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Sample records for mode-of-action based approach

  1. Chapter 14. Approaches for Evaluation of Mode of Action.

    Science.gov (United States)

    Cellular and molecular approaches vastly expand the possibilities for revealing the underlying mechanisms of developmental toxicity. The typical teratology screening test examines near-term fetuses after exposure throughout organogenesis and evaluates the potential for an exposur...

  2. Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T

    2007-05-11

    A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr approach recommended by the USEPA Guidelines for Cancer Risk Assessment to oach address uncertainty in carcinogenic mode of action of certain chemicals when risk is extrapolated from bioassay data. These Guidelines recognize that some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches to low low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient t to parameterize a biologically based model that reliably o extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach - similar to that used in reference dose procedures for classic toxicity endpoints - can address MOA uncertainty in a way that avoids explicit modeling of low low-dose risk as a function of administere administered or internal dose. Even when a 'nonlinear' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was i illustrated llustrated for a likely DMOA rodent carcinogen naphthalene, specifically to the issue of risk extrapolation from bioassay data on naphthalene naphthalene-induced nasal tumors in rats. Bioassay data, supplemental toxicokinetic data, and related physiologically based p

  3. Systems Biology and Mode of Action Based Risk Assessment.

    Science.gov (United States)

    The application of systems biology approaches has greatly increased in the past decade largely as a consequence of the human genome project and technological advances in genomics and proteomics. Systems approaches have been used in the medical & pharmaceutical realm for diagnost...

  4. Computational Chemistry-based Acute Aquatic Toxicity Mode of Action Assignment

    Science.gov (United States)

    The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

  5. Computational Chemistry-based Acute Aquatic Toxicity Mode of Action Assignment

    Science.gov (United States)

    The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

  6. Innovative mode of action based in vitro assays for detection of marine neurotoxins

    NARCIS (Netherlands)

    Nicolas, J.A.Y.

    2015-01-01

    Innovative mode of action based in vitro assays for detection of marine neurotoxins J. Nicolas, P.J.M. Hendriksen, T.F.H. Bovee, I.M.C.M. Rietjens Marine biotoxins are naturally occurring compounds produced by particular phytoplankton species. These toxins often accumulate in seafood and thereby

  7. Evidence-based modeling of mode-of-action for functional ingredients influencing Alzheimer’s disease through neurotrophin pathway

    Directory of Open Access Journals (Sweden)

    Erfan Younesi

    2014-08-01

    Full Text Available Background: Brain-derived neurotrophic factor (BDNF is the most widely expressed member of the neurotrophin family in the human brain and is crucially involved in the development of neural circuits, modulation of synaptic plasticity, and regulation of cognitive functions, including learning and memory. Many studies have shown the association of altered BDNF levels with neurodegenerative and neuropsychiatric disorders. However, BDNF is not able to cross the blood-brain barrier and, thus, its delivery to the nervous system is a challenge. Therefore, functional diets with the ability to induce production of BDNF in the brain may offer an alternative route. The objective of this study was three-fold: first, to find out diets that are causally linked to the agonistic activity of BDNF in the neurotrophin signaling pathway; second and mainly, to investigate mode-of-action of these functional diets through systems-based mechanistic modeling in the context of Alzheimer’s disease; and third, to demonstrate the proof-of-concept application of systems biology methods, that are well established in the pharmaceutical sector, to the emerging field of functional food. Methods: In the first step, two cause-and-effect models of BDNF signaling in two states, i.e. normal state and Alzheimer’s disease state, were constructed using published knowledge in scientific literature and pathway databases. A “differential model analysis” between the two states was performed by which mechanistic mode-of-action of BDNF in neurotrophin signaling pathway could be explained with a high molecular resolution in both normal and disease states. The BDNF mode-of-action model was further validated using the “biomarkerguided validation” approach. In the second step, scientific evidence on the effect of various functional diets on BDNF levels and BDNF-related biological processes or outcomes was harvested from biomedical literature using a disease-specific semantic search

  8. An integrated approach for prospectively investigating a mode-of-action for rodent liver effects

    Energy Technology Data Exchange (ETDEWEB)

    LeBaron, Matthew J., E-mail: MJLeBaron@dow.com [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Geter, David R., E-mail: dave.geter@gmail.com [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Rasoulpour, Reza J. [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Gollapudi, B. Bhaskar, E-mail: BBGollapudi@dow.com [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Thomas, Johnson, E-mail: JThomas4@dow.com [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Murray, Jennifer, E-mail: AMurray@dow.com [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Kan, H. Lynn, E-mail: HLKan@dow.com [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Wood, Amanda J., E-mail: AJWood@dow.com [Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674 (United States); Elcombe, Cliff, E-mail: CliffElcombe@cxrbiosciences.com [CXR Biosciences, 2 James Lindsay Place, Dundee Technopole, Dundee, DD1 5JJ, Scotland (United Kingdom); Vardy, Audrey, E-mail: audrey_vardy@europe.bd.com [CXR Biosciences, 2 James Lindsay Place, Dundee Technopole, Dundee, DD1 5JJ, Scotland (United Kingdom); McEwan, Jillian, E-mail: jillian.mcewan@rtmcewan.co.uk [CXR Biosciences, 2 James Lindsay Place, Dundee Technopole, Dundee, DD1 5JJ, Scotland (United Kingdom); Terry, Claire, E-mail: CTerry@dow.com [Dow AgroSciences, Abingdon, Oxfordshire (United Kingdom); Billington, Richard, E-mail: RBillington@dow.com [Dow AgroSciences, Abingdon, Oxfordshire (United Kingdom)

    2013-07-15

    Registration of new plant protection products (e.g., herbicide, insecticide, or fungicide) requires comprehensive mammalian toxicity evaluation including carcinogenicity studies in two species. The outcome of the carcinogenicity testing has a significant bearing on the overall human health risk assessment of the substance and, consequently, approved uses for different crops across geographies. In order to understand the relevance of a specific tumor finding to human health, a systematic, transparent, and hypothesis-driven mode of action (MoA) investigation is, appropriately, an expectation by the regulatory agencies. Here, we describe a novel approach of prospectively generating the MoA data by implementing additional end points to the standard guideline toxicity studies with sulfoxaflor, a molecule in development. This proactive MoA approach results in a more robust integration of molecular with apical end points while minimizing animal use. Sulfoxaflor, a molecule targeting sap-feeding insects, induced liver effects (increased liver weight due to hepatocellular hypertrophy) in an initial palatability probe study for selecting doses for subsequent repeat-dose dietary studies. This finding triggered the inclusion of dose-response investigations of the potential key events for rodent liver carcinogenesis, concurrent with the hazard assessment studies. As predicted, sulfoxaflor induced liver tumors in rats and mice in the bioassays. The MoA data available by the time of the carcinogenicity finding supported the conclusion that the carcinogenic potential of sulfoxaflor was due to CAR/PXR nuclear receptor activation with subsequent hepatocellular proliferation. This MoA was not considered to be relevant to humans as sulfoxaflor is unlikely to induce hepatocellular proliferation in humans and therefore would not be a human liver carcinogen. - Highlights: • We prospectively generated MoA data into standard guideline toxicity studies. • A proactive MoA approach

  9. Inhibition of Listeria monocytogenes on Ready-to-Eat Meats Using Bacteriocin Mixtures Based on Mode-of-Action

    Directory of Open Access Journals (Sweden)

    Paul Priyesh Vijayakumar

    2017-03-01

    Full Text Available Bacteriocin-producing (Bac+ lactic acid bacteria (LAB comprising selected strains of Lactobacillus curvatus, Lactococcus lactis, Pediococcus acidilactici, and Enterococcus faecium and thailandicus were examined for inhibition of Listeria monocytogenes during hotdog challenge studies. The Bac+ strains, or their cell-free supernatants (CFS, were grouped according to mode-of-action (MOA as determined from prior studies. Making a mixture of as many MOAs as possible is a practical way to obtain a potent natural antimicrobial mixture to address L. monocytogenes contamination of RTE meat products (i.e., hotdogs. The heat resistance of the bacteriocins allowed the use of pasteurization to eliminate residual producer cells for use as post-process surface application or their inclusion into hotdog meat emulsion during cooking. The use of Bac+ LAB comprising 3× MOAs directly as co-inoculants on hotdogs was not effective at inhibiting L. monocytogenes. However, the use of multiple MOA Bac+ CFS mixtures in a variety of trials demonstrated the effectiveness of this approach by showing a >2-log decrease of L. monocytogenes in treatment samples and 6–7 log difference vs. controls. These data suggest that surface application of multiple mode-of-action bacteriocin mixtures can provide for an Alternative 2, and possibly Alternative 1, process category as specified by USDA-FSIS for control of L. monocytogenes on RTE meat products.

  10. Machine Learning and Molecular Dynamics Based Insights into Mode of Actions of Insulin Degrading Enzyme Modulators.

    Science.gov (United States)

    Jamal, Salma; Goyal, Sukriti; Shanker, Asheesh; Grover, Abhinav

    2017-01-01

    Alzheimer's disease (AD) is one of the most common lethal neurodegenerative disorders having impact on the lives of millions of people worldwide. The disease lacks effective treatment options and the unavailability of the drugs to cure the disease necessitates the development of effectual anti-Alzheimer drugs. Several mechanisms have been reported underlying the association of the two disorders, diabetes and dementia, one among which is the insulin-degrading enzyme (IDE) which is known to degrade insulin as well beta-amyloid peptides. The present study is aimed to generate accurate classification models using machine learning techniques, which could identify IDE modulators from a bioassay dataset consisting of IDE inhibitors as well as non-inhibitors. The identified compounds were subjected to docking and Molecular dynamics (MD) studies for an in-depth analysis of the binding modes along with the complex stability. This study proposes that the identified potential active compounds, STK026154 (PubChem ID: CID2927418) with Glide score of -7.70 kcal/mol and BAS05901102 (PubChem ID: CID3152845) with Glide score of -7.06 kcal/mol, could serve as promising leads for the development of novel drugs against AD. The present study shows that such in silico approaches can be effectively used to discover and select active compounds from unseen data for accelerated drug development process. The machine learning models generated in the present study were used to screen Traditional Chinese Medicine (TCM) database to identify the phytocompounds already been reported to have therapeutic effects against AD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Cytotoxicity and preliminary mode of action studies of novel 2-aryl-4-thiopyrone-based organometallics.

    Science.gov (United States)

    Schmidlehner, Melanie; Flocke, Lea S; Roller, Alexander; Hejl, Michaela; Jakupec, Michael A; Kandioller, Wolfgang; Keppler, Bernhard K

    2016-01-14

    Organometallic complexes with thiopyrone-based ligands have shown promising cytotoxic activity in vitro. To investigate the impact of the ligand backbone modification of these biologically active compounds and enhance the solubility in aqueous solution, the (thio)pyrone scaffold was modified via Suzuki-Miyaura coupling reaction and converted into corresponding organometallic Ru(ii) and Rh(iii) complexes. Characterization of the synthesized compounds was carried out by means of 1D and 2D NMR, ESI MS, and also by X-ray diffraction analysis. The stability in aqueous solution was investigated via(1)H NMR spectroscopy. Due to the close structural resemblance to flavonoids, topoisomerase inhibition, the cytotoxicity in human cancer cell lines as well as ROS generation was investigated by means of the topoisomerase II drug screening assay, the MTT assay and DCFH-DA assay, respectively.

  12. Mode of Action of Glyphosate

    Science.gov (United States)

    Although glyphosate is the most used and studied herbicide in the world, the available information is not enough to fully understand its mode of action. The molecular site of action of glyphosate is the enzyme 5-enolpyruvlyshikimate-3-phosphate synthase (EPSPS). It is the only known compound that ...

  13. Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

    Science.gov (United States)

    Labib, Sarah; Bourdon-Lacombe, Julie; Kuo, Byron; Buick, Julie K.; Lemieux, France; Williams, Andrew; Halappanavar, Sabina; Malik, Amal; Luijten, Mirjam; Aubrecht, Jiri; Hyduke, Daniel R.; Fornace, Albert J.; Swartz, Carol D.; Recio, Leslie; Yauk, Carole L.

    2015-01-01

    Toxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying toxicogenomics has never been done. We conducted a case study to evaluate the utility of toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in perturbed pathways with animal tissues. Quantitatively, the PODs for traditional and transcriptional approaches were similar (liver 1.2 vs. 1.0 mg/kg-bw/day; lung 0.8 vs. 3.7 mg/kg-bw/day; forestomach 0.5 vs. 7.4 mg/kg-bw/day). RA3, which applied toxicogenomics in the absence of apical toxicology data, demonstrates that this approach provides useful information in data-poor situations. Overall, our study supports the use of toxicogenomics as a relatively fast and cost-effective tool for hazard identification, preliminary evaluation of potential carcinogens, and carcinogenic potency, in addition to identifying current limitations and practical questions for future work. PMID:25605026

  14. [Modes of action of IUDs].

    Science.gov (United States)

    Janaud, A

    1982-05-01

    There are between 14-17 million women in the world, excluding China, who wear an IUD, or about 3-5% of all married women younger than 45. Studies on the mode of action of IUDs have been conducted mostly on laboratory animals; they show that ovulation and fecundation are not inhibited by the presence of an IUD. Contrary to what was generally believed, the latest studies have shown that the principle mode of action of the IUD is not its anti-implantation effect, but it depends on the adjustment inside the uterine cavity between the size of the uterine cavity itself, and the size and shape of the device. Endometrial modifications caused by IUDs include inflammatory phenomena, and inhibition of endometrial maturation. Moreover, copper IUDs act directly on spermatozoa and on endometrial steroid receptors. It is still not clear what role prostaglandins play in the mechanism of action of IUDs. Incidence of ectopic pregnancy is not greater in IUD wearers than in women who do not use contraception. Follicle stimulating hormone and luteinizing hormone levels also are comparable in IUD wearers and in nonwearers. IUD wearers have a shorter luteal phase, which entails an earlier menstrual bleeding due to the antifibrinolytic action of the IUD; progesterone levels are identical in users and in nonusers of IUDs.

  15. Evaluating Aquatic invertebrate vulnerability to insecticides based on intrinsic sensitivuty, biological traits, and toxic mode of action

    NARCIS (Netherlands)

    Rico, A.; Brink, van den P.J.

    2015-01-01

    In the present study, the authors evaluated the vulnerability of aquatic invertebrates to insecticides based on their intrinsic sensitivity and their population-level recovery potential. The relative sensitivity of invertebrates to 5 different classes of insecticides was calculated at the genus, fam

  16. Selective antimicrobial activity and mode of action of adepantins, glycine-rich peptide antibiotics based on anuran antimicrobial peptide sequences.

    Science.gov (United States)

    Ilić, Nada; Novković, Mario; Guida, Filomena; Xhindoli, Daniela; Benincasa, Monica; Tossi, Alessandro; Juretić, Davor

    2013-03-01

    A challenge when designing membrane-active peptide antibiotics with therapeutic potential is how to ensure a useful antibacterial activity whilst avoiding unacceptable cytotoxicity for host cells. Understanding their mode of interaction with membranes and the reasons underlying their ability to distinguish between bacterial and eukaryotic cytoplasmic cells is crucial for any rational attempt to improve this selectivity. We have approached this problem by analysing natural helical antimicrobial peptides of anuran origin, using a structure-activity database to determine an antimicrobial selectivity index (SI) relating the minimal inhibitory concentration against Escherichia coli to the haemolytic activity (SI=HC(50)/MIC). A parameter that correlated strongly with SI, derived from the lengthwise asymmetry of the peptides' hydrophobicity (sequence moment), was then used in the "Designer" algorithm to propose novel, highly selective peptides. Amongst these are the 'adepantins', peptides rich in glycines and lysines that are highly selective for Gram-negative bacteria, have an exceptionally low haemolytic activity, and are less than 50% homologous to any other natural or synthetic antimicrobial peptide. In particular, they showed a very high SI for E. coli (up to 400) whilst maintaining an antimicrobial activity in the 0.5-4μM range. Experiments with monomeric, dimeric and fluorescently labelled versions of the adepantins, using different bacterial strains, host cells and model membrane systems provided insight into their mechanism of action.

  17. Characterization, mode of action, and efficacy of twelve silica-based acaricides against poultry red mite (Dermanyssus gallinae) in vitro.

    Science.gov (United States)

    Schulz, Johanna; Berk, Jutta; Suhl, Johanna; Schrader, Lars; Kaufhold, Stefan; Mewis, Inga; Hafez, Hafez Mohammed; Ulrichs, Christian

    2014-09-01

    Poultry red mite infestation still is an unsolved problem in poultry farms. Legal regulations, residue risks, and resistances limit chemical control of mites. Alternatives to chemical acaricides for control of poultry red mite are silica-based products, which have as a main constituent silicon dioxide. The acaricidal effect is attributed to sorptive properties of the particles, which result in the mite's death by desiccation. In the present study, the acaricidal efficacy of 12 products containing natural or synthetic silica, 9 in powder form, and 3 for liquid application was tested under laboratory conditions. Mite mortality was measured at several intervals and the mean lethal time (LT₅₀) determined by Probit analysis after Abbott's correction. The LT₅₀ values of the products significantly differed (Tukey's HSD p < 0.05). LT₅₀ values of powdery formulations ranged from 5.1 to 18.7 h and overlapped with those of the fluid ones which ranged from 5.5 to 12.7 h. In order to explain the differences in efficacy of the tested silica products, further characterizations were carried out. X-ray fluorescence, specific surface, cation exchange capacity (CEC), and water absorption capacity (WAC) were measured. Furthermore, electron microscopy was conducted and different products compared. Silicon dioxide content (ranging from 65 to 89% for powders and 57 to 80% for fluids) had no significant impact on efficacy, while specific surface and CEC (2.4-23.2 mEq 100(-1) g(-1) for powders and 18-30.8 mEq 100(-1) g(-1)) were positively and WAC (1.3-4.4 wt% for powders and 3.3-4.8 wt% for fluids) negatively related to the acaricidal efficacy. Influence of these parameters on acaricidal efficacy was significant according to the results of a stepwise regression analysis (p < 0.01).

  18. Case study: an evaluation of the human relevance of the synthetic pyrethroid metofluthrin-induced liver tumors in rats based on mode of action.

    Science.gov (United States)

    Yamada, Tomoya; Uwagawa, Satoshi; Okuno, Yasuyoshi; Cohen, Samuel M; Kaneko, Hideo

    2009-03-01

    In recent years, mode of action (MOA) frameworks have been developed through the International Life Sciences Institute Risk Science Institute and the International Programme on Chemical Safety, including an evaluation of the human relevance of the animal MOA data. In the present paper, the MOA for rat liver tumors induced by Metofluthrin is first analyzed through this framework based on data from studies on Metofluthrin and information on related chemicals from the literature. The human relevance of the rat liver carcinogenic response is then discussed based upon the human relevance framework. Two-year treatment with high dose of Metofluthrin produced hepatocellular tumors in both sexes of the Wistar rats. Metofluthrin induced CYP2B (increased smooth endoplasmic reticulum), resulted in increased liver weights which were associated with centrilobular hepatocyte hypertrophy, and induction of increased hepatocellular DNA replications. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. Furthermore, CYP2B induction by Metofluthrin was shown to involve activation of the constitutive androstane receptor in rat hepatocytes. Based on the evidence, including a comparison with the results with another chemical, phenobarbital, acting by a similar MOA, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans.

  19. Discovery of drug mode of action and drug repositioning from transcriptional responses

    OpenAIRE

    Iorio, Francesco; Bosotti, Roberta; Scacheri, Emanuela; Belcastro, Vincenzo; Mithbaokar, Pratibha; Ferriero, Rosa; Murino, Loredana; Tagliaferri, Roberto; Brunetti-Pierri, Nicola; Isacchi, Antonella; di Bernardo, Diego

    2010-01-01

    A bottleneck in drug discovery is the identification of the molecular targets of a compound (mode of action, MoA) and of its off-target effects. Previous approaches to elucidate drug MoA include analysis of chemical structures, transcriptional responses following treatment, and text mining. Methods based on transcriptional responses require the least amount of information and can be quickly applied to new compounds. Available methods are inefficient and are not able to support network pharmac...

  20. A Critical Review of Mode of Action (MOA) Assignment ...

    Science.gov (United States)

    There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human health toxicology. With increasing calls to assess thousands of chemicals, some of which have little available information other than structure, clear understanding how each of these MOA schemes was devised, what information they are based on, and the limitations of each approach is critical. Several groups are developing low-tier methods to more easily classify or assess chemicals, using approaches such as the ecological threshold of concern (eco-TTC) and chemical-activity. Evaluation of these approaches and determination of their domain of applicability is partly dependent on the MOA classification that is used. The most commonly used MOA classification schemes for ecotoxicology include Verhaar and Russom (included in ASTER), both of which are used to predict acute aquatic toxicity MOA. Verhaar is a QSAR-based system that classifies chemicals into one of 4 classes, with a 5th class specified for those chemicals that are not classified in the other 4. ASTER/Russom includes 8 classifications: narcotics (3 groups), oxidative phosphorylation uncouplers, respiratory inhibitors, electrophiles/proelectrophiles, AChE inhibitors, or CNS seizure agents. Other methodologies include TEST (Toxicity Estimation Software Tool), a computational chemistry-based application that allows prediction to one of 5 broad MOA

  1. Mode of action of insect repellents

    Science.gov (United States)

    The mode of action of DEET and other insect repellents has been a topic of interest since the discovery of DEET in the mid twentieth century. Nearly 60 years have passed since DEET applied topically to the skin was shown to be effective in preventing mosquito bites. With the discovery and characte...

  2. Untargeted Metabolomics To Ascertain Antibiotic Modes of Action.

    Science.gov (United States)

    Vincent, Isabel M; Ehmann, David E; Mills, Scott D; Perros, Manos; Barrett, Michael P

    2016-04-01

    Deciphering the mode of action (MOA) of new antibiotics discovered through phenotypic screening is of increasing importance. Metabolomics offers a potentially rapid and cost-effective means of identifying modes of action of drugs whose effects are mediated through changes in metabolism. Metabolomics techniques also collect data on off-target effects and drug modifications. Here, we present data from an untargeted liquid chromatography-mass spectrometry approach to identify the modes of action of eight compounds: 1-[3-fluoro-4-(5-methyl-2,4-dioxo-pyrimidin-1-yl)phenyl]-3-[2-(trifluoromethyl)phenyl]urea (AZ1), 2-(cyclobutylmethoxy)-5'-deoxyadenosine, triclosan, fosmidomycin, CHIR-090, carbonyl cyanidem-chlorophenylhydrazone (CCCP), 5-chloro-2-(methylsulfonyl)-N-(1,3-thiazol-2-yl)-4-pyrimidinecarboxamide (AZ7), and ceftazidime. Data analysts were blind to the compound identities but managed to identify the target as thymidylate kinase for AZ1, isoprenoid biosynthesis for fosmidomycin, acyl-transferase for CHIR-090, and DNA metabolism for 2-(cyclobutylmethoxy)-5'-deoxyadenosine. Changes to cell wall metabolites were seen in ceftazidime treatments, although other changes, presumably relating to off-target effects, dominated spectral outputs in the untargeted approach. Drugs which do not work through metabolic pathways, such as the proton carrier CCCP, have no discernible impact on the metabolome. The untargeted metabolomics approach also revealed modifications to two compounds, namely, fosmidomycin and AZ7. An untreated control was also analyzed, and changes to the metabolome were seen over 4 h, highlighting the necessity for careful controls in these types of studies. Metabolomics is a useful tool in the analysis of drug modes of action and can complement other technologies already in use.

