulations and is practiced extensively in the region for the treatment of a wide variety of diseases. In recent years, several reports describe in depth studies of the molecular ingredients of traditional Chinese medicines on the biological activities including anti-bacterial activities. The availability of a well-curated dataset of molecular ingredients of traditional Chinese medicines and accurate in-silico cheminformatics models for data mining for antitubercular agents and computational filters to prioritize molecules has prompted us to search for potential hits from these datasets. Results. We used a consensus approach to predict molecules with potential antitubercular activities from a large dataset of molecular ingredients of traditional Chinese medicines available in the public domain. We further prioritized 160 molecules based on five computational filters (SMARTSfilter) so as to avoid potentially undesirable molecules. We further examined the molecules for permeability across Mycobacterial cell wall and for potential activities against non-replicating and drug tolerant Mycobacteria. Additional in-depth literature surveys for the reported antitubercular activities of the molecular ingredients and their sources were considered for drawing support to prioritization. Conclusions. Our analysis suggests that datasets of molecular ingredients of traditional Chinese medicines offer a new opportunity to mine for potential biological activities. In this report, we suggest a proof-of-concept methodology to prioritize molecules for further experimental assays using a variety of computational tools. We also additionally suggest that a subset of prioritized molecules could be used for evaluation for tuberculosis due to their additional effect against non-replicating tuberculosis as well as the additional hepato-protection offered by

  18. Effect of potassium sources on the antioxidant activity of eggplant¹

    Directory of Open Access Journals (Sweden)

    Douglas José Marques

    2014-12-01

    Full Text Available Potassium participates in the essential processes in plant physiology, however, the effects of K sources on plant metabolism have been little studied. Also, in certain cases, K sources and concentrations may cause undesirable effects, e.g., soil salinization. The objective was to evaluate the effect of K sources and levels on the enzyme activity of the antioxidant system and protein content in eggplant (Solanum melongena L. leaves and to determine the most suitable K sources for these physiological characteristics. The experiment was conducted in randomized blocks, in a 2 × 4 factorial design, consisting of two K sources (KCl and K2SO4 and rates (250, 500, 750, and 1000 kg ha-1 K2O, with four replications. The following variables were evaluated: plant height, number of leaves per plant, superoxide dismutase (SOD, catalase (CAT, and leaf protein content. There was an increase in CAT activity with increasing K levels until 30 days after transplanting (DAT, when K2SO4 was applied and until 60 DAT, when KCl was used; after this period, the enzyme activity decreased under both sources. The activity of SOD increased in the presence of KCl, but was reduced with the application of K2SO4. For both K sources, increasing rates reduced the protein content and number of leaves per plant, and this reduction was greater under KCl application. Thus it was concluded that KCl tends more strongly to salinize the soil than K2SO4. Both for KCl and for K2SO4, the increasing rates adversely affected the activities of CAT and SOD and the levels of leaf protein in eggplant. The potential of KCl to reduce the enzyme activity of SOD and CAT, leaf protein content and plant growth of eggplant was stronger than that of K2SO4.

  19. Assessment of herbal drugs for promising anti-Candida activity.

    Science.gov (United States)

    Soliman, Sameh S M; Semreen, Mohammad H; El-Keblawy, Ali A; Abdullah, Arbab; Uppuluri, Priya; Ibrahim, Ashraf S

    2017-05-08

    Microbial infections are diverse and cause serious human diseases. Candida albicans infections are serious healthcare-related infections that are complicated by its morphological switching from yeast to hyphae, resistant biofilm formation and mixed infections with bacteria. Due to the increase in drug resistance to currently used antimicrobial agents and the presence of undesirable side effects, the need for safe and effective novel therapies is important. Compounds derived from plants are known for their medicinal properties including antimicrobial activities. The purpose of the study was to compare and evaluate the anti-Candida activities of several medicinal plants in order for the selection of a herbal drug for human use as effective antimicrobial. The selection was taking into considerations two important parameters; parameters related to the selected drug including activity, stability, solubility and toxicity and parameters related to the pathogen including its different dynamic growth and its accompanied secondary bacterial infections. Seven different plants including Avicennia marina (Qurm), Fagonia indica (Shoka'a), Lawsania inermis (Henna), Portulaca oleracea (Baq'lah), Salvadora persica (Souwak), Ziziphus spina- Christi (Sidr) and Asphodelus tenuifolius (Kufer) were ground and extracted with ethanol. The ethanol extracts were evaporated and the residual extract dissolved in water prior to testing against Candida albicans in its different morphologies. The antibacterial and cytotoxic effects of the plants extracts were also tested. Out of the seven tested plants, L. inermis and P. oleracea showed significant anti-Candida activity with MIC ~10 μg/mL. Furthermore, both plant extracts were able to inhibit C. albicans growth at its dynamic growth phases including biofilm formation and age resistance. Accompanied secondary bacterial infections can complicate Candida pathogenesis. L. inermis and P. oleracea extracts showed effective antibacterial activities

  20. Physical Activity Basics

    Science.gov (United States)

    ... Weight Breastfeeding Micronutrient Malnutrition State and Local Programs Physical Activity Basics Recommend on Facebook Tweet Share Compartir How much physical activity do you need? Regular physical activity helps ...

  1. Time kinetics of physical activity, sitting, and quality of life measures within a regional workplace: a cross-sectional analysis.

    Science.gov (United States)

    Lindsay, Daniel B; Devine, Sue; Sealey, Rebecca M; Leicht, Anthony S

    2016-08-15

    Interventions to increase physical activity and reduce sedentary behaviours within the workplace have been previously investigated. However, the evolution of these constructs without intervention has not been well documented. This retrospective study explored the natural progression or time kinetics of physical activity, sedentary behaviours and quality of life in a professional skilled workplace where focussed interventions were lacking. Participants (n = 346) employed as full-time staff members at a regional university completed an online survey in 2013 assessing physical activity and sedentary behaviours via the International Physical Activity Questionnaire, and quality of life via the Short-Form 36v2 questionnaire. Differences between that cohort of participants and an initial sample of similar participants (2009, n = 297), accounting for gender and staff categories (academic vs. professional), were examined using ANCOVAs with working hours as a co-variate. In comparison to the initial cohort, the follow-up cohort reported significantly less leisure-time, total walking, total vigorous and total physical activity levels, and lower overall physical health for quality of life (p physical activity levels (p workplace interventions, total physical activity levels were lower with sedentary behaviours greater at a rate twice that reported previously. Continuation of these undesirable health behaviours may impact negatively on worker productivity and health at a greater rate than that currently reported. Workplace interventions targeting sedentary behaviours and physical activity should be actively incorporated into organisations to counteract the alarming behavioural trends found in this study to maintain and/or enhance employee health and productivity.

  2. Time kinetics of physical activity, sitting, and quality of life measures within a regional workplace: a cross–sectional analysis

    Directory of Open Access Journals (Sweden)

    Daniel B. Lindsay

    2016-08-01

    Full Text Available Abstract Background Interventions to increase physical activity and reduce sedentary behaviours within the workplace have been previously investigated. However, the evolution of these constructs without intervention has not been well documented. This retrospective study explored the natural progression or time kinetics of physical activity, sedentary behaviours and quality of life in a professional skilled workplace where focussed interventions were lacking. Methods Participants (n = 346 employed as full-time staff members at a regional university completed an online survey in 2013 assessing physical activity and sedentary behaviours via the International Physical Activity Questionnaire, and quality of life via the Short-Form 36v2 questionnaire. Differences between that cohort of participants and an initial sample of similar participants (2009, n = 297, accounting for gender and staff categories (academic vs. professional, were examined using ANCOVAs with working hours as a co-variate. Results In comparison to the initial cohort, the follow-up cohort reported significantly less leisure-time, total walking, total vigorous and total physical activity levels, and lower overall physical health for quality of life (p < 0.05. In contrast, the follow-up cohort reported a significantly greater weekly sitting time, greater mental health scores for quality of life and greater total moderate physical activity levels (p < 0.05 compared to the initial cohort. Conclusions Over a 4-year timeframe and without focussed workplace interventions, total physical activity levels were lower with sedentary behaviours greater at a rate twice that reported previously. Continuation of these undesirable health behaviours may impact negatively on worker productivity and health at a greater rate than that currently reported. Workplace interventions targeting sedentary behaviours and physical activity should be actively incorporated into organisations to

  3. Study of antioxidant activity and free radical scavenging power of ...

    African Journals Online (AJOL)

    According to the undesirable effects of many chemical preservatives in food products such as oilseed extraction industry, the possibility of substituting these materials with effective compounds of herbal plants have been considered by the researchers. In this study, at first, the Physalis Alkekengi flower extract was extracted ...

  4. Time and activity sequence prediction of business process instances

    DEFF Research Database (Denmark)

    Polato, Mirko; Sperduti, Alessandro; Burattin, Andrea

    2018-01-01

    The ability to know in advance the trend of running process instances, with respect to different features, such as the expected completion time, would allow business managers to timely counteract to undesired situations, in order to prevent losses. Therefore, the ability to accurately predict...

  5. Effect of fertilization on biological activity of community of soil streptomycetes

    Directory of Open Access Journals (Sweden)

    Ivana CHAROUSOVÁ

    2016-12-01

    Full Text Available The search for new natural mechanisms to inhibit the growth of phytopathogenic microorganisms has become widely widespread. Therefore, the main objective of the present study was determination of antimicrobial activities of actinomycetes isolated from agricultural soil, which was fertilized mainly by organic fertilizers, against 8 selected phytopathogenic strains. Among the actinomycetes, Streptomyces species have been extensively studied, because they have been recognized as an important source of secondary metabolites, which can suppress the growth of undesirable pests in crops. The results indicated that the richest source of Streptomyces colonies was soil fertilized with compost (103 x104 CFU*g-1 dry soil. On the basis of morphological signs, total of 65 isolates were selected and examined for antimicrobial activities. Isolates exhibited the best activity against Gram negative bacterium Clavibacter michiganensis subsp. sepedonicus, disease agent of “ring rot” of potatoes and against fungus Fusarium poae, disease agent of Fusarium head blight of wheat. Twelve isolates exhibited promising broad-spectrum activity against tested organisms. On the basis of results, six of them were selected for further screening. Comparison of polyphasic studies with available literature led to identification of biological active strains S. olivochromogenes (13SC11, S. avermitilis (13SC2, S. rishiriensis (13SC13, S. globisporus (13SC19, S. sampsonii (13SPC10 and S. avidinii (13SPC4. After quantification analysis of various enzymes, tested isolates produced alkaline phosphatase, leucinearylamidase, valinearylamidase, acid phosphatase, naphtol-AS-BI-phosphohydrolase, glucosidase in high values (>40 nmol and were positive for nitrate reduction, hydrolysis of gelatin, urease, and esculin. These isolates can be used in the development of new biopesticides anf biofertilizers with antibacterial and antifungal effect.

  6. Towards Low-Cost Effective and Homogeneous Thermal Activation of Shape Memory Polymers

    Directory of Open Access Journals (Sweden)

    Andrés Díaz Lantada

    2013-11-01

    Full Text Available A typical limitation of intelligent devices based on the use of shape-memory polymers as actuators is linked to the widespread use of distributed heating resistors, via Joule effect, as activation method, which involves several relevant issues needing attention, such as: (a Final device size is importantly increased due to the additional space required for the resistances; (b the use of resistances limits materials’ strength and the obtained devices are normally weaker; (c the activation process through heating resistances is not homogeneous, thus leading to important temperature differences among the polymeric structure and to undesirable thermal gradients and stresses, also limiting the application fields of shape-memory polymers. In our present work we describe interesting activation alternatives, based on coating shape-memory polymers with different kinds of conductive materials, including textiles, conductive threads and conductive paint, which stand out for their easy, rapid and very cheap implementation. Distributed heating and homogeneous activation can be achieved in several of the alternatives studied and the technical results are comparable to those obtained by using advanced shape-memory nanocomposites, which have to deal with complex synthesis, processing and security aspects. Different combinations of shape memory epoxy resin with several coating electrotextiles, conductive films and paints are prepared, simulated with the help of thermal finite element method based resources and characterized using infrared thermography for validating the simulations and overall design process. A final application linked to an active catheter pincer is detailed and the advantages of using distributed heating instead of conventional resistors are discussed.

  7. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Physical Activity Basics Needs for Adults Needs for Children What Counts Needs for Older Adults Needs for ... Adding Physical Activity to Your Life Activities for Children Activities for Older Adults Overcoming Barriers Measuring Physical ...

  8. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Needs for Pregnant or Postpartum Women Physical Activity & Health Adding Physical Activity to Your Life Activities for ... Tools Community Strategies Worksite Physical Activity Steps to Wellness Walkability Audit Tool Sample Audit Glossary Selected References ...

  9. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Adults Need More Physical Activity MMWR Data Highlights State Indicator Report on Physical Activity, 2014 Recommendations & Guidelines ... Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local Programs Measuring Physical Activity Intensity Recommend ...

  10. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... for Older Adults Needs for Pregnant or Postpartum Women Physical Activity & Health Adding Physical Activity to Your ... Activity, 2014 Recommendations & Guidelines Fact Sheets & Infographics Social Media Tools Community Strategies BE Active: Connecting Routes + Destinations ...

  11. Physical Activity Guidelines

    Science.gov (United States)

    ... use this site. health.gov Physical Activity Guidelines Physical Activity Physical activity is key to improving the health of the Nation. Based on the latest science, the Physical Activity Guidelines for Americans is an essential resource ...

  12. Facts about Physical Activity

    Science.gov (United States)

    ... Micronutrient Malnutrition State and Local Programs Facts about Physical Activity Recommend on Facebook Tweet Share Compartir Some ... Activity Guideline for aerobic activity than older adults. Physical activity and socioeconomic status Adults with more education ...

  13. Engineering and Technology Challenges for Active Debris Removal

    Science.gov (United States)

    Liou, Jer-Chyi

    2011-01-01

    After more than fifty years of space activities, the near-Earth environment is polluted with man-made orbital debris. The collision between Cosmos 2251 and the operational Iridium 33 in 2009 signaled a potential collision cascade effect, also known as the "Kessler Syndrome", in the environment. Various modelling studies have suggested that the commonly-adopted mitigation measures will not be sufficient to stabilize the future debris population. Active debris removal must be considered to remediate the environment. This paper summarizes the key issues associated with debris removal and describes the technology and engineering challenges to move forward. Fifty-four years after the launch of Sputnik 1, satellites have become an integral part of human society. Unfortunately, the ongoing space activities have left behind an undesirable byproduct orbital debris. This environment problem is threatening the current and future space activities. On average, two Shuttle window panels are replaced after every mission due to damage by micrometeoroid or orbital debris impacts. More than 100 collision avoidance maneuvers were conducted by satellite operators in 2010 to reduce the impact risks of their satellites with respect to objects in the U.S. Space Surveillance Network (SSN) catalog. Of the four known accident collisions between objects in the SSN catalog, the last one, collision between Cosmos 2251 and the operational Iridium 33 in 2009, was the most significant. It was the first ever accidental catastrophic destruction of an operational satellite by another satellite. It also signaled the potential collision cascade effect in the environment, commonly known as the "Kessler Syndrome," predicted by Kessler and Cour-Palais in 1978 [1]. Figure 1 shows the historical increase of objects in the SSN catalog. The majority of the catalog objects are 10 cm and larger. As of April 2011, the total objects tracked by the SSN sensors were more than 22,000. However, approximately 6000 of

  14. H1N1 vaccination in Sjögren's syndrome triggers polyclonal B cell activation and promotes autoantibody production.

    Science.gov (United States)

    Brauner, Susanna; Folkersen, Lasse; Kvarnström, Marika; Meisgen, Sabrina; Petersen, Sven; Franzén-Malmros, Michaela; Mofors, Johannes; Brokstad, Karl A; Klareskog, Lars; Jonsson, Roland; Westerberg, Lisa S; Trollmo, Christina; Malmström, Vivianne; Ambrosi, Aurelie; Kuchroo, Vijay K; Nordmark, Gunnel; Wahren-Herlenius, Marie

    2017-10-01

    Vaccination of patients with rheumatic disease has been reported to result in lower antibody titres than in healthy individuals. However, studies primarily include patients on immunosuppressive therapy. Here, we investigated the immune response of treatment-naïve patients diagnosed with primary Sjögren's syndrome (pSS) to an H1N1 influenza vaccine. Patients with Sjögren's syndrome without immunomodulatory treatment and age-matched and gender-matched healthy controls were immunised with an H1N1 influenza vaccine and monitored for serological and cellular immune responses. Clinical symptoms were monitored with a standardised form. IgG class switch and plasma cell differentiation were induced in vitro in purified naïve B cells of untreated and hydroxychloroquine-treated patients and healthy controls. Gene expression was assessed by NanoString technology. Surprisingly, treatment-naïve patients with Sjögren's syndrome developed higher H1N1 IgG titres of greater avidity than healthy controls on vaccination. Notably, off-target B cells were also triggered resulting in increased anti-EBV and autoantibody titres. Endosomal toll-like receptor activation of naïve B cells in vitro revealed a greater propensity of patient-derived cells to differentiate into plasmablasts and higher production of class switched IgG. The amplified plasma cell differentiation and class switch could be induced in cells from healthy donors by preincubation with type 1 interferon, but was abolished in hydroxychloroquine-treated patients and after in vitro exposure of naïve B cells to chloroquine. This comprehensive analysis of the immune response in autoimmune patients to exogenous stimulation identifies a mechanistic basis for the B cell hyperactivity in Sjögren's syndrome, and suggests that caution is warranted when considering vaccination in non-treated autoimmune patients. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights

  15. Active knee joint flexibility and sports activity

    DEFF Research Database (Denmark)

    Hahn, Thomas; Foldspang, Anders; Vestergaard, E

    1999-01-01

    was significantly higher in women than in men and significantly positively associated with weekly hours of swimming and weekly hours of competitive gymnastics. Active knee flexion was significantly positively associated with participation in basketball, and significantly negatively associated with age and weekly......The aim of the study was to estimate active knee flexion and active knee extension in athletes and to investigate the potential association of each to different types of sports activity. Active knee extension and active knee flexion was measured in 339 athletes. Active knee extension...... hours of soccer, European team handball and swimming. The results point to sport-specific adaptation of active knee flexion and active knee extension. Udgivelsesdato: 1999-Apr...