  3. 基于代谢组学的杀菌剂作用机理研究%Study on Antifungal Modes-of-Action Based on Metabolomics

    Institute of Scientific and Technical Information of China (English)

    陈溪; 纪明山

    2013-01-01

    Metabolomics had so far been a valuable high-throughput screening tool for bioactive substances, and it was widely applied to life science and showed a promising perspective. The concept, empirical method, analytical method, data processing, application of metabolomics was summarized, and its potentials in biology, medicine, pesticide sphere were prospected. In this foundation, the development direction through the studies on antifungal metabolomics was rised. Through high-throughput screening and data processing as device, metabolic fingerprint library was established, and a method which can quickly screen unknown modes-of-action antifungal was set up. Metabolomics has important future trends in new drug research, drug toxicology analysis and assessment, and it might be a important breakthrough in pesticide study.%目前代谢组学是生物活性物质高效筛选的重要工具,在生命科学领域得到了越来越广泛的应用并展现出良好的前景.综述了代谢组学的概念、实验方法、分析方法、数据处理以及在生物、医药领域的应用及农药学领域的研究前景.并在此基础上,提出了利用代谢组学研究杀菌剂作用机理可能的发展方向.以高通量检测和数据处理为手段,建立代谢指纹图谱库,创建一个可以快速筛查未知杀菌剂作用机理的方法,在新型农药的研制、毒理学分析、安全评价等领域具有广阔的前景,将成为农药现代研究的一个重要突破口.

  4. Mode of action based risk assessment of the botanical food-borne alkenylbenzene apiol from parsley using physiologically based kinetic (PBK) modelling and read-across from safrole

    NARCIS (Netherlands)

    Alajlouni, A.M.; Al-Malahmeh, A.J.; Kiwamoto, Reiko; Wesseling, Sebastiaan; Soffers, A.E.M.F.; Al-Subeihi, A.A.A.; Vervoort, Jacques; Rietjens, I.M.C.M.

    2016-01-01

    The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene apiol in order to facilitate risk assessment based on read-across from the related alkenylbenzene safrole. Model predictions indicate that in rat liver the formation of the 1'-sulfoxy metabolite is about

  5. Mode of action based risk assessment of the botanical food-borne alkenylbenzene apiol from parsley using physiologically based kinetic (PBK) modelling and read-across from safrole.

    Science.gov (United States)

    Alajlouni, Abdalmajeed M; Al Malahmeh, Amer J; Kiwamoto, Reiko; Wesseling, Sebastiaan; Soffers, Ans E M F; Al-Subeihi, Ala A A; Vervoort, Jacques; Rietjens, Ivonne M C M

    2016-03-01

    The present study developed physiologically-based kinetic (PBK) models for the alkenylbenzene apiol in order to facilitate risk assessment based on read-across from the related alkenylbenzene safrole. Model predictions indicate that in rat liver the formation of the 1'-sulfoxy metabolite is about 3 times lower for apiol than for safrole. These data support that the lower confidence limit of the benchmark dose resulting in a 10% extra cancer incidence (BMDL10) that would be obtained in a rodent carcinogenicity study with apiol may be 3-fold higher for apiol than for safrole. These results enable a preliminary risk assessment for apiol, for which tumor data are not available, using a BMDL10 value of 3 times the BMDL10 for safrole. Based on an estimated BMDL10 for apiol of 5.7-15.3 mg/kg body wt per day and an estimated daily intake of 4 × 10(-5) mg/kg body wt per day, the margin of exposure (MOE) would amount to 140,000-385,000. This indicates a low priority for risk management. The present study shows how PBK modelling can contribute to the development of alternatives for animal testing, facilitating read-across from compounds for which in vivo toxicity studies on tumor formation are available to compounds for which these data are unavailable.

  6. Antiproliferative effects of ruthenium-based nucleolipidic nanoaggregates in human models of breast cancer in vitro: insights into their mode of action

    Science.gov (United States)

    Irace, Carlo; Misso, Gabriella; Capuozzo, Antonella; Piccolo, Marialuisa; Riccardi, Claudia; Luchini, Alessandra; Caraglia, Michele; Paduano, Luigi; Montesarchio, Daniela; Santamaria, Rita

    2017-01-01

    Looking for new metal-based anticancer treatments, in recent years many ruthenium complexes have been proposed as effective and safe potential drugs. In this context we have recently developed a novel approach for the in vivo delivery of Ru(III) complexes, preparing stable ruthenium-based nucleolipidic nanoaggregates endowed with significant antiproliferative activity. Herein we describe the cellular response to our ruthenium-containing formulations in selected models of human breast cancer. By in vitro bioscreens in the context of preclinical studies, we have focused on their ability to inhibit breast cancer cell proliferation by the activation of the intrinsic apoptotic pathway, possibly via mitochondrial perturbations involving Bcl-2 family members and predisposing to programmed cell death. In addition, the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation by metal-based chemotherapeutics is a challenging, yet very promising strategy for targeted therapy development in aggressive cancer diseases, such as triple-negative breast cancer with limited treatment options. These outcomes provide valuable, original knowledge on ruthenium-based candidate drugs and new insights for future optimized cancer treatment protocols. PMID:28349991

  7. Circular bacteriocins: biosynthesis and mode of action.

    Science.gov (United States)

    Gabrielsen, Christina; Brede, Dag A; Nes, Ingolf F; Diep, Dzung B

    2014-11-01

    Circular bacteriocins are a group of N-to-C-terminally linked antimicrobial peptides, produced by Gram-positive bacteria of the phylum Firmicutes. Circular bacteriocins generally exhibit broad-spectrum antimicrobial activity, including against common food-borne pathogens, such as Clostridium and Listeria spp. These peptides are further known for their high pH and thermal stability, as well as for resistance to many proteolytic enzymes, properties which make this group of bacteriocins highly promising for potential industrial applications and their biosynthesis of particular interest as a possible model system for the synthesis of highly stable bioactive peptides. In this review, we summarize the current knowledge on this group of bacteriocins, with emphasis on the recent progress in understanding circular bacteriocin genetics, biosynthesis, and mode of action; in addition, we highlight the current challenges and future perspectives for the application of these peptides.

  8. iTRAQ-based proteomic analysis of LI-F type peptides produced by Paenibacillus polymyxa JSa-9 mode of action against Bacillus cereus.

    Science.gov (United States)

    Han, Jinzhi; Gao, Peng; Zhao, Shengming; Bie, Xiaomei; Lu, Zhaoxin; Zhang, Chong; Lv, Fengxia

    2017-01-06

    LI-F type peptides (AMP-jsa9) produced by Paenibacillus polymyxa JSa-9 are a group of cyclic lipodepsipeptide antibiotics that exhibit a broad antimicrobial spectrum against Gram-positive bacteria and filamentous fungi, especially Bacillus cereus and Fusarium moniliforme. In this study, to better understand the antibacterial mechanism of AMP-jsa9 against B. cereus, the ultrastructure of AMP-jsa9-treated B. cereus cells was observed by both atomic force microscopy and transmission electron microscopy, and quantitative proteomic analysis was performed on proteins extracted from treated and untreated bacterial cells by using isobaric tag for relative and absolute quantitation (iTRAQ) labeling and LC-MS/MS analysis to access differentially expressed proteins. Furthermore, multiple experiments were conducted to validate the results of the proteomic analysis, including determinations of ATP, NAD((+))H, NADP((+))H, reactive oxygen species (ROS), the activities of catalase (CAT) and superoxide dismutase (SOD), and the relative expression of target genes by quantitative real-time PCR. Bacterial cells exposed to AMP-jsa9 showed irregular surfaces with bleb projections and concaves; we hypothesize that AMP-jsa9 penetrated the cell wall and was anchored on the cytoplasmic membrane and that ROS accumulated in the cell membrane after treatment with AMP-jsa9, modulating the bacterial membrane properties and increasing membrane permeability. Consequently, the blebs were formed on the cell wall by the impulsive force of the leakage of intercellular contents. iTRAQ-based proteomic analysis detected a total of 1317 proteins, including 176 differentially expressed proteins (75 upregulated (fold >2) and 101 downregulated (fold <0.5)). Based on proteome analysis, the putative pathways of AMP-jsa9 action against B. cereus can be summarized as: (i) inhibition of bacterial sporulation, thiamine biosynthesis, energy metabolism, DNA transcription and translation, and cell wall biosynthesis

  9. (-)-Carvone: antispasmodic effect and mode of action.

    Science.gov (United States)

    Souza, Fábia Valéria M; da Rocha, Marcelly Barbosa; de Souza, Damião P; Marçal, Rosilene Moretti

    2013-03-01

    (-)-Carvone is a monoterpene ketone found in spearmint (Mentha spicata var. crispa) essential oil that is widely used as an odor and flavor additive. An intestinal antispasmodic effect was recently reported for (-)-carvone, and it has been shown to be more potent than its (+)-antipode. The mechanism of (-)-carvone action in the intestines has not been investigated. To gain a better understanding of the (-)-carvone antispasmodic effect, we investigated its pharmacological effects in the guinea pig ileum. Terminal portions of the ileum were mounted for isotonic contraction recordings. The effect of (-)-carvone was compared with that of the classical calcium channel blocker (CCB) verapamil. In isolated ileal smooth muscle, (-)-carvone did not produce direct contractile or relaxation responses and did not modify electrically elicited contractions or low K(+)-evoked contractions. The submaximal contractions induced by histamine (p<0.001), BaCl2 (p<0.05), and carbachol (p<0.01) were significantly reduced by (-)-carvone. The contractile response elicited by high concentrations of carbachol was reduced but not abolished by (-)-carvone. No additive action was detected with co-incubation of (-)-carvone and verapamil on carbachol-induced contraction. (-)-Carvone reduced the contraction induced by high K(+) and was almost 100 times more potent than verapamil. Thus, (-)-carvone showed a typical and potent CCB-like action. Many effects described for both (-)-carvone and spearmint oil can be explained as a CCB-like mode of action.

  10. Understanding the cellular mode of action of vernakalant using a computational model: answers and new questions

    Directory of Open Access Journals (Sweden)

    Loewe Axel

    2015-09-01

    Full Text Available Vernakalant is a new antiarrhythmic agent for the treatment of atrial fibrillation. While it has proven to be effective in a large share of patients in clinical studies, its underlying mode of action is not fully understood. In this work, we aim to link experimental data from the subcellular, tissue, and system level using an in-silico approach. A Hill’s equation-based drug model was extended to cover the frequency dependence of sodium channel block. Two model variants were investigated: M1 based on subcellular data and M2 based on tissue level data. 6 action potential (AP markers were evaluated regarding their dose, frequency and substrate dependence. M1 comprising potassium, sodium, and calcium channel block reproduced the reported prolongation of the refractory period. M2 not including the effects on potassium channels reproduced reported AP morphology changes on the other hand. The experimentally observed increase of ERP accompanied by a shortening of APD90 was not reproduced. Thus, explanations for the drug-induced changes are provided while none of the models can explain the effects in their entirety. These results foster the understanding of vernakalant’s cellular mode of action and point out relevant gaps in our current knowledge to be addressed in future in-silico and experimental research on this aspiring antiarrhythmic agent.

  11. Kyleo ® - mode of action under examination

    Directory of Open Access Journals (Sweden)

    Heibertshausen, Dagmar

    2014-02-01

    Full Text Available Kyleo® with two known active substances (ai is an innovative, modern herbicide for resistance management. Kyleo® contains 160 g/l 2,4-D and 240 g/l glyphosate. With an application rate of 5,0 l/ha, it shows a far better, faster effect on weeds such as field horsetail (Equisetum arvense, volunteer oilseed rape (Brassica napus and couch grass (Agropyron repens compared to a tank mix or the reference products (RP. This is explained by an unique new formulation technology that for the first time combines 2,4-D as acid and glyphosate as MIPA salt together with FHS. The new form of 2,4-D is lipophilic with better leaf absorption and greater photolytic degradation in the upper layers of soil. Tests with radioactive marked substances have verified the systemic properties of both ai compared to RP. The displacement of 2,4-D into the plant roots was demonstrated 48 h after application (hpt. 98% glyphosate absorption was observed in rape and couch grass – 10% (rape respectively 25% (couch grass greater than with RP. Higher absorption of the ai is characterised by a swifter effect, with stronger, visible symptoms after 24 h in rape and 96 h in couch grass. The rainfastness of Kyleo® was tested in greenhouse (GH trials with rape. Comparability of the test objects was simulated with a uniform glyphosate quantity of 360 g/ha and 10 l/m² simulated precipitation. 24% improved effect compared to RP was verified for 1 hpt rainfall, while 4% improved effect was recorded for rain simulation after 6 hpt. GH trials with wheat and a comparable glyphosate application quantity of 290 g/ha revealed differences of 23% and 22% compared to RP for rain simulation of 1 hpt and 6 hpt. Kyleo® stands out with a swift effect and better rainfastness. The results presented here prove a systemic mode of action, good rainfastness and swift effect of Kyleo.

  12. Definition of primary mode of action of a combination product. Final rule.

    Science.gov (United States)

    2005-08-25

    The Food and Drug Administration (FDA) is amending its combination product regulations to define "mode of action'' (MOA) and "primary mode of action" (PMOA). Along with these definitions, the final rule sets forth an algorithm the agency will use to assign combination products to an agency component for regulatory oversight when the agency cannot determine with reasonable certainty which mode of action provides the most important therapeutic action of the combination product. Finally, the final rule will require a sponsor to base its recommendation of the agency component with primary jurisdiction for regulatory oversight of its combination product by using the PMOA definition and, if appropriate, the assignment algorithm. The final rule is intended to promote the public health by codifying the agency's criteria for the assignment of combination products in transparent, consistent, and predictable terms.

  13. Mini Review: Mode of Action of Mosquito Repellents

    Science.gov (United States)

    2013-01-01

    Mini review: Mode of action of mosquito repellents Joseph C. Dickens ⇑, Jonathan D. Bohbot United States Department of Agriculture, Agricultural...Modulation a b s t r a c t The mode of action of mosquito repellents remains a controversial topic. However, electrophysiological studies and molecular...annoyance that can disrupt outdoor activities. The use of repellents decreases contacts between mosquitoes and their hosts, and may even lower the rate of

  14. Prediction of aquatic toxicity mode of action using linear discriminant and random forest models

    Science.gov (United States)

    The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

  15. Triclosan Decreases Rat Thyroxine: Mode-of-Action, Developmental Susceptibility and Human Relevance

    Science.gov (United States)

    Triclosan (TCS) decreases serum thyroxine (T4) in the rat. In vivo and in vitro approaches were used to address three uncertainties: by what mode-of-action (MOA) does TCS decrease T4; does TCS decrease T4 developmentally; and, are effects observed in rats relevant to humans? To t...

  16. Mode of Action of Polyamine Analogues on the Growth and Biochemistry of Leishmanial Cells.

    Science.gov (United States)

    1981-09-15

    information on the biochemical properties of parasites has hampered the development of new drugs and indeed no revolutionary new therapeutic approaches...of the parasites and the elucidation of the mode of action of known drugs are prerequisites for the development of new drugs . It would be ideal to

  17. Prediction of aquatic toxicity mode of action using linear discriminant and random forest models

    Science.gov (United States)

    The ability to determine the mode of action (MOA) for a diverse group of chemicals is a critical part of ecological risk assessment and chemical regulation. However, existing MOA assignment approaches in ecotoxicology have been limited to a relatively few MOAs, have high uncertai...

  18. Spontaneous bacteriocin resistance in Listeria monocytogenes as a susceptibility screen for identifying different mechanisms of resistance and modes of action by bacteriocins of lactic acid bacteria.

    Science.gov (United States)

    Macwana, Sunita; Muriana, Peter M

    2012-01-01

    A practical system was devised for grouping bacteriocins of lactic acid bacteria (LAB) based on mode of action as determined by changes in inhibitory activity to spontaneously-acquired bacteriocin resistance (Bac(R)). Wild type Listeria monocytogenes 39-2 was sensitive to five bacteriocins produced by 3 genera of LAB: pediocin PA-1 and pediocin Bac3 (Pediococcus), lacticin FS97 and lacticin FS56 (Lactococcus), and curvaticin FS47 (Lactobacillus). A spontaneous Bac(R) derivative of L. monocytogenes 39-2 obtained by selective recovery against lacticin FS56 provided complete resistance to the bacteriocin made by Lactococcus lactis FS56. The lacticin FS56-resistant strain of L. monocyotgenes 39-2 was also cross-resistant to curvaticin FS47 and pediocin PA-1, but not to lacticin FS97 or pediocin Bac3. The same pattern of cross-resistance was also observed with Bac(R) isolates obtained with L. monocytogenes Scott A-2. A spontaneous mutation that renders a strain cross-resistant to different bacteriocins indicates that they share a common mechanism of resistance due to similar modes of action of the bacteriocins. Spontaneous resistance was acquired to other bacteriocins (in aggregate) by following the same procedure against which the Bac(R) strain was still sensitive. In subsequent challenge assays, mixtures of bacteriocins of different modes of action provided greater inhibition than mixtures of bacteriocins of the same mode of action (as determined by our screening method). This study identifies a methodical approach to classify bacteriocins into functional groups based on mechanism of resistance (i.e., mode of action) that could be used for identifying the best mixture of bacteriocins for use as biopreservatives.

  19. Mode of Action (MOA) Assignment Classifications for Ecotoxicology: Evaluation of Available Methods

    Science.gov (United States)

    There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human toxicology. With increasing calls to assess 1000s of chemicals, some of which have little available information other tha...

  20. A Critical Review of Mode of Action (MOA) Assignment Classifications for Ecotoxicology

    Science.gov (United States)

    There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human health toxicology. With increasing calls to assess thousands of chemicals, some of which have little available informatio...

  1. Mode of Action (MOA) Assignment Classifications for Ecotoxicology: Evaluation of Available Methods

    Science.gov (United States)

    There are various structure-based classification schemes to categorize chemicals based on mode of action (MOA) which have been applied for both eco and human toxicology. With increasing calls to assess 1000s of chemicals, some of which have little available information other tha...

  2. Evaluation of carcinogenic modes of action for pesticides in fruit on the Swedish market using a text-mining tool

    OpenAIRE

    Silins, Ilona; Korhonen, Anna; Stenius, Ulla

    2014-01-01

    Toxicity caused by chemical mixtures has emerged as a significant challenge for toxicologists and risk assessors. Information on individual chemicals' modes of action is an important part of the hazard identification step. In this study, an automatic text mining-based tool was employed as a method to identify the carcinogenic modes of action of pesticides frequently found in fruit on the Swedish market. The current available scientific literature on the 26 most common pesticides found in appl...

  3. How benthic diatoms within natural communities respond to eight common herbicides with different modes of action.

    Science.gov (United States)

    Wood, Rebecca J; Mitrovic, Simon M; Lim, Richard P; Kefford, Ben J

    2016-07-01

    Herbicides are common pollutants of rivers in agricultural regions. These contaminants include various types of chemicals with different modes of toxic action. Herbicides can have toxic effects on freshwater benthic diatoms, the base of the aquatic food web. We examined the effects of (non-mixture) herbicide exposure to the health of diatoms for eight common herbicides with three different modes of action; the photosystem II (PSII) inhibitors: atrazine, simazine, hexazinone, tebuthiuron and diuron; two auxinic herbicides: MCPA and 2,4-D; and the EPSP synthase inhibitor: glyphosate. Benthic diatoms within riverine communities were exposed to each herbicide in rapid toxicity tests at concentrations of 50, 200 and 500μgL(-1). The most sensitive taxa were Gomphonema spp. and Encyonema gracilis. Navicula cryptotenella was the most tolerant to herbicide exposure. There was no significant effect of the different herbicide modes of action at the community level. Herbicide mode of action did not alter which taxa were most sensitive within the community and sensitivity rankings of the dominant diatom taxa were similar for each of the eight herbicides. The consistency of the results between herbicides suggests that freshwater benthic diatoms may be suitable in situ indicators for detecting the toxicity of herbicides with differing modes of action. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Intracervical tents: usage and mode of action.

    Science.gov (United States)

    Johnson, N

    1989-06-01

    Topical prostaglandins and intracervical tents at present comprise the most widely used methods for priming of the cervix before surgery. While tents and prostaglandins are comparable in terms of shortening the time interval between labor induction and delivery, tents do not initiate powerful myometrial contractions and thus are not associated with the complication of uterine hypertonus. In early abortion, tents are regarded as superior to prostaglandins, estrogen, and relaxin. In the midtrimester abortion, however, best results are achieved through the combined use of tents and prostaglandins. This approach facilitates a shorter abortion time, a lesser risk of sepsis, and use of a lower dose of prostaglandin. The effect of the particular type of tent selected--Clamicel, Dilapan, or Laminaria--is related to the initial state of the cervix, with the best results achieved in the soft patulous cervix of young pregnant women. Laminaria tents are declining in popularity as a result of their lengthy duration of action, unreliability, pain, or insertion and as the tent expands, and need for several insertions of multiple tents. The synthetic Dilapan tent does not share the disadvantages of inconsistency, long duration of action, and risk of sepsis, but tends to fragment and fracture so that the distal portion remains within the uterus. Lamicel, a polyvinyl alcohol sponge impregnated with magnesium sulfate, has a less impressive speed of action than Dilapan (3 hours and 2 hours, respectively), yet its softness makes it easy to withdraw without fragmentation or fracture. Lamicel has been used successfully in 1st-trimester abortion, before induction of labor or IUD insertion, for hysteroscopy and removal of lost IUDs, and in formal diagnostic curettage.

  5. Effect and mode of action of some systemic nematicides

    NARCIS (Netherlands)

    Bunt, J.A.

    1975-01-01

    In this study, nematicidal effects, mode of action and specific characters of some systemic nematicides were studied, in search of substitutes for the widely used soil fumigants that require high dosages. The thesis comprises:- a review of literature,- development of techniques,- a test for nematici

  6. Mode of action of the 2-nitroimidazole derivative benznidazole.

    Science.gov (United States)

    Polak, A; Richle, R

    1978-02-01

    Using cultures of Trypanosoma cruzi cells in a liquid medium, the mode of action of the 2-nitroimidazole derivative benznidazole was examined. Benznidazole inhibits protein synthesis and RNA synthesis in T. cruzy. The DNA synthesis is only slightly decreased and no effect on the aerobic respiration of T. cruzi was observed.

  7. Ocean Acidification Has Multiple Modes of Action on Bivalve Larvae

    Science.gov (United States)

    Waldbusser, George G.; Hales, Burke; Langdon, Chris J.; Haley, Brian A.; Schrader, Paul; Brunner, Elizabeth L.; Gray, Matthew W.; Miller, Cale A.; Gimenez, Iria; Hutchinson, Greg

    2015-01-01

    Ocean acidification (OA) is altering the chemistry of the world’s oceans at rates unparalleled in the past roughly 1 million years. Understanding the impacts of this rapid change in baseline carbonate chemistry on marine organisms needs a precise, mechanistic understanding of physiological responses to carbonate chemistry. Recent experimental work has shown shell development and growth in some bivalve larvae, have direct sensitivities to calcium carbonate saturation state that is not modulated through organismal acid-base chemistry. To understand different modes of action of OA on bivalve larvae, we experimentally tested how pH, PCO2, and saturation state independently affect shell growth and development, respiration rate, and initiation of feeding in Mytilus californianus embryos and larvae. We found, as documented in other bivalve larvae, that shell development and growth were affected by aragonite saturation state, and not by pH or PCO2. Respiration rate was elevated under very low pH (~7.4) with no change between pH of ~ 8.3 to ~7.8. Initiation of feeding appeared to be most sensitive to PCO2, and possibly minor response to pH under elevated PCO2. Although different components of physiology responded to different carbonate system variables, the inability to normally develop a shell due to lower saturation state precludes pH or PCO2 effects later in the life history. However, saturation state effects during early shell development will carry-over to later stages, where pH or PCO2 effects can compound OA effects on bivalve larvae. Our findings suggest OA may be a multi-stressor unto itself. Shell development and growth of the native mussel, M. californianus, was indistinguishable from the Mediterranean mussel, Mytilus galloprovincialis, collected from the southern U.S. Pacific coast, an area not subjected to seasonal upwelling. The concordance in responses suggests a fundamental OA bottleneck during development of the first shell material affected only by

  8. Ocean Acidification Has Multiple Modes of Action on Bivalve Larvae.

    Science.gov (United States)

    Waldbusser, George G; Hales, Burke; Langdon, Chris J; Haley, Brian A; Schrader, Paul; Brunner, Elizabeth L; Gray, Matthew W; Miller, Cale A; Gimenez, Iria; Hutchinson, Greg

    2015-01-01

    Ocean acidification (OA) is altering the chemistry of the world's oceans at rates unparalleled in the past roughly 1 million years. Understanding the impacts of this rapid change in baseline carbonate chemistry on marine organisms needs a precise, mechanistic understanding of physiological responses to carbonate chemistry. Recent experimental work has shown shell development and growth in some bivalve larvae, have direct sensitivities to calcium carbonate saturation state that is not modulated through organismal acid-base chemistry. To understand different modes of action of OA on bivalve larvae, we experimentally tested how pH, PCO2, and saturation state independently affect shell growth and development, respiration rate, and initiation of feeding in Mytilus californianus embryos and larvae. We found, as documented in other bivalve larvae, that shell development and growth were affected by aragonite saturation state, and not by pH or PCO2. Respiration rate was elevated under very low pH (~7.4) with no change between pH of ~ 8.3 to ~7.8. Initiation of feeding appeared to be most sensitive to PCO2, and possibly minor response to pH under elevated PCO2. Although different components of physiology responded to different carbonate system variables, the inability to normally develop a shell due to lower saturation state precludes pH or PCO2 effects later in the life history. However, saturation state effects during early shell development will carry-over to later stages, where pH or PCO2 effects can compound OA effects on bivalve larvae. Our findings suggest OA may be a multi-stressor unto itself. Shell development and growth of the native mussel, M. californianus, was indistinguishable from the Mediterranean mussel, Mytilus galloprovincialis, collected from the southern U.S. Pacific coast, an area not subjected to seasonal upwelling. The concordance in responses suggests a fundamental OA bottleneck during development of the first shell material affected only by

  9. Ocean Acidification Has Multiple Modes of Action on Bivalve Larvae.

    Directory of Open Access Journals (Sweden)

    George G Waldbusser

    Full Text Available Ocean acidification (OA is altering the chemistry of the world's oceans at rates unparalleled in the past roughly 1 million years. Understanding the impacts of this rapid change in baseline carbonate chemistry on marine organisms needs a precise, mechanistic understanding of physiological responses to carbonate chemistry. Recent experimental work has shown shell development and growth in some bivalve larvae, have direct sensitivities to calcium carbonate saturation state that is not modulated through organismal acid-base chemistry. To understand different modes of action of OA on bivalve larvae, we experimentally tested how pH, PCO2, and saturation state independently affect shell growth and development, respiration rate, and initiation of feeding in Mytilus californianus embryos and larvae. We found, as documented in other bivalve larvae, that shell development and growth were affected by aragonite saturation state, and not by pH or PCO2. Respiration rate was elevated under very low pH (~7.4 with no change between pH of ~ 8.3 to ~7.8. Initiation of feeding appeared to be most sensitive to PCO2, and possibly minor response to pH under elevated PCO2. Although different components of physiology responded to different carbonate system variables, the inability to normally develop a shell due to lower saturation state precludes pH or PCO2 effects later in the life history. However, saturation state effects during early shell development will carry-over to later stages, where pH or PCO2 effects can compound OA effects on bivalve larvae. Our findings suggest OA may be a multi-stressor unto itself. Shell development and growth of the native mussel, M. californianus, was indistinguishable from the Mediterranean mussel, Mytilus galloprovincialis, collected from the southern U.S. Pacific coast, an area not subjected to seasonal upwelling. The concordance in responses suggests a fundamental OA bottleneck during development of the first shell material

  10. Why have no new herbicide modes of action appeared in recent years?

    Science.gov (United States)

    Duke, Stephen O

    2012-04-01

    Herbicides with new modes of action are badly needed to manage the evolution of resistance of weeds to existing herbicides. Yet no major new mode of action has been introduced to the market place for about 20 years. There are probably several reasons for this. New potential products may have remained dormant owing to concerns that glyphosate-resistant (GR) crops have reduced the market for a new herbicide. The capture of a large fraction of the herbicide market by glyphosate with GR crops led to significantly diminished herbicide discovery efforts. Some of the reduced herbicide discovery research was also due to company consolidations and the availability of more generic herbicides. Another problem might be that the best herbicide molecular target sites may have already been discovered. However, target sites that are not utilized, for which there are inhibitors that are highly effective at killing plants, suggests that this is not true. Results of modern methods of target site discovery (e.g. gene knockout methods) are mostly not public, but there is no evidence of good herbicides with new target sites coming from these approaches. In summary, there are several reasons for a long dry period for new herbicide target sites; however, the relative magnitude of each is unclear. The economic stimulus to the herbicide industry caused by the evolution of herbicide-resistant weeds, especially GR weeds, may result in one or more new modes of action becoming available in the not too distant future. Copyright © 2011 Society of Chemical Industry.

  11. Non-Membrane Permeabilizing Modes of Action of Antimicrobial Peptides on Bacteria.

    Science.gov (United States)

    Scocchi, Marco; Mardirossian, Mario; Runti, Giulia; Benincasa, Monica

    2016-01-01

    Antimicrobial peptides (AMPs) are a large class of innate immunity effectors with a remarkable capacity to inactivate microorganisms. Their ability to kill bacteria by membranolytic effects has been well established. However, a lot of evidence points to alternative, non-lytic modes of action for a number of AMPs, which operate through interactions with specific molecular targets. It has been reported that non-membrane-permeabilizing AMPs can bind to and inhibit DNA, RNA or protein synthesis processes, inactivate essential intracellular enzymes, or affect membrane septum formation and cell wall synthesis. This minireview summarizes recent findings on these alternative, non-lytic modes of antimicrobial action with an emphasis to the experimental approaches used to clarify each step of their intracellular action, i.e. the cell penetration mechanism, intracellular localization and molecular mechanisms of antibacterial action. Despite the fact that such data exists for a large number of peptides, our analysis indicates that only for a small number of AMPs sufficient data have been collected to support a mode of action with an authentic and substantial contribution by intracellular targeting. In most cases, peptides with non-lytic features have not been thoroughly analyzed, or only a single aspect of their mode of action has been taken into consideration and therefore their mechanism of action can only be hypothesized. A more detailed knowledge of this class of AMPs would be important in the design of novel antibacterial agents against unexploited targets, endowed with the capacity to penetrate into pathogen cells and kill them from within.

  12. Evaluation of carcinogenic modes of action for pesticides in fruit on the Swedish market using a text-mining tool.

    Science.gov (United States)

    Silins, Ilona; Korhonen, Anna; Stenius, Ulla

    2014-01-01

    Toxicity caused by chemical mixtures has emerged as a significant challenge for toxicologists and risk assessors. Information on individual chemicals' modes of action is an important part of the hazard identification step. In this study, an automatic text mining-based tool was employed as a method to identify the carcinogenic modes of action of pesticides frequently found in fruit on the Swedish market. The current available scientific literature on the 26 most common pesticides found in apples and oranges was evaluated. The literature was classified according to a taxonomy that specifies the main type of scientific evidence used for determining carcinogenic properties of chemicals. The publication profiles of many pesticides were similar, containing evidence for both genotoxic and non-genotoxic modes of action, including effects such as oxidative stress, chromosomal changes and cell proliferation. We also found that 18 of the 26 pesticides studied here had previously caused tumors in at least one animal species, findings which support the mode of action data. This study shows how a text-mining tool could be used to identify carcinogenic modes of action for a group of chemicals in large quantities of text. This strategy could support the risk assessment process of chemical mixtures.

  13. Evaluation of carcinogenic modes of action for pesticides in fruit on the Swedish market using a text-mining tool

    Directory of Open Access Journals (Sweden)

    Ilona eSilins

    2014-06-01

    Full Text Available Toxicity caused by chemical mixtures has emerged as a significant challenge for toxicologists and risk assessors. Information on individual chemicals’ modes of action is an important part of the hazard identification step. In this study, an automatic text mining-based tool was employed as a method to identify the carcinogenic modes of action of pesticides frequently found in fruit on the Swedish market. The current available scientific literature on the 26 most common pesticides found in apples and oranges was evaluated. The literature was classified according to a taxonomy that specifies the main type of scientific evidence used for determining carcinogenic properties of chemicals. The publication profiles of many pesticides were similar, containing evidence for both genotoxic and non-genotoxic modes of action, including effects such as oxidative stress, chromosomal changes and cell proliferation. We also found that 18 of the 26 pesticides studied here had previously caused tumors in at least one animal species, findings which support the mode of action data. This study demonstrates how a text-mining tool could be used to identify carcinogenic modes of action for a group of chemicals in large quantities of text. The strategy could support the risk assessment process of chemical mixtures.

  14. Genotoxic potential of glyphosate formulations: mode-of-action investigations.

    Science.gov (United States)

    Heydens, William F; Healy, Charles E; Hotz, Kathy J; Kier, Larry D; Martens, Mark A; Wilson, Alan G E; Farmer, Donna R

    2008-02-27

    A broad array of in vitro and in vivo assays has consistently demonstrated that glyphosate and glyphosate-containing herbicide formulations (GCHF) are not genotoxic. Occasionally, however, related and contradictory data are reported, including findings of mouse liver and kidney DNA adducts and damage following intraperitoneal (ip) injection. Mode-of-action investigations were therefore undertaken to determine the significance of these contradictory data while concurrently comparing results from ip and oral exposures. Exposure by ip injection indeed produced marked hepatic and renal toxicity, but oral administration did not. The results suggest that ip injection of GCHF may induce secondary effects mediated by local toxicity rather than genotoxicity. Furthermore, these results continue to support the conclusion that glyphosate and GCHF are not genotoxic under exposure conditions that are relevant to animals and humans.

  15. Genomic tools to profile antibiotic mode of action.

    Science.gov (United States)

    Cardona, Silvia T; Selin, Carrie; Gislason, April S

    2015-01-01

    The increasing emergence of antimicrobial multiresistant bacteria is of great concern to public health. While these bacteria are becoming an ever more prominent cause of nosocomial and community-acquired infections worldwide, the antibiotic discovery pipeline has been stalled in the last few years with very few efforts in the research and development of novel antibacterial therapies. Some of the root causes that have hampered current antibiotic drug development are the lack of understanding of the mode of action (MOA) of novel antibiotic molecules and the poor characterization of the bacterial physiological response to antibiotics that ultimately causes resistance. Here, we review how bacterial genetic tools can be applied at the genomic level with the goal of profiling resistance to antibiotics and elucidating antibiotic MOAs. Specifically, we highlight how chemical genomic detection of the MOA of novel antibiotic molecules and antibiotic profiling by next-generation sequencing are leveraging basic antibiotic research to unprecedented levels with great opportunities for knowledge translation.

  16. Mosquitocidal bacterial toxins: diversity, mode of action and resistance phenomena

    Directory of Open Access Journals (Sweden)

    Charles Jean-François

    2000-01-01

    Full Text Available Bacteria active against dipteran larvae (mosquitoes and black flies include a wide variety of Bacillus thuringiensis and B. sphaericus strains, as well as isolates of Brevibacillus laterosporus and Clostridium bifermentans. All display different spectra and levels of activity correlated with the nature of the toxins, mainly produced during the sporulation process. This paper describes the structure and mode of action of the main mosquitocidal toxins, in relationship with their potential use in mosquito and/or black fly larvae control. Investigations with laboratory and field colonies of mosquitoes that have become highly resistant to the B. sphaericus Bin toxin have shown that several mechanisms of resistance are involved, some affecting the toxin/receptor binding step, others unknown.

  17. Metabolic responses of Eisenia fetida after sub-lethal exposure to organic contaminants with different toxic modes of action

    Energy Technology Data Exchange (ETDEWEB)

    McKelvie, Jennifer R.; Wolfe, David M.; Celejewski, Magda A. [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada); Alaee, Mehran [Environment Canada, 867 Lakeshore Rd., P.O. Box 5050, Burlington, ON L7R 4A6 (Canada); Simpson, Andre J. [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada); Simpson, Myrna J., E-mail: myrna.simpson@utoronto.ca [Department of Physical and Environmental Sciences, University of Toronto, 1265 Military Trail Toronto, ON M1C 1A4 (Canada)

    2011-12-15

    Nuclear magnetic resonance (NMR) - based metabolomics has the potential to identify toxic responses of contaminants within a mixture in contaminated soil. This study evaluated the metabolic response of Eisenia fetida after exposure to an array of organic compounds to determine whether contaminant-specific responses could be identified. The compounds investigated in contact tests included: two pesticides (carbaryl and chlorpyrifos), three pharmaceuticals (carbamazephine, estrone and caffeine), two persistent organohalogens (Aroclor 1254 and PBDE 209) and two industrial compounds (nonylphenol and dimethyl phthalate). Control and contaminant-exposed metabolic profiles were distinguished using principal component analysis and potential contaminant-specific biomarkers of exposure were found for several contaminants. These results suggest that NMR-based metabolomics offers considerable promise for differentiating between the different toxic modes of action (MOA) associated with sub-lethal toxicity to earthworms. - Highlights: > NMR-based earthworm metabolomic analysis of the toxic mode of action of various environmental contaminants. > Organic chemicals with different toxic modes of action resulted in varied metabolomic responses for E. fetida. > NMR-based metabolomics differentiates between the different modes of action associated with sub-lethal toxicity. - {sup 1}H NMR metabolomics was used to identify potential biomarkers of organic contaminant exposure in Eisenia fetida earthworms.

  18. Exposure assessment of the cumulative intake of pesticides with dissimilar mode of action

    DEFF Research Database (Denmark)

    Jensen, Bodil Hamborg; Petersen, Annette; Christiansen, Sofie

    Risk assessment of pesticides is currently based on the no observed adverse effect levels (NOAELs) for effects of single compounds. However, humans might be exposed to a mixture of pesticides at the same time and the exposure could occur from more pesticides with endocrine disrupting effects....... In this study the effects of combined exposure from four endocrine disrupting pesticides have been investigated (procymidone, mancozeb, tebuconazole, and prochloraz). The four pesticides have dissimilar mode of actions. On the background of the potency for each pesticide to a given effect, a relative potency...... factor and the cumulative acute exposure of the pesticides have been estimated....

  19. Machine learning algorithms for mode-of-action classification in toxicity assessment.

    Science.gov (United States)

    Zhang, Yile; Wong, Yau Shu; Deng, Jian; Anton, Cristina; Gabos, Stephan; Zhang, Weiping; Huang, Dorothy Yu; Jin, Can

    2016-01-01

    Real Time Cell Analysis (RTCA) technology is used to monitor cellular changes continuously over the entire exposure period. Combining with different testing concentrations, the profiles have potential in probing the mode of action (MOA) of the testing substances. In this paper, we present machine learning approaches for MOA assessment. Computational tools based on artificial neural network (ANN) and support vector machine (SVM) are developed to analyze the time-concentration response curves (TCRCs) of human cell lines responding to tested chemicals. The techniques are capable of learning data from given TCRCs with known MOA information and then making MOA classification for the unknown toxicity. A novel data processing step based on wavelet transform is introduced to extract important features from the original TCRC data. From the dose response curves, time interval leading to higher classification success rate can be selected as input to enhance the performance of the machine learning algorithm. This is particularly helpful when handling cases with limited and imbalanced data. The validation of the proposed method is demonstrated by the supervised learning algorithm applied to the exposure data of HepG2 cell line to 63 chemicals with 11 concentrations in each test case. Classification success rate in the range of 85 to 95 % are obtained using SVM for MOA classification with two clusters to cases up to four clusters. Wavelet transform is capable of capturing important features of TCRCs for MOA classification. The proposed SVM scheme incorporated with wavelet transform has a great potential for large scale MOA classification and high-through output chemical screening.

  20. Probiotics as beneficial microbes in aquaculture: an update on their multiple modes of action: a review.

    Science.gov (United States)

    Zorriehzahra, Mohammad Jalil; Delshad, Somayeh Torabi; Adel, Milad; Tiwari, Ruchi; Karthik, K; Dhama, Kuldeep; Lazado, Carlo C

    2016-12-01

    Wide and discriminate use of antibiotics has resulted in serious biological and ecological concerns, especially the emergence of antibiotic resistance. Probiotics, known as beneficial microbes, are being proposed as an effective and eco-friendly alternative to antibiotics. They were first applied in aquaculture species more than three decades ago, but considerable attention had been given only in the early 2000s. Probiotics are defined as live or dead, or even a component of the microorganisms that act under different modes of action in conferring beneficial effects to the host or to its environment. Several probiotics have been characterized and applied in fish and a number of them are of host origin. Unlike some disease control alternatives being adapted and proposed in aquaculture where actions are unilateral, the immense potential of probiotics lies on their multiple mechanisms in conferring benefits to the host fish and the rearing environment. The staggering number of probiotics papers in aquaculture highlights the multitude of advantages from these microorganisms and conspicuously position them in the dynamic search for health-promoting alternatives for cultured fish. This paper provides an update on the use of probiotics in finfish aquaculture, particularly focusing on their modes of action. It explores the contemporary understanding of their spatial and nutritional competitiveness, inhibitory metabolites, environmental modification capability, immunomodulatory potential and stress-alleviating mechanism. This timely update affirms the importance of probiotics in fostering sustainable approaches in aquaculture and provides avenues in furthering its research and development.

  1. Temporally resolved GC-MS-based metabolic profiling of herbicide treated plants treated reveals that changes in polar primary metabolites alone can distinguish herbicides of differing mode of action.

    Science.gov (United States)

    Trenkamp, Sandra; Eckes, Peter; Busch, Marco; Fernie, Alisdair R

    2009-09-01

    We conducted a comprehensive metabolic phenotyping of primary metabolism of photosynthetic tissue of Arabidopsis thaliana following spray treatment with a number of commercially used herbicides using a well established gas-chromatography mass-spectrometry profiling method. Applying this technique we were able to identify and quantify in excess of 80 polar metabolites and based on a combination of co-elution with standards and prediction from the mass spectra a similar number of lipophillic components within two chromatographic runs. The herbicides selected were glufosinate, sulcotrione, AE944 [N2-(1-ethyl-3-phenylpropyl)-6-(1-fluoro-1-methylethyl)-1,3,5-triazine-2,4-diamine], foramsulfuron, benfuresate and glyphosate. We determined causal changes in the metabolite profiles by following their time-dependent changes using a serial sampling strategy. The resultant profiles were compared both by looking at the largest changes in a metabolite by metabolite manner and by performance of statistical analyses. These data revealed that analysis of the polar metabolites allows clear separation of the compounds under test. This finding is discussed in the context of current strategies for agrochemical discovery. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-008-0149-8) contains supplementary material, which is available to authorized users.

  2. Testosterone and the Male Skeleton: A Dual Mode of Action

    Directory of Open Access Journals (Sweden)

    Mieke Sinnesael

    2011-01-01

    Full Text Available Testosterone is an important hormone for both bone gain and maintenance in men. Hypogonadal men have accelerated bone turnover and increased fracture risk. In these men, administration of testosterone inhibits bone resorption and maintains bone mass. Testosterone, however, is converted into estradiol via aromatization in many tissues including male bone. The importance of estrogen receptor alpha activation as well of aromatization of androgens into estrogens was highlighted by a number of cases of men suffering from an inactivating mutation in the estrogen receptor alpha or in the aromatase enzyme. All these men typically had low bone mass, high bone turnover and open epiphyses. In line with these findings, cohort studies have confirmed that estradiol contributes to the maintenance of bone mass after reaching peak bone mass, with an association between estradiol and fractures in elderly men. Recent studies in knock-out mice have increased our understanding of the role of androgens and estrogens in different bone compartments. Estrogen receptor activation, but not androgen receptor activation, is involved in the regulation of male longitudinal appendicular skeletal growth in mice. Both the androgen and the estrogen receptor can independently mediate the cancellous bone-sparing effects of sex steroids in male mice. Selective KO studies of the androgen receptor in osteoblasts in male mice suggest that the osteoblast in the target cell for androgen receptor mediated maintenance of trabecular bone volume and coordination of bone matrix synthesis and mineralization. Taken together, both human and animal studies suggest that testosterone has a dual mode of action on different bone surfaces with involvement of both the androgen and estrogen receptor.