  16. Catalytic dehydrogenation of isobutane in the presence of hydrogen over Cs-modified Ni2P supported on active carbon

    Science.gov (United States)

    Xu, Yanli; Sang, Huanxin; Wang, Kang; Wang, Xitao

    2014-10-01

    In this article, an environmentally friendly non-noble-metal class of Cs-Ni2P/active carbon (AC) catalyst was prepared and demonstrated to exhibit enhanced catalytic performance in isobutane dehydrogenation. The results of activity tests reveal that Ni/AC catalyst was highly active for isobutane cracking, which led to the formation of abundant methane and coke. After the introduction of phosphorus through impregnation with ammonium di-hydrogen phosphate and H2-temperature programmed reduction, undesired cracking reactions were effectively inhibited, and the selectivity to isobutene and stability of catalyst increased remarkably. The characterization results indicate that, after the addition of phosphorous, the improvement of dehydrogenation selectivity is ascribed to the partial positive charges carried on Ni surface in Ni2P particles, which decreases the strength of Nisbnd C bond between Ni and carbonium-ion intermediates and the possibility of excessive dehydrogenation. In addition, Cs-modified Ni2P/AC catalysts display much higher catalytic performance as compared to Ni2P/AC catalyst. Cs-Ni2P-6.5 catalyst has the highest catalytic performance, and the selectivity to isobutene higher than 93% can be obtained even after 4 h reaction. The enhancement in catalytic performance of the Cs-modified catalysts is mainly attributed to the function of Cs to improve the dispersion of Ni2P particles, transfer electron from Cs to Ni, and decrease acid site number and strength.

  17. APOBEC3G inhibits HIV-1 RNA elongation by inactivating the viral trans-activation response element.

    Science.gov (United States)

    Nowarski, Roni; Prabhu, Ponnandy; Kenig, Edan; Smith, Yoav; Britan-Rosich, Elena; Kotler, Moshe

    2014-07-29

    Deamination of cytidine residues in viral DNA is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient human immunodeficiency virus type 1 (HIV-1) replication. dC-to-dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. Here, we demonstrate that A3G provides an additional layer of defense against HIV-1 infection dependent on inhibition of proviral transcription. HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription. We further show that free single-stranded DNA (ssDNA) termini are not essential for A3G activity and a gap of CCC motif blocked with juxtaposed DNA or RNA on either or 3'+5' ends is sufficient for A3G deamination. These results identify A3G as an efficient mutator and that deamination of (-)SSDNA results in an early block of HIV-1 transcription. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Measuring Physical Activity Intensity

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    Full Text Available ... gov . Physical Activity Physical Activity Basics Needs for Adults Needs for Children What Counts Needs for Older Adults Needs for ... Adding Physical Activity to Your Life Activities for Children Activities for Older Adults Overcoming Barriers Measuring Physical Activity Intensity Target Heart ...

  19. Effectiveness of Higher Fatty Acids C8, C10 and C12, Dimethyl Dicarbonate and Sulphur Dioxide for Inhibition of Re-fermentation and Malolactic Activities in Wine

    Directory of Open Access Journals (Sweden)

    Mojmír Baroň

    2014-01-01

    Full Text Available The issue of preventing the re-fermentation and protection against undesirable malolactic fermentation (MLF in order to safe content of acids in wine is very complicated. In this paper the saturated higher fatty acids (HFA – C8, C10 and C12, dimethyldicarbonate (DMDC and sulphur dioxide (SO2 were tested. The re-fermentation test showed the strongest inhibition power at ratio 2:8, 1:9 and 0:10 as C8:C10 acids – 65 days without re-fermentation. MLF experiments confirmed that addition of SO2 into the fermenting media causes rapid inhibition of lactic acid bacteria metabolic activity. Malic acid concentrations were proportionally decreasing during 6 days of experiment and at the end the content of this acid varied between 0.16 and 0.22 g/L, the only exception formed a variant with the addition of SO2 (1.57 g/L of malic acid. After calculation of the average consumption rate of malic acid, the results showed the inhibition power – SO2 (81.05% followed by variant of 40 mg/L mixture of HFA (40.76%, a variant of 200 mg/L of DMDC (31.98% and a variant of 20 mg/L mixture of HFA (12.59%. The addition of HFA can significantly reduce the dosage of other preservatives, especially SO2. Based on results, this method can be recommend in the production of wines with residual sugar and also wines made from over-mature material to prevent undesirable MLF.

  20. The Effect of Kanamycin and Tetracycline on Growth and Photosynthetic Activity of Two Chlorophyte Algae

    Directory of Open Access Journals (Sweden)

    Khawaja Muhammad Imran Bashir

    2016-01-01

    Full Text Available Antibiotics are routinely used in microalgae culture screening, stock culture maintenance, and genetic transformation. By studying the effect of antibiotics on microalgae growth, we can estimate the least value to inhibit growth of undesired pathogens in algal culture. We studied the effect of kanamycin and tetracycline on the growth and photosynthetic activity of two chlorophyte microalgae, Dictyosphaerium pulchellum and Micractinium pusillum. We measured CFU mL−1 on agar plates, optical density, fluorescence yields, and photosynthetic inhibition. Our results showed a significant effect of kan and tet on the tested microalgae species except tet, which showed a minor effect on M. pusillum. Both antibiotics are believed to interact with the protein synthesis machinery; hence, the inhibitory effect of the tested antibiotics was further confirmed by isolation and quantification of the whole cell protein. A significant reduction in protein quantity was observed at concentrations more than 5 mg L−1, except M. pusillum, which showed only a slight reduction in protein quantity even at the maximum tested concentration of tet (30 mg L−1. This study can further aid in aquaculture industry, for the maintenance of the microalgae stock cultures and it can also help the microalgae genetic engineers in the construction of molecular markers.

  1. Long alkyl-chain imidazolium ionic liquids: Antibiofilm activity against phototrophic biofilms.

    Science.gov (United States)

    Reddy, G Kiran Kumar; Nancharaiah, Y V; Venugopalan, V P

    2017-07-01

    Biofilm formation is problematic and hence undesirable in medical and industrial settings. In addition to bacteria, phototrophic organisms are an integral component of biofilms that develop on surfaces immersed in natural waters. 1-Alkyl-3-methyl imidazolium ionic liquids (IL) with varying alkyl chain length were evaluated for their influence on the formation of monospecies (Navicula sp.) and multispecies biofilms under phototrophic conditions. An IL with a long alkyl side chain, 1-hexadecyl-3-methylimidaazolium chloride ([C 16 (MIM)][Cl]) retarded growth, adhesion and biofilm formation of Navicula sp. at concentrations as low as 5μM. Interestingly, [C 16 (MIM)][Cl] was very effective in preventing multispecies phototrophic biofilms on fibre reinforced plastic surfaces immersed in natural waters (fresh and seawater). SYTOX ® Green staining and chlorophyll leakage assay confirmed that the biocidal activity of the IL was exerted through cell membrane disruption. The data show that [C 16 (MIM)][Cl] is a potent inhibitor of phototrophic biofilms at micromolar concentrations and a promising agent for biofilm control in re-circulating cooling water systems. This is the first report that ionic liquids inhibit biofilm formation by phototrophic organisms which are important members of biofilms in streams and cooling towers. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Marked antigiardial activity of Yucca baccata extracts: a potential natural alternative for treating protozoan infections.

    Science.gov (United States)

    Quihui-Cota, Luis; León-Trujillo, Rocio; Astiazarán-García, Humberto; Esparza-Romero, Julián; del Refugio Robles, María; Robles-Zepeda, Ramón E; Canett, Rafael; Sánchez-Escalante, Jesús

    2014-01-01

    Human giardiosis is a public health problem in Mexico, where the national prevalence was estimated to be up to 68%. Misuse of antiprotozoal drugs may result in low effectiveness and undesirable side effects. Research on natural products is a good strategy for discovering more effective antiparasitic compounds. This study evaluated the antigiardial activity of extracts of Yucca baccata, which is native to northwestern Mexico. Forty-two gerbils (females) were weighed and orally inoculated with 5 × 10(6) Giardia trophozoites. Two gerbils were selected at random to confirm infection. Forty living gerbils were randomly allocated into 5 treatment groups (8 per group). Gerbils were randomly assigned to be treated with 24.4 mg/mL, 12.2 mg/mL, and 6.1 mg/mL of extracts, metronidazole (2 mg/mL) or PBS, which were intragastrically administered once per day for 3 days. Nine gerbils died during the study course. On day 10 postinfection, gerbils were euthanized and trophozoites were quantified. Yucca extracts reduced, albeit not significantly, the trophozoite counts in the duodenum segment. Only the high-extract concentration significantly reduced the trophozoite counts in the proximal segment and it was similar to that of metronidazole. Extracts of Y. baccata may represent an effective and natural therapeutic alternative for human giardiosis.

  3. Classification of Error Related Brain Activity in an Auditory Identification Task with Conditions of Varying Complexity

    Science.gov (United States)

    Kakkos, I.; Gkiatis, K.; Bromis, K.; Asvestas, P. A.; Karanasiou, I. S.; Ventouras, E. M.; Matsopoulos, G. K.

    2017-11-01

    The detection of an error is the cognitive evaluation of an action outcome that is considered undesired or mismatches an expected response. Brain activity during monitoring of correct and incorrect responses elicits Event Related Potentials (ERPs) revealing complex cerebral responses to deviant sensory stimuli. Development of accurate error detection systems is of great importance both concerning practical applications and in investigating the complex neural mechanisms of decision making. In this study, data are used from an audio identification experiment that was implemented with two levels of complexity in order to investigate neurophysiological error processing mechanisms in actors and observers. To examine and analyse the variations of the processing of erroneous sensory information for each level of complexity we employ Support Vector Machines (SVM) classifiers with various learning methods and kernels using characteristic ERP time-windowed features. For dimensionality reduction and to remove redundant features we implement a feature selection framework based on Sequential Forward Selection (SFS). The proposed method provided high accuracy in identifying correct and incorrect responses both for actors and for observers with mean accuracy of 93% and 91% respectively. Additionally, computational time was reduced and the effects of the nesting problem usually occurring in SFS of large feature sets were alleviated.

  4. Marked Antigiardial Activity of Yucca baccata Extracts: A Potential Natural Alternative for Treating Protozoan Infections

    Directory of Open Access Journals (Sweden)

    Luis Quihui-Cota

    2014-01-01

    Full Text Available Human Giardiosis is a public health problem in Mexico, where the national prevalence was estimated to be up to 68%. Misuse of antiprotozoal drugs may result in low effectiveness and undesirable side effects. Research on natural products is a good strategy for discovering more effective antiparasitic compounds. This study evaluated the antigiardial activity of extracts of Yucca baccata, which is native to northwestern Mexico. Forty-two gerbils (females were weighed and orally inoculated with 5×106 Giardia trophozoites. Two gerbils were selected at random to confirm infection. Forty living gerbils were randomly allocated into 5 treatment groups (8 per group. Gerbils were randomly assigned to be treated with 24.4 mg/mL, 12.2 mg/mL, and 6.1 mg/mL of extracts, metronidazole (2 mg/mL or PBS, which were intragastrically administered once per day for 3 days. Nine gerbils died during the study course. On day 10 postinfection, gerbils were euthanized and trophozoites were quantified. Yucca extracts reduced, albeit not significantly, the trophozoite counts in the duodenum segment. Only the high-extract concentration significantly reduced the trophozoite counts in the proximal segment and it was similar to that of metronidazole. Extracts of Y. baccata may represent an effective and natural therapeutic alternative for human giardiosis.

  5. Cooking with Active Oxygen and Solid Alkali: A Promising Alternative Approach for Lignocellulosic Biorefineries.

    Science.gov (United States)

    Jiang, Yetao; Zeng, Xianhai; Luque, Rafael; Tang, Xing; Sun, Yong; Lei, Tingzhou; Liu, Shijie; Lin, Lu

    2017-10-23

    Lignocellulosic biomass, a matrix of biopolymers including cellulose, hemicellulose, and lignin, has gathered increasing attention in recent years for the production of chemicals, fuels, and materials through biorefinery processes owing to its renewability and availability. The fractionation of lignocellulose is considered to be the fundamental step to establish an economical and sustainable lignocellulosic biorefinery. In this Minireview, we summarize a newly developed oxygen delignification for lignocellulose fractionation called cooking with active oxygen and solid alkali (CAOSA), which can fractionate lignocellulose into its constituents and maintain its processable form. In the CAOSA approach, environmentally friendly chemicals are applied instead of undesirable chemicals such as strong alkalis and sulfides. Notably, the alkali recovery for this process promises to be relatively simple and does not require causticizing or sintering. These features make the CAOSA process an alternative for both lignocellulose fractionation and biomass pretreatment. The advantages and challenges of CAOSA are also discussed to provide a comprehensive perspective with respect to existing strategies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Evaluating the Antimicrobial Activity of Methonolic Extract of Rhus Succedanea Leaf Gall

    Directory of Open Access Journals (Sweden)

    Savitri Shrestha

    2013-12-01

    Full Text Available Introduction: The worldwide increased bacterial resistance to antibiotics and the undesirable side effects associated with constant use of synthetic drugs has prompted the search for novel antimicrobial agents, particularly those manufactured from plants. This study is designed to ascertain the antibacterial potential of Rhus succedanea leaf gall extracts on the growth of gram-positive and gram–negative bacteria. Methods: The methanolic and hexane extract of different concentrations (100, 250, and 500 μg/ml were prepared and their antibacterial efficacy was tested against clinical isolates of Escherichia coli, Salmonella typhi, Micrococcus luteus, and Staphylococcus aureus using agar well diffusion method and the size of inhibition zone was measured in millimeters. Results: The methanol and hexane extracts differed significantly in their antimicrobial activity with methanol extract showing a potent inhibitory activity in the range of 16±2 to 23±1, which was almost equal to the values of ciprofloxacin (25±3, used as a standard. Further, the methanol extract was mostly potent and effective in inhibiting the growth of gram-negative bacteria, namely, E. coli, when compared to gram –positive bacteria stains, which are responsible for antimicrobial activities. The phytochemical screening showed positive results for the presence of steroids, triterpenes, alkaloids, and carbohydrates. Conclusion: The potent antibacterial activity of Rhus succedanea leaf gall extracts indicates its useful therapeutic application against bacterial infection. Furthermore, this study indicates that the extract might be exploited as natural drug for the treatment of infectious diseases and could be useful in understanding the relations between traditional cures and current medications.

  7. Effect of gamma irradiation on the pigments and the biological activities of methanolic extracts from leaves of centipedegrass (Eremochloa ophiuroides Munro)

    International Nuclear Information System (INIS)

    Lee, Eun Mi; Lee, Seung Sik; Bai, Hyoung-Woo; Cho, Jae-Young; Kim, Tae Hoon; Chung, Byung Yeoup

    2013-01-01

    Extracts from centipedegrass (Eremochloa ophiuroides Munro) have been previously identified as having beneficial effects medically and cosmetically. In this study, the effects of gamma irradiation on pigment removal and biological activities of centipedegrass extracts to promote industrial application were investigated. The methanolic extracts were exposed to gamma irradiation at dose ranging from 2 to 20 kGy. The major pigments of centipedegrass extracts, cyanidin-3-O-glucoside and cyanidin-3-O-(6″-malonyl-)glucoside, were found to be effectively removed by gamma irradiation above 10 kGy. Although the reddish-orange color of the cyanidins was markedly decreased by gamma irradiation, the biological activities were relatively unaffected. The biological activities such as 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity, inhibition of tyrosinase activity, and inhibition of elastase activity in methanolic extracts were modulated from 50.5% to 70.2%, from 50.9% to 65.8% and from 65.6% to 94.0%, respectively. Surprisingly, the biological activities have the highest activities after 6–8 kGy of gamma irradiation. These results indicate that despite pigment degradation, biological activities were maintained or increased by gamma irradiation. Based on these results, gamma irradiation may be a useful tool to remove the undesirable reddish-orange color present in centipedegrass without any loss of biological activities, thereby promoting its utility in industrial applications such as manufacturing of cosmetic products. - Highlights: • The pigments of centipedegrass extracts were decreased by gamma irradiation. • The contents of maysin and its derivatives were slightly changed by gamma irradiation. • The biological activities of centipedegrass extracts were retained or increased by gamma irradiation

  8. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... gov . Physical Activity Physical Activity Basics Needs for Adults Needs for Children What Counts Needs for Older Adults Needs for Pregnant or Postpartum Women Physical Activity & ...