  3. Global network analysis of drug tolerance, mode of action and virulence in methicillin-resistant S. aureus

    Directory of Open Access Journals (Sweden)

    Shirran Sally

    2011-05-01

    Full Text Available Abstract Background Staphylococcus aureus is a major human pathogen and strains resistant to existing treatments continue to emerge. Development of novel treatments is therefore important. Antimicrobial peptides represent a source of potential novel antibiotics to combat resistant bacteria such as Methicillin-Resistant Staphylococcus aureus (MRSA. A promising antimicrobial peptide is ranalexin, which has potent activity against Gram-positive bacteria, and particularly S. aureus. Understanding mode of action is a key component of drug discovery and network biology approaches enable a global, integrated view of microbial physiology, including mechanisms of antibiotic killing. We developed a systems-wide functional association network approach to integrate proteome and transcriptome profiles, enabling study of drug resistance and mode of action. Results The functional association network was constructed by Bayesian logistic regression, providing a framework for identification of antimicrobial peptide (ranalexin response modules from S. aureus MRSA-252 transcriptome and proteome profiling. These signatures of ranalexin treatment revealed multiple killing mechanisms, including cell wall activity. Cell wall effects were supported by gene disruption and osmotic fragility experiments. Furthermore, twenty-two novel virulence factors were inferred, while the VraRS two-component system and PhoU-mediated persister formation were implicated in MRSA tolerance to cationic antimicrobial peptides. Conclusions This work demonstrates a powerful integrative approach to study drug resistance and mode of action. Our findings are informative to the development of novel therapeutic strategies against Staphylococcus aureus and particularly MRSA.

  4. Combining QSAR modeling and text-mining techniques to link chemical structures and carcinogenic modes of action

    Directory of Open Access Journals (Sweden)

    Georgios Papamokos

    2016-08-01

    Full Text Available There is an increasing need for new reliable non-animal based methods to predict and test toxicity of chemicals. QSAR, a computer-based method linking chemical structures with biological activities, is used in predictive toxicology. In this study we tested the approach to combine QSAR data with literature profiles of carcinogenic modes of action automatically generated by a text-mining tool. The aim was to generate data patterns to identify associations between chemical structures and biological mechanisms related to carcinogenesis. Using these two methods, individually and combined, we evaluated 96 rat carcinogens of the hematopoietic system, liver, lung and skin. We found that skin and lung rat carcinogens were mainly mutagenic, while the group of carcinogens affecting the hematopoietic system and the liver also included a large proportion of non-mutagens. The automatic literature analysis showed that mutagenicity was a frequently reported endpoint in the literature of these carcinogens, however less common endpoints such as immunosuppression and hormonal receptor-mediated effects were also found in connection with some of the carcinogens, results of potential importance for certain target organs. The combined approach, using QSAR and text-mining techniques, could be useful for identifying more detailed information on biological mechanisms and the relation with chemical structures. The method can be particularly useful in increasing the understanding of structure and activity relationships for non-mutagens.

  5. Combining QSAR Modeling and Text-Mining Techniques to Link Chemical Structures and Carcinogenic Modes of Action.

    Science.gov (United States)

    Papamokos, George; Silins, Ilona

    2016-01-01

    There is an increasing need for new reliable non-animal based methods to predict and test toxicity of chemicals. Quantitative structure-activity relationship (QSAR), a computer-based method linking chemical structures with biological activities, is used in predictive toxicology. In this study, we tested the approach to combine QSAR data with literature profiles of carcinogenic modes of action automatically generated by a text-mining tool. The aim was to generate data patterns to identify associations between chemical structures and biological mechanisms related to carcinogenesis. Using these two methods, individually and combined, we evaluated 96 rat carcinogens of the hematopoietic system, liver, lung, and skin. We found that skin and lung rat carcinogens were mainly mutagenic, while the group of carcinogens affecting the hematopoietic system and the liver also included a large proportion of non-mutagens. The automatic literature analysis showed that mutagenicity was a frequently reported endpoint in the literature of these carcinogens, however, less common endpoints such as immunosuppression and hormonal receptor-mediated effects were also found in connection with some of the carcinogens, results of potential importance for certain target organs. The combined approach, using QSAR and text-mining techniques, could be useful for identifying more detailed information on biological mechanisms and the relation with chemical structures. The method can be particularly useful in increasing the understanding of structure and activity relationships for non-mutagens.

  6. Antibiotic resistance modulation and modes of action of (--α-pinene in Campylobacter jejuni.

    Directory of Open Access Journals (Sweden)

    Jasna Kovač

    Full Text Available The aim of the study was to investigate the mode of action of (--α-pinene in terms of its modulation of antibiotic resistance in Campylobacter jejuni. Broth microdilution and ethidium bromide accumulation assays were used to evaluate the (--α-pinene antimicrobial activity, modulation of antimicrobial resistance, and inhibition of antimicrobial efflux. The target antimicrobial efflux systems were identified using an insertion mutagenesis approach, and C. jejuni adaptation to (--α-pinene was evaluated using DNA microarrays. Knock-out mutants of the key up-regulated transcriptional regulators hspR and hrcA were constructed to investigate their roles in C. jejuni adaptation to several stress factors, including osmolytes, and pH, using Biolog phenotypical microarrays. Our data demonstrate that (--α-pinene efficiently modulates antibiotic resistance in C. jejuni by decreasing the minimum inhibitory concentrations of ciprofloxacin, erythromycin and triclosan by up to 512-fold. Furthermore, (--α-pinene promotes increased expression of cmeABC and another putative antimicrobial efflux gene, Cj1687. The ethidium bromide accumulation was greater in the wild-type strain than in the antimicrobial efflux mutant strains, which indicates that these antimicrobial efflux systems are a target of action of (--α-pinene. Additionally, (--α-pinene decreases membrane integrity, which suggests that enhanced microbial influx is a secondary mode of action of (--α-pinene. Transcriptomic analysis indicated that (--α-pinene disrupts multiple metabolic pathways, and particularly those involved in heat-shock responses. Thus, (--α-pinene has significant activity in the modulation of antibiotic resistance in C. jejuni, which appears to be mediated by multiple mechanisms that include inhibition of microbial efflux, decreased membrane integrity, and metabolic disruption. These data warrant further studies on (--α-pinene to develop its use in the control of antibiotic

  7. Enhancing pressure ulcer prevention using wound dressings: what are the modes of action?

    Science.gov (United States)

    Call, Evan; Pedersen, Justin; Bill, Brian; Black, Joyce; Alves, Paulo; Brindle, C Tod; Dealey, Carol; Santamaria, Nick; Clark, Michael

    2015-08-01

    Recent clinical research has generated interest in the use of sacral wound dressings as preventive devices for patients at risk of ulceration. This study was conducted to identify the modes of action through which dressings can add to pressure ulcer prevention, for example, shear and friction force redistribution and pressure distribution. Bench testing was performed using nine commercially available dressings. The use of dressings can reduce the amplitude of shear stress and friction reaching the skin of patients at risk. They can also effectively redirect these forces to wider areas which minimises the mechanical loads upon skeletal prominences. Dressings can redistribute pressure based upon their effective Poisson ratio and larger deflection areas, providing greater load redistribution.

  8. Unraveling the antibacterial mode of action of a clay from the Colombian Amazon.

    Science.gov (United States)

    Londono, Sandra Carolina; Williams, Lynda B

    2016-04-01

    Natural antibacterial clays can inhibit growth of human pathogens; therefore, understanding the antibacterial mode of action may lead to new applications for health. The antibacterial modes of action have shown differences based on mineralogical constraints. Here we investigate a natural clay from the Colombian Amazon (AMZ) known to the Uitoto natives as a healing clay. The physical and chemical properties of the AMZ clay were compared to standard reference materials: smectite (SWy-1) and kaolinite (API #5) that represent the major minerals in AMZ. We tested model Gram-negative (Escherichia coli ATCC #25922) and Gram-positive (Bacillus subtilis ATCC #6633) bacteria to assess the clay's antibacterial effectiveness against different bacterial types. The chemical and physical changes in the microbes were examined using bioimaging and mass spectrometry of clay digests and aqueous leachates. Results indicate that a single dose of AMZ clay (250 mg/mL) induced a 4-6 order of magnitude reduction in cell viability, unlike the reference clays that did not impact bacterial survival. AMZ clay possesses a relatively high specific surface area (51.23 m(2)/g) and much higher total surface area (278.82 m(2)/g) than the reference clays. In aqueous suspensions (50 mg clay/mL water), soluble metals are released and the minerals buffer fluid pH between 4.1 and 4.5. We propose that the clay facilitates chemical interactions detrimental to bacteria by absorbing nutrients (e.g., Mg, P) and potentially supplying metals (e.g., Al) toxic to bacteria. This study demonstrates that native traditional knowledge can direct scientific studies.

  9. Stratum corneum hydration : mode of action of moisturizers on a molecular level

    NARCIS (Netherlands)

    Caussin, Julia

    2009-01-01

    In this thesis, the mode of action of stratum corneum moisturizers is studied using a variety of techniques: cryo-scanning electron microscopy, freeze fracture transmission electron microscopy, small angle X-ray diffraction and Fourier transform infrared spectroscopy.

  10. Mode of Action for Reproductive and Hepatic Toxicity Inferred from a Genomic Study of Triazole Antifungals

    Science.gov (United States)

    The mode of action for the reproductive toxicity of triazole antifungals have been previously characterized by an observed increased in serum testosterone, hepatotoxicity, and reduced insemination and fertility indices. In order to refine our mechanistic understanding of these m...

  11. Stratum corneum hydration : mode of action of moisturizers on a molecular level

    NARCIS (Netherlands)

    Caussin, Julia

    2009-01-01

    In this thesis, the mode of action of stratum corneum moisturizers is studied using a variety of techniques: cryo-scanning electron microscopy, freeze fracture transmission electron microscopy, small angle X-ray diffraction and Fourier transform infrared spectroscopy.

  12. Mixture toxicity of three toxicants with similar and dissimilar modes of action to Daphnia magna.

    Science.gov (United States)

    Syberg, Kristian; Elleby, Anders; Pedersen, Henrik; Cedergreen, Nina; Forbes, Valery E

    2008-03-01

    Mixture toxicity of similar- and dissimilar-acting toxicants can be predicted by the models concentration addition (CA) and independent action (IA) using single substance toxicity data. Knowledge of the toxicants mode of action is thus required in order to use the models. In order to test the predictive capability of the models, we conducted Daphnia magna 48 h immobilization experiments with three toxicants with known modes of action (dimethoate, pirimicarb and linear alkyl benzene sulfonate) singly, and in binary and ternary mixtures. Our results indicate that CA and IA predict binary mixtures of similar- and dissimilar-acting toxicants equally well. CA and IA also equally predicted the ternary mixture consisting of both similar- and dissimilar-acting chemicals. The paper discusses the concept of mode of action and the implications the definition of mode of action has on the choice of reference model for mixture toxicity studies.

  13. [Study progress on the mode of action of praziquantel against schistosomes].

    Science.gov (United States)

    Xiao, Shu-Hua

    2007-12-01

    Praziquantel is the only effective drug of choice against five human species of schistosomes. Main advantages of praziquantel include convenient oral administration, high safety and efficacy as well as short treatment course. To better understand the mode of action of praziquantel against schistosomes would be helpful for further development of new broad-spectrum anthelminthics. This paper summarizes the 30 years' research progress on the mode of action of the drug against schistosomes proceeded by domestic and abroad laboratories.

  14. Research strategy for developing key information on bromate's mode of action.

    Science.gov (United States)

    Bull, Richard J; Cottruvo, Joseph A

    2006-04-17

    Bromate is produced when ozone is used to treat waters that contain trace amounts of bromide ion. It is also a contaminant of hypochlorite solutions produced by electrolysis of salt that contains bromide. Both ozone and hypochlorite are extensively used to disinfect drinking water, a process that is credited with reducing the incidence of waterborne infections diseases around the world. In studies on experimental animals, bromate has been consistently demonstrated to induce cancer, although there is evidence of substantial species differences in sensitivity (rat>mouse>hamster). There are no data to indicate bromate is carcinogenic in humans. An issue that is critical to the continued use of ozone as a disinfectant for drinking water in bromide-containing waters depends heavily on whether current predictions of carcinogenic risk based on carcinogenic responses in male rats treated with bromate are accurate at the much lower exposure levels of humans. Thiol-dependent oxidative damage to guanine in DNA is a plausible mode of action for bromate-induced cancer. However, other mechanisms may contribute to the response, including the accumulation of alpha2u-globulin in the kidney of the male rat. To provide direction to institutions that have an interest in clarifying the toxicological risks that bromate in drinking water might pose, a workshop funded by the Awwa Research Foundation was convened to lay out a research strategy that, if implemented, could clarify this important public health issue. The technical issues that underlie the deliberations of the workshop are provided in a series of technical papers. The present manuscript summarizes the conclusions of the workgroup with respect to the type and timing of research that should be conducted. The research approach is outlined in four distinct phases that lay out alternative directions as the research plan is implemented. Phase I is designed to quantify pre-systemic degradation, absorption, distribution, and

  15. Bioavailability links mode of action can improve the long-term field risk assessment for tilapia exposed to arsenic.

    Science.gov (United States)

    Tsai, Jeng-Wei; Chen, Wei-Yu; Ju, Yun-Ru; Liao, Chung-Min

    2009-05-01

    The objective of this paper was to develop a mechanistic-based framework to explicitly incorporate the factors controlling the bioavailability, toxicodynamics and mode of action to enhance predictive ability of arsenic (As) toxicity to protect the health of farmed tilapia Oreochromis mossambicus. We linked the biotic ligand model and damage assessment model to develop a toxicokinetic model for elucidating the site-specific temporal changes of As bioavailability and to characterize how the fish regulate the metal toxicity. We built a bioavailability-mode of action-based growth toxicity model by linking a bioenergetic growth model and damage assessment model to predict how the As affects on the tilapia growth in the entire life span in site-specific field ecosystems. Here we show that the proposed model well describes the water-chemistry-dependent toxicokinetics and toxicodynamics variations of As to tilapia. We selected two local tilapia farms with different water chemistries located at southwestern Taiwan coast region to implement the proposed algorithm to predict the risk of As exposure. Results indicate that the growth toxicity of O. mossambicus in Taihsi is more sensitive than that in Peimen. We found that the effect of ion competition on the As bioavailability and their ecotoxicological effects on tilapia are more obvious in Taihsi comparing with that in Peimen. We suggested that the proposed bioavailability- and mode of action-based framework can be used to capture the biological response and regulation of tilapia to As exposures. It is applicable for a site-specific and long-term ecotoxicological risk assessment.

  16. A Flow Cytometry Method for Rapidly Assessing Mycobacterium tuberculosis Responses to Antibiotics with Different Modes of Action.

    Science.gov (United States)

    Hendon-Dunn, Charlotte Louise; Doris, Kathryn Sarah; Thomas, Stephen Richard; Allnutt, Jonathan Charles; Marriott, Alice Ann Neville; Hatch, Kim Alexandra; Watson, Robert James; Bottley, Graham; Marsh, Philip David; Taylor, Stephen Charles; Bacon, Joanna

    2016-07-01

    Current methods for assessing the drug susceptibility of Mycobacterium tuberculosis are lengthy and do not capture information about viable organisms that are not immediately culturable under standard laboratory conditions as a result of antibiotic exposure. We have developed a rapid dual-fluorescence flow cytometry method using markers for cell viability and death. We show that the fluorescent marker calcein violet with an acetoxy-methyl ester group (CV-AM) can differentiate between populations of M. tuberculosis growing at different rates, while Sytox green (SG) can differentiate between live and dead mycobacteria. M. tuberculosis was exposed to isoniazid or rifampin at different concentrations over time and either dual stained with CV-AM and SG and analyzed by flow cytometry or plated to determine the viability of the cells. Although similar trends in the loss of viability were observed when the results of flow cytometry and the plate counting methods were compared, there was a lack of correlation between these two approaches, as the flow cytometry analysis potentially captured information about cell populations that were unable to grow under standard conditions. The flow cytometry approach had an additional advantage in that it could provide insights into the mode of action of the drug: antibiotics targeting the cell wall gave a flow cytometry profile distinct from those inhibiting intracellular processes. This rapid drug susceptibility testing method could identify more effective antimycobacterials, provide information about their potential mode of action, and accelerate their progress to the clinic.

  17. Mode of action and human relevance of THF-induced mouse liver tumors.

    Science.gov (United States)

    Choi, Christopher J; Rushton, Erik K; Vardy, Audrey; Higgins, Larry; Augello, Andrea; Parod, Ralph J

    2017-07-05

    In a National Toxicology Program (NTP) bioassay, inhalation of tetrahydrofuran (THF) induced liver tumors in female B6C3F1 mice but not in male mice or rats of either sex. Since THF is not genotoxic, the NTP concluded this carcinogenic activity was likely mediated via non-genotoxic modes of action (MOA). Based on evidence that THF and phenobarbital share a similar MOA, female Car/Pxr knock-out mice were orally exposed to THF to evaluate the potential role of CAR activation in the MOA for THF-induced liver tumors. Because data from this oral study with Car/Pxr knock-out mice (C57Bl/6) and the inhalation studies with wild type mice (B6C3F1) reported by NTP and others were derived from different strains, oral studies with wild type B6C3F1 and C57Bl/6 mice were conducted to ensure THF responses in both strains were comparable. As seen in inhalation studies with THF, oral exposure of wild type female mice to a maximum tolerated dose of THF increased total P450 content, CAR-related P450 activities, and hepatocyte proliferation; these effects were not observed in Car/Pxr knock-out female mice. This finding supports the hypothesis THF-induced carcinogenicity is likely mediated via CAR activation that has limited, if any, relevance to humans. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  18. Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

    Directory of Open Access Journals (Sweden)

    Auda A. Eltahla

    2015-09-01

    Full Text Available The hepatitis C virus (HCV is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp has been targeted for antiviral development, and direct-acting antivirals (DAA have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.

  19. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance.

    Science.gov (United States)

    Ghannoum, M A; Rice, L B

    1999-10-01

    The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

  20. Current models of the mode of action of Bacillus thuringiensis insecticidal crystal proteins: a critical review.

    Science.gov (United States)

    Vachon, Vincent; Laprade, Raynald; Schwartz, Jean-Louis

    2012-09-15

    Bacillus thuringiensis (Bt) Cry toxins constitute the active ingredient in the most widely used biological insecticides and insect-resistant transgenic crops. A clear understanding of their mode of action is necessary for improving these products and ensuring their continued use. Accordingly, a long history of intensive research has established that their toxic effect is due primarily to their ability to form pores in the plasma membrane of the midgut epithelial cells of susceptible insects. In recent years, a rather elaborate model involving the sequential binding of the toxins to different membrane receptors has been developed to describe the events leading to membrane insertion and pore formation. However, it was also proposed recently that, in contradiction with this mechanism, Bt toxins function by activating certain intracellular signaling pathways which lead to the necrotic death of their target cells without the need for pore formation. Because work in this field has largely focused, for several years, on the elaboration and promotion of these two models, the present revue examines in detail the experimental evidence on which they are based. It is concluded that the presently available information still supports the notion that Bt Cry toxins act by forming pores, but most events leading to their formation, following binding of the activated toxins to their receptors, remain relatively poorly understood.

  1. Differential Gel Electrophoresis (DIGE) Evaluation of Naphthoimidazoles Mode of Action: A Study in Trypanosoma cruzi Bloodstream Trypomastigotes

    Science.gov (United States)

    Brunoro, Giselle Villa Flor; Faça, Vitor Marcel; Caminha, Marcelle Almeida; Ferreira, André Teixeira da Silva; Trugilho, Monique; de Moura, Kelly Cristina Gallan; Perales, Jonas; Valente, Richard Hemmi; Menna-Barreto, Rubem Figueiredo Sadok

    2016-01-01

    Background The obligate intracellular protozoan Trypanosoma cruzi is the causative agent of Chagas disease, a neglected illness affecting millions of people in Latin America that recently entered non-endemic countries through immigration, as a consequence of globalization. The chemotherapy for this disease is based mainly on benznidazole and nifurtimox, which are very efficient nitroderivatives against the acute stage but present limited efficacy during the chronic phase. Our group has been studying the trypanocidal effects of naturally occurring quinones and their derivatives, and naphthoimidazoles derived from β-lapachone N1, N2 and N3 were the most active. To assess the molecular mechanisms of action of these compounds, we applied proteomic techniques to analyze treated bloodstream trypomastigotes, which are the clinically relevant stage of the parasite. Methodology/Principal Findings The approach consisted of quantification by 2D-DIGE followed by MALDI-TOF/TOF protein identification. A total of 61 differentially abundant protein spots were detected when comparing the control with each N1, N2 or N3 treatment, for 34 identified spots. Among the differentially abundant proteins were activated protein kinase C receptor, tubulin isoforms, asparagine synthetase, arginine kinase, elongation factor 2, enolase, guanine deaminase, heat shock proteins, hypothetical proteins, paraflagellar rod components, RAB GDP dissociation inhibitor, succinyl-CoA ligase, ATP synthase subunit B and methionine sulfoxide reductase. Conclusion/Significance Our results point to different modes of action for N1, N2 and N3, which indicate a great variety of metabolic pathways involved and allow for novel perspectives on the development of trypanocidal agents. PMID:27551855

  2. Mode of action of Chrysosporium lucknowense C1 a-l-arabinohydrolases

    NARCIS (Netherlands)

    Kuhnel, S.; Westphal, Y.; Hinz, S.W.A.; Schols, H.A.; Gruppen, H.

    2011-01-01

    The mode of action of four Chrysosporium lucknowense C1 a-l-arabinohydrolases was determined to enable controlled and effective degradation of arabinan. The active site of endoarabinanase Abn1 has at least six subsites, of which the subsites -1 to +2 have to be occupied for hydrolysis. Abn1 was able

  3. Odorant receptor modulation: Ternary paradigm for mode of action of insect repellents

    Science.gov (United States)

    The modulation of insect behavior for the purpose of controlling the spread of infectious diseases has been the task of a few insect repellents for which the mechanistic modes of action on odorant receptors (ORs) are unclear. Here, we study the effects of the repellents DEET and IR3535, and a novel ...

  4. Study of the mode of action of a polygalacturonase from the phytopathogen Burkholderia cepacia

    DEFF Research Database (Denmark)

    Massa, C.; Clausen, Mads Hartvig; Stojan, J.

    2007-01-01

    of pectins. The mode of action of BcPeh28A on different substrates has been investigated and its enzymatic mechanism elucidated. The hydrolysis of polygalacturonate indicates that BcPeh28A is a non-processive enzyme that releases oligomers with chain lengths ranging from two to eight. By inspection...

  5. Mode of Action Profiles for Pesticide Compounds with Rodent Liver Tumor Outcomes

    Science.gov (United States)

    Mode of action (MOA) provides a central framework for assessing human relevance of adverse health outcomes observed in nonclinical safety studies. The goal of this study was to characterize MOA profiles for known rodent liver tumorigens identified from a database of pesticides as...

  6. Mixture toxicity of three toxicants with similar and dissimilar modes of action to Daphnia magna

    DEFF Research Database (Denmark)

    Syberg, K.; Engell-Kofoed, Anders Elleby; Pedersen, H.;

    2008-01-01

    Mixture toxicity of similar- and dissimilar-acting toxicants can be predicted by the models concentration addition (CA) and independent action (IA) using single substance toxicity data. Knowledge of the toxicants mode of action is thus required in order to use the models. In order to test the pre...

  7. Application of mass spectrometric techniques to delineate the modes-of-action of anticancer metallodrugs

    NARCIS (Netherlands)

    Hartinger, Christian G.; Groessl, Michael; Meier, Samuel M.; Casini, Angela; Dyson, Paul J.

    2013-01-01

    Mass spectrometry (MS) has emerged as an important tool for studying anticancer metallodrugs in complex biological samples and for characterising their interactions with biomolecules and potential targets on a molecular level. The exact modes-of-action of these coordination compounds and especially

  8. Mode of action of the phenylpyrrole fungicide fenpiclonil in Fusarium sulphureum.

    NARCIS (Netherlands)

    Jespers, A.B.K.

    1994-01-01

    In the last few decades, plant disease control has become heavily dependent on fungicides. Most modem fungicides were discovered by random synthesis and empirical optimization of lead structures. In general, these fungicides have specific modes of action and meet modem enviromnental criteria. A disa

  9. Exposure assessment of the cumulative intake of pesticides with dissimilar mode of action

    DEFF Research Database (Denmark)

    Jensen, Bodil Hamborg; Petersen, Annette; Christiansen, Sofie

    . In this study the effects of combined exposure from four endocrine disrupting pesticides have been investigated (procymidone, mancozeb, tebuconazole, and prochloraz). The four pesticides have dissimilar mode of actions. On the background of the potency for each pesticide to a given effect, a relative potency...

  10. Toxicity of mixtures of nephrotoxicants with similar or dissimilar mode of action

    NARCIS (Netherlands)

    Jonker, D.; Woutersen, R.A.; Feron, V.J.

    1996-01-01

    The toxicity of mixtures of chemicals with the same target organ was examined in rats using nephrotoxicants with similar or dissimilar modes of action. In a 4-wk feeding study, lysinoalanine, mercuric chloride, hexachloro-1,3-butadiene and d-limonene, each affecting renal proximal tubular cells but

  11. Challenges in assigning endocrine-specific modes of action: Recommendations for researchers and regulators.

    Science.gov (United States)

    Mihaich, Ellen M; Schäfers, Christoph; Dreier, David A; Hecker, Markus; Ortego, Lisa; Kawashima, Yukio; Dang, Zhi-Chao; Solomon, Keith

    2017-03-01

    As regulatory programs evaluate substances for their endocrine-disrupting properties, careful study design and data interpretation are needed to distinguish between responses that are truly endocrine specific and those that are not. This is particularly important in regulatory environments where criteria are under development to identify endocrine-disrupting properties to enable hazard-based regulation. Irrespective of these processes, most jurisdictions use the World Health Organization/International Programme on Chemical Safety definition of an endocrine disruptor, requiring that a substance is demonstrated to cause a change in endocrine function that consequently leads to an adverse effect in an intact organism. Such a definition is broad, and at its most cautious might capture many general mechanisms that would not specifically denote an endocrine disruptor. In addition, endocrine responses may be adaptive in nature, designed to maintain homeostasis rather than induce an irreversible adverse effect. The likelihood of indirect effects is increased in (eco)toxicological studies that require the use of maximum tolerated concentrations or doses, which must produce some adverse effect. The misidentification of indirect effects as truly endocrine mediated has serious consequences for prompting animal- and resource-intensive testing and regulatory consequences. To minimize the risk for misidentification, an objective and transparent weight-of-evidence procedure based on biological plausibility, essentiality, and empirical evidence of key events in an adverse outcome pathway is recommended to describe the modes of action that may be involved in toxic responses in nontarget organisms. Confounding factors such as systemic toxicity, general stress, and infection can add complexity to such an evaluation and should be considered in the weight of evidence. A recommended set of questions is proffered to help guide researchers and regulators in discerning endocrine and

  12. Efficacy and Mode of Action of Kaolin in the Control of Empoasca vitis and Zygina rhamni (Hemiptera: Cicadellidae) in Vineyards.

    Science.gov (United States)

    Tacoli, Federico; Pavan, Francesco; Cargnus, Elena; Tilatti, Elisabetta; Pozzebon, Alberto; Zandigiacomo, Pietro

    2017-06-01

    During 2015, the influence of kaolin applications and bunch-zone leaf removal on the grapevine leafhoppers, Empoasca vitis (Göthe) and Zygina rhamni Ferrari, and their egg parasitoids (Anagrus spp.) was tested in four vineyards of northeastern Italy. The mode of action of kaolin on E. vitis nymphs was also investigated in the laboratory. In the treated plots, kaolin was applied at a rate of 2% w/v on two occasions separated by 5-6 d. In two vineyards, it was applied either on the whole canopy or the bunch zone at the beginning of the E. vitis second generation (preventive criterion), and in the other two vineyards, it was applied to the whole canopy at the peak of the E. vitis third generation (curative criterion). Both the preventive and curative kaolin applications caused a significant decrease in the populations of E. vitis and Z. rhamni nymphs. The effect of the preventive applications was persistent and was associated with reduced E. vitis leaf symptoms. Kaolin did not influence the activity of Anagrus spp. Bunch-zone leaf removal did not affect leafhopper populations. Laboratory experiments showed that inhibition of feeding was the main mode of action through which kaolin affected nymph populations. Based on these outcomes, kaolin could be a valuable alternative to synthetic insecticides in controlling grapevine leafhoppers. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  13. Antibacterial Effects and Mode of Action of Selected Essential Oils Components against Escherichia coli and Staphylococcus aureus

    Directory of Open Access Journals (Sweden)

    Julio Cesar Lopez-Romero

    2015-01-01

    Full Text Available Bacterial resistance has been increasingly reported worldwide and is one of the major causes of failure in the treatment of infectious diseases. Natural-based products, including plant secondary metabolites (phytochemicals, may be used to surpass or reduce this problem. The objective of this study was to determine the antibacterial effect and mode of action of selected essential oils (EOs components: carveol, carvone, citronellol, and citronellal, against Escherichia coli and Staphylococcus aureus. The minimum inhibitory concentration (MIC and minimum bactericidal concentration (MBC were assessed for the selected EOs components. Moreover, physicochemical bacterial surface characterization, bacterial surface charge, membrane integrity, and K+ leakage assays were carried out to investigate the antimicrobial mode of action of EOs components. Citronellol was the most effective molecule against both pathogens, followed by citronellal, carveol, and carvone. Changes in the hydrophobicity, surface charge, and membrane integrity with the subsequent K+ leakage from E. coli and S. aureus were observed after exposure to EOs. This study demonstrates that the selected EOs have significant antimicrobial activity against the bacteria tested, acting on the cell surface and causing the disruption of the bacterial membrane. Moreover, these molecules are interesting alternatives to conventional antimicrobials for the control of microbial infections.

  14. Studies on the mode of action of the antifungal hexapeptide PAF26.

    Science.gov (United States)

    Muñoz, Alberto; López-García, Belén; Marcos, Jose F

    2006-11-01

    The small antimicrobial peptide PAF26 (Ac-RKKWFW-NH(2)) has been identified by a combinatorial approach and shows preferential activity toward filamentous fungi. In this work, we investigated the mode of action and inhibitory effects of PAF26 on the fungus Penicillium digitatum. The dye Sytox Green was used to demonstrate that PAF26 induced cell permeation. However, microscopic observations showed that sub-MIC concentrations of PAF26 produced both alterations of hyphal morphology (such as altered polar growth and branching) and chitin deposition in areas of no detectable permeation. Analysis of dose-response curves of inhibition and permeation suggested that growth inhibition is not solely a consequence of permeation. In order to shed light on the mode of PAF26 action, its antifungal properties were compared with those of melittin, a well-known pore-forming peptide that kills through cytolysis. While the 50% inhibitory concentrations and MICs of the two peptides against P. digitatum mycelium were comparable, they differed markedly in their fungicidal activities toward conidia and their hemolytic activities toward human red blood cells. Kinetic studies showed that melittin quickly induced Penicillium cell permeation, while PAF26-induced Sytox Green uptake was significantly slower and less efficient. Therefore, the ultimate growth inhibition and morphological alterations induced by PAF26 for P. digitatum are not likely a result of conventional pore formation. Fluorescently labeled PAF26 was used to demonstrate its specific in vivo interaction and translocation inside germ tubes and hyphal cells, at concentrations as low as 0.3 muM (20 times below the MIC), at which no inhibitory, morphological, or permeation effects were observed. Interestingly, internalized PAF26 could bind to cellular RNAs, since in vitro nonspecific RNA binding activity of PAF26 was demonstrated by electrophoretic mobility shift assays. We propose that PAF26 is a short, de novo-designed penetratin

  15. Understanding the mode of action of a pterostilbene derivative as anti-inflammatory agent.

    Science.gov (United States)

    Nikhil, Kumar; Sharan, Shruti; Palla, Srinivasa Rao; Sondhi, Sham M; Peddinti, Rama Krishna; Roy, Partha

    2015-09-01

    Inflammatory response plays an important role not only in the normal physiology, but also in the pathology of certain diseases such as cancers. In our previous study, we found a novel derivative of pterostilbene (PTER), to be an effective inducer of apoptosis in human breast and prostate cancer cells affecting various cellular targets. Herein, we further attempted to investigate its anti-inflammatory potential followed by its probable mode of action. The newly developed compound was tested for its anti-inflammatory actions in lipopolysaccharide (LPS) stimulated RAW264.7 macrophages and carrageenan induced rat paw edema models. Our data showed that the derivative inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as the downstream products like nitric oxide (NO) and PGE2, at much lower doses as compared to PTER. This effect was found to be associated with the inhibition of phosphorylation/degradation of IκB-α and nuclear translocation of the p-NFκB p65. Moreover, inhibition of mitogen-activated protein kinases (MAPKs) and activator protein-1 (AP-1) was also observed. In addition, the newly developed compound also reduced the paw edema, the tissue content of NO, PGE2 and expression of iNOS and COX-2 proteins within the tissues after λ-carrageenan stimulation. Taken together, our findings provide the possibility that the PTER derivative might have enhanced cancer chemopreventive potential based on its stronger anti-NFκB and anti-inflammatory activities as compared to its natural counterpart, i.e., PTER. Thus, this compound can be used towards the development of an effective anti-inflammatory agent.

  16. Cancer mode of action, weight of evidence, and proposed cancer reference value for hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX).

    Science.gov (United States)

    Sweeney, Lisa M; Okolica, Michelle R; Gut, Chester P; Gargas, Michael L

    2012-11-01

    Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX, CAS No. 121-82-4) is a component of munitions formulations, and has been detected in groundwater samples collected at various US military sites. Clean up target levels for RDX may be derived based on consideration of acceptable cumulative human exposure as expressed in toxicity reference values. Evaluations of the cancer weight of evidence and possible modes of action (MOA) for RDX-induced cancer were conducted. It was concluded that the available data provide suggestive evidence of human carcinogenic potential for RDX. While a mutagenic/genotoxic MOA for RDX is unlikely, no alterative MOA is strongly supported by the available data. A nonlinear (threshold) approach to the assessment of human cancer risk was recommended, and a recommended chronic cancer reference dose of 0.08mg/kg/day was derived. For comparison only, computations using a linear approach were also conducted, yielding a cancer risk specific dose of 0.000235mg/kg/day for 1 in 10(5) risk; this value is 2.6-fold higher the current US EPA risk specific dose for 1 in 10(5) risk. Thus, cleanup standards based on human health risk from RDX exposure could potentially depend on the willingness of risk managers to accept a nonlinear MOA and nonlinear toxicity risk value derivation. Published by Elsevier Inc.

  17. Dual mode of action of Bt proteins: protoxin efficacy against resistant insects

    OpenAIRE

    2015-01-01

    Transgenic crops that produce Bacillus thuringiensis (Bt) proteins for pest control are grown extensively, but insect adaptation can reduce their effectiveness. Established mode of action models assert that Bt proteins Cry1Ab and Cry1Ac are produced as inactive protoxins that require conversion to a smaller activated form to exert toxicity. However, contrary to this widely accepted paradigm, we report evidence from seven resistant strains of three major crop pests showing that Cry1Ab and Cry1...

  18. Anti-tumour cytotoxin produced by human monocytes: studies on its mode of action.

    OpenAIRE

    Matthews, N.

    1983-01-01

    Human monocytes can be induced to synthesize a cytotoxin which affects certain tumour cell lines. The interaction of monocyte cytotoxin with a susceptible cell line (L929) has been studied to obtain clues to the mode of action of the cytotoxin. The cytotoxin acts directly on the cells rather than on the culture medium and is cytotoxic at higher concentrations and cytostatic at lower concentrations. First signs of cell damage appear about 20 h after contact with the cytotoxin which must be pre...

  19. Competitive exclusion as a mode of action of a novel Bacillus cereus aquaculture biological agent

    CSIR Research Space (South Africa)

    Lalloo, R

    2010-01-01

    Full Text Available (Kumar et al. 2006; Newaj-Fyzul et al. 2007). Potential mechanisms of biological agents against 7 pathogens include competition for adhesion sites, production of enzymes, immune stimulation, 8 synthesis of antimicrobials, competitive exclusion..., the ability 20 to reduce the concentration of waste ions in reticulated aquaculture, physiological tolerance to 21 environmental conditions and bio-safety (Lalloo et al. 2007; Lalloo et al. 2008) renders the B. 22 Mode of action B. cereus 14 cereus isolate...

  20. Metabolic responses of Eisenia fetida after sub-lethal exposure to organic contaminants with different toxic modes of action.

    Science.gov (United States)

    McKelvie, Jennifer R; Wolfe, David M; Celejewski, Magda A; Alaee, Mehran; Simpson, André J; Simpson, Myrna J

    2011-12-01

    Nuclear magnetic resonance (NMR)--based metabolomics has the potential to identify toxic responses of contaminants within a mixture in contaminated soil. This study evaluated the metabolic response of Eisenia fetida after exposure to an array of organic compounds to determine whether contaminant-specific responses could be identified. The compounds investigated in contact tests included: two pesticides (carbaryl and chlorpyrifos), three pharmaceuticals (carbamazephine, estrone and caffeine), two persistent organohalogens (Aroclor 1254 and PBDE 209) and two industrial compounds (nonylphenol and dimethyl phthalate). Control and contaminant-exposed metabolic profiles were distinguished using principal component analysis and potential contaminant-specific biomarkers of exposure were found for several contaminants. These results suggest that NMR-based metabolomics offers considerable promise for differentiating between the different toxic modes of action (MOA) associated with sub-lethal toxicity to earthworms.

  1. A preliminary operational classification system for nonmutagenic modes of action for carcinogenesis.

    Science.gov (United States)

    Hattis, D; Chu, M; Rahmioglu, N; Goble, R; Verma, P; Hartman, K; Kozlak, M

    2009-01-01

    This article proposes a system of categories for nonmutagenic modes of action for carcinogenesis. The classification is of modes of action rather than individual carcinogens, because the same compound can affect carcinogenesis in more than one way. Basically, we categorize modes of action as: (1) co-initiation (facilitating the original mutagenic changes in stem and progenitor cells that start the cancer process) (e.g. induction of activating enzymes for other carcinogens); (2) promotion (enhancing the relative growth vs differentiation/death of initiated clones (e.g. inhibition of growth-suppressing cell-cell communication); (3) progression (enhancing the growth, malignancy, or spread of already developed tumors) (e.g. suppression of immune surveillance, hormonally mediated growth stimulation for tumors with appropriate receptors by estrogens); and (4) multiphase (e.g., "epigenetic" silencing of tumor suppressor genes). A priori, agents that act at relatively early stages in the process are expected to manifest greater relative susceptibility in early life, whereas agents that act via later stage modes will tend to show greater susceptibility for exposures later in life.

  2. Toxicity of 13 different antibiotics towards freshwater green algae Pseudokirchneriella subcapitata and their modes of action.

    Science.gov (United States)

    Fu, Ling; Huang, Tao; Wang, Shuo; Wang, Xiaohong; Su, Limin; Li, Chao; Zhao, Yuanhui

    2017-02-01

    Although modes of action (MOAs) play a key role in the understanding of the toxic mechanism of chemicals, the MOAs have not been investigated for antibiotics to green algae. This paper is to discriminate excess toxicity from baseline level and investigate the MOAs of 13 different antibiotics to algae by using the determined toxicity values. Comparison of the toxicities shows that the inhibitors of protein synthesis to bacteria, such as azithromycin, doxycycline, florfenicol and oxytetracycline, exhibit significantly toxic effects to algae. On the other hand, the cell wall synthesis inhibitors, such as cefotaxime and amoxicillin, show relatively low toxic effects to the algae. The concentrations determined by HPLC indicate that quinocetone and amoxicillin can be easily photodegraded or hydrolyzed during the toxic tests. The toxic effects of quinocetone and amoxicillin to the algae are attributed to not only their parent compounds, but also their metabolites. Investigation on the mode of action shows that, except rifampicin, all the tested antibiotics exhibit excess toxicity to Pseudokirchneriella subcapitata (P. subcapitata). These antibiotics can be identified as reactive modes of action to the algae. They act as electrophilic mechanism of action to P. subcapitata. These results are valuable for the understanding of the toxic mechanism to algae.

  3. Global nutritional profiling for mutant and chemical mode-of-action analysis in filamentous fungi.

    Science.gov (United States)

    Tanzer, Matthew M; Arst, Herbert N; Skalchunes, Amy R; Coffin, Marie; Darveaux, Blaise A; Heiniger, Ryan W; Shuster, Jeffrey R

    2003-12-01

    We describe a method for gene function discovery and chemical mode-of-action analysis via nutrient utilization using a high throughput Nutritional Profiling platform suitable for filamentous microorganisms. We have optimized the growth conditions for each fungal species to produce reproducible optical density growth measurements in microtiter plates. We validated the Nutritional Profiling platform using a nitrogen source utilization assay to analyze 21 Aspergillus nidulans strains with mutations in the master nitrogen regulatory gene, areA. Analysis of these data accurately reproduced expected results and provided new data to demonstrate that this platform is suitable for fine level phenotyping of filamentous fungi. Next, we analyzed the differential responses of two fungal species to a glutamine synthetase inhibitor, illustrating chemical mode-of-action analysis. Finally, a comparative phenotypic study was performed to characterize carbon catabolite repression in four fungal species using a carbon source utilization assay. The results demonstrate differentiation between two Aspergillus species and two diverse plant pathogens and provide a wealth of new data on fungal nutrient utilization. Thus, these assays can be used for gene function and chemical mode-of-action analysis at the whole organism level as well as interspecies comparisons in a variety of filamentous fungi. Additionally, because uniform distribution of growth within wells is maintained, comparisons between yeast and filamentous forms of a single organism can be performed.

  4. Mode of action of Bacillus thuringiensis Cry and Cyt toxins and their potential for insect control.

    Science.gov (United States)

    Bravo, Alejandra; Gill, Sarjeet S; Soberón, Mario

    2007-03-15

    Bacillus thuringiensis Crystal (Cry) and Cytolitic (Cyt) protein families are a diverse group of proteins with activity against insects of different orders--Lepidoptera, Coleoptera, Diptera and also against other invertebrates such as nematodes. Their primary action is to lyse midgut epithelial cells by inserting into the target membrane and forming pores. Among this group of proteins, members of the 3-Domain Cry family are used worldwide for insect control, and their mode of action has been characterized in some detail. Phylogenetic analyses established that the diversity of the 3-Domain Cry family evolved by the independent evolution of the three domains and by swapping of domain III among toxins. Like other pore-forming toxins (PFT) that affect mammals, Cry toxins interact with specific receptors located on the host cell surface and are activated by host proteases following receptor binding resulting in the formation of a pre-pore oligomeric structure that is insertion competent. In contrast, Cyt toxins directly interact with membrane lipids and insert into the membrane. Recent evidence suggests that Cyt synergize or overcome resistance to mosquitocidal-Cry proteins by functioning as a Cry-membrane bound receptor. In this review we summarize recent findings on the mode of action of Cry and Cyt toxins, and compare them to the mode of action of other bacterial PFT. Also, we discuss their use in the control of agricultural insect pests and insect vectors of human diseases.

  5. Evaluation of acute toxicity, antibacterial activity, and mode of action of the hydroethanolic extract of Piper umbellatum L.

    Science.gov (United States)

    da Silva, Iberê Ferreira; de Oliveira, Ruberlei Godinho; Mendes Soares, Ilsamar; da Costa Alvim, Tarso; Donizeti Ascêncio, Sérgio; de Oliveira Martins, Domingos Tabajara

    2014-01-01

    Piper umbellatum L., Piperaceae, is a shrub that grows up to 3m high. It is commonly known as "capeba" or "pariparoba" in Brazil. Tea prepared using the leaves of this plant is employed in the treatment of infections and inflammatory processes in different countries. Approximately 50 compounds, notably from the flavonoid, alkaloid, terpene, and sterol classes, have been isolated from the leaves of Piper umbellatum. To evaluate the acute toxicity, antibacterial activity, and mode of action of the hydroethanolic extract of Piper umbellatum leaves (HEPu). Acute toxicity of HEPu against CHO-K1 cells was evaluated using a cytotoxicity assay with Alamar Blue and that against mice was assessed by the Hippocratic test. Antibacterial activity of HEPu was tested using the broth microdilution method using a panel of clinically relevant bacteria, and the effects of HEPu on the bacterial membrane were analyzed in detail. A preliminary phytochemical analysis based on coloration/precipitation was performed according to procedure described in the literature. Secondary metabolites detected were analyzed and confirmed by thin layer chromatography (TLC), spectrophotometry, and high performance liquid chromatography (HPLC). Piper umbellatum did not appear to be toxic in the in vitro (IC50>200 µg/mL) cytotoxicity test. When administered in vivo at doses up to 2000 mg/kg p.o., HEPu did not cause any signs or symptoms of toxicity in mice. It demonstrated a good spectrum of antibacterial activity and its mode of action appeared to be associated with changes in the permeability of bacterial membranes; it led to increased entry of hydrophobic antibiotics, efflux of K(+), and nucleotide leakage. Preliminary phytochemical analysis revealed the presence of flavonoids, alkaloids, terpenes, and sterols in the extract. Spectrophotometric and HPLC analysis revealed the presence of the flavonoids rutin and quercetin. In summary, HEPu has antibacterial activity and low acute toxicity in vitro and

  6. Thymus vulgaris essential oil and thymol against Alternaria alternata (Fr.) Keissler: effects on growth, viability, early infection and cellular mode of action.