  9. Activities of Daily Living

    Science.gov (United States)

    ... With Parkinson's › Managing Parkinson's › Activities of Daily Living Activities of Daily Living Sometimes Parkinson’s disease (PD) can complicate the basic daily activities a person with living with Parkinson’s once did ...

  10. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... on this page will be unavailable. For more information about this message, please visit this page: About CDC.gov . ... Activity & Health Adding Physical Activity to Your Life Activities for ...

  11. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... activity: relative intensity and absolute intensity. Relative Intensity The level of effort required by a person to do an activity. When using relative intensity, people pay attention to how physical activity affects their heart rate ...

  12. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... More Physical Activity MMWR Data Highlights State Indicator Report on Physical Activity, 2014 Recommendations & Guidelines Fact Sheets & Infographics Social Media Tools Community Strategies Worksite Physical Activity Steps to Wellness ...

  13. Measuring Physical Activity Intensity

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    Full Text Available ... 45 David, Age 65 Harold, Age 67 Data & Statistics Facts About Physical Activity Data, Trends and Maps ... by the body per minute of activity. The table below lists examples of activities classified as moderate- ...

  14. Physical Activity Assessment

    Science.gov (United States)

    Current evidence convincingly indicates that physical activity reduces the risk of colon and breast cancer. Physical activity may also reduce risk of prostate cancer. Scientists are also evaluating potential relationships between physical activity and other cancers.

  15. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Activity, 2014 Recommendations & Guidelines Fact Sheets & Infographics Social Media Tools Community Strategies Worksite Physical Activity Steps to ... counts as aerobic activity, watch this video: Windows Media Player, 4:48 More videos Here are some ...

  16. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Needs for Pregnant or Postpartum Women Physical Activity & Health Adding Physical Activity to Your Life Activities for ... Obesity , National Center for Chronic Disease Prevention and Health Promotion Email Recommend Tweet YouTube Instagram Listen Watch ...

  17. Measuring Physical Activity Intensity

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    Full Text Available ... Activities for Children Activities for Older Adults Overcoming Barriers Measuring Physical Activity Intensity Target Heart Rate & Estimated ... YouTube Instagram Listen Watch RSS ABOUT About CDC Jobs Funding LEGAL Policies Privacy FOIA No Fear Act ...

  18. Non-Alcoholic Fatty Liver Disease: The Bile Acid-Activated Farnesoid X Receptor as an Emerging Treatment Target

    Directory of Open Access Journals (Sweden)

    Michael Fuchs

    2012-01-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is currently evolving as the most common liver disease worldwide. It may progress to liver cirrhosis and liver cancer and is poised to represent the most common indication for liver transplantation in the near future. The pathogenesis of NAFLD is multifactorial and not fully understood, but it represents an insulin resistance state characterized by a cluster of cardiovascular risk factors including obesity, dyslipidemia, hyperglycemia, and hypertension. Importantly, NAFLD also has evolved as independent risk factor for cardiovascular disease. Unfortunately thus far no established treatment does exist for NAFLD. The bile acid-activated nuclear farnesoid X receptor (FXR has been shown to play a role not only in bile acid but also in lipid and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. This review discusses the body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects.

  19. Active contours driven by local and global fitted image models for image segmentation robust to intensity inhomogeneity.

    Directory of Open Access Journals (Sweden)

    Farhan Akram

    Full Text Available This paper presents a region-based active contour method for the segmentation of intensity inhomogeneous images using an energy functional based on local and global fitted images. A square image fitted model is defined by using both local and global fitted differences. Moreover, local and global signed pressure force functions are introduced in the solution of the energy functional to stabilize the gradient descent flow. In the final gradient descent solution, the local fitted term helps extract regions with intensity inhomogeneity, whereas the global fitted term targets homogeneous regions. A Gaussian kernel is applied to regularize the contour at each step, which not only smoothes it but also avoids the computationally expensive re-initialization. Intensity inhomogeneous images contain undesired smooth intensity variations (bias field that alter the results of intensity-based segmentation methods. The bias field is approximated with a Gaussian distribution and the bias of intensity inhomogeneous regions is corrected by dividing the original image by the approximated bias field. In this paper, a two-phase model is first derived and then extended to a four-phase model to segment brain magnetic resonance (MR images into the desired regions of interest. Experimental results with both synthetic and real brain MR images are used for a quantitative and qualitative comparison with state-of-the-art active contour methods to show the advantages of the proposed segmentation technique in practical terms.

  20. Complement activation-related pseudoallergy in dogs following intravenous administration of a liposomal formulation of meglumine antimoniate

    Directory of Open Access Journals (Sweden)

    Raul R. Ribeiro

    2013-08-01

    Full Text Available The increasing use of nanotechnologies in advanced therapies has allowed the observation of specific adverse reactions related to nanostructures. The toxicity of a novel liposome formulation of meglumine antimoniate in dogs with visceral leishmaniasis after single dose has been investigated. Groups of 12 animals received by the intravenous route a single dose of liposomal meglumine antimoniate (group I [GI], 6.5 mg Sb/kg, empty liposomes (GII or isotonic saline (GIII. Evaluation of hematological and biochemical parameters showed no significant changes 4 days after administration. No undesired effects were registered in the GIII. However, adverse reactions were observed in 67.7% of dogs from both groups that received liposomal formulations. The side effects began moments after bolus administration and disappeared during the first 15 minutes after treatment. Prostation, sialorrhea and defecation were the most frequent clinical signs, registered in 33.3% and 41.6 % of animals from the groups GI and GII, respectively. Tachypnea, mydriasis, miosis, vomiting and cyanosis were also registered in both groups. The adverse reactions observed in this study were attributed to the activation of the complement system by lipid vesicles in a phenomenon known as Complement Activation-Related Pseudoallergy (CARPA. The influence of the physical-chemical characteristics of liposomal formulation in the triggering of CARPA is discussed.

  1. Nanoparticle Delivery of Artesunate Enhances the Anti-tumor Efficiency by Activating Mitochondria-Mediated Cell Apoptosis

    Science.gov (United States)

    Liu, Rui; Yu, Xiwei; Su, Chang; Shi, Yijie; Zhao, Liang

    2017-06-01

    Artemisinin and its derivatives were considered to exert a broad spectrum of anti-cancer activities, and they induced significant anti-cancer effects in tumor cells. Artemisinin and its derivatives could be absorbed quickly, and they were widely distributed, selectively killing tumor cells. Since low concentrations of artesunate primarily depended on oncosis to induce cell death in tumor cells, its anti-tumor effects were undesirable and limited. To obtain better anti-tumor effects, in this study, we took advantage of a new nanotechnology to design novel artesunate-loaded bovine serum albumin nanoparticles to achieve the mitochondrial accumulation of artesunate and induce mitochondrial-mediated apoptosis. The results showed that when compared with free artesunate's reliance on oncotic death, artesunate-loaded bovine serum albumin nanoparticles showed higher cytotoxicity and their significant apoptotic effects were induced through the distribution of artesunate in the mitochondria. This finding indicated that artesunate-loaded bovine serum albumin nanoparticles damaged the mitochondrial integrity and activated mitochondrial-mediated cell apoptosis by upregulating apoptosis-related proteins and facilitating the rapid release of cytochrome C.

  2. Highly Selective TiN-Supported Highly Dispersed Pt Catalyst: Ultra Active toward Hydrogen Oxidation and Inactive toward Oxygen Reduction.

    Science.gov (United States)

    Luo, Junming; Tang, Haibo; Tian, Xinlong; Hou, Sanying; Li, Xiuhua; Du, Li; Liao, Shijun

    2018-01-31

    The severe dissolution of the cathode catalyst, caused by an undesired oxygen reduction reaction at the anode during startup and shutdown, is a fatal challenge to practical applications of polymer electrolyte membrane fuel cells. To address this important issue, according to the distinct structure-sensitivity between the σ-type bond in H 2 and the π-type bond in O 2 , we design a HD-Pt/TiN material by highly dispersing Pt on the TiN surface to inhibit the unwanted oxygen reduction reaction. The highly dispersed Pt/TiN catalyst exhibits excellent selectivity toward hydrogen oxidation and oxygen reduction reactions. With a Pt loading of 0.88 wt %, our catalyst shows excellent hydrogen oxidation reaction activity, close to that of commercial 20 wt % Pt/C catalyst, and much lower oxygen reduction reaction activity than the commercial 20 wt % Pt/C catalyst. The lack of well-ordered Pt facets is responsible for the excellent selectivity of the HD-Pt/TiN materials toward hydrogen oxidation and oxygen reduction reactions. Our work provides a new and cost-effective solution to design selective catalysts toward hydrogen oxidation and oxygen reduction reactions, making the strategy of using oxygen-tolerant anode catalyst to improve the stability of polymer electrolyte membrane fuel cells during startup and shutdown more affordable and practical.

  3. Active contours driven by local and global fitted image models for image segmentation robust to intensity inhomogeneity

    Science.gov (United States)

    Garcia, Miguel Angel; Puig, Domenec

    2017-01-01

    This paper presents a region-based active contour method for the segmentation of intensity inhomogeneous images using an energy functional based on local and global fitted images. A square image fitted model is defined by using both local and global fitted differences. Moreover, local and global signed pressure force functions are introduced in the solution of the energy functional to stabilize the gradient descent flow. In the final gradient descent solution, the local fitted term helps extract regions with intensity inhomogeneity, whereas the global fitted term targets homogeneous regions. A Gaussian kernel is applied to regularize the contour at each step, which not only smoothes it but also avoids the computationally expensive re-initialization. Intensity inhomogeneous images contain undesired smooth intensity variations (bias field) that alter the results of intensity-based segmentation methods. The bias field is approximated with a Gaussian distribution and the bias of intensity inhomogeneous regions is corrected by dividing the original image by the approximated bias field. In this paper, a two-phase model is first derived and then extended to a four-phase model to segment brain magnetic resonance (MR) images into the desired regions of interest. Experimental results with both synthetic and real brain MR images are used for a quantitative and qualitative comparison with state-of-the-art active contour methods to show the advantages of the proposed segmentation technique in practical terms. PMID:28376124

  4. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Physical Activity, 2014 Recommendations & Guidelines Fact Sheets & Infographics Social Media Tools Community Strategies BE Active: Connecting Routes + Destinations Real-World Examples ...

  5. Physical activity and obesity

    National Research Council Canada - National Science Library

    Bouchard, Claude; Katzmarzyk, Peter T

    2010-01-01

    ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2 The Physical Activity and Exercise Continuum 7 Darren Warburton Definition of Health, Physical Activity, and Exercise . . . . . . . 7 The Continuum...

  6. Non-CpG Oligonucleotides Exert Adjuvant Effects by Enhancing Cognate B Cell-T Cell Interactions, Leading to B Cell Activation, Differentiation, and Isotype Switching

    Directory of Open Access Journals (Sweden)

    Melinda Herbáth

    2015-01-01

    Full Text Available Natural and synthetic nucleic acids are known to exert immunomodulatory properties. Notably, nucleic acids are known to modulate immune function via several different pathways and various cell types, necessitating a complex interpretation of their effects. In this study we set out to compare the effects of a CpG motif containing oligodeoxynucleotide (ODN with those of a control and an inhibitory non-CpG ODN during cognate B cell-T cell interactions. We employed an antigen presentation system using splenocytes from TCR transgenic DO11.10 mice and the ovalbumin peptide recognized by the TCR as model antigen. We followed early activation events by measuring CD69 expression, late activation by MHC class II expression, cell division and antibody production of switched, and nonswitched isotypes. We found that both of the tested non-CpG ODN exerted significant immunomodulatory effects on early T cell and on late B cell activation events. Importantly, a synergism between non-CpG effects and T cell help acting on B cells was observed, resulting in enhanced IgG production following cognate T cell-B cell interactions. We propose that non-CpG ODN may perform as better adjuvants when a strong antigen-independent immune activation, elicited by CpG ODNs, is undesirable.

  7. Non-CpG Oligonucleotides Exert Adjuvant Effects by Enhancing Cognate B Cell-T Cell Interactions, Leading to B Cell Activation, Differentiation, and Isotype Switching

    Science.gov (United States)

    Herbáth, Melinda; Papp, Krisztián; Erdei, Anna; Prechl, József

    2015-01-01

    Natural and synthetic nucleic acids are known to exert immunomodulatory properties. Notably, nucleic acids are known to modulate immune function via several different pathways and various cell types, necessitating a complex interpretation of their effects. In this study we set out to compare the effects of a CpG motif containing oligodeoxynucleotide (ODN) with those of a control and an inhibitory non-CpG ODN during cognate B cell-T cell interactions. We employed an antigen presentation system using splenocytes from TCR transgenic DO11.10 mice and the ovalbumin peptide recognized by the TCR as model antigen. We followed early activation events by measuring CD69 expression, late activation by MHC class II expression, cell division and antibody production of switched, and nonswitched isotypes. We found that both of the tested non-CpG ODN exerted significant immunomodulatory effects on early T cell and on late B cell activation events. Importantly, a synergism between non-CpG effects and T cell help acting on B cells was observed, resulting in enhanced IgG production following cognate T cell-B cell interactions. We propose that non-CpG ODN may perform as better adjuvants when a strong antigen-independent immune activation, elicited by CpG ODNs, is undesirable. PMID:26380319

  8. Antitumor effects of a natural anthracycline analog (Aloin) involve altered activity of antioxidant enzymes in HeLaS3 cells.

    Science.gov (United States)

    Nićiforović, Ana; Adzić, Miroslav; Spasić, Snezana D; Radojcić, Marija B

    2007-08-01

    The antiproliferative and cytotoxic potential of the natural anthracycline aloin from Aloe vera was tested on human uterine carcinoma HeLaS3 cells. Aloin showed a pronounced antiproliferative effect at physiological concentration (IC50 = 97 microM), caused cell cycle arrest in the S phase and markedly increased HeLaS3 cell apoptosis (to 24%). In the concentration range of 20-100 microM, its action was accompanied by remarkable changes in the activity of almost all antioxidant enzymes: MnSOD activity was increased many fold, while CuZnSOD and iNOS activities were inhibited. Moreover, inhibition of CuZnSOD was shown to occur by direct aloin interaction with the enzyme. As catalase activity was not changed, it is suggested that such conditions were responsible for antiproliferative and cytotoxic effects owing to accumulation of H2O2. Aloin alone was a more potent proapoptotic agent than a 2 Gy fractional dose of ionizing radiation or a combination of the two. Compared to other currently used therapeutics, aloin, due to its less undesirable side effects and antimetastatic potential, may prove to be the agent of choice on which clinical protocols for the treatment of human cervical carcinoma should rely in future.

  9. Activation, decay heat, and waste classification studies of the European DEMO concept

    Science.gov (United States)

    Gilbert, M. R.; Eade, T.; Bachmann, C.; Fischer, U.; Taylor, N. P.

    2017-04-01

    Inventory calculations have a key role to play in designing future fusion power plants because, for a given irradiation field and material, they can predict the time evolution in chemical composition, activation, decay heat, gamma-dose, gas production, and even damage (dpa) dose. For conceptual designs of the European DEMO fusion reactor such calculations provide information about the neutron shielding requirements, maintenance schedules, and waste disposal prospects; thereby guiding future development. Extensive neutron-transport and inventory calculations have been performed for a reference DEMO reactor model with four different tritium-breeding blanket concepts. The results have been used to chart the post-operation variation in activity and decay heat from different vessel components, demonstrating that the shielding performance of the different blanket concepts—for a given blanket thickness—varies significantly. Detailed analyses of the simulated nuclide inventories for the vacuum vessel (VV) and divertor highlight the most dominant radionuclides, potentially suggesting how changes in material composition could help to reduce activity. Minor impurities in the raw composition of W used in divertor tiles, for example, are shown to produce undesirable long-lived radionuclides. Finally, waste classifications, based on UK regulations, and a recycling potential limit, have been applied to estimate the time-evolution in waste masses for both the entire vessel (including blanket modules, VV, divertor, and some ex-vessel components) and individual components, and also to suggest when a particular component might be suitable for recycling. The results indicate that the large mass of the VV will not be classifiable as low level waste on the 100 year timescale, but the majority of the divertor will be, and that both components will be potentially recyclable within that time.