    Science.gov (United States)

    Perina, Fabiano J; Amaral, Douglas C; Fernandes, Rafael S; Labory, Claudia Rg; Teixeira, Glauco A; Alves, Eduardo

    2015-10-01

    In initial assays, Thymus vulgaris essential oil (TEO) has demonstrated activity against several plant-pathogenic fungi and has reduced the fungal diseases to levels comparable with commercial fungicides. Thus, the goal of this work was to identify the mode of action in fungi of TEO and its major compound thymol (TOH) at the cellular level using an ultrastructure approach. TEO from leaves and TOH had minimum inhibitory concentrations (MICs) of 500 and 250 µg mL(-1) respectively against A. alternata; under the same conditions, MIC for a commercial fungicide was 1250 µg mL(-1) . Ultrastructure analysis showed that TOH phenolic substance prevented fungal growth, reduced fungal viability and prevented the penetration in fruits by a cell wall/plasma membrane interference mode of action with organelles targeted for destruction in the cytoplasm. Such mode of action differs from protective and preventive-curative commercial fungicides used as pattern control. These findings suggest that TOH was responsible for the antifungal activity of TEO. Therefore, both the essential oil and its major substance have potential for use in the development of new phenolic structures and analogues to control Alternaria brown spot disease caused by Alternaria alternata. © 2014 Society of Chemical Industry.

  7. Combined effects of estrogenic chemicals with the same mode of action using an estrogen receptor binding bioassay.

    Science.gov (United States)

    Yang, Rong; Li, Na; Ma, Mei; Wang, Zijian

    2014-11-01

    The increasing amounts of various estrogenic chemicals coexisting in the aquatic environment may pose environmental risks. While the concept of estradiol equivalent (EEQ) has been frequently applied in studying estrogenic mixtures, few experiments have been done to prove its reliability. In this study, the reliability of EEQ and the related model concentration addition (CA) was verified based on the two-hybrid recombinant yeast bioassay when all mixture components had the same mode of action and target of action. Our results showed that the measured estrogenic effects could be well predicted by CA and EEQ for all laboratory-made mixtures using two designs, despite the varying estrogenic activity, concentration levels and ratios of the test chemicals. This suggests that when an appropriate endpoint and its relevant bioassay are chosen, CA should be valid and the application of EEQ in predicting the effect of non-equi-effect mixtures is feasible.

  8. Essential oils in food preservation: mode of action, synergies, and interactions with food matrix components

    Directory of Open Access Journals (Sweden)

    Morten eHyldgaard

    2012-01-01

    Full Text Available Essential oils are aromatic and volatile liquids extracted from plants. The chemicals in essential oils are secondary metabolites, which play an important role in plant defence as they often possess antimicrobial properties. The interest in essential oils and their application in food preservation has been amplified in recent years by an increasingly negative consumer perception of synthetic preservatives. Furthermore, food-borne diseases are a growing public health problem worldwide, calling for more effective preservation strategies. The antibacterial properties of essential oils and their constituents have been documented extensively. Pioneering work has also elucidated the mode of action of a few essential oil constituents, but detailed knowledge about most of the compounds' mode of action is still lacking. This knowledge is particularly important to predict their effect on different microorganisms, how they interact with food matrix components, and how they work in combination with other antimicrobial compounds. The main obstacle for using essential oil constituents as food preservatives is that they are most often not potent enough as single components, and they cause negative organoleptic effects when added in sufficient amounts to provide an antimicrobial effect. Exploiting synergies between several compounds has been suggested as a solution to this problem. However, little is known about which interactions lead to synergistic, additive, or antagonistic effects. Such knowledge could contribute to design of new and more potent antimicrobial blends, and to understand the interplay between the constituents of crude essential oils. The purpose of this review is to provide an overview of current knowledge about the antibacterial properties and antibacterial mode of action of essential oils and their constituents, and to identify research avenues that can facilitate implementation of essential oils as natural preservatives in foods.

  9. Essential oils in food preservation: mode of action, synergies, and interactions with food matrix components.

    Science.gov (United States)

    Hyldgaard, Morten; Mygind, Tina; Meyer, Rikke Louise

    2012-01-01

    Essential oils are aromatic and volatile liquids extracted from plants. The chemicals in essential oils are secondary metabolites, which play an important role in plant defense as they often possess antimicrobial properties. The interest in essential oils and their application in food preservation has been amplified in recent years by an increasingly negative consumer perception of synthetic preservatives. Furthermore, food-borne diseases are a growing public health problem worldwide, calling for more effective preservation strategies. The antibacterial properties of essential oils and their constituents have been documented extensively. Pioneering work has also elucidated the mode of action of a few essential oil constituents, but detailed knowledge about most of the compounds' mode of action is still lacking. This knowledge is particularly important to predict their effect on different microorganisms, how they interact with food matrix components, and how they work in combination with other antimicrobial compounds. The main obstacle for using essential oil constituents as food preservatives is that they are most often not potent enough as single components, and they cause negative organoleptic effects when added in sufficient amounts to provide an antimicrobial effect. Exploiting synergies between several compounds has been suggested as a solution to this problem. However, little is known about which interactions lead to synergistic, additive, or antagonistic effects. Such knowledge could contribute to design of new and more potent antimicrobial blends, and to understand the interplay between the constituents of crude essential oils. The purpose of this review is to provide an overview of current knowledge about the antibacterial properties and antibacterial mode of action of essential oils and their constituents, and to identify research avenues that can facilitate implementation of essential oils as natural preservatives in foods.

  10. Cyclic Ketoenols – Acaricides and Insecticides with a Novel Mode of Action

    Directory of Open Access Journals (Sweden)

    Dejan Marčić

    2011-01-01

    Full Text Available Modern crop protection industry puts great efforts into the investigation and development of pesticides (insecticides, acaricides with a novel mode of action, primarily because of increasingly important problem of resistance of pest organisms to pesticides.Resistance of many pest arthropod species (insects and mites to insecticides and/or acaricides became a global phenomenon in the last decades. Therefore, pest management heavily relies on constant introduction of novel active ingredients in use, i.e. onthe alternative use of a number of compounds with different modes of action in order to save the longevity of newly developed products. Among pest arthropods, according to the potential for resistance development and a number of documented cases, spider mites (Acari: Tetranychidae, especially species Tetranychus urticae and Panonychusulmi, as well as certain species of whiteflies and leaf aphids (Homoptra: Aleyrodidae,Aphididae stand out. In 2002, the company Bayer CropScience introduced spirodiclofen, a tetronic acid derivative and the first cyclic ketoenol, acaricide with a wide spectrum and a novel mode of action – inhibition of acetyl-CoA-carboxylase. Soon after, spiromesifen was introduced, also a derivative of tetronic acid, acaricide and insecticide intended for control of phytophagous mites and whiteflies. Spirotetramat, a tetramic acid derivative, and the third member of the ketoenol group, was recently commercialised as an insecticide efficient against whiteflies,leaf aphids and other harmful Homoptera. In this paper are presented the most significant properties of cyclic ketoenols, aiming at pointing to the possibilities and prospects of their use, but also to potential problems and limitations.

  11. Essential Oils in Food Preservation: Mode of Action, Synergies, and Interactions with Food Matrix Components

    Science.gov (United States)

    Hyldgaard, Morten; Mygind, Tina; Meyer, Rikke Louise

    2012-01-01

    Essential oils are aromatic and volatile liquids extracted from plants. The chemicals in essential oils are secondary metabolites, which play an important role in plant defense as they often possess antimicrobial properties. The interest in essential oils and their application in food preservation has been amplified in recent years by an increasingly negative consumer perception of synthetic preservatives. Furthermore, food-borne diseases are a growing public health problem worldwide, calling for more effective preservation strategies. The antibacterial properties of essential oils and their constituents have been documented extensively. Pioneering work has also elucidated the mode of action of a few essential oil constituents, but detailed knowledge about most of the compounds’ mode of action is still lacking. This knowledge is particularly important to predict their effect on different microorganisms, how they interact with food matrix components, and how they work in combination with other antimicrobial compounds. The main obstacle for using essential oil constituents as food preservatives is that they are most often not potent enough as single components, and they cause negative organoleptic effects when added in sufficient amounts to provide an antimicrobial effect. Exploiting synergies between several compounds has been suggested as a solution to this problem. However, little is known about which interactions lead to synergistic, additive, or antagonistic effects. Such knowledge could contribute to design of new and more potent antimicrobial blends, and to understand the interplay between the constituents of crude essential oils. The purpose of this review is to provide an overview of current knowledge about the antibacterial properties and antibacterial mode of action of essential oils and their constituents, and to identify research avenues that can facilitate implementation of essential oils as natural preservatives in foods. PMID:22291693

  12. Meeting Report: Mode(s) of Action of Asbestos and Related Mineral Fibers

    OpenAIRE

    Gwinn, Maureen R.; DeVoney, Danielle; Jarabek, Annie M.; Sonawane, Babasaheb; Wheeler, John; Weissman, David N.; Masten, Scott; Thompson, Claudia

    2011-01-01

    Background: Although asbestos in general is well known to cause a range of neoplastic and non-neoplastic human health effects, not all asbestos fiber types have the same disease-causing potential, and the mode of action (MOA) of specific types of asbestos and related fibers for various health outcomes are not well understood. Objectives: A workshop was held to discuss the state of the science of the MOA for asbestos-related disease. The objective was to review the range of asbestos-induced he...

  13. Mode of action of antimicrobial proteins, pore-forming toxins and biologically active

    Directory of Open Access Journals (Sweden)

    O Schmidt

    2005-07-01

    Full Text Available Antimicrobial peptides and pore-forming toxins are important effectors in innate immune defencereactions. But their mode of action, comprising the insertion into cholesterol-containing membranes isnot known. Here we explore the mechanical implications of pore-formation by extracellular proteinassemblies that drive cellular uptake reactions by leverage-mediated (LM processes, whereoligomeric adhesion molecules bent membrane-receptors around ‘hinge’-like lipophorin particles. Theinteractions of antimicrobial peptides, pore-forming toxins and biologically active proteins with LMassembliesprovide a new paradigm for the configurational specificity and sterical selectivity ofbiologically active peptides.

  14. Search for aflatoxin and trichothecene production inhibitors and analysis of their modes of action.

    Science.gov (United States)

    Sakuda, Shohei; Yoshinari, Tomoya; Furukawa, Tomohiro; Jermnak, Usuma; Takagi, Keiko; Iimura, Kurin; Yamamoto, Toshiyoshi; Suzuki, Michio; Nagasawa, Hiromichi

    2015-01-01

    Mycotoxin contamination of crops is a serious problem throughout the world because of its impact on human and animal health as well as economy. Inhibitors of mycotoxin production are useful not only for developing effective methods to prevent mycotoxin contamination, but also for investigating the molecular mechanisms of secondary metabolite production by fungi. We have been searching for mycotoxin production inhibitors among natural products and investigating their modes of action. In this article, we review aflatoxin and trichothecene production inhibitors, including our works on blasticidin S, methyl syringate, cyclo(L-Ala-L-Pro), respiration inhibitors, and precocene II.

  15. Mode of Action for Natural Products Isolated From Essential Oils of Two Trees Is Different From Available Mosquito Adulticides

    Science.gov (United States)

    2010-01-01

    chemicals currently used in mosquito control. KEY WORDS mode of action, mosquitoes, nookatone, thymoquinone, carvacrol Commercial insecticides used in...food (Tetra Holding, Blacksburg, VA). Pupae produced in a single day were separated from larvae in cohorts of 600 and put into 35- by 35- by 35-cm...ofAedes aegypti, Culex quinquefasciatusSay, andAnopheles quadri- maculatus Say to 19 pesticides with different modes of action. J. Med. Entomol. 45: 82Ð87

  16. A quantitative weight of evidence assessment of confidence in modes-of-action and their human relevance.

    Science.gov (United States)

    Dekant, Wolfgang; Bridges, James; Scialli, Anthony R

    2017-08-22

    A quantitative weight of evidence (QWoE) methodology was developed to assess confidence in postulated mode(s) of action for adverse effects in animal toxicity studies. The QWoE is appropriate for assessing adverse effects as relevant endpoints for classification and labeling purposes. The methodology involves definition of mode of actions and scoring supporting data for all key steps using predefined criteria for quality and relevance/strength of effects. Scores for all key steps are summarized, and the summary score is compared to the maximal achievable score for the mode of action. The ratio of the summary score to the maximal achievable scores gives an indication of confidence in a specific mode of action in animals. The mode of action in animals with highest confidence is then taken forward to assess appropriateness to humans. If one of the key steps cannot occur in humans, the mode of action is not relevant to humans. The methodology developed is applied to four case studies. Copyright © 2017. Published by Elsevier Inc.

  17. Mode of Action of the Natural Insecticide, Decaleside Involves Sodium Pump Inhibition

    Science.gov (United States)

    Rajashekar, Yallappa; Shivanandappa, Thimmappa

    2017-01-01

    Decalesides are a new class of natural insecticides which are toxic to insects by contact via the tarsal gustatory chemosensilla. The symptoms of their toxicity to insects and the rapid knockdown effect suggest neurotoxic action, but the precise mode of action and the molecular targets for decaleside action are not known. We have presented experimental evidence for the involvement of sodium pump inhibition in the insecticidal action of decaleside in the cockroach and housefly. The knockdown effect of decaleside is concomitant with the in vivo inhibition of Na+, K+ -ATPase in the head and thorax. The lack of insecticidal action by experimental ablation of tarsi or blocking the tarsal sites with paraffin correlated with lack of inhibition of Na+- K+ ATPase in vivo. Maltotriose, a trisaccharide, partially rescued the toxic action of decaleside as well as inhibition of the enzyme, suggesting the possible involvement of gustatory sugar receptors. In vitro studies with crude insect enzyme preparation and purified porcine Na+, K+ -ATPase showed that decaleside competitively inhibited the enzyme involving the ATP binding site. Our study shows that the insecticidal action of decaleside via the tarsal gustatory sites is causally linked to the inhibition of sodium pump which represents a unique mode of action. The precise target(s) for decaleside in the tarsal chemosensilla and the pathway linked to inhibition of sodium pump and the insecticidal action remain to be understood. PMID:28125742

  18. EFFICACY AND MODES OF ACTION OF RESISTANCE INDUCERS ON TWO WHEAT SPECIES AGAINST MYCOSPHAERELLA GRAMINICOLA.

    Science.gov (United States)

    Somai-Jemmali, L; Randoux, B; Siah, A; Ors, M; Halama, P; Reignault, Ph; Hamada, W

    2014-01-01

    Plant resistance inducers could be an alternative to conventional fungicides to control in a more durable and environmentally friendly manner fungal pathogens. Here, we tested the protection efficacy and the modes of action of four resistance inducers (R1, R2, R3 and R4) against the causal agent of Septoria tritici blotch, Mycosphaerella graminicola, the most frequently occurring pathogen on wheat crops worldwide. The four inducers were tested on two wheat cultivars, Premio (a French bread wheat cultivar) and Karim (a Tunisian durum wheat cultivar), each inoculated with a bread-wheat or a durum-wheat adapted isolate; respectively. All inducers exhibited in the greenhouse a significant protection level on both cultivars regarding disease symptoms (necrosis and chlorosis) and sporulation (pycnidium density). The most efficient inducer was R3 which showed 84% symptom reduction, while the less efficient one was R2 with only a 39% reduction. None of the studied inducers showed direct biocide effect against the fungus, except R4 which displayed a significant in planta inhibition of spore germination. Further investigations revealed that all inducers elicited the plant defence enzymes peroxidase and lipoxygenase, but the activity levels varied depending on the considered inducer. In addition, the effect of resistance inducers on the infection process and the fungal cell-wall degrading enzymes xylanases and glucanases was also investigated. Our study allowed us to find out four efficient resistance inducers on wheat against M. graminicola and to establish data about the modes of action of these inducers.

  19. Analysis of genotoxicity and the carcinogenic mode of action for ortho-phenylphenol.

    Science.gov (United States)

    Brusick, David

    2005-06-01

    Ortho-phenylphenol (OPP) and its sodium salt (SOPP) are commercial products that have wide human exposure and have been shown in several studies to be rodent carcinogens. Genetic toxicology data were assessed in an attempt to understand the carcinogenic mode of action of OPP and SOPP. More than 130 studies were evaluated to determine if OPP, SOPP, or any of their enzymatic or nonenzymatic breakdown products react directly with DNA to induce mutation, changes in chromosome structure or number, DNA repair, or nonspecific DNA damage including strand breakage or covalent binding. The genotoxicity databases for OPP and SOPP are not only large but heterogeneous, requiring weight-of-evidence methods to arrive at a conclusion regarding their genotoxic properties and potential. Evidence derived from the available studies leads to the conclusion that study results showing OPP/SOPP directly interacting with DNA are equivocal. Clastogenicity was the most consistent type of genetic toxicity produced by OPP/SOPP (and their break-down products) and was consistently associated with other intracellular preneoplastic toxicity produced at super-threshold concentrations. The weight of evidence from the combined database supports the hypothesis that OPP/SOPP-induced DNA damage is a threshold-dependent response associated with target tissue toxicity, most likely induced by their breakdown products phenylhydroquinone and phenylbenzoquinone. It is possible that this threshold-dependent clastogenicity could contribute to the carcinogenic mode of action for OPP or SOPP.

  20. Synergy and Mode of Action of Ceftazidime plus Quercetin or Luteolin on Streptococcus pyogenes

    Directory of Open Access Journals (Sweden)

    Supatcharee Siriwong

    2015-01-01

    Full Text Available Streptococcus pyogenes causes streptococcal toxic shock syndrome. The recommended therapy has been often failure through the interfering of beta-lactamase-producing bacteria (BLPB. The present study was to investigate antibacterial activity, synergy, and modes of action of luteolin and quercetin using alone and plus ceftazidime against S. pyogenes. The MICs of ceftazidime, luteolin, and quercetin against all S. pyogenes were 0.50, 128, and 128 µg mL−1, respectively. A synergistic effect was exhibited on luteolin and quercetin plus ceftazidime against these strains at fractional inhibitory concentration indices 0.37 and 0.27, respectively, and was confirmed by the viable count. These combinations increased cytoplasmic membrane (CM permeability, caused irregular cell shape, peptidoglycan, and CM damage, and decreased nucleic acid but increased proteins in bacterial cells. Enzyme assay demonstrated that these flavonoids had an inhibitory activity against β-lactamase. In summary, this study provides evidence that the inhibitory mode of action of luteolin and quercetin may be mediated via three mechanisms: (1 inhibiting of peptidoglycan synthesis, (2 increasing CM permeability, and (3 decreasing nucleic acid but increasing the protein contents of bacterial cells. So, luteolin and quercetin propose the high potential to develop adjunct to ceftazidime for the treatment of coexistence of the BLPB and S. pyogenes infections.

  1. Perfluoroalkyl acids and related chemistries--toxicokinetics and modes of action.

    Science.gov (United States)

    Andersen, Melvin E; Butenhoff, John L; Chang, Shu-Ching; Farrar, David G; Kennedy, Gerald L; Lau, Christopher; Olsen, Geary W; Seed, Jennifer; Wallace, Kendall B

    2008-03-01

    The perfluoroalkyl acid salts (both carboxylates and sulfonates, hereafter designated as PFAAs) and their derivatives are important chemicals that have numerous consumer and industrial applications. However, recent discoveries that some of these compounds have global distribution, environmental persistence, presence in humans and wildlife, as well as toxicity in laboratory animal models, have generated considerable scientific, regulatory, and public interest on an international scale. The Society of Toxicology Contemporary Concepts in Toxicology Symposium, entitled "Perfluoroalkyl Acids and Related Chemistries: Toxicokinetics and Modes-of-Action Workshop" was held February 14-16, 2007 at the Westin Arlington Gateway, Arlington, VA. In addition to the Society of Toxicology, this symposium was sponsored by 3M Company, DuPont, Plastics Europe, and the U.S. Environmental Protection Agency. The objectives of this 3-day meeting were to (1) provide an overview of PFAA toxicity and description of recent findings with the sulfonates, carboxylates, and telomer alcohols; (2) address the toxicokinetic profiles of various PFAAs among animal models and humans, and the biological processes that are responsible for these observations; (3) examine the possible modes of action that determine the PFAA toxicities observed in animal models, and their relevance to human health risks; and (4) identify the critical research needs and strategies to fill the existing informational gaps that hamper risk assessment of these chemicals. This report summarizes the discourse that occurred during the symposium.

  2. Mode of action of lactococcin R produced by Lactococcus lactis R.

    Science.gov (United States)

    Yildirim, Zeliha; Yildirim, Metin; Johnson, Michael G

    2004-04-01

    We investigated the mode of action and factors affecting adsorption of lactoccocin R produced by Lactococcus lactis R. It was found that lactococcin R adsorbed to all Gram-positive but not to the Gram-negative bacteria tested and its adsorption was dependent on pH. It was observed that the binding of lactococcin R was prevented by anions of several salts (Cl-, PO4(-3)) and lipoteichoic acid. Pretreatments of sensitive cells and cell walls with detergents, organic solvents or enzymes did not reduce subsequent binding of lactococcin R. However, treatment of cell wall preparations with methanol:chloroform and hot 20% trichloroacetic acid (TCA) caused such walls to lose their ability to adsorb lactococcin R. Sensitive cells treated with lactococcin R lost high amounts of intracellular K+ ions, UV-absorbing materials and became more permeable to o-nitrophenol-beta-D-glactopyranoside (ONPG). In addition, different lactococcin R concentrations (0-2560 AU/mL) decreased the colony counts of Listeria monocytogenes by 99% and also a reduction in the absorbance values. These results show that the mode of action of lactococcin R is bactericidal rather than bacteriostatic.

  3. Mode of action and functional significance of 7alpha-hydroxypregnenolone stimulating locomotor activity

    Directory of Open Access Journals (Sweden)

    Shogo eHaraguchi

    2011-08-01

    Full Text Available Previous studies over the past two decades have demonstrated that the brain and other nervous systems possess key steroidogenic enzymes and produces pregnenolone and other various neurosteroids in vertebrates in general. Recently, 7alpha-hydroxypregnenolone, a novel bioactive neurosteroid, was identified in the brain of newts and quail. Importantly, this novel neurosteroid is produced from pregnenolone through the enzymatic activity of cytochrome P4507alpha and acts on brain tissue as a neuronal modulator to stimulate locomotor activity in these vertebrates. Subsequently, the mode of action of 7alpha-hydroxypregnenolone was demonstrated. 7alpha-Hydroxypregnenolone stimulates locomotor activity through activation of the dopaminergic system. To understand the functional significance of 7alpha-hydroxypregnenolone in the regulation of locomotor activity, diurnal and seasonal changes in 7alpha-hydroxypregnenolone synthesis were further characterized. Melatonin derived from the pineal gland and eyes regulates 7alpha-hydroxypregnenolone synthesis in the brain, thus inducing diurnal locomotor changes. Prolactin, an adenohypophyseal hormone, regulates 7alpha-hydroxypregnenolone synthesis in the brain, and also induces seasonal locomotor changes. In addition, 7alpha-hydroxypregnenolone mediates corticosterone action to modulate locomotor activity under stress. This review summarizes the current knowledge regarding the mode of action and functional significance of 7alpha-hydroxypregnenolone, a newly identified bioactive neurosteroid stimulating locomotor activity.