  10. Reprogramming movements: Extraction of motor intentions from cortical ensemble activity when movement goals change

    Directory of Open Access Journals (Sweden)

    Peter James Ifft

    2012-07-01

    Full Text Available The ability to inhibit unwanted movements and change motor plans is essential for behaviors of advanced organisms. The neural mechanisms by which the primate motor system rejects undesired actions have received much attention during the last decade, but it is not well understood how this neural function could be utilized to improve the efficiency of brain-machine interfaces (BMIs. Here we employed linear discriminant analysis (LDA and a Wiener filter to extract motor plan transitions from the activity of ensembles of sensorimotor cortex neurons. Two rhesus monkeys, chronically implanted with multielectrode arrays in primary motor (M1 and primary sensory (S1 cortices, were overtrained to produce reaching movements with a joystick towards visual targets upon their presentation. Then, the behavioral task was modified to include a distracting target that flashed for 50, 150 or 250 ms (25% of trials each followed by the true target that appeared at a different screen location. In the remaining 25% of trials, the initial target stayed on the screen and was the target to be approached. M1 and S1 neuronal activity represented both the true and distracting targets, even for the shortest duration of the distracting event. This dual representation persisted both when the monkey initiated movements towards the distracting target and then made corrections and when they moved directly towards the second, true target. The Wiener filter effectively decoded the location of the true target, whereas the LDA classifier extracted the location of both targets from ensembles of 50-250 neurons. Based on these results, we suggest developing real-time BMIs that inhibit unwanted movements represented by brain activity while enacting the desired motor outcome concomitantly.

  11. Waveguide generated mitigation of speckle and scintillation on an actively illuminated target

    Science.gov (United States)

    Moore, Trevor D.; Raynor, Robert A.; Spencer, Mark F.; Schmidt, Jason D.

    2016-09-01

    Active illumination is often used when passive illumination cannot produce enough signal intensity to be a reliable imaging method. However, an increase in signal intensity is often achieved by using highly coherent laser sources, which produce undesirable effects such as speckle and scintillation. The deleterious effects of speckle and scintillation are often so immense that the imaging camera cannot receive intelligible data, thereby rendering the active illumination technique useless. By reducing the spatial coherence of the laser beam that is actively illuminating the object, it is possible to reduce the corruption of the received data caused by speckle and scintillation. The waveguide method discussed in this paper reduces spatial coherence through multiple total internal reflections, which create multiple virtual sources of diverse path lengths. The differing path lengths between the virtual sources and the target allow for the temporal coherence properties of the laser to be translated into spatial coherence properties. The resulting partial spatial coherence helps to mitigate the self-interference of the beam as it travels through the atmosphere and reflects off of optically rough targets. This mitigation method results in a cleaner, intelligible image that may be further processed for the intended use, unlike its unmitigated counterpart. Previous research has been done to independently reduce speckle or scintillation by way of spatial incoherence, but there has been no focus on modeling the waveguide, specifically the image plane the waveguide creates. Utilizing a ray-tracing method we can determine the coherence length of the source necessary to create incoherent spots in the image plane, as well as accurately modeling the image plane.

  12. Development of a graphical user interface for sgRNAcas9 and its application.

    Science.gov (United States)

    Zhao, Chang-zhi; Zhang, Yi; Li, Guang-lei; Chen, Ji-liang; Li, Jing-Jin; Ren, Rui-min; Ni, Pan; Zhao, Shu-hong; Xie, Sheng-song

    2015-10-01

    The CRISPR/Cas9 genome editing technique is a powerful tool for researchers. However, off-target effects of the Cas9 nuclease activity is a recurrent concern of the CRISPR system. Thus, designing sgRNA (single guide RNA) with minimal off-target effects is very important. sgRNAcas9 is a software package, which can be used to design sgRNA and to evaluate potential off-target cleavage sites. In this study, a graphical user interface for sgRNAcas9 was developed using the Java programming language. In addition, off-target effect for sgRNAs was evaluated according to mismatched number and "seed sequence" specification. Moreover, sgRNAcas9 software was used to design 34 124 sgRNAs, which can target 4691 microRNA (miRNA) precursors from human, mouse, rat, pig, and chicken. In particular, the off-target effect of a sgRNA targeting to human miR-206 precursor was analyzed, and the on/off-target activity of this sgRNA was validated by T7E1 assay in vitro. Taken together, these data showed that the interface can simplify the usage of the sgRNAcas9 program, which can be used to design sgRNAs for the majority of miRNA precursors. We also found that the GC% of those sgRNAs ranged from 40% to 60%. In summary, the sgRNAcas9 software can be easily used to design sgRNA with minimal off-target effects for any species. The software can be downloaded from BiooTools website (http://www.biootools.com/).

  13. Criminalisation of Activism

    DEFF Research Database (Denmark)

    Uldam, Julie

    Different forms of political participation involve different challenges. This paper focuses on challenges to radical activism and particularly the criminalisation of activism.......Different forms of political participation involve different challenges. This paper focuses on challenges to radical activism and particularly the criminalisation of activism....

  14. Increasing Youth Physical Activity with Activity Calendars

    Science.gov (United States)

    Eckler, Seth

    2016-01-01

    Physical educators often struggle with ways to get their students to be active beyond the school day. One strategy to accomplish this is the use of physical activity calendars (PACs). The purpose of this article is to support the use of PACs and give practical advice for creating effective PACs.

  15. Physical Activity During School

    DEFF Research Database (Denmark)

    Østergaard, Lars Domino

    It is important, not only on health grounds, to exercise and to be physically active. In school, physical activities have shown to improve the students’ academic behaviour resulting in improved attention and information processing as well as enhanced coping. To stimulate and motivate students...... to be even more active during school hours further enhancing their academic behaviour, it is important to know when, why and how they are active, and their attitude towards different types of physical activities. Therefore, the aim of this study was to categorize the physical activities attended by students...... during school hours and to elucidate their attitude towards the different types of activities. The data consisted of observations of lessons followed by group interviews. Analyses of the observations revealed six categories of physical activities, varying from mandatory physical activities, activities...

  16. Active ageing technologies

    DEFF Research Database (Denmark)

    Lassen, Aske Juul

    ‘sites of active aging’ in Denmark. By presenting three technologies of active aging (billiards at an activity center for elderly persons, dancing tiles for rehabilitation after falls and an online fitness community for elderly persons) the paper suggests that active aging is more than regimes...... in their socio-material practices form active aging. Hence, active aging is a mutual entanglement (Callon and Rabeharisoa 2004) between technologies, practices and subjectivities. The paper is based on four months of participant observations and 17 in-depth interviews with elderly persons conducted at three...... of physical and productive activity; e.g. that a game of billiards is a technology of active aging. Thus, active aging is enacted in the socio-material practices of the technologies in this paper. The paper contributes with a strengthening of the concept of active aging, by focusing on entangled practices...

  17. A simple procedure for the purification of active fractions in aqueous extracts of plants with allelopathic properties

    Directory of Open Access Journals (Sweden)

    Fabian Borghetti

    2013-03-01

    Full Text Available Most studies conducted to test the allelopathic activity of plant parts have made use of water as solvent. However, the presence of polar, water-soluble substances, such as proteins and carbohydrates, tends to hamper the purification of active compounds. In this study, we present a simple purification procedure that separates the active fraction of the extract from the undesirable substances, thus facilitating the search for active molecules through standard chromatographic methods. Aqueous leaf extracts of three Cerrado species (Caryocar brasiliense, Qualea parviflora and Eugenia dysenterica were prepared at 5% concentration (w/v and stored at 4ºC (crude extracts. After 24 h, these solutions were filtered and freeze-dried. The powder obtained was dissolved in methanol, filtered again, evaporated and dissolved in water for bioassays (purified extracts. For the bioassays, seedlings of Sesamum indicum were grown for five days in aqueous solutions prepared from crude and purified extracts at concentrations ranging from 0.1% to 1.0% (w/v. Seedling growth in distilled water was set as a control. In comparison with the control, we found that test solutions prepared from both crude and purified extracts significantly inhibited sesame seedling growth. However, solutions prepared from purified extracts were two to ten times more inhibitory to seedling growth than were those prepared from crude extracts. The inhibition of root growth ranged from 35% to 77%, depending on the plant species, at a concentration as low as 0.1%. Roots were more affected than were shoots. The effects of purified extracts on seedling morphology were similar to those observed when crude extracts were employed, indicating that the procedure of purification of crude extracts did not interfere with the mode of action of the active substances

  18. Who is actively denitrifying in activated sludge?

    DEFF Research Database (Denmark)

    Hansen, Aviaja Anna; Nielsen, Jeppe Lund

    Denitrification is of crucial importance in nitrogen removal from wastewater. However, due to the polyphyletic taxonomy of denitrifiers, little is known about the composition and ecophysiology of the actively denitrifying community in activated sludge. To identify the active denitrifiers in a full......-scale wastewater treatment plant the transcripts (mRNA) of the nirS, nirK and nosZ denitrification genes expressed under acetate or amino acid consumption were amplified, sequenced and identified. This revealed that the majority of the denitrifiers belonged to Alpha- and Betaproteobacteria, while only few...

  19. Construction of a viral T2A-peptide based knock-in mouse model for enhanced Cre recombinase activity and fluorescent labeling of podocytes.

    Science.gov (United States)

    Koehler, Sybille; Brähler, Sebastian; Braun, Fabian; Hagmann, Henning; Rinschen, Markus M; Späth, Martin R; Höhne, Martin; Wunderlich, F Thomas; Schermer, Bernhard; Benzing, Thomas; Brinkkoetter, Paul T

    2017-06-01

    Podocyte injury is a key event in glomerular disease leading to proteinuria and opening the path toward glomerular scarring. As a consequence, glomerular research strives to discover molecular mechanisms and signaling pathways affecting podocyte health. The hNphs2.Cre mouse model has been a valuable tool to manipulate podocyte-specific genes and to label podocytes for lineage tracing and purification. Here we designed a novel podocyte-specific tricistronic Cre mouse model combining codon improved Cre expression and fluorescent cell labeling with mTomato under the control of the endogenous Nphs2 promoter using viral T2A-peptides. Independent expression of endogenous podocin, codon improved Cre, and mTomato was confirmed by immunofluorescence, fluorescent activated cell sorting and protein analyses. Nphs2 pod.T2A.ciCre.T2A.mTomato/wild-type mice developed normally and did not show any signs of glomerular disease or off-target effects under basal conditions and in states of disease. Nphs2 pod.T2A.ciCre.T2A.mTomato/wild-type -mediated gene recombination was superior to conventional hNphs2.Cre mice-mediated gene recombination. Last, we compared Cre efficiency in a disease model by mating Nphs2 pod.T2A.ciCre.T2A.mTomato/wild-type and hNphs2.Cre mice to Phb2 fl/fl mice. The podocyte-specific Phb2 knockout by Nphs2 pod.T2A.ciCre.T2A.mTomato/wild-type mice resulted in an aggravated glomerular injury as compared to a podocyte-specific Phb2 gene deletion triggered by hNphs2.Cre. Thus, we generated the first tricistronic podocyte mouse model combining enhanced Cre recombinase efficiency and fluorescent labeling in podocytes without the need for additional matings with conventional reporter mouse lines. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  20. Specific enkephalin-degrading aminopeptidase activity in the HPT and HPO axes of rats with breast cancer induced by N-methyl nitrosourea.

    Science.gov (United States)

    Carrera, María del Pilar; Ramírez-Expósito, María Jesús; Valenzuela, María Teresa; García, María Jesús; Mayas, María Dolores; Arias de Saavedra, José Manuel; Sánchez, Rafael; Pérez, María del Carmen; Martínez-Martos, José Manuel

    2005-01-15

    State and function of breast depend on an endocrinological balance, the upsetting of which can be a factor favorable to the development of cancer. Enkephalins (ENK) have been considered as a particular form of adaptation to defense to the organism against neoplastic processes. However, ENK may modify the endocrine functions of glands such as the ovary or the thyroid through the hypothalamus-pituitary axis, acting direct or indirectly as endocrine, paracrine or autocrine stimulatory growth factors. The present work analyses enkephalin-degrading tyrosyl aminopeptidase (EDA) activity in the hypothalamus-pituitary-thyroid (HPT) and hypothalamus-pituitary-ovary (HPO) axes in a rat model of breast cancer induced by N-methyl-nitrosourea (NMU) to state the relationship between ENK levels modification through EDA activity at different neuroendocrine levels and breast cancer. Results obtained show a decrease in EDA activity in hypothalamus, anterior and posterior pituitary, thyroid and ovary, suggesting increased levels of ENK in all these locations. These ENK may induce breast cancer cell growth and progression not only at breast level, but also acting at several neuroendocrine levels such as the HPT and HPO axes, inducing an unbalance of several other hormones, which could also facilitate the progression of cancer as an undesirable concomitant effect.

  1. Advanced Chemical Reduction of Reduced Graphene Oxide and Its Photocatalytic Activity in Degrading Reactive Black 5

    Directory of Open Access Journals (Sweden)

    Christelle Pau Ping Wong

    2015-10-01

    Full Text Available Textile industries consume large volumes of water for dye processing, leading to undesirable toxic dyes in water bodies. Dyestuffs are harmful to human health and aquatic life, and such illnesses as cholera, dysentery, hepatitis A, and hinder the photosynthetic activity of aquatic plants. To overcome this environmental problem, the advanced oxidation process is a promising technique to mineralize a wide range of dyes in water systems. In this work, reduced graphene oxide (rGO was prepared via an advanced chemical reduction route, and its photocatalytic activity was tested by photodegrading Reactive Black 5 (RB5 dye in aqueous solution. rGO was synthesized by dispersing the graphite oxide into the water to form a graphene oxide (GO solution followed by the addition of hydrazine. Graphite oxide was prepared using a modified Hummers’ method by using potassium permanganate and concentrated sulphuric acid. The resulted rGO nanoparticles were characterized using ultraviolet-visible spectrophotometry (UV-Vis, X-ray powder diffraction (XRD, Raman, and Scanning Electron Microscopy (SEM to further investigate their chemical properties. A characteristic peak of rGO-48 h (275 cm−1 was observed in the UV spectrum. Further, the appearance of a broad peak (002, centred at 2θ = 24.1°, in XRD showing that graphene oxide was reduced to rGO. Based on our results, it was found that the resulted rGO-48 h nanoparticles achieved 49% photodecolorization of RB5 under UV irradiation at pH 3 in 60 min. This was attributed to the high and efficient electron transport behaviors of rGO between aromatic regions of rGO and RB5 molecules.

  2. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Guidelines Fact Sheets & Infographics Social Media Tools Community Strategies BE Active: Connecting Routes + Destinations Real-World Examples ... 4, 2015 Page last updated: June 4, 2015 Content source: Division of Nutrition, Physical Activity, and Obesity , ...

  3. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Intensity The amount of energy used by the body per minute of activity. The table below lists ... upon the amount of energy used by the body while doing the activity. Top of Page Moderate ...

  4. Antitubercular activities of quinolones

    Indian Academy of Sciences (India)

    . (Sz). Using this index antitubercular activities of N-2,4-difluorophenyl quinolones are subjected to quantitative structure–activity relationship analysis. The potential of Sz related to the Wiener index (W) is critically discussed. In addition, Huckel ...

  5. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Data, Trends and Maps Surveillance Systems Resources & Publications Reports Adults Need More Physical Activity MMWR Data Highlights State Indicator Report on Physical Activity, 2014 Recommendations & Guidelines Fact Sheets & ...

  6. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Button Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and ... Button Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and ...

  7. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Button Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local ... Button Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local ...

  8. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local ... Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local ...

  9. Guide to Physical Activity

    Science.gov (United States)

    ... minutes Stairwalking for 15 minutes Sporting Activities Playing volleyball for 45–60 minutes Playing touch football for ... strenuous activities. Competitive sports, such as tennis and volleyball, can provide an enjoyable form of exercise for ...

  10. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Strategies BE Active: Connecting Routes + Destinations Real-World Examples Implementation Resource Guide Visual Guide Worksite Physical Activity ... Implementation Maintaining Interest Needs Assessment Evaluating Success CDC’s Example ... Stairwell Appearance Motivational Signs Installing Music Other ...

  11. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... an activity. When using relative intensity, people pay attention to how physical activity affects their heart rate ... Obesity , National Center for Chronic Disease Prevention and Health Promotion Email Recommend Tweet YouTube Instagram Listen Watch ...

  12. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... for a breath. Absolute Intensity The amount of energy used by the body per minute of activity. ... or vigorous-intensity based upon the amount of energy used by the body while doing the activity. ...

  13. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local Programs ... Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local Programs ...

  14. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... About Physical Activity Data, Trends and Maps Surveillance Systems Resources & Publications Reports Adults Need More Physical Activity ... Email CDC-INFO U.S. Department of Health & Human Services HHS/Open USA.gov Top

  15. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... What's this? Submit Button Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient ... What's this? Submit Button Our Division About Us Nutrition Physical Activity Overweight & Obesity Healthy Weight Breastfeeding Micronutrient ...

  16. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... CDC A-Z SEARCH A B C D E F G H I J K L M ... Physical Activity Data, Trends and Maps Surveillance Systems Resources & Publications Reports Adults Need More Physical Activity MMWR ...

  17. USAID Activity Locations

    Data.gov (United States)

    US Agency for International Development — The USAID Activities dataset is a snapshot of activities supported by USAID including their geographical locations within countries at the time of the snapshot. The...

  18. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Compartir For more help with what counts as aerobic activity, watch this video: Windows Media Player, 4: ... ways to understand and measure the intensity of aerobic activity: relative intensity and absolute intensity. Relative Intensity ...

  19. Family Activities for Fitness

    Science.gov (United States)

    Grosse, Susan J.

    2009-01-01

    This article discusses how families can increase family togetherness and improve physical fitness. The author provides easy ways to implement family friendly activities for improving and maintaining physical health. These activities include: walking, backyard games, and fitness challenges.

  20. Balance Food and Activity

    Science.gov (United States)

    ... Choosing Foods for Your Family Eating Healthy When Eating Out Food Shopping Tips Fun Family Recipes Healthy Cooking ... Recipes Healthy Cooking and Snacking Eating Healthy When Eating Out Tips for Eating Right Get Active Physical Activity ...

  1. Activity-based design

    DEFF Research Database (Denmark)

    Andersen, Peter Bøgh

    2006-01-01

      In many types of activities communicative and material activities are so intertwined that the one cannot be understood without taking the other into account. This is true of maritime and hospital work that are used as examples in the paper. The spatial context of the activity is also important:...... and automatic machinery can replace one another in an activity. It also gives an example of how to use the framework for design....

  2. Global physical activity levels

    DEFF Research Database (Denmark)

    Hallal, Pedro C; Andersen, Lars Bo; Bull, Fiona C

    2012-01-01

    -income countries. The proportion of 13-15-year-olds doing fewer than 60 min of physical activity of moderate to vigorous intensity per day is 80·3% (80·1-80·5); boys are more active than are girls. Continued improvement in monitoring of physical activity would help to guide development of policies and programmes...

  3. Measurement of Physical Activity.

    Science.gov (United States)

    Dishman, Rod K.; Washburn, Richard A.; Schoeller, Dale A.

    2001-01-01

    Valid assessment of physical activity must be unobtrusive, practical to administer, and specific about physical activity type, frequency, duration, and intensity. Assessment methods can be categorized according to whether they provide direct or indirect (e.g., self-report) observation of physical activity, body motion, physiological response…

  4. Comparing Active Vision Models

    NARCIS (Netherlands)

    Croon, G.C.H.E. de; Sprinkhuizen-Kuyper, I.G.; Postma, E.O.

    2009-01-01

    Active vision models can simplify visual tasks, provided that they can select sensible actions given incoming sensory inputs. Many active vision models have been proposed, but a comparative evaluation of these models is lacking. We present a comparison of active vision models from two different

  5. Comparing active vision models

    NARCIS (Netherlands)

    Croon, G.C.H.E. de; Sprinkhuizen-Kuyper, I.G.; Postma, E.O.

    2009-01-01

    Active vision models can simplify visual tasks, provided that they can select sensible actions given incoming sensory inputs. Many active vision models have been proposed, but a comparative evaluation of these models is lacking. We present a comparison of active vision models from two different

  6. Regenerative potential and anti-bacterial activity of tetracycline loaded apatitic nanocarriers for the treatment of periodontitis

    International Nuclear Information System (INIS)

    Madhumathi, K; Sampath Kumar, T S

    2014-01-01

    Current treatment of periodontal infections includes mechanical debridement, administration of antibiotics and bone grafting. Oral administration of antibiotics results in undesirable side effects, while current modes of local administration are affected by problems concerning allergic response to the polymeric carrier agents. We have developed an osteoconductive drug delivery system composed of apatitic nanocarriers capable of providing sustained delivery of drugs in the periodontium. Calcium deficient hydroxyapatite (CDHA) nanocarriers of different Ca/P ratios were synthesized and characterized using the x-ray diffraction method, transmission electron microscopy, inductively coupled plasma atomic emission spectroscopy, Fourier transform infrared spectroscopy and the BET gas isotherm method. Loading and release studies performed with tetracycline showed a sustained release of up to 88% in phosphate buffered saline over a period of five days. Antibacterial activity studies showed that the tetracycline loaded CDHA (TC-CDHA) nanocarriers were effective against S. aureus and E. coli bacteria. The biocompatibility of the TC-CDHA nanocarriers was demonstrated using an alamar blue assay and further characterized by cell uptake studies. Interestingly, cell uptake of drug loaded CDHA also increased the cellular proliferation of human periodontal ligament fibroblast cells. Hence, it can be concluded that the CDHA nanocarriers are ideal drug delivery agents and have bone regenerative potential for local periodontal applications. (paper)

  7. Surface functionalisation of polypropylene hernia-repair meshes by RF-activated plasma polymerisation of acrylic acid and silver nanoparticles

    International Nuclear Information System (INIS)

    Nisticò, Roberto; Rosellini, Andrea; Rivolo, Paola; Faga, Maria Giulia; Lamberti, Roberta; Martorana, Selanna; Castellino, Micaela; Virga, Alessandro; Mandracci, Pietro; Malandrino, Mery; Magnacca, Giuliana

    2015-01-01

    Graphical abstract: - Highlights: • Polypropylene meshes for hernioplasty were surface functionalised via plasma-polymerisation to confer adhesive properties. • Subsequently, silver nanoparticles were loaded to add antibacterial activity. • Materials were physico-chemical characterised and adhesive properties evaluated. - Abstract: Hernia diseases are among the most common and diffuse causes of surgical interventions. Unfortunately, still nowadays there are different phenomena which can cause the hernioplasty failure, for instance post-operative prostheses displacements and proliferation of bacteria in the surgical site. In order to limit these problems, commercial polypropylene (PP) and polypropylene/Teflon (PP/PTFE) bi-material meshes were surface functionalised to confer adhesive properties (and therefore reduce undesired displacements) using polyacrylic acid synthesized by plasma polymerisation (PPAA). A broad physico-chemical and morphological characterisation was carried out and adhesion properties were investigated by means of atomic force microscopy (AFM) used in force/distance (F/D) mode. Once biomedical devices surface was functionalised by PPAA coating, metallic silver nanoparticles (AgNPs) with antimicrobial properties were synthesised and loaded onto the polymeric prostheses. The effect of the PPAA, containing carboxylic functionalities, adhesive coating towards AgNPs loading capacity was verified by means of X-ray photoelectron spectroscopy (XPS). Preliminary measurement of the Ag loaded amount and release in water were also investigated via inductively coupled plasma atomic emission spectroscopy (ICP-AES). Promising results were obtained for the functionalised biomaterials, encouraging future in vitro and in vivo tests

  8. Demonstration of a multiscale modeling technique: prediction of the stress–strain response of light activated shape memory polymers

    International Nuclear Information System (INIS)

    Beblo, Richard V; Weiland, Lisa Mauck

    2010-01-01

    Presented is a multiscale modeling method applied to light activated shape memory polymers (LASMPs). LASMPs are a new class of shape memory polymer (SMPs) being developed for adaptive structures applications where a thermal stimulus is undesirable. LASMP developmental emphasis is placed on optical manipulation of Young's modulus. A multiscale modeling approach is employed to anticipate the soft and hard state moduli solely on the basis of a proposed molecular formulation. Employing such a model shows promise for expediting down-selection of favorable formulations for synthesis and testing, and subsequently accelerating LASMP development. An empirical adaptation of the model is also presented which has applications in system design once a formulation has been identified. The approach employs rotational isomeric state theory to build a molecular scale model of the polymer chain yielding a list of distances between the predicted crosslink locations, or r-values. The r-values are then fitted with Johnson probability density functions and used with Boltzmann statistical mechanics to predict stress as a function of the strain of the phantom polymer network. Empirical adaptation for design adds junction constraint theory to the modeling process. Junction constraint theory includes the effects of neighboring chain interactions. Empirical fitting results in numerically accurate Young's modulus predictions. The system is modular in nature and thus lends itself well to being adapted to other polymer systems and development applications

  9. Strategies to Extend Bread and GF Bread Shelf-Life: From Sourdough to Antimicrobial Active Packaging and Nanotechnology

    Directory of Open Access Journals (Sweden)

    Valentina Melini

    2018-02-01

    Full Text Available Bread is a staple food worldwide. It commonly undergoes physico-chemical and microbiological changes which impair its quality and shelf-life. Staling determines organoleptic impairment, whereas microbiological spoilage causes visible mould growth and invisible production of mycotoxins. To tackle this economic and safety issue, the bakery industry has been working to identify treatments which allow bread safety and extended shelf-life. Physical methods and chemical preservatives have long been used. However, new frontiers have been recently explored. Sourdough turned out an ancient but novel technology to preserve standard and gluten-free bread. Promising results have also been obtained by application of alternative bio-preservation techniques, including antifungal peptides and plant extracts. Active packaging, with absorbing and/or releasing compounds effective against bread staling and/or with antimicrobials preventing growth of undesirable microorganisms, showed up an emerging area of food technology which can confer many preservation benefits. Nanotechnologies are also opening up a whole universe of new possibilities for the food industry and the consumers. This work thus aims to provide an overview of opportunities and challenges that traditional and innovative anti-staling and anti-spoilage methods can offer to extend bread shelf-life and to provide a basis for driving further research on nanotechnology applications into the bakery industry.

  10. Delayed condensation and frost formation on superhydrophobic carbon soot coatings by controlling the presence of hydrophilic active sites

    Science.gov (United States)

    Esmeryan, Karekin D.; Castano, Carlos E.; Mohammadi, Reza; Lazarov, Yuliyan; Radeva, Ekaterina I.

    2018-02-01

    Condensation frosting is an undesired natural phenomenon that could be impeded efficiently using appropriate wettability and morphologically patterned surfaces. The icephobic properties of carbon soot and the fabrication scalability of its synthesis method are a good foundation for anti-frosting applications; however, the fundamentals of frost growth and spreading on sooted surfaces have not been examined yet. In this study, we investigate the anti-frosting performance of three groups of superhydrophobic soot coatings by means of 16 MHz quartz crystal microbalances (QCMs). The analysis of the real-time sensor signal of each soot coated QCM pattern shows that frost formation and its propagation velocity depend on the quantity of oxygen functionalities and structural defects in the material. In turn, the reduction of both parameters shifts the onset of frost growth to temperatures below  -20 °C, whereas the interdroplet ice bridging is slowed by a factor of four. Moreover, high-resolution scanning electron micrographs of the samples imply delamination upon defrosting of the soot with spherical-like morphology via polar interactions driven mechanism. These results reveal an opportunity for control of frost incipiency on sooted surfaces by adjusting the synthesis conditions and depositing soot coatings with as low as possible content of hydrophilic active sites.

  11. Study of carbonitriding thermochemical treatment by plasma screen in active with pressures main austenitic stainless steels AISI 409 and AISI 316L; Estudo do tratamento termoquimico de carbonitretacao por plasma em tela ativa com pressoes variaveis nos acos inoxidaveis austenitico AISI 316L e ferririco AISI 409

    Energy Technology Data Exchange (ETDEWEB)

    Melo, M.S.; Oliveira, A.M.; Leal, V.S.; Sousa, R.R.M. de; Alves Junior, C. [Centro Federal de Educacao Tecnologica do Maranhao (CEFET/MA), Sao Luis, MA (Brazil); Centro Federal de Educacao Tecnologica do Piaui (CEFET/PI), Teresina, PI (Brazil); Universidade Federal do Rio Grande do Norte (DF/UFRN), Natal, RN (Brazil). Dept. de Fisica. Labplasma

    2010-07-01

    The technique called Active Screen Plasma Nitriding (ASPN) is being used as an alternative once it offers several advantages with respect to conventional DC plasma. In this method, the plasma does not form directly in the sample's surface but on a screen, in such a way that undesired effects such as the edge effect is minimized. Stainless steels present not very satisfactory wearing characteristics. However, plasma carbonitriding has been used as to improve its resistance to wearing due to the formation of a fine surface layer with good properties. In this work, samples of stainless steel AISI 316L and AISI 409 were treated at pressures of 2.5 and 5 mbar. After the treatments they were characterized by microhardness, microscopy and Xray diffraction. Microscopy and hardness analysis showed satisfactory layers and toughness in those steels. (author)

  12. Proteolytic activities in yeast.

    Science.gov (United States)

    Saheki, T; Holzer, H

    1975-03-28

    Studies on the mechanism and time course of the activation of proteinases A (EC 3.4.23.8), B (EC 3.4.22.9) and C (EC 3.4.12.--) in crude yeast extracts at pH 5.1 and 25 degrees C showed that the increase in proteinase B activity is paralleled with the disappearance of proteinase B inhibitor. Addition of purified proteinase A to fresh crude extracts accelerates the inactivation of the proteinase B inhibitor and the appearance of maximal activities of proteinases B and C. The decrease of proteinase B inhibitor activity and the increase of proteinase B activity are markedly retarded by the addition of pepstatin. Because 10-minus 7 M pepstatin completely inhibits proteinase A without affecting proteinase B activity, this is another indication for the role of proteinase A during the activation of proteinase B. Whereas extracts of yeast grown on minimal medium reached maximal activation of proteinases B and C after 20 h of incubation at pH 5.1 and 25 degrees C, extracts of yeast grown on complete medium had to be incubated for about 100 h. In the latter case, the addition of proteinas A results in maximal activation of proteinases B and C and disappearance of proteinase B inhibitor activity only after 10--20 h of incubation. With the optimal conditions, the maximal activities of proteinases A, B and C, as well as of the proteinase B inhibitor, were determined in crude extracts of yeast that had been grown batchwise for different lengths of time either on minimal or on complete medium. Upon incubation, all three proteinases were activated by several times their initial activity. This reflects the existence of proteolytically degradable inhibitors of the three proteinases and together with the above mentioned observations it demonstrates that the "activation" of yeast proteinases A, B and C upon incubation results from the proteolytic digestion of inhibitors rather than from activation of inactive zymogens by limited proteolysis.

  13. Heterogeneous Active Matter

    Science.gov (United States)

    Kolb, Thomas; Klotsa, Daphne

    Active systems are composed of self-propelled (active) particles that locally convert energy into motion and exhibit emergent collective behaviors, such as fish schooling and bird flocking. Most works so far have focused on monodisperse, one-component active systems. However, real systems are heterogeneous, and consist of several active components. We perform molecular dynamics simulations of multi-component active matter systems and report on their emergent behavior. We discuss the phase diagram of dynamic states as well as parameters where we see mixing versus segregation.

  14. Piperine activates human pregnane X receptor to induce the expression of cytochrome P450 3A4 and multidrug resistance protein 1

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yue-Ming; Lin, Wenwei; Chai, Sergio C.; Wu, Jing; Ong, Su Sien [Department of Chemical Biology and Therapeutics, St. Jude Children' s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 (United States); Schuetz, Erin G. [Department of Pharmaceutical Sciences, St. Jude Children' s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 (United States); Chen, Taosheng, E-mail: taosheng.chen@stjude.org [Department of Chemical Biology and Therapeutics, St. Jude Children' s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 (United States)

    2013-10-01

    Activation of the pregnane X receptor (PXR) and subsequently its target genes, including those encoding drug transporters and metabolizing enzymes, while playing substantial roles in xenobiotic detoxification, might cause undesired drug-drug interactions. Recently, an increased awareness has been given to dietary components for potential induction of diet–drug interactions through activation of PXR. Here, we studied, whether piperine (PIP), a major component extracted from the widely-used daily spice black pepper, could induce PXR-mediated expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1). Our results showed that PIP activated human PXR (hPXR)-mediated CYP3A4 and MDR1 expression in human hepatocytes, intestine cells, and a mouse model; PIP activated hPXR by recruiting its coactivator SRC-1 in both cellular and cell-free systems; PIP bound to the hPXR ligand binding domain in a competitive ligand binding assay in vitro. The dichotomous effects of PIP on induction of CYP3A4 and MDR1 expression observed here and inhibition of their activity reported elsewhere challenges the potential use of PIP as a bioavailability enhancer and suggests that caution should be taken in PIP consumption during drug treatment in patients, particularly those who favor daily pepper spice or rely on certain pepper remedies. - Highlights: • Piperine induces PXR-mediated CYP3A4 and MDR1 expression. • Piperine activates PXR by binding to PXR and recruiting coactivator SRC-1. • Piperine induces PXR activation in vivo. • Caution should be taken in piperine consumption during drug treatment.

  15. Active transmembrane drug transport in microgravity: a validation study using an ABC transporter model [v1; ref status: indexed, http://f1000r.es/41n

    Directory of Open Access Journals (Sweden)

    Sergi Vaquer

    2014-08-01

    Full Text Available Abstract Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay® (Solvo Biotechnology, Hungary was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2 trans-membrane estradiol-17-β-glucuronide (E17βG transport activity, when activated by adenosine-tri-phosphate (ATP during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology

  16. Heteromultivalent targeting of integrin αvβ3 and neuropilin 1 promotes cell survival via the activation of the IGF-1/insulin receptors.