  4. Acetylcholinesterase in Biofouling Species: Characterization and Mode of Action of Cyanobacteria-Derived Antifouling Agents.

    Science.gov (United States)

    Almeida, Joana R; Freitas, Micaela; Cruz, Susana; Leão, Pedro N; Vasconcelos, Vitor; Cunha, Isabel

    2015-07-24

    Effective and ecofriendly antifouling (AF) compounds have been arising from naturally produced chemicals. The objective of this study is to use cyanobacteria-derived agents to investigate the role of acetylcholinesterase (AChE) activity as an effect and/or mode of action of promising AF compounds, since AChE inhibitors were found to inhibit invertebrate larval settlement. To pursue this objective, in vitro quantification of AChE activity under the effect of several cyanobacterial strain extracts as potential AF agents was performed along with in vivo AF (anti-settlement) screening tests. Pre-characterization of different cholinesterases (ChEs) forms present in selected tissues of important biofouling species was performed to confirm the predominance of AChE, and an in vitro AF test using pure AChE activity was developed. Eighteen cyanobacteria strains were tested as source of potential AF and AChE inhibitor agents. Results showed effectiveness in selecting promising eco-friendly AF agents, allowing the understanding of the AF biochemical mode of action induced by different compounds. This study also highlights the potential of cyanobacteria as source of AF agents towards invertebrate macrofouling species.

  5. Multiple Modes of Action of the Squamocin in the Midgut Cells of Aedes aegypti Larvae

    Science.gov (United States)

    de Paula, Sérgio Oliveira; Martins, Gustavo Ferreira; Zanuncio, José Cola

    2016-01-01

    Annonaceous acetogenins are botanical compounds with good potential for use as insecticides. In the vector, Aedes aegypti (L.) (Diptera: Culicidae), squamocin (acetogenin) has been reported to be a larvicide and cytotoxic, but the modes of action of this molecule are still poorly understood. This study evaluated the changes in the cell morphology, and in the expression of genes, for autophagy (Atg1 and Atg8), for membrane ion transporter V-ATPase, and for water channel aquaporin-4 (Aqp4) in the midgut of A. aegypti larvae exposed to squamocin from Annona mucosa Jacq. (Annonaceae). Squamocin showed cytotoxic action with changes in the midgut epithelium and digestive cells of A. aegypti larvae, increase in the expression for autophagy gene Atg1 and Atg8, decrease in the expression of V-ATPase, decrease in the expression of Aqp4 gene in LC20 and inhibition of Apq4 genes in the midgut of this vector in LC50. These multiple modes of action for squamocin are described for the first time in insects, and they are important because different sites of action of squamocin from A. mucosa may reduce the possibility of resistance of A. aegypti to this molecule. PMID:27532504

  6. Mode of Action of Lactoperoxidase as Related to Its Antimicrobial Activity: A Review

    Directory of Open Access Journals (Sweden)

    F. Bafort

    2014-01-01

    Full Text Available Lactoperoxidase is a member of the family of the mammalian heme peroxidases which have a broad spectrum of activity. Their best known effect is their antimicrobial activity that arouses much interest in in vivo and in vitro applications. In this context, the proper use of lactoperoxidase needs a good understanding of its mode of action, of the factors that favor or limit its activity, and of the features and properties of the active molecules. The first part of this review describes briefly the classification of mammalian peroxidases and their role in the human immune system and in host cell damage. The second part summarizes present knowledge on the mode of action of lactoperoxidase, with special focus on the characteristics to be taken into account for in vitro or in vivo antimicrobial use. The last part looks upon the characteristics of the active molecule produced by lactoperoxidase in the presence of thiocyanate and/or iodide with implication(s on its antimicrobial activity.

  7. Membrane Active Peptides: Modes-of-Action, Phase Transitions, and Supramolecular Assemblies

    Science.gov (United States)

    Huang, Huey W.

    1997-03-01

    Recent discoveries showed that 20-40 amino-acid peptides are used as very effective antimicrobials in the host-defense systems throughout the animal kingdom, including human. What distinguishes these peptide antimicrobials from the conventional antibiotics is that they attack the lipid matrix of the cytoplasmic membranes rather than protein targets. So the central questions are what are their modes-of-action and how do their distinguish the bacterial cell membranes from the host-cell membranes? Many of these peptides have very simple structures--they are helices with amphiphilic side chains. Despite such simplicities, their interactions with membranes are complex and interesting. The talk will discuss the optical, x-ray and neutron techniques for studying such systems and the experimental as well as theoretical results. The mode-of-action is a phase transition controlled by the concentration of the peptide bound to the membrane. The specificities with respect to membranes are achieved by having different critical concentrations for different lipid composistions of the membrane.

  8. Using mode of action information to improve regulatory decision-making: an ECETOC/ILSI RF/HESI workshop overview.

    Science.gov (United States)

    Carmichael, Neil; Bausen, Melanie; Boobis, Alan R; Cohen, Samuel M; Embry, Michelle; Fruijtier-Pölloth, Claudia; Greim, Helmut; Lewis, Richard; Bette Meek, M E; Mellor, Howard; Vickers, Carolyn; Doe, John

    2011-03-01

    The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the International Life Sciences Institute (ILSI) Research Foundation (RF), and the ILSI Health and Environmental Sciences Institute (HESI) hosted a workshop in November 2009 to review current practice in the application of mode of action (MOA) considerations in chemical risk assessment. The aim was to provide a rationale for a more general, but flexible approach and to propose steps to facilitate broader uptake and use of the MOA concept. There was consensus amongst the workshop participants that it will require substantial effort and cooperation from the multiple disciplines involved to embrace a common, consistent, and transparent approach. Setting up a repository of accepted MOAs and associated guidance concerning appropriate data to support specific MOAs for critical effects would facilitate categorization of chemicals and allow predictions of toxicity outcomes by read-across. This should in future contribute to the reduction of toxicity testing in animals. The workshop participants also acknowledged the value and importance of human data and the importance of integrating information from biological pathway analyses into current MOA/human relevance frameworks.

  9. Reconsidering the nature and mode of action of metabolite retrograde signals from the chloroplast

    Directory of Open Access Journals (Sweden)

    Gonzalo Martín Estavillo

    2013-01-01

    Full Text Available Plant organelles produce retrograde signals to alter nuclear gene expression in order to coordinate their biogenesis, maintain homeostasis or optimize their performance under adverse conditions. Many signals of different chemical nature have been described in the past decades, including chlorophyll intermediates, reactive oxygen species and adenosine derivatives. While the effects of retrograde signalling on gene expression are well understood, the initiation and transport of the signals and their mode of action have either not been resolved, or are a matter of speculation. Moreover, retrograde signalling should be consider as part of a broader cellular network, instead of as separate pathways, required to adjust to changing physiologically relevant conditions. Here we summarize current plastid retrograde signalling models in plants, with a focus on new signalling pathways, SAL1-PAP, MEcPP and β- cyclocitral, and outline missing links or future areas of research that we believe need to be addressed to have a better understanding of plant intracellular signalling networks.

  10. Sulfoxaflor and the sulfoximine insecticides: chemistry, mode of action and basis for efficacy on resistant insects.

    Science.gov (United States)

    Sparks, Thomas C; Watson, Gerald B; Loso, Michael R; Geng, Chaoxian; Babcock, Jon M; Thomas, James D

    2013-09-01

    The sulfoximines, as exemplified by sulfoxaflor ([N-[methyloxido[1-[6-(trifluoromethyl)-3-pyridinyl]ethyl]-λ(4)-sulfanylidene] cyanamide] represent a new class of insecticides. Sulfoxaflor exhibits a high degree of efficacy against a wide range of sap-feeding insects, including those resistant to neonicotinoids and other insecticides. Sulfoxaflor is an agonist at insect nicotinic acetylcholine receptors (nAChRs) and functions in a manner distinct from other insecticides acting at nAChRs. The sulfoximines also exhibit structure activity relationships (SAR) that are different from other nAChR agonists such as the neonicotinoids. This review summarizes the sulfoximine SAR, mode of action and the biochemistry underlying the observed efficacy on resistant insect pests, with a particular focus on sulfoxaflor.

  11. Dual mode of action of Bt proteins: protoxin efficacy against resistant insects.

    Science.gov (United States)

    Tabashnik, Bruce E; Zhang, Min; Fabrick, Jeffrey A; Wu, Yidong; Gao, Meijing; Huang, Fangneng; Wei, Jizhen; Zhang, Jie; Yelich, Alexander; Unnithan, Gopalan C; Bravo, Alejandra; Soberón, Mario; Carrière, Yves; Li, Xianchun

    2015-10-12

    Transgenic crops that produce Bacillus thuringiensis (Bt) proteins for pest control are grown extensively, but insect adaptation can reduce their effectiveness. Established mode of action models assert that Bt proteins Cry1Ab and Cry1Ac are produced as inactive protoxins that require conversion to a smaller activated form to exert toxicity. However, contrary to this widely accepted paradigm, we report evidence from seven resistant strains of three major crop pests showing that Cry1Ab and Cry1Ac protoxins were generally more potent than the corresponding activated toxins. Moreover, resistance was higher to activated toxins than protoxins in eight of nine cases evaluated in this study. These data and previously reported results support a new model in which protoxins and activated toxins kill insects via different pathways. Recognizing that protoxins can be more potent than activated toxins against resistant insects may help to enhance and sustain the efficacy of transgenic Bt crops.

  12. Modes of action of fraxinellone against the tobacco budworm,Heliothis virescens

    Institute of Scientific and Technical Information of China (English)

    Zhi Long Liu; Shuit Hung Ho; Swee Hock Goh

    2009-01-01

    Fraxinellone significantly reduced the relative growth rate, food consumption rate as well as the efficiency of conversion of ingested food into biomass of Heliothis virescens when incorporated into artificial diets at concentrations of 4.31 × 10-5 mol/L and above. After being fed with fraxinellone-treated diets for 24 h, the larval midguts of H. virescens possess significantly lower activities of a-amylase and non-specific proteases and higher activities ofcytochrome P450s. In vitro, the compound did not inhibit the activities of α-amylase and non-specific proteases extracted from the larval midguts. Clear evidence of post-ingestive toxicity of fraxinellone to midgut cells was observed under an electron microscope. The modes of action of the compound against insects were discussed.

  13. Probiotics as beneficial microbes in aquaculture: an update on their multiple modes of action: a review

    DEFF Research Database (Denmark)

    Zorriehzahra, Mohammad Jalil; Delshad, Somayeh Torabi; Adel, Milad

    2016-01-01

    Wide and discriminate use of antibiotics has resulted in serious biological and ecological concerns, especially the emergence of antibiotic resistance. Probiotics, known as beneficial microbes, are being proposed as an effective and eco-friendly alternative to antibiotics. They were first applied...... in aquaculture species more than three decades ago, but considerable attention had been given only in the early 2000s. Probiotics are defined as live or dead, or even a component of the microorganisms that act under different modes of action in conferring beneficial effects to the host or to its environment....... Several probiotics have been characterized and applied in fish and a number of them are of host origin. Unlike some disease control alternatives being adapted and proposed in aquaculture where actions are unilateral, the immense potential of probiotics lies on their multiple mechanisms in conferring...

  14. Nanovesicle encapsulation of antimicrobial peptide P34: physicochemical characterization and mode of action on Listeria monocytogenes

    Science.gov (United States)

    da Silva Malheiros, Patrícia; Sant'Anna, Voltaire; Micheletto, Yasmine Miguel Serafini; da Silveira, Nadya Pesce; Brandelli, Adriano

    2011-08-01

    Antimicrobial peptide P34, a substance showing antibacterial activity against pathogenic and food spoilage bacteria, was encapsulated in liposomes prepared from partially purified soybean phosphatidylcholine, and their physicochemical characteristics were evaluated. The antimicrobial activity was estimated by agar diffusion assay using Listeria monocytogenes ATCC 7644 as indicator strain. A concentration of 3,200 AU/mL of P34 was encapsulated in nanovesicles and stocked at 4 °C. No significant difference ( p > 0.05) in the biological activity of free and encapsulated P34 was observed through 24 days. Size and PDI of liposomes, investigated by light scattering analysis, were on average 150 nm and 0.22 respectively. Zeta potential was -27.42 mV. There was no significant change ( p > 0.05) in the physicochemical properties of liposomes during the time of evaluation. The liposomes presented closed spherical morphology as visualized by transmission electron microscopy (TEM). The mode of action of liposome-encapsulated P34 under L. monocytogenes cells was investigated by TEM. Liposomes appeared to adhere but not fuse with the bacterial cell wall, suggesting that the antimicrobial is released from nanovesicles to act against the microorganism. The effect of free and encapsulated P34 was tested against L. monocytogenes, showing that free bacteriocin inhibited the pathogen more quickly than the encapsulated P34. Liposomes prepared with low-cost lipid showed high encapsulation efficiency for a new antimicrobial peptide and were stable during storage. The mode of action against the pathogen L. monocytogenes was characterized.

  15. Effectiveness and mode of action of whitening dentifrices on enamel extrinsic stains.

    Science.gov (United States)

    Alshara, Salem; Lippert, Frank; Eckert, George J; Hara, Anderson T

    2014-01-01

    This study was conducted in order to investigate the mode of action and the whitening effect of whitening dentifrices. Two hundred fifty-six bovine enamel specimens (10 × 10 mm(2)) were prepared, partially stained, and assigned into eight groups (n = 32): six whitening dentifrices, one nonwhitening and deionized water (negative control), and further divided in two subgroups (n = 16), according to the test model: chemical (dentifrice slurry treatment only) or chemo-mechanical (slurry + toothbrushing). Specimens were treated with dentifrice slurries 2 ×/day for 1 min and toothbrushed or not, according to each model. In between dentifrice treatments, specimens were artificially stained for 5 h. This protocol was repeated for 5 days and enamel color changes (∆E) were measured after each day (days 1-5). The abrasive level of the dentifrices was determined following the ISO11609 guidelines. In the chemo-mechanical model, the whitening action of all dentifrices was observed after day 1, being higher than the negative control group (p 0.05). Differences on ∆E among dentifrices were observed, and they seemed to correlate well with their abrasive level (r(2) = 0.80). In the chemical model, no significant differences were observed among groups (p > 0.05), with ∆E remaining constant throughout the study. Higher ∆E values were observed in the chemo-mechanical model compared to the chemical (p dentifrices were effective in whitening stained enamel and their mode of action showed to be mainly mechanical (toothbrushing abrasion). The abrasive level of dentifrices seems to determine its whitening effectiveness.

  16. EEG alpha activity reflects motor preparation rather than the mode of action selection.

    Science.gov (United States)

    Deiber, Marie-Pierre; Sallard, Etienne; Ludwig, Catherine; Ghezzi, Catherine; Barral, Jérôme; Ibañez, Vicente

    2012-01-01

    Alpha-band activity (8-13 Hz) is not only suppressed by sensory stimulation and movements, but also modulated by attention, working memory and mental tasks, and could be sensitive to higher motor control functions. The aim of the present study was to examine alpha oscillatory activity during the preparation of simple left or right finger movements, contrasting the external and internal mode of action selection. Three preparation conditions were examined using a precueing paradigm with S1 as the preparatory and S2 as the imperative cue: Full, laterality instructed by S1; Free, laterality freely selected and None, laterality instructed by S2. Time-frequency (TF) analysis was performed in the alpha frequency range during the S1-S2 interval, and alpha motor-related amplitude asymmetries (MRAA) were also calculated. The significant MRAA during the Full and Free conditions indicated effective external and internal motor response preparation. In the absence of specific motor preparation (None), a posterior alpha event-related desynchronization (ERD) dominated, reflecting the main engagement of attentional resources. In Full and Free motor preparation, posterior alpha ERD was accompanied by a midparietal alpha event-related synchronization (ERS), suggesting a concomitant inhibition of task-irrelevant visual activity. In both Full and Free motor preparation, analysis of alpha power according to MRAA amplitude revealed two types of functional activation patterns: (1) a motor alpha pattern, with predominantly midparietal alpha ERS and large MRAA corresponding to lateralized motor activation/visual inhibition and (2) an attentional alpha pattern, with dominating right posterior alpha ERD and small MRAA reflecting visuospatial attention. The present results suggest that alpha oscillatory patterns do not resolve the selection mode of action, but rather distinguish separate functional strategies of motor preparation.

  17. EEG alpha activity reflects motor preparation rather than the mode of action selection

    Directory of Open Access Journals (Sweden)

    Marie-Pierre eDeiber

    2012-08-01

    Full Text Available Alpha-band activity (8-13 Hz is suppressed by sensory stimulation and movements, modulated by attention, working memory and mental tasks and may be sensitive to higher motor control functions. The aim of the present study was to examine alpha oscillatory activity during the preparation of simple left or right finger movements, contrasting the external and internal mode of action selection. Three preparation conditions were examined using a precueing paradigm with S1 as the preparatory and S2 as the imperative cue: Full, laterality instructed by S1; Free, laterality freely selected and None, laterality instructed by S2. Time-frequency analysis was performed in the alpha frequency range during the S1-S2 interval, and alpha motor-related amplitude asymmetries (MRAA were also calculated. The significant MRAA during the Full and Free conditions indicated effective external and internal motor response preparation. In the absence of specific motor preparation (None, a posterior alpha power decrease (event-related desynchronization, ERD dominated, reflecting the main engagement of attentional resources. In Full and Free motor preparation, posterior alpha ERD was accompanied by a midparietal alpha power increase (event-related synchronization, ERS, suggesting a concomitant inhibition of task-irrelevant visual activity. In both Full and Free motor preparation, analysis of alpha power according to MRAA amplitude revealed two types of functional activation patterns: 1 a motor alpha pattern, with predominantly midparietal alpha ERS and large MRAA corresponding to lateralized motor activation/visual inhibition and 2 an attentional alpha pattern, with dominating right posterior alpha ERD and small MRAA reflecting visuospatial attention. The present results suggest that alpha oscillatory patterns do not resolve the selection mode of action, but rather distinguish separate functional strategies of motor preparation. 

  18. An exploratory investigation of various modes of action and potential adverse outcomes of fluoxetine in marine mussels

    Energy Technology Data Exchange (ETDEWEB)

    Franzellitti, Silvia, E-mail: silvia.franzellitti@unibo.it [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); University of Bologna, Department of Biological, Geological, and Environmental Sciences, via Selmi 3, 40100 Bologna (Italy); Buratti, Sara; Capolupo, Marco [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); Du, Bowen; Haddad, Samuel P. [Department of Environmental Science, Baylor University, Waco, TX 76798 (United States); Chambliss, C. Kevin [Department of Chemistry and Biochemistry, Baylor University, Waco, TX 76798 (United States); Brooks, Bryan W. [Department of Environmental Science, Baylor University, Waco, TX 76798 (United States); Fabbri, Elena [University of Bologna, Interdepartment Centre for Environmental Science Research, via S. Alberto 163, 48123 Ravenna (Italy); University of Bologna, Department of Biological, Geological, and Environmental Sciences, via Selmi 3, 40100 Bologna (Italy)

    2014-06-01

    Highlights: • Mode of action (MOA) related endpoints and biomarkers of toxicity were assessed in mussels exposed to fluoxetine (FX). • Significant FX bioaccumulation was observed in tissues of mussels exposed to 30 and 300 ng/L FX. • Alterations of cAMP-related cell signaling were observed in exposed mussels as part of the MOA of FX. • FX reduced the health status of mussels inducing lysosomal effects in digestive gland and antioxidant responses in gills. • The importance of considering additional MOAs and adverse outcome pathways for FX impacts on mussels is highlighted. - Abstract: The present study investigated possible adverse outcome pathways (AOPs) of the antidepressant fluoxetine (FX) in the marine mussel Mytilus galloprovincialis. An evaluation of molecular endpoints involved in modes of action (MOAs) of FX and biomarkers for sub-lethal toxicity were explored in mussels after a 7-day administration of nominal FX concentrations encompassing a range of environmentally relevant values (0.03–300 ng/L). FX bioaccumulated in mussel tissues after treatment with 30 and 300 ng/L FX, resulting in bioconcentration factor (BCF) values ranging from 200 to 800, which were higher than expected based solely on hydrophobic partitioning models. Because FX acts as a selective serotonin (5-HT) re-uptake inhibitor increasing serotonergic neurotransmission at mammalian synapses, cell signaling alterations triggered by 5-HT receptor occupations were assessed. cAMP levels and PKA activities were decreased in digestive gland and mantle/gonads of FX-treated mussels, consistent with an increased occupation of 5-HT1 receptors negatively coupled to the cAMP/PKA pathway. mRNA levels of a ABCB gene encoding the P-glycoprotein were also significantly down-regulated. This membrane transporter acts in detoxification towards xenobiotics and in altering pharmacokinetics of antidepressants; moreover, it is under a cAMP/PKA transcriptional regulation in mussels. Potential stress

  19. Development of linear and threshold no significant risk levels for inhalation exposure to titanium dioxide using systematic review and mode of action considerations.

    Science.gov (United States)

    Thompson, Chad M; Suh, Mina; Mittal, Liz; Wikoff, Daniele S; Welsh, Brian; Proctor, Deborah M

    2016-10-01

    Titanium dioxide (TiO2) has been characterized as a poorly soluble particulate (PSP) with low toxicity. It is well accepted that low toxicity PSPs such as TiO2 induce lung tumors in rats when deposition overwhelms particle clearance mechanisms. Despite the sensitivity of rats to PSPs and questionable relevance of PSP-induced tumors to humans, TiO2 is listed as a possible human carcinogen by some agencies and regulators. Thus, environmental toxicity criteria for TiO2 are needed for stakeholders to evaluate potential risks from environmental exposure and regulatory compliance. A systematic review of the literature was conducted to characterize the available data and identify candidate datasets upon which toxicity values could be derived. Key to this assessment, a survey of mechanistic data relevant for lung cancer was used to support quantitative inhalation risk assessment approaches. A total of 473 human studies were identified, 7 of which were epidemiological studies that met inclusion criteria to quantitatively characterize carcinogenic endpoints in humans. None of these studies supported derivation of toxicity criteria; therefore, animal data were used to derived safety values for TiO2 using different dose-metrics (regional deposited dose ratios, TiO2 particle surface area lung burden, and volumetric overload of alveolar macrophages), benchmark dose modeling, and different low-dose extrapolation approaches. Based on empirical evidence and mechanistic support for nonlinear mode of action involving particle overload, chronic inflammation and cell proliferation, a no significant risk level (NSRL) of 300 μg/day was derived. By comparison, low-dose linear extrapolation from tumor incidence in the rat lung resulted in an NSRL value of 44 μg/day. These toxicity values should be useful for stakeholders interested in assessing risks from environmental exposure to respirable TiO2.