    Science.gov (United States)

    Jia, Tao; Choi, Jungyoon; Ciccione, Jéremy; Henry, Maxime; Mehdi, Ahmad; Martinez, Jean; Eymin, Béatrice; Subra, Gilles; Coll, Jean-Luc

    2018-02-01

    Angiogenesis strongly depends on the activation of integrins, especially integrin α v β 3 , and of neuropilin-1 (NRP-1), a co-receptor of VEGFR2. Dual-targeted molecules that simultaneously block both of them are expected have increased anti-angiogenic and antitumor activity. Toward this goal, we generated bifunctional 40 nm-sized silica nanoparticles (NPs) coated with controlled amounts of cRGD and ATWLPPR peptides and studied their affinity, selectivity and biological activity in HUVECs. Sub-nanomolar concentrations of NPs grafted either with ATWLPPR alone or in combination with cRGD exhibit potent and specific antagonist activity against VEGFR2/AKT signaling. However, a 1 nM concentration of the cRGD/ATWLPPR-heteromultivalent particles (RGD/ATW-NPs) also blocks the phosphorylation of VEGFR2 while co-inducing an unexpected long-lasting activation of AKT via IGF-1R/IR-AKT/GSK3β/eNOS signaling that stimulates cell survival and abrogates the intrinsic toxicity of silica-NPs to serum-starved HUVECs. We also showed that their repeated intravenous administration was associated with the proliferation of human U87MG tumor cells engrafted in nude mice and a dilatation of the tumor blood vessels. We present biochemical evidence for the complex cross-talk generated by the binding of the heteromultivalent NPs with α v β 3 -integrin and with NRP1. In particular, we show for the first time that such heteromultivalent NPs can trans-activate IGF-1/insulin receptors and exert dose-dependent pro-survival activity. This study demonstrates the difficulties in designing targeted silica-based NPs for antiangiogenic therapies and the possible risks posed by undesirable side effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Accessibility, activity participation and location of activities

    DEFF Research Database (Denmark)

    Næss, Petter

    2006-01-01

    By investigating relationships between residential location and the availability of facilities, location of activities, trip distances, activity participation and trip frequencies, this paper seeks to contribute to a more detailed and nuanced understanding of the relationships between residential...... location and the amount of daily-life travel in an urban region. The empirical data are from a comprehensive study of residential location and travel in Copenhagen Metropolitan Area. Differences between inner- and outer-area residents in activity frequencies and trip frequencies are modest and partly...... outweigh each other. However, differences in trip distances due to the location of the dwelling relative to concentrations of facilities translate into substantially longer total travelling distances among suburbanites than among inner-city residents....

  18. MODELING TRENDS OF INVESTMENT AND CONSTRUCTION ACTIVITIES OF THE RUSSIAN FEDERATION

    Directory of Open Access Journals (Sweden)

    Geraskina Inna Nikolaevna

    2017-11-01

    Full Text Available Subject: the results of the study are particularly relevant in the modern system of cyclical crisis generated by the change of Kondratieff’s long waves of economic development and technological structures. From the point of view of synergetics, these processes have the ability to trigger a new order having spontaneous transformation due to endogenous factors. Qualitatively predictable fluctuations in the socio-economic environment and management may lead to self-organization and sustainable development of the economic system. Construction and investment activity of Russia in the majority of cases was investigated by economists without a detailed understanding of system characteristics, inherent properties and laws, which are identified from the results of economic-mathematical modeling. Research objectives: 1. Timely and qualitative prediction of moments of crisis in the investment and construction activities of Russia; 2. Modeling of management activities for the purpose of transitioning to the desired path of development of economic system; 3. Creation of a model that is simple enough for practical use by economists and the use of public data sets in it; studying influence of the bifurcation diagram at a certain time and bypassing the critical points of the system that lead to undesirable outcome. Materials and methods: approximation of the statistical data sets, regression analysis, phase analysis, differential modeling. Results: The authors developed a mathematical model that allows us to use statistical data on investment and construction activities and accurately forecast the chances of recession of the system, and also identify the sensitivity of order parameters to the dynamics of control variables, bifurcation states and behavior of the object under certain management conditions. Conclusions: the paper presents an approach to modeling and forecasting the trends of development of complex cyclic and stochastic subsystem of the national

  19. NEA activities in 1980. 9. Activity Report

    International Nuclear Information System (INIS)

    1981-01-01

    This report describes the main features of the Agency's work during 1980 and discusses the state and prospects of the nuclear industry in OECD countries. Trends in nuclear power, radiological and environmental impacts of nuclear fuel cycle activities, nuclear safety research and licensing, nuclear law, nuclear development and fuel cycle studies technical co-operation, nuclear science organisation and administration are reviewed

  20. Marine Biology Activities. Ocean Related Curriculum Activities.

    Science.gov (United States)

    Pauls, John

    The ocean affects all of our lives. Therefore, awareness of and information about the interconnections between humans and oceans are prerequisites to making sound decisions for the future. Project ORCA (Ocean Related Curriculum Activities) has developed interdisciplinary curriculum materials designed to meet the needs of students and teachers…

  1. Lectures Abandoned: Active Learning by Active Seminars

    DEFF Research Database (Denmark)

    Christensen, Henrik Bærbak; Corry, Aino Vonge

    2012-01-01

    engi- neering course in software architecture to employ a range of active learning techniques. The course was constrained by the study administration's traditional assignment of a three hour lecturing slot and as such we had to make techniques that tted this imposed constraint. Our contribution is ac...

  2. The Active Reader: What Is Active?

    Science.gov (United States)

    van Woerkum, Cees

    2012-01-01

    How writers can adapt to their readers is an important issue in effective communication strategies, and certainly crucial in the case of functional texts. Therefore, it is necessary to look at how readers are constructed as partners in a communication co-production. This article explores the concept of the "active reader," which is getting more…

  3. Factor XII Contact Activation.

    Science.gov (United States)

    Naudin, Clément; Burillo, Elena; Blankenberg, Stefan; Butler, Lynn; Renné, Thomas

    2017-11-01

    Contact activation is the surface-induced conversion of factor XII (FXII) zymogen to the serine protease FXIIa. Blood-circulating FXII binds to negatively charged surfaces and this contact to surfaces triggers a conformational change in the zymogen inducing autoactivation. Several surfaces that have the capacity for initiating FXII contact activation have been identified, including misfolded protein aggregates, collagen, nucleic acids, and platelet and microbial polyphosphate. Activated FXII initiates the proinflammatory kallikrein-kinin system and the intrinsic coagulation pathway, leading to formation of bradykinin and thrombin, respectively. FXII contact activation is well characterized in vitro and provides the mechanistic basis for the diagnostic clotting assay, activated partial thromboplastin time. However, only in the past decade has the critical role of FXII contact activation in pathological thrombosis been appreciated. While defective FXII contact activation provides thromboprotection, excess activation underlies the swelling disorder hereditary angioedema type III. This review provides an overview of the molecular basis of FXII contact activation and FXII contact activation-associated disease states. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  4. Lower cytotoxicity, high stability, and long-term antibacterial activity of a poly(methacrylic acid)/isoniazid/rifampin nanogel against multidrug-resistant intestinal Mycobacterium tuberculosis.

    Science.gov (United States)

    Chen, Tao; Li, Qiang; Guo, Lina; Yu, Li; Li, Zhenyan; Guo, Huixin; Li, Haicheng; Zhao, Meigui; Chen, Liang; Chen, Xunxun; Zhong, Qiu; Zhou, Lin; Wu, Ting

    2016-01-01

    To overcome the undesirable side effects and reduce the cytotoxicity of isoniazid (INH) and rifampin (RMP) in the digestive tract, a poly(methacrylic acid) (PMAA) nanogel was developed as a carrier of INH and RMP. This PMAA/INH/RMP nanogel was prepared as a treatment for intestinal tuberculosis caused by multidrug-resistant Mycobacterium tuberculosis (MTB). The morphology, size, and in vitro release properties were evaluated in a simulated gastrointestinal medium, and long-term antibacterial performance, cytotoxicity, stability, and activity of this novel PMAA/INH/RMP nanogel against multidrug-resistant MTB in the intestine were investigated. Our results indicate that the PMAA/INH/RMP nanogel exhibited extended antibacterial activity by virtue of its long-term release of INH and RMP in the simulated gastrointestinal medium. Further, this PMAA/INH/RMP nanogel exhibited lower cytotoxicity than did INH or RMP alone, suggesting that this PMAA/INH/RMP nanogel could be a more useful dosage form than separate doses of INH and RMP for intestinal MTB. The novel aspects of this study include the cytotoxicity study and the three-phase release profile study, which might be useful for other researchers in this field. Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.

  5. Active ageing technologies

    DEFF Research Database (Denmark)

    Lassen, Aske Juul

    In the recent decade the concept of active aging has become important in the Western hemisphere. The World Health Organization and The European Union have staged active aging as a core policy area and initiated programs of physical activity, independence and prolonged working lives among...... the elderly. As part of this rearticulation of old age, many new technologies take form. This paper uses a wide concept of technologies (devices, regimes, strategies and ways of doing) and argues that technologies form active aging subjectivities, and on the other hand, that these subjectivities...... in their socio-material practices form active aging. Hence, active aging is a mutual entanglement (Callon and Rabeharisoa 2004) between technologies, practices and subjectivities. The paper is based on four months of participant observations and 17 in-depth interviews with elderly persons conducted at three...

  6. Participatory Activities in Practice

    DEFF Research Database (Denmark)

    Gottlieb, Frederik; Sørensen, Vicki

    Through a series of participatory activities within a product development project, we analyse how these activities influence the design process and how new meaning is created through the interaction of crossing intentions (Larsen, 2010). By focusing on a specific theme in the project we reflect...... on how participatory activities are a key part in establishing important interactions between participants resulting in new design approaches. At other times participatory activities become a part of blurring these new approaches when performing new participatory activities towards developing new...... iterations of the concept in focus. We conclude that participatory activities can play a key part in the uptake of user knowledge but that a participatory innovation approach of establishing collaboration between crossing intentions can as well be considered provocative and as such, result in resistance...

  7. Mechanics of active surfaces

    Science.gov (United States)

    Salbreux, Guillaume; Jülicher, Frank

    2017-09-01

    We derive a fully covariant theory of the mechanics of active surfaces. This theory provides a framework for the study of active biological or chemical processes at surfaces, such as the cell cortex, the mechanics of epithelial tissues, or reconstituted active systems on surfaces. We introduce forces and torques acting on a surface, and derive the associated force balance conditions. We show that surfaces with in-plane rotational symmetry can have broken up-down, chiral, or planar-chiral symmetry. We discuss the rate of entropy production in the surface and write linear constitutive relations that satisfy the Onsager relations. We show that the bending modulus, the spontaneous curvature, and the surface tension of a passive surface are renormalized by active terms. Finally, we identify active terms which are not found in a passive theory and discuss examples of shape instabilities that are related to active processes in the surface.

  8. Lupus Activity in Pregnancy

    OpenAIRE

    Clowse, Megan E. B.

    2007-01-01

    Pregnancy in a woman with Systemic Lupus Erythematosus (SLE) can be complicated by both lupus activity and pregnancy mishaps. The majority of recent studies demonstrate an increase in lupus activity during pregnancy, perhaps exacerbated by hormonal shifts required to maintain pregnancy. Increased lupus activity, in turn, prompts an elevated risk for poor pregnancy outcomes, including stillbirth, preterm birth, low birth weight, and preeclamspsia. Fortunately, the majority of pregnancies in wo...

  9. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Content source: Division of Nutrition, Physical Activity, and Obesity , National Center for Chronic Disease Prevention and Health Promotion Email Recommend Tweet YouTube Instagram ...

  10. CDBG Public Services Activity

    Data.gov (United States)

    Department of Housing and Urban Development — CDBG activity related to public services, including senior services, legal services, youth services, employment training, health services, homebuyer counseling, food...

  11. CDBG Economic Development Activity

    Data.gov (United States)

    Department of Housing and Urban Development — CDBG activity related to economic development, including commercial or industrial rehab, commercial or industrial land acquisition, commercial or industrial...

  12. Activated carbons and gold

    International Nuclear Information System (INIS)

    McDougall, G.J.; Hancock, R.D.

    1980-01-01

    The literature on activated carbon is reviewed so as to provide a general background with respect to the effect of source material and activation procedure on carbon properties, the structure and chemical nature of the surface of the activated carbon, and the nature of absorption processes on carbon. The various theories on the absorption of gold and silver from cyanide solutions are then reviewed, followed by a discussion of processes for the recovery of gold and silver from cyanide solutions using activated carbon, including a comparison with zinc precipitation

  13. Social and Physical Environmental Factors Influencing Adolescents' Physical Activity in Urban Public Open Spaces: A Qualitative Study Using Walk-Along Interviews.

    Directory of Open Access Journals (Sweden)

    Linde Van Hecke

    Full Text Available Most previous studies examining physical activity in Public Open Spaces (POS focused solely on the physical environment. However, according to socio-ecological models the social environment is important as well. The aim of this study was to determine which social and physical environmental factors affect adolescents' visitation and physical activity in POS in low-income neighbourhoods. Since current knowledge on this topic is limited, especially in Europe, qualitative walk-along interviews were used to obtain detailed and context-specific information. Participants (n = 30, aged 12-16 years, 64% boys were recruited in POS in low-income neighbourhoods in Brussels, Ghent and Antwerp (Belgium. Participants were interviewed while walking in the POS with the interviewer. Using this method, the interviewer could observe and ask questions while the participant was actually experiencing the environment. All audio-recorded interviews were transcribed and analysed using Nvivo 10 software and thematic analysis was used to derive categories and subcategories using a grounded theory approach. The most important subcategories that were supportive of visiting POS and performing physical activity in POS were; accessibility by foot/bicycle/public transport, located close to home/school, presence of (active friends and family, cleanliness of the POS and features, availability of sport and play facilities, large open spaces and beautiful sceneries. The most important subcategories that were unsupportive of visiting POS and physical activity in POS were; presence of undesirable users (drug users, gangs and homeless people, the behaviour of other users and the cleanliness of the POS and features. Social factors appeared often more influential than physical factors, however, it was the combination of social and physical factors that affected adolescents' behaviour in POS. Easily accessible POS with high quality features in the proximity of adolescents' home or school

  14. Social and Physical Environmental Factors Influencing Adolescents’ Physical Activity in Urban Public Open Spaces: A Qualitative Study Using Walk-Along Interviews

    Science.gov (United States)

    Van Hecke, Linde; Deforche, Benedicte; Van Dyck, Delfien; De Bourdeaudhuij, Ilse; Veitch, Jenny; Van Cauwenberg, Jelle

    2016-01-01

    Most previous studies examining physical activity in Public Open Spaces (POS) focused solely on the physical environment. However, according to socio-ecological models the social environment is important as well. The aim of this study was to determine which social and physical environmental factors affect adolescents’ visitation and physical activity in POS in low-income neighbourhoods. Since current knowledge on this topic is limited, especially in Europe, qualitative walk-along interviews were used to obtain detailed and context-specific information. Participants (n = 30, aged 12–16 years, 64% boys) were recruited in POS in low-income neighbourhoods in Brussels, Ghent and Antwerp (Belgium). Participants were interviewed while walking in the POS with the interviewer. Using this method, the interviewer could observe and ask questions while the participant was actually experiencing the environment. All audio-recorded interviews were transcribed and analysed using Nvivo 10 software and thematic analysis was used to derive categories and subcategories using a grounded theory approach. The most important subcategories that were supportive of visiting POS and performing physical activity in POS were; accessibility by foot/bicycle/public transport, located close to home/school, presence of (active) friends and family, cleanliness of the POS and features, availability of sport and play facilities, large open spaces and beautiful sceneries. The most important subcategories that were unsupportive of visiting POS and physical activity in POS were; presence of undesirable users (drug users, gangs and homeless people), the behaviour of other users and the cleanliness of the POS and features. Social factors appeared often more influential than physical factors, however, it was the combination of social and physical factors that affected adolescents’ behaviour in POS. Easily accessible POS with high quality features in the proximity of adolescents’ home or school may

  15. Social and Physical Environmental Factors Influencing Adolescents' Physical Activity in Urban Public Open Spaces: A Qualitative Study Using Walk-Along Interviews.

    Science.gov (United States)

    Van Hecke, Linde; Deforche, Benedicte; Van Dyck, Delfien; De Bourdeaudhuij, Ilse; Veitch, Jenny; Van Cauwenberg, Jelle

    2016-01-01

    Most previous studies examining physical activity in Public Open Spaces (POS) focused solely on the physical environment. However, according to socio-ecological models the social environment is important as well. The aim of this study was to determine which social and physical environmental factors affect adolescents' visitation and physical activity in POS in low-income neighbourhoods. Since current knowledge on this topic is limited, especially in Europe, qualitative walk-along interviews were used to obtain detailed and context-specific information. Participants (n = 30, aged 12-16 years, 64% boys) were recruited in POS in low-income neighbourhoods in Brussels, Ghent and Antwerp (Belgium). Participants were interviewed while walking in the POS with the interviewer. Using this method, the interviewer could observe and ask questions while the participant was actually experiencing the environment. All audio-recorded interviews were transcribed and analysed using Nvivo 10 software and thematic analysis was used to derive categories and subcategories using a grounded theory approach. The most important subcategories that were supportive of visiting POS and performing physical activity in POS were; accessibility by foot/bicycle/public transport, located close to home/school, presence of (active) friends and family, cleanliness of the POS and features, availability of sport and play facilities, large open spaces and beautiful sceneries. The most important subcategories that were unsupportive of visiting POS and physical activity in POS were; presence of undesirable users (drug users, gangs and homeless people), the behaviour of other users and the cleanliness of the POS and features. Social factors appeared often more influential than physical factors, however, it was the combination of social and physical factors that affected adolescents' behaviour in POS. Easily accessible POS with high quality features in the proximity of adolescents' home or school may stimulate

  16. Requirement of Simultaneous Assessment of Crystal- and Supernatant-Related Entomotoxic Activities of Bacillus thuringiensis Strains for Biocontrol-Product Development

    Directory of Open Access Journals (Sweden)

    Ronaldo Costa Argôlo-Filho

    2014-05-01

    Full Text Available Bioinsecticides with lower concentrations of endospores/crystals and without loss of efficiency are economically advantageous for pest biocontrol. In addition to Cry proteins, other Bacillus thuringiensis (Bt toxins in culture supernatants (SN have biocontrol potential (e.g., Vip3A, Cry1I, Sip1, whereas others are unwanted (β-exotoxins, as they display widespread toxicity across taxa. A strain simultaneously providing distinct toxin activities in crystals and SN would be desirable for bioinsecticides development; however, strains secreting β-exotoxins should be discarded, independently of other useful entomotoxins. Entomotoxicity of crystals and SN from a Brazilian Bt tolworthi strain (Btt01 was tested against Spodoptera frugiperda to assess the potential for biocontrol-product development based on more than one type of toxin/activity. Tests showed that 107 endospores mL−1 caused >80% of larvae mortality, suggesting Btt01 may be used in similar concentrations as those of other Bt-based biopesticides. When it was applied to cornfields, a significant 60% reduction of larvae infestation was observed. However, bioassays with Btt01 SN revealed a thermostable toxic activity. Physicochemical characterization strongly suggests the presence of unwanted β-exotoxins, with isolate-specific temporal variation in its secretion. Knowledge of the temporal pattern of secretion/activity in culture for all forms of toxins produced by a single strain is required to both detect useful activities and avoid the potential lack of identification of undesirable toxins. These findings are discussed in the contexts of commercial Bt product development, advantages of multiple-activity strains, and care and handling recommended for large-scale fermentation systems.

  17. Shoulder muscle activity and function in common shoulder rehabilitation exercises.

    Science.gov (United States)

    Escamilla, Rafael F; Yamashiro, Kyle; Paulos, Lonnie; Andrews, James R

    2009-01-01

    The rotator cuff performs multiple functions during shoulder exercises, including glenohumeral abduction, external rotation (ER) and internal rotation (IR). The rotator cuff also stabilizes the glenohumeral joint and controls humeral head translations. The infraspinatus and subscapularis have significant roles in scapular plane abduction (scaption), generating forces that are two to three times greater than supraspinatus force. However, the supraspinatus still remains a more effective shoulder abductor because of its more effective moment arm. Both the deltoids and rotator cuff provide significant abduction torque, with an estimated contribution up to 35-65% by the middle deltoid, 30% by the subscapularis, 25% by the supraspinatus, 10% by the infraspinatus and 2% by the anterior deltoid. During abduction, middle deltoid force has been estimated to be 434 N, followed by 323 N from the anterior deltoid, 283 N from the subscapularis, 205 N from the infraspinatus, and 117 N from the supraspinatus. These forces are generated not only to abduct the shoulder but also to stabilize the joint and neutralize the antagonistic effects of undesirable actions. Relatively high force from the rotator cuff not only helps abduct the shoulder but also neutralizes the superior directed force generated by the deltoids at lower abduction angles. Even though anterior deltoid force is relatively high, its ability to abduct the shoulder is low due to a very small moment arm, especially at low abduction angles. The deltoids are more effective abductors at higher abduction angles while the rotator cuff muscles are more effective abductors at lower abduction angles. During maximum humeral elevation the scapula normally upwardly rotates 45-55 degrees, posterior tilts 20-40 degrees and externally rotates 15-35 degrees. The scapular muscles are important during humeral elevation because they cause these motions, especially the serratus anterior, which contributes to scapular upward rotation

  18. Fuzzy-predictive direct power control implementation of a grid connected photovoltaic system, associated with an active power filter

    International Nuclear Information System (INIS)

    Ouchen, Sabir; Betka, Achour; Abdeddaim, Sabrina; Menadi, Abdelkrim

    2016-01-01

    Highlights: • An implementation on dSPACE 1104 of a double stage grid connected photovoltaic system, associated with an active power filter. • A fuzzy logic controller for maximum power point tracking of photovoltaic generator using a boost converter. • Predictive direct power control almost eliminates the effect of harmonics under a unite power factor. • The robustness of control strategies was examined in different irradiance level conditions. - Abstract: The present paper proposes a real time implementation of an optimal operation of a double stage grid connected photovoltaic system, associated with a shunt active power filter. On the photovoltaic side, a fuzzy logic based maximum power point taking control is proposed to track permanently the optimum point through an adequate tuning of a boost converter regardless the solar irradiance variations; whereas, on the grid side, a model predictive direct power control is applied, to ensure both supplying a part of the load demand with the extracted photovoltaic power, and a compensation of undesirable harmonic contents of the grid current, under a unity power factor operation. The implementation of the control strategies is conducted on a small scale photovoltaic system, controlled via a dSPACE 1104 single card. The obtained experimental results show on one hand, that the proposed Fuzzy logic based maximum power taking point technique provides fast and high performances under different irradiance levels while compared with a sliding mode control, and ensures 1.57% more in efficiency. On the other hand, the predictive power control ensures a flexible settlement of active power amounts exchanges with the grid, under a unity power functioning. Furthermore, the grid current presents a sinusoidal shape with a tolerable total harmonic distortion coefficient 4.71%.

  19. NEA activities in 1983. 12. Activity report

    International Nuclear Information System (INIS)

    1984-01-01

    This report describes the main features of the Agency's work during 1983 and discusses the state and prospects of the nuclear industry in OECD countries. Trends in nuclear power, nuclear development and the fuel cycles nuclear safety technology and licensing, radiological and environmental impacts of nuclear fuel cycle activities, legal affairs, nuclear science, joint undertakings and other NEA joint projects, organisation and administration are reviewed

  20. Activity and potential role of licofelone in the management of osteoarthritis

    Directory of Open Access Journals (Sweden)

    Arrigo FG Cicero

    2007-04-01

    Full Text Available Arrigo FG Cicero, Luca Laghi“D. Campanacci” Clinical Medicine & Applied Biotechnology Dept. Sant’Orsola-Malpighi Hospital – University of Bologna Via Massarenti, 9, 40138 Bologna, ItalyAbstract: Osteoarthritis is the most common form of arthritis. It is a progressive joint disease associated with aging. It may be found in the knees, hips, or other joints. It is estimated that costs associated with osteoarthritis exceed 2% of the gross national product in developed countries. Nonsteroidal anti-inflammatory drugs (NSAIDs are a mainstay in the treatment of inflammatory disease and are among the most widely used drugs worldwide. The main limitation in using NSAIDs consists in their side-effects, including gastrointestinal ulcerogenic activity and bronchospasm. The mechanism of action of these drugs is attributed to the inhibition of cyclooxygenase (COX, and, consequently, the conversion of arachidonic acid into prostaglandins. It is hypothesized that the undesirable side-effects of NSAIDs are due to the inhibition of COX-1 (constitutive isoform, whereas the beneficial effects are related to the inhibition of COX-2 (inducible isoform. Arachidonic acid can also be converted to leukotrienes (LTs by the action of 5-lipoxygenase (5-LOX. Licofelone, a LOX/COX competitive inhibitor, decreases the production of proinflammatory leukotrienes and prostaglandins (which are involved in the pathophysiology of osteoarthritis and in gastrointestinal (GI damage induced by NSAIDs and has the potential to combine good analgesic and anti-inflammatory effects with excellent GI tolerability. Preliminary data with this drug seem promising, but further well-designed clinical trials of this agent in the elderly will be necessary before a final evaluation is possible.Keywords: LOX/COX inhibitor, Licofelone, leukotrienes, osteoarthritis, nonsteroidal anti-inflammatory drugs

  1. NEA activities in 1982

    International Nuclear Information System (INIS)

    1983-01-01

    This report presents an account of the activities of the Nuclear Energy Agency. It deals with current nuclear trends, nuclear development and the fuel cycle, nuclear safety research and licensing, radiological and environmental impacts of nuclear fuel cycle activities, legal affairs, nuclear science, joint undertakings, and, organization and administration

  2. Coordinating Shared Activities

    Science.gov (United States)

    Clement, Bradley

    2004-01-01

    Shared Activity Coordination (ShAC) is a computer program for planning and scheduling the activities of an autonomous team of interacting spacecraft and exploratory robots. ShAC could also be adapted to such terrestrial uses as helping multiple factory managers work toward competing goals while sharing such common resources as floor space, raw materials, and transports. ShAC iteratively invokes the Continuous Activity Scheduling Planning Execution and Replanning (CASPER) program to replan and propagate changes to other planning programs in an effort to resolve conflicts. A domain-expert specifies which activities and parameters thereof are shared and reports the expected conditions and effects of these activities on the environment. By specifying these conditions and effects differently for each planning program, the domain-expert subprogram defines roles that each spacecraft plays in a coordinated activity. The domain-expert subprogram also specifies which planning program has scheduling control over each shared activity. ShAC enables sharing of information, consensus over the scheduling of collaborative activities, and distributed conflict resolution. As the other planning programs incorporate new goals and alter their schedules in the changing environment, ShAC continually coordinates to respond to unexpected events.

  3. Activity report 2002

    International Nuclear Information System (INIS)

    2002-01-01

    This annual report deals with the activities, the program management and the financial aspects of the ANDRA (National Agency for the radioactive wastes management) during 2002. After a presentation of the activities during the year 2002, it provides the financial accounting, data on company cash, the ANDRA missions and publications. (A.L.B.)

  4. Physical Activity Questionnaire

    Directory of Open Access Journals (Sweden)

    Kostencka Alicja

    2016-11-01

    Full Text Available Study aim: The aim of the study was to determine the weekly energy expenditure measuring MET/min/week based on data collected through the Canada Fitness Survey (CFS, according to the classification used in the International Physical Activity Questionnaire (IPAQ, and to verify the adopted method to assess the level of physical activity in students of physical education.

  5. Elementary Environmental Activities.

    Science.gov (United States)

    Larson, Robert J.

    This guide presents suggestions for field trips, out-of-doors activities, material for centers, and individualized activities in the teaching of elementary school science and particularly environmental education at the elementary level. The guide includes a section on preparation and procedures for conducting field trips, including sample…

  6. Obesity and physical activity.

    NARCIS (Netherlands)

    Westerterp, K.R.

    1999-01-01

    Department of Human Biology, Maastricht University, The Netherlands. k.westerterp@hb.unimaas.nl OBJECTIVES: Three aspects of obesity and physical activity are reviewed: whether the obese are inactive; how the activity level can be increased; and which are the effects of an increase in physical

  7. Peak Longevity Physical Activity

    Science.gov (United States)

    People who engage in three to five times the recommended minimum level of leisure-time physical activity derive the greatest benefit in terms of mortality reduction when compared with people who do not engage in leisure-time physical activity.

  8. Learning Activities for Toddlers.

    Science.gov (United States)

    Texas Child Care, 1996

    1996-01-01

    Suggests activities to help toddlers develop skills in the four important areas of self-help, creativity, world mastery, and coordination. Activities include hand washing, button practice, painting, movement and music, bubble making, creation of a nature mural, and a shoe print trail. (TJQ)

  9. Respirometry in activated sludge

    NARCIS (Netherlands)

    Spanjers, H.

    1993-01-01

    The purpose of the study was (1) to develop a respiration meter capable of continuously measuring, using different procedures, the oxygen uptake rate of activated sludge and (2) to expand knowledge about respiration related characteristics of wastewater and activated sludge.

    A

  10. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... CDC’s Example StairWELL Stairwell Appearance Motivational Signs Installing Music Other Ideas to Consider Tracking Stair Usage Project ... an activity. When using relative intensity, people pay attention to how physical activity affects their heart rate ...

  11. Activation analysis. Detection limits

    International Nuclear Information System (INIS)

    Revel, G.

    1999-01-01

    Numerical data and limits of detection related to the four irradiation modes, often used in activation analysis (reactor neutrons, 14 MeV neutrons, photon gamma and charged particles) are presented here. The technical presentation of the activation analysis is detailed in the paper P 2565 of Techniques de l'Ingenieur. (A.L.B.)

  12. Reflections on Activity Theory

    Science.gov (United States)

    Bakhurst, David

    2009-01-01

    It is sometimes suggested that activity theory represents the most important legacy of Soviet philosophy and psychology. But what exactly "is" activity theory? The canonical account in the West is given by Engestrom, who identifies three stages in the theory's development: from Vygotsky's insights, through Leontiev's articulation of the…

  13. RTE activity report 2005

    International Nuclear Information System (INIS)

    2006-01-01

    The RTE (electric power transport network) is the french manger of the electric power transport. This activity report provides information on the company results for the year 2005: panorama of the year, management and organization, the place of RTE in the european market, the customers, the industrial tool, the environment the human resources, the international activity and the management report. (A.L.B.)

  14. Habitats, activities, and signs

    DEFF Research Database (Denmark)

    Andersen, Peter Bøgh; Brynskov, Martin

    2004-01-01

    Digital habitats is a framework for designing and modeling environments for activities that involve mobile and embedded computing systems. This paper 1) introduces the basic concepts of the framework, i.e. activity, thematic role, and the three ‘dimensions’ of a habitat: physical, informational...

  15. Measuring Children's Physical Activity

    DEFF Research Database (Denmark)

    Schneller, Mikkel Bo; Bentsen, Peter; Nielsen, Glen

    2017-01-01

    INTRODUCTION: Accelerometer-based physical activity monitoring has become the method of choice in many large-scale physical activity (PA) studies. However, there is an ongoing debate regarding the placement of the device, the determination of device wear time, and how to solve a lack of participant...

  16. Mental activity and culture

    NARCIS (Netherlands)

    Hofstede, Gert Jan

    2018-01-01

    How does culture affect mental activity? That question, applied to the design of social agents, is tackled in this chapter. Mental activity acts on the perceived outside world. It does so in three steps: perceive, interpret, select action. We see that when culture is taken into account, objective

  17. Activation force splines

    DEFF Research Database (Denmark)

    Engell-Nørregård, Morten Pol; Erleben, Kenny

    We present a method for simulating the active contraction of deformable models, usable for interactive animation of soft deformable objects. We present a novel physical principle as the governing equation for the coupling between the low dimensional 1D activation force model and the higher...

  18. Carbon activity meter

    International Nuclear Information System (INIS)

    Roy, P.; Krankota, J.L.

    1975-01-01

    A carbon activity meter utilizing an electrochemical carbon cell with gaseous reference electrodes having particular application for measuring carbon activity in liquid sodium for the LMFBR project is described. The electrolyte container is electroplated with a thin gold film on the inside surface thereof, and a reference electrode consisting of CO/CO 2 gas is used. (U.S.)

  19. Measuring Physical Activity Intensity

    Medline Plus

    Full Text Available ... Obesity Healthy Weight Breastfeeding Micronutrient Malnutrition State and Local Programs Measuring Physical Activity Intensity Recommend on Facebook Tweet Share Compartir For more help with what counts as aerobic activity, watch this video: Windows Media Player, 4:48 More videos Here are some ...

  20. Cosmogenic activation: Recent results

    Science.gov (United States)

    Kudryavtsev, Vitaly A.

    2018-01-01

    Activation of materials is known to cause background events in underground experiments that may affect the sensitivity of these experiments to rare event searches. The most common source of activation is the exposure of materials to cosmic rays at the surface of the Earth but other various sources of neutrons may also be dangerous. Different computer codes provide estimates of production rates of radioactive isotopes due to activation but their results are sometimes inconsistent. High-sensitivity experiments looking for dark matter, neutrino-less double-beta decay or neutrinos from various sources, although affected by activation, provide crucial tests of models used in the codes. Recent calculations and measurements of activation rates are discussed in this paper.

  1. Local Worlds of Activation

    DEFF Research Database (Denmark)

    Jacobsson, Kerstin; Hollertz, Katarina; Garsten, Christina

    2017-01-01

    . This article studies local activation policy and practice in three Swedish municipalities, representing three distinct ‘local worlds of activation’. The analysis shows that policy orientations in the municipalities studied ranged from ‘work-first’ to ‘life-first’ approaches to activation. Governance...... arrangements and the role of private services and actors in service delivery differed significantly too, ranging from strictly market-based forms of governance to classical public administration. The article moreover shows how the different activation approaches were reflected in the radically different usages...... of Coordination Unions, as multi-party collaborate organisational structures established for activation policy implementation for certain target groups. Thus, activation must be approached not as a fixed and universal policy for social inclusion, but as susceptible to local practice and hence open to influence...

  2. Ras activation by SOS

    DEFF Research Database (Denmark)

    Iversen, Lars; Tu, Hsiung-Lin; Lin, Wan-Chen

    2014-01-01

    SOS molecules catalyzing nucleotide exchange in H-Ras. Single-molecule kinetic traces revealed that SOS samples a broad distribution of turnover rates through stochastic fluctuations between distinct, long-lived (more than 100 seconds), functional states. The expected allosteric activation of SOS...... by Ras-guanosine triphosphate (GTP) was conspicuously absent in the mean rate. However, fluctuations into highly active states were modulated by Ras-GTP. This reveals a mechanism in which functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather......Activation of the small guanosine triphosphatase H-Ras by the exchange factor Son of Sevenless (SOS) is an important hub for signal transduction. Multiple layers of regulation, through protein and membrane interactions, govern activity of SOS. We characterized the specific activity of individual...

  3. Active chiral fluids.

    Science.gov (United States)

    Fürthauer, S; Strempel, M; Grill, S W; Jülicher, F

    2012-09-01

    Active processes in biological systems often exhibit chiral asymmetries. Examples are the chirality of cytoskeletal filaments which interact with motor proteins, the chirality of the beat of cilia and flagella as well as the helical trajectories of many biological microswimmers. Here, we derive constitutive material equations for active fluids which account for the effects of active chiral processes. We identify active contributions to the antisymmetric part of the stress as well as active angular momentum fluxes. We discuss four types of elementary chiral motors and their effects on a surrounding fluid. We show that large-scale chiral flows can result from the collective behavior of such motors even in cases where isolated motors do not create a hydrodynamic far field.

  4. Active Photonic Devices

    Science.gov (United States)

    Della Valle, Giuseppe; Osellame, Roberto

    The chapter is devoted to active photonic devices fabricated by fs-laser writing. After a brief introduction focused on the role played by fs-laser written active devices, Sect. 10.2 briefly reviews the spectroscopical properties of the most interesting active ions so far exploited, namely erbium, ytterbium, neodimium, and bismuth. In Sect. 10.3 the main figures of merit for an active waveguide, namely the internal gain, the insertion loss, the net gain, and the noise figure are introduced and the experimental procedure for accurate gain measurement is also detailed. A thorough review of the active photonic devices demonstrated with the femtosecond laser microfabrication technique is presented in Sects. 10.4, 10.5, and 10.6, where several active waveguides and amplifiers, prototypal lasers, as well as more functionalized laser devices (operating under single longitudinal mode or stable mode-locking regime) are illustrated, respectively. Finally, conclusions and future perspectives of femtosecond-laser micromachining of active photonic devices are provided.

  5. Emotionally Intense Science Activities

    Science.gov (United States)

    King, Donna; Ritchie, Stephen; Sandhu, Maryam; Henderson, Senka

    2015-08-01

    Science activities that evoke positive emotional responses make a difference to students' emotional experience of science. In this study, we explored 8th Grade students' discrete emotions expressed during science activities in a unit on Energy. Multiple data sources including classroom videos, interviews and emotion diaries completed at the end of each lesson were analysed to identify individual student's emotions. Results from two representative students are presented as case studies. Using a theoretical perspective drawn from theories of emotions founded in sociology, two assertions emerged. First, during the demonstration activity, students experienced the emotions of wonder and surprise; second, during a laboratory activity, students experienced the intense positive emotions of happiness/joy. Characteristics of these activities that contributed to students' positive experiences are highlighted. The study found that choosing activities that evoked strong positive emotional experiences, focused students' attention on the phenomenon they were learning, and the activities were recalled positively. Furthermore, such positive experiences may contribute to students' interest and engagement in science and longer term memorability. Finally, implications for science teachers and pre-service teacher education are suggested.

  6. Titanium dioxide nanoparticles induce human eosinophil adhesion onto endothelial EA.hy926 cells via activation of phosphoinositide 3-kinase/Akt cell signalling pathway.

    Science.gov (United States)

    Murphy-Marion, Maxime; Girard, Denis

    2018-02-01

    The use of nanoparticles (NPs) for developing new therapeutic strategies in a variety of diseases is gaining increasing attention. However, NPs could possess undesired effects, including pro-inflammatory activities. Despite the fact that several studies reported that NPs may induce or exacerbate eosinophilic inflammation in vivo in rodents, the information regarding the direct interaction between NPs and human eosinophils is lacking. In the present study, we test the possibility that NPs could alter the capacity of human eosinophils to adhere onto a cellular substratum. Using a panel of NPs, we found that several were able to increase the adhesion of human eosinophil onto endothelial EA.hy926 cells. Among them, TiO 2 NPs were the most potent and we therefore pursue this study with these NPs. TiO 2 NPs were found to increase the adhesion of eosinophils in a concentration dependent fashion. TiO 2 NPs did not alter the cell surface expression of a panel of cellular adhesion molecules, but CD29. Indeed, a weak to moderate, but significant, decrease of CD29 was observed after 30min but returned to normal levels after 90min. TiO 2 NPs were found to activate Akt, one important target of phosphoinositide 3-kinase (PI3K). However, despite the fact that cells were fully responsive to the cytokine GM-CSF activating both Akt and Erk-1/2, TiO 2 NPs did not activate Erk-1/2. Using a pharmacological approach with the PI3K/Akt inhibitor, wortmannin, the ability of TiO 2 NPs to activate Akt was drastically inhibited and, further, their capacity to increase adhesion of eosinophils was reversed. This study provides insights into the effects of NPs on the biology of human eosinophils indicating that as other agents, NPs, namely TiO 2 NPs, can induce intracellular events associated with a cellular function, adhesion. Copyright © 2017 Elsevier GmbH. All rights reserved.

  7. Oxidative stress and platelet activation during on-pump and off-pump coronary artery bypass grafting in patients with double grafted vessels

    Directory of Open Access Journals (Sweden)

    Petar Vukicevic

    2016-11-01

    Full Text Available This study aimed to evaluate the oxidative stress status and two markers of platelet activation and reactivity in off-pump versus on-pump coronary artery bypass surgery. Study groups of 65 patients with double coronary artery bypass grafting were divided into cardiopulmonary bypass (CPB and off-pump coronary artery bypass groups. In serial blood samples, lipid hydroperoxides (LOOH, serum paraoxonase (PON1, advanced oxidation protein products (AOPP, total sulfhydryl groups (tSHG and red blood cell distribution width (RDW to platelet (Plt ratio (RPR and mean platelet volume (MPV to platelet (Plt ratio (MPR index were determined to compare the extent of oxidative stress and platelet activation. The MPR and RPR rose significantly in the post-operative period (P < 0.001 in both groups. The increase was higher in the CPB group, but this difference reached borderline significance at 48 h post-operatively. The AOPP/tSHG index increased 6 h after surgery, preceded by a significant fall of the PON1/LOOH ratio, more evident in the CPB group. Multiple linear regression analysis showed explicit connection between these markers and surgery-related clinical conditions. Receiver operating characteristic analysis enabled estimation of the clinical accuracy of oxidative plus platelet-related indices in prediction of surgery caused complications (area under the curve for the model consisted of oxidative stress parameters and platelet activation indices was above 0.9, P < 0.001. Results showed higher oxidative stress and undesirable platelet activation in the CPB group. Oxidative status markers and platelet activity indices showed good clinical accuracy to predict the development of possible surgical complications.

  8. Molecular Docking, Molecular Dynamics, and Structure-Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists.

    Science.gov (United States)

    Noha, Stefan M; Schmidhammer, Helmut; Spetea, Mariana

    2017-06-21

    Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure-activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3-7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

  9. Mnemonic activation by SPECT

    International Nuclear Information System (INIS)

    Migneco, O.; Darcourt, J.; Benoit, M; Malandain, G.; Thirion, J.P.; Robert, Ph.; Vidal, R.; Desvignes, Ph.; Benoliel, J.; Ayache, N.; Bussiere, F.

    1997-01-01

    Data of literature show that SPECT is able to detect cerebral activations induced by sensory-motor stimuli. The facts are not clearly established in what concerns the cognitive activations the amplitude of which is lower. We have studied an activation paradigm such as the Grober and Bruschke test which implies the long term explicit memory. It comprises a visual presentation of words followed by their indexed recall. By using a two-day protocol, 2 SPECTs were achieved in 4 healthy right-handed voluntaries as follows: one of activation (A) and one of control (B). The fifth subject benefited by a SPECT B and of an MRI. The injection for the examination A has been done during the indexed recall stage and for the examination B at the moment when the patient repeated several times the same 3 words. The SPECT data were collected 1 hour after the injection of 370 MBq of ECD making use of a 3-head camera equipped with UHR fan collimators and ending by a LMH on the reconstructed images of 8 mm. The MRI has been achieved by means of a Signa 1.5 Tesla magnet. The SPECT A and B of the subjects 1 to 4 were matched elastically to that of the subject 5 and that of the subject 5 was rigidly matched on its MRI. In this way the individual activation cards of the 4 subjects could be averaged and superimposed on the MRI of the 5. subject. One observes an internal temporal activation (maximal activation of left tonsil, +25% and right uncus, +23%) and a right cingulum activation (maximal activation, +25%), in agreement with the neuro-physiological data. The elastic matching makes possible the inter-subject averaging, what increases the signal-to-noise ratio of activation. The inter-modality rigid matching facilitates the anatomical localisation of the activation site. With these adapted tools, the cognitive activation is thus possible by SPECT and opens perspectives for early diagnosis of neurological troubles, namely of Alzheimer's disease

  10. IPSN's 2001 activity report

    International Nuclear Information System (INIS)

    2001-01-01

    This report summarizes the 2001 activities and operation of the French institute of nuclear protection and safety (IPSN) which has become the institute of radioprotection and nuclear safety (IRSN) after its merging with the office of protection against ionizing radiations (OPRI). IPSN's activities cover: the safety of nuclear facilities, the safety of nuclear wastes, the management of emergencies, the management of sensible materials, the protection of the environment and of the public health, some research activities with foreign partners (central and eastern Europe, Asia..), and a partnership with the GRS, the German homologue of IPSN. (J.S.)

  11. Activity report 1977

    International Nuclear Information System (INIS)

    Krishnan, L.V.; Lee, S.M.; Sahoo, D.; Sreedharan, O.M.; Srinivasan, G.

    1979-05-01

    The Research and Development (R and D) activities of the Reactor Research Centre, Kalpakkam, during the year 1977 are reported. The report is presented in the form of individual summaries of R and D activities most of which are connected with the FBTR project. These R and D activities deal with various aspects of the FBTR project such as reactor physics, reactor design, reactor engineering, fabrication, testing and quality assurance of reactor materials and components, reactor chemistry, reactor safety, reprocessing, systems analysis and instrumentation. (M.G.B.)

  12. Inspector measurement verification activities

    International Nuclear Information System (INIS)

    George, R.S.; Crouch, R.

    e most difficult and complex activity facing a safeguards inspector involves the verification of measurements and the performance of the measurement system. Remeasurement is the key to measurement verification activities. Remeasurerements using the facility's measurement system provide the bulk of the data needed for determining the performance of the measurement system. Remeasurements by reference laboratories are also important for evaluation of the measurement system and determination of systematic errors. The use of these measurement verification activities in conjunction with accepted inventory verification practices provides a better basis for accepting or rejecting an inventory. (U.S.)

  13. Creative activity and inclusion

    Directory of Open Access Journals (Sweden)

    Shemanov A.Yu.

    2013-09-01

    Full Text Available The aim of the article was to analyze the inclusion potential of art creative activity, namely of theatre performance, in people with disabilities. The article provides examples of disagreements in understanding the significance of these art activities for exercising the rights of people with disabilities to contribute to culture and art and some problems arising here. The conclusion is made that theatre art performed by people with disabilities is gradually changing its function: from being a means of self-affirmation to the determination of its specific place in overall theatre process. These changes confirm the inclusion potential of theatre art activity.

  14. Active Directory cookbook

    CERN Document Server

    Hunter, Laura

    2008-01-01

    When you need practical hands-on support for Active Directory, the updated edition of this extremely popular Cookbook provides quick solutions to more than 300 common (and uncommon) problems you might encounter when deploying, administering, and automating Microsoft's network directory service. For the third edition, Active Directory expert Laura E. Hunter offers troubleshooting recipes based on valuable input from Windows administrators, in addition to her own experience. You'll find solutions for the Lightweight Directory Access Protocol (LDAP), ADAM (Active Directory Application Mode), m

  15. A neutron activation detector

    International Nuclear Information System (INIS)

    Ambardanishvili, T.S.; Kolomiitsev, M.A.; Zakharina, T.Y.; Dundua, V.J.; Chikhladze, N.V.

    1973-01-01

    The present invention concerns a neutron activation detector made from a moulded and hardened composition. According to the invention, that composition contains an activable substance constituted by at least two chemical elements and/or compounds of at least two chemical elements. Each of these chemical elements is capable of reacting with the neutrons forming radio-active isotopes with vatious levels of energy during desintegration. This neutron detector is mainly suitable for measuring integral thermal neutron and fast neutron fluxes during irradiation of the sample, and also for measuring the intensities of neutron fields [fr

  16. Forecast of auroral activity

    International Nuclear Information System (INIS)

    Lui, A.T.Y.

    2004-01-01

    A new technique is developed to predict auroral activity based on a sample of over 9000 auroral sites identified in global auroral images obtained by an ultraviolet imager on the NASA Polar satellite during a 6-month period. Four attributes of auroral activity sites are utilized in forecasting, namely, the area, the power, and the rates of change in area and power. This new technique is quite accurate, as indicated by the high true skill scores for forecasting three different levels of auroral dissipation during the activity lifetime. The corresponding advanced warning time ranges from 22 to 79 min from low to high dissipation levels

  17. Scientific activities 1979

    International Nuclear Information System (INIS)

    1981-01-01

    The scientific activities and achievements of the Nuclear Research Center Democritus for the year 1979 are presented in the form of a list of 78 projects giving title, objectives, commencement year, responsible of each project, developed activities and the pertaining lists of publications. The 15 chapters of this work cover the activities of the main Divisions of the Democritus NRC: Electronics, Biology, Physics, Chemistry, Health Physics, Reactor, Radioisotopes, Environmental Radioactivity, Soil Science, Computer Center, Uranium Exploration, Medical Service, Technological Applications and Training. (T.A.)

  18. The Activity of Play

    DEFF Research Database (Denmark)

    Pichlmair, Martin

    This paper presents Activity Theory as a framework for understanding the action of playing games with the intention of building a foundation for the creation of new game design tools and methods. Activity Theory, an epistemological framework rooted in Soviet psychology of the first half of the 20th...... century, has a long history and was only recently applied to HCI (Nardi 1996) and games (P. Barr et al. 2007), where Barr succeeded in situating play in the Activity Theory framework. Based on his work to establish a framework for analysing systems of values in games, this paper maps different levels...

  19. Activation neutron detector

    International Nuclear Information System (INIS)

    Ambardanishvili, T.S.; Kolomiitsev, M.A.; Zakharina, T.Y.; Dundua, V.J.; Chikhladze, N.V.

    1976-01-01

    An activation neutron detector made as a moulded and cured composition of a material capable of being neutron-activated is described. The material is selected from a group consisting of at least two chemical elements, a compound of at least two chemical elements and their mixture, each of the chemical elements and their mixture, each of the chemical elements being capable of interacting with neutrons to form radioactive isotopes having different radiation energies when disintegrating. The material capable of being neutron-activated is distributed throughout the volume of a polycondensation resin inert with respect to neutrons and capable of curing. 17 Claims, No Drawings

  20. Orthogonalizing crusher and diffusion-encoding gradients to suppress undesired echo pathways in the twice-refocused spin echo diffusion sequence.

    Science.gov (United States)

    Nagy, Zoltán; Thomas, David L; Weiskopf, Nikolaus

    2014-02-01

    The twice-refocused spin echo sequence is widely used in diffusion imaging due to its excellent performance in reducing eddy currents. The three radio frequency pulses give rise to eight separate signal pathways. Because there is no general solution for the size and arrangement for crusher gradients, with constant size and orientation, that is effective for all arbitrary diffusion-sensitizing b-values and directions, this article introduces and validates a solution whereby the crusher and diffusion-encoding gradients are always kept orthogonal, thus ensuring their independence. The cancellation of the crusher and diffusion gradients was demonstrated. Subsequently, crusher gradients were implemented in such a way that they were always orthogonal to the diffusion gradient. Phantom and in-vivo experiments were performed to ascertain that orthogonally implemented crusher gradients alleviate the problem without lowering image quality. In all experiments, when the crusher gradients' action was cancelled by the diffusion-encoding gradients artifactual signal modulation was observed. When orthogonal gradients were implemented the artifacts were eliminated without detrimental effects on image quality. Orthogonal crushers are easy to implement and can be used for any variant of diffusion imaging sequences (e.g., diffusion tensor imaging, fiber diameter mapping) where the twice-refocused scheme is used. Copyright © 2013 Wiley Periodicals, Inc.