  20. Differential scanning fluorometry signatures as indicators of enzyme inhibitor mode of action: case study of glutathione S-transferase.

    Directory of Open Access Journals (Sweden)

    Wendy A Lea

    Full Text Available Differential scanning fluorometry (DSF, also referred to as fluorescence thermal shift, is emerging as a convenient method to evaluate the stabilizing effect of small molecules on proteins of interest. However, its use in the mechanism of action studies has received far less attention. Herein, the ability of DSF to report on inhibitor mode of action was evaluated using glutathione S-transferase (GST as a model enzyme that utilizes two distinct substrates and is known to be subject to a range of inhibition modes. Detailed investigation of the propensity of small molecule inhibitors to protect GST from thermal denaturation revealed that compounds with different inhibition modes displayed distinct thermal shift signatures when tested in the presence or absence of the enzyme's native co-substrate glutathione (GSH. Glutathione-competitive inhibitors produced dose-dependent thermal shift trendlines that converged at high compound concentrations. Inhibitors acting via the formation of glutathione conjugates induced a very pronounced stabilizing effect toward the protein only when GSH was present. Lastly, compounds known to act as noncompetitive inhibitors exhibited parallel concentration-dependent trends. Similar effects were observed with human GST isozymes A1-1 and M1-1. The results illustrate the potential of DSF as a tool to differentiate diverse classes of inhibitors based on simple analysis of co-substrate dependency of protein stabilization.

  1. A Reexamination of the PPAR-α Activation Mode of Action as a Basis for Assessing Human Cancer Risks of Environmental Contaminants

    Science.gov (United States)

    Guyton, Kathryn Z.; Chiu, Weihsueh A.; Bateson, Thomas F.; Jinot, Jennifer; Scott, Cheryl Siegel; Brown, Rebecca C.; Caldwell, Jane C.

    2009-01-01

    Background Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator–activated receptor-α (PPAR-α) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-α agonists is irrelevant to human carcinogenic risk. Data synthesis Herein, we review recent studies that experimentally challenge the PPAR-α activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-α activation in a transgenic mouse model. We further examine whether relative potency for PPAR-α activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-α agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis. Conclusions Our review and analyses raise questions about the hypothesized PPAR-α activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-α agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-α. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation. PMID:20049115

  2. Mode of action of a family 75 chitosanase from Streptomyces avermitilis.

    Science.gov (United States)

    Heggset, Ellinor B; Tuveng, Tina R; Hoell, Ingunn A; Liu, Zhanliang; Eijsink, Vincent G H; Vårum, Kjell M

    2012-06-11

    Chitooligosaccharides (CHOS) are oligomers composed of glucosamine and N-acetylglucosamine with several interesting bioactivities that can be produced from enzymatic cleavage of chitosans. By controlling the degree of acetylation of the substrate chitosan, the enzyme, and the extent of enzyme degradation, CHOS preparations with limited variation in length and sequence can be produced. We here report on the degradation of chitosans with a novel family 75 chitosanase, SaCsn75A from Streptomyces avermitilis . By characterizing the CHOS preparations, we have obtained insight into the mode of action and subsite specificities of the enzyme. The degradation of a fully deacetylated and a 31% acetylated chitosan revealed that the enzyme degrade these substrates according to a nonprocessive, endo mode of action. With the 31% acetylated chitosan as substrate, the kinetics of the degradation showed an initial rapid phase, followed by a second slower phase. In the initial faster phase, an acetylated unit (A) is productively bound in subsite -1, whereas deacetylated units (D) are bound in the -2 subsite and the +1 subsite. In the slower second phase, D-units bind productively in the -1 subsite, probably with both acetylated and deacetylated units in the -2 subsite, but still with an absolute preference for deacetylated units in the +1 subsite. CHOS produced in the initial phase are composed of deacetylated units with an acetylated reducing end. In the slower second phase, higher amounts of low DP fully deacetylated oligomers (dimer and trimer) are produced, while the higher DP oligomers are dominated by compounds with acetylated reducing ends containing increasing amounts of internal acetylated units. The degradation of chitosans with varying degrees of acetylation to maximum extents of degradation showed that increasingly longer oligomers are produced with increasing degree of acetylation, and that the longer oligomers contain sequences of consecutive acetylated units

  3. IDENTIFICATION AND MODE OF ACTION OF ANTIBACTERIAL COMPONENTS FROM MELASTOMA MALABATHRICUM LINN LEAVES

    Directory of Open Access Journals (Sweden)

    Mourouge Saadi Alwash

    2013-01-01

    Full Text Available The present study aimed to assess the antibacterial activity of the methanol extract of Melastoma Malabathricum Leaves (MMML, active fraction of M. Malabathricum Leaves (ML5 and isolated kaempferol-3-O-(2",6"-di-O-p-trans-coumaroyl-β-glucopyranoside (Kf and to describe the preliminary mode of action against Gram-positive and Gram-negative bacteria. The MMML extract was fractionated by Vacuum Liquid Chromatography (VLC to afford M. malabathricum Leaves fractions (ML1-ML6 of increasing polarities. Bioassay-guided fractionation (direct-TLC bioautography revealed that fraction of M. Malabathricum Leaves (ML5 had the highest antibacterial activity. Therefore, the ML5 was further subjected to Column Chromatography (CC to afford Kaempferol-3-O-(2",6"-di-O-p-trans-coumaroyl-β-glucopyranoside (Kf. The compound structure was elucidated using data obtained from 1H NMR and 13C NMR spectra. Antibacterial activity of MMML, ML5 and bioactive constituents Kf against Staphylococcus aureus reference strain, Methicillin-Resistant S. aureus reference strain (MRSA, 11 clinical MRSA isolates, 3 clinical Pseudomonas aeruginosa isolates and P. aeruginosa reference strain was evaluated through disk diffusion method and Minimum Inhibitory Concentration (MIC. The time kill assay and field emission scanning electron microscopy was used to determine the preliminary mode of action. The data obtained from disk diffusion method and MIC showed that the MMML, ML5 and Kf showed antibacterial activity against all test bacteria with various values. Generally, the ML5 and Kf exhibited the highest antibacterial activity with the largest zones of inhibition and lowest MIC values against S. aureus and all tested MRSA. The MMML exerted the strongest killing effect against all tested bacteria while the overall performance of ML5 and Kf were significantly more effective against S. aureus and MRSA than P. aeruginosa. Field emission scanning electron microscopy revealed irregular

  4. Fluensulfone is a nematicide with a mode of action distinct from anticholinesterases and macrocyclic lactones.

    Science.gov (United States)

    Kearn, James; Ludlow, Elizabeth; Dillon, James; O'Connor, Vincent; Holden-Dye, Lindy

    2014-02-01

    Plant parasitic nematodes infest crops and present a threat to food security worldwide. Currently available chemical controls e.g. methyl bromide, organophosphates and carbamates have an unacceptable level of toxicity to non-target organisms and are being withdrawn from use. Fluensulfone is a new nematicide of the fluoroalkenyl thioether group that has significantly reduced environmental impact with low toxicity to non-target insects and mammals. Here, we show that the model genetic organism Caenorhabditis elegans is susceptible to the irreversible nematicidal effects of fluensulfone. Whilst the dose required is higher than that which has nematicidal activity against Meloidogyne spp. the profile of effects on motility, egg-hatching and survival is similar to that reported for plant parasitic nematodes. C. elegans thus provides a tractable experimental paradigm to analyse the effects of fluensulfone on nematode behaviour. We find that fluensulfone has pleiotropic actions and inhibits development, egg-laying, egg-hatching, feeding and locomotion. In the case of feeding and locomotion, an early excitation precedes the gross inhibition. The profile of these effects is notably distinct from other classes of anthelmintic and nematicide: the inhibition of motility caused by fluensulfone is not accompanied by the hypercontraction which is characteristic of organophosphates and carbamates and C. elegans mutants that are resistant to the carbamate aldicarb and the macrocyclic lactone ivermectin retain susceptibility to fluensulfone. These data indicate fluensulfone's mode of action is distinct from currently available nematicides and it therefore presents a promising new chemical entity for crop protection.

  5. Discovery and mode of action of afoxolaner, a new isoxazoline parasiticide for dogs.

    Science.gov (United States)

    Shoop, Wesley L; Hartline, Eric J; Gould, Brandon R; Waddell, Molly E; McDowell, Richard G; Kinney, John B; Lahm, George P; Long, Jeffrey K; Xu, Ming; Wagerle, Ty; Jones, Gail S; Dietrich, Robert F; Cordova, Daniel; Schroeder, Mark E; Rhoades, Daniel F; Benner, Eric A; Confalone, Pat N

    2014-04-02

    Afoxolaner is an isoxazoline compound characterized by a good safety profile and extended effectiveness against fleas and ticks on dogs following a single oral administration. In vitro membrane feeding assay data and in vivo pharmacokinetic studies in dogs established an afoxolaner blood concentration of 0.1-0.2 μg/ml to be effective against both fleas (Ctenocephalides felis) and ticks (Dermacentor variabilis). Pharmacokinetic profiles in dogs following a 2.5mg/kg oral dosage demonstrated uniform and predictable afoxolaner plasma concentrations above threshold levels required for efficacy for more than one month. Dose ranging and a 5-month multi-dose experimental study in dogs, established that the 2.5mg/kg oral dosage was highly effective against fleas and ticks, and produced predictable and reproducible pharmacokinetics following repeated dosing. Mode of action studies showed that afoxolaner blocked native and expressed insect GABA-gated chloride channels with nanomolar potency. Afoxolaner has comparable potency between wild type channels and channels possessing the A302S (resistance-to-dieldrin) mutation. Lack of cyclodiene cross-resistance for afoxolaner was confirmed in comparative Drosophila toxicity studies, and it is concluded that afoxolaner blocked GABA-gated chloride channels via a site distinct from the cyclodienes.

  6. The possible role of quinate in the mode of action of glyphosate and acetolactate synthase inhibitors.

    Science.gov (United States)

    Orcaray, Luis; Igal, María; Marino, Daniel; Zabalza, Ana; Royuela, Mercedes

    2010-03-01

    The herbicide glyphosate inhibits the biosynthesis of aromatic amino acids by blocking the shikimate pathway. Imazethapyr and chlorsulfuron are two herbicides that act by inhibiting branched-chain amino acid biosynthesis. These herbicides stimulate secondary metabolism derived from the aromatic amino acids. The aim of this study was to test if they cause any cross-effect in the amino acid content and if they have similar effects on the shikimate pathway. The herbicides inhibiting two different amino acid biosynthesis pathways showed a common pattern in general content of free amino acids. There was a general increase in total free amino acid content, with a transient decrease in the proportion of amino acids whose pathways were specifically inhibited. Afterwards, an increase in these inhibited amino acids was detected; this was probably related to proteolysis. All herbicides caused quinate accumulation. Exogenous application of quinate arrested growth, decreased net photosynthesis and stomatal conductance and was ultimately lethal, similarly to glyphosate and imazethapyr. Quinate accumulation was a common effect of the two different classes of herbicide. Moreover, exogenous quinate application had phytotoxic effects, showing that this plant metabolite can trigger the toxic effects of the herbicides. This ability to mimic the herbicide effects suggests a possible link between the mode of action of these herbicides and the potential role of quinate as a natural herbicide.

  7. Toward an understanding of the mode of action of fluoroquinolone drugs

    Science.gov (United States)

    Neugebauer, U.; Schmid, U.; Baumann, K.; Holzgrabe, U.; Schmitt, M.; Popp, J.

    2007-07-01

    Fluoroquinolones are important antibacterial drugs. They were found to interfere with the gyrase-DNA complex which causes cell death. However, the detailed mode of action on a molecular level is so far not understood. In this contribution Raman spectroscopy is chosen as a non-invasive technique to first characterize the individual involved components: fluoroquinolone drugs, and the biological targets DNA and gyrase; and second to study the influence of the fluoroquinolones on bacteria in in-vivo experiments. The use of UV resonance Raman spectroscopy with excitation at 244 nm allows the investigation of the drugs and the biological targets in aqueous solution at biological low concentrations (a few μM). Raman bands associated with the action of the enzyme gyrase could be identified in in-vitro mixing experiments. In-vivo experiments with bacteria experiencing varying drug concentrations revealed changes in the vibrational bands of the protein and DNA components within the bacterial cell caused by the action of the drug. Due to the complexity of the bacterial spectra advanced multivariate statistics in combination with variable selection methods proved to be useful in the data analysis.

  8. New insights into the mode of action of the lantibiotic salivaricin B

    Science.gov (United States)

    Barbour, Abdelahhad; Tagg, John; Abou-Zied, Osama K.; Philip, Koshy

    2016-01-01

    Salivaricin B is a 25 amino acid polycyclic peptide belonging to the type AII lantibiotics and first shown to be produced by Streptococcus salivarius. In this study we describe the bactericidal mode of action of salivaricin B against susceptible Gram-positive bacteria. The killing action of salivaricin B required micro-molar concentrations of lantibiotic whereas the prototype lantibiotic nisin A was shown to be potent at nano-molar levels. Unlike nisin A, salivaricin B did not induce pore formation or dissipate the membrane potential in susceptible cells. This was established by measuring the fluorescence of the tryptophan residue at position 17 when salivaricin B interacted with bacterial membrane vesicles. The absence of a fluorescence blue shift indicates a failure of salivaricin B to penetrate the membranes. On the other hand, salivaricin B interfered with cell wall biosynthesis, as shown by the accumulation of the final soluble cell wall precursor UDP-MurNAc-pentapeptide which is the backbone of the bacterial peptidoglycan. Transmission electron microscopy of salivaricin B-treated cells showed a reduction in cell wall thickness together with signs of aberrant septum formation in the absence of visible changes to cytoplasmic membrane integrity. PMID:27526944

  9. Hypothetical mode of action of earthworm extract with hepatoprotective and antioxidant properties

    Institute of Scientific and Technical Information of China (English)

    Mariappan BALAMURUGAN; Kasi PARTHASARATHI; Lalpet Souri RANGANATHAN; Edwin L. COOPER

    2008-01-01

    The hepatoprotective potential of earthworm extract (EE) (Lampito mauritii, Kinberg) was evaluated against paracetamol-induced liver injury in Wistar albino rat, in comparison with silymarin, the standard hepatoprotective drug. We observed a reduction in liver antioxidants, such as glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx),and catalase (CAT) and in serum total protein, and an increase in serum alkaline phosphatase (ALP), serum aspertate aminotranferase (AST), serum alanine aminotranferase (ALT), bilirubin and liver thiobarbituric acid reactive substances (TBARS) due to liver injury in the paracetamol-administered rats (2 g/kg). On the contrary, increased activities of liver GSH, SOD, GPx,CAT and serum total protein level, and decrease in the contents of serum ALP, AST, ALT, bilirubin and liver TBARS were observed in rats administered with different doses of EE (100, 200 and 300 mg/kg), which are similar to the activities of hepatoprotective drug silymarin (150 mg/kg). The mode of action of EE as evidenced by the above parameters may suggest that EE, on the one hand, prevents the formation of the reactive oxygen groups, or scavenges these groups, thereby preventing the damage on the hepatic cells, and, on the other hand, modulates the genes responsible for synthesis of antioxidant enzymes such as GPx, CAT and SOD in liver tissue and decreases the serum enzymatic activities such as ALP, AST and ALT.

  10. Modes of action for biological control of Botrytis cinerea by antagonistic bacteria

    Directory of Open Access Journals (Sweden)

    Rana HAIDAR

    2017-01-01

    Full Text Available The role of beneficial bacteria in biocontrol of plant diseases, particularly those caused by the necrotrophic fungus Botrytis cinerea, has been investigated by testing many bacteria under laboratory and field conditions. Bacteria may protect plants against B. cinerea by direct antagonistic interactions between biocontrol agents and this pathogen, as well as indirect effects through the induction of host resistance. This review focuses on various bacteria that act as biological control agents (BCAs of B. cinerea and their associated mechanisms. The modes of action (MoAs include: i synthesis of anti-fungal metabolites, such as antibiotics, cell wall-degrading enzymes and volatile organic compounds (VOCs; ii competition for nutrients and/or a niche; and iii induction of host resistance. The challenge for development of BCAs is to reduce the variability of efficiency and to prove persistence under a large range of conditions. We discuss the advantages and drawbacks of MoA for future applications of bacteria in the field and in post-harvest storage, as well as combination of different MoAs as a strategy to achieve a more regular efficacy.

  11. The plant cell wall integrity maintenance mechanism-concepts for organization and mode of action.

    Science.gov (United States)

    Hamann, Thorsten

    2015-02-01

    One of the main differences between plant and animal cells are the walls surrounding plant cells providing structural support during development and protection like an adaptive armor against biotic and abiotic stress. During recent years it has become widely accepted that plant cells use a dedicated system to monitor and maintain the functional integrity of their walls. Maintenance of integrity is achieved by modifying the cell wall and cellular metabolism in order to permit tightly controlled changes in wall composition and structure. While a substantial amount of evidence supporting the existence of the mechanism has been reported, knowledge regarding its precise mode of action is still limited. The currently available evidence suggests similarities of the plant mechanism with respect to both design principles and molecular components involved to the very well characterized system active in the model organism Saccharomyces cerevisiae. There the system has been implicated in cell morphogenesis as well as response to abiotic stresses such as osmotic challenges. Here the currently available knowledge on the yeast system will be reviewed initially to provide a framework for the subsequent discussion of the plant cell wall integrity maintenance mechanism. The review will then end with a discussion on possible design principles for the cell wall integrity maintenance mechanism and the function of the plant turgor pressure in this context. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  12. Coral snake venoms: mode of action and pathophysiology of experimental envenomation

    Directory of Open Access Journals (Sweden)

    Oswald Vital Brazil

    1987-06-01

    Full Text Available Coral snakes, the New World Elapidae, are included in the genera Micniroides and Micrurus. The genus Mlcrurus comprises nearly all coral snake species and those which are responsible for human snake-bite accidents. The following generalizations concerning the effects induced by their venoms, and their venom-properties can be made. Coral snake venoms are neurotoxic, producing loss of muscle strenght and death by respiratory paralysis. Local edema and necrosis are not induced nor blood coagulation or hemorrhages. Proteolysis activity is absent or of very low grade. They display phospholipase A2 activity. Nephrotoxic effects are not evoked. The main toxins from elapid venoms are postsynaptic and presynaptic neurotoxins and cardiotoxins. Phospholipases A2 endowed with myonecrotic or cardiotoxin-like properties are important toxic components from some elapid venoms. The mode of action of Micrurus frontalis, M. lemniscatus, M. corallinus and M. fulvius venoms has been investigated in isolated muscle preparations and is here discussed. It is shown that while M. frontalis and M. lemniscatus venoms must contain only neurotoxins that act at the cholinergic end-plate receptor (postsynaptic neurotoxins, M. corallinus venom also inhibits evoked acetylcholine release by the motor nerve endings (presynaptic neurotoxin-like effect and M. fulvius induces muscle fiber membrane depolarization (cardiotoxin-like effect. The effects produced by M. corallinus and M. fulvius venoms in vivo in dogs and M. frontalis venom in dogs and monkeys are also reported.

  13. A Bayesian network model for predicting aquatic toxicity mode of action using two dimensional theoretical molecular descriptors-abstract

    Science.gov (United States)

    The mode of toxic action (MoA) has been recognized as a key determinant of chemical toxicity but MoA classification in aquatic toxicology has been limited. We developed a Bayesian network model to classify aquatic toxicity mode of action using a recently published dataset contain...

  14. MODE OF ACTION: NEUROTOXICITY INDUCED BY THYROID HORMONE DISRUPTION DURING DEVELOPMENT - HEARING LOSS RESULTING FROM EXPOSURE TO PHAHS.

    Science.gov (United States)

    A manuscript summarizes a workshop aimed at developing a framework to determine the relevancy of animal modes-of-action for extrapolation to humans. This specific report used animal data on the neurodevelopmental effects of hypothyroidism to test the framework. Propylthiouracil,...

  15. Role of membrane disturbance and oxidative stress in the mode of action underlying the toxicity of differently charged polystyrene nanoparticles

    NARCIS (Netherlands)

    Bhattacharjee, S.; Ershov, D.S.; Islam, M.A.; Kämpfer, A.M.; Maslowska, K.A.; Gucht, van der J.; Alink, G.M.; Marcelis, A.T.M.; Zuilhof, H.; Rietjens, I.M.C.M.

    2014-01-01

    Surface charge is often hypothesized to influence toxicity of nanoparticles (NPs) including polymeric nanoparticles (PNPs) while oxidative stress is considered to be an important mode of action (MOA) for such toxicity. In order to investigate the role of membrane disturbance and oxidative stress in

  16. Maggot therapy´s modes of action : effect of maggot secretions on microbiological, haematological and immunological processes

    NARCIS (Netherlands)

    Plas, Maartje Jeriena Adriana van der

    2009-01-01

    The work described in this thesis focussed on the modes of action of maggot therapy in chronic wounds, especially related to the inflammatory phase of wound healing. For this purpose, the effect of maggot excretions and/or secretions on microbiological, haematological and immunological processes was

  17. Resistance mutation conserved between insects and mites unravels the benzoylurea insecticide mode of action on chitin biosynthesis.

    Science.gov (United States)

    Douris, Vassilis; Steinbach, Denise; Panteleri, Rafaela; Livadaras, Ioannis; Pickett, John Anthony; Van Leeuwen, Thomas; Nauen, Ralf; Vontas, John

    2016-12-20

    Despite the major role of chitin biosynthesis inhibitors such as benzoylureas (BPUs) in the control of pests in agricultural and public health for almost four decades, their molecular mode of action (MoA) has in most cases remained elusive. BPUs interfere with chitin biosynthesis and were thought to interact with sulfonylurea receptors that mediate chitin vesicle transport. Here, we uncover a mutation (I1042M) in the chitin synthase 1 (CHS1) gene of BPU-resistant Plutella xylostella at the same position as the I1017F mutation reported in spider mites that confers etoxazole resistance. Using a genome-editing CRISPR/Cas9 approach coupled with homology-directed repair (HDR) in Drosophila melanogaster, we introduced both substitutions (I1056M/F) in the corresponding fly CHS1 gene (kkv). Homozygous lines bearing either of these mutations were highly resistant to etoxazole and all tested BPUs, as well as buprofezin-an important hemipteran chitin biosynthesis inhibitor. This provides compelling evidence that BPUs, etoxazole, and buprofezin share in fact the same molecular MoA and directly interact with CHS. This finding has immediate effects on resistance management strategies of major agricultural pests but also on mosquito vectors of serious human diseases such as Dengue and Zika, as diflubenzuron, the standard BPU, is one of the few effective larvicides in use. The study elaborates on how genome editing can directly, rapidly, and convincingly elucidate the MoA of bioactive molecules, especially when target sites are complex and hard to reconstitute in vitro.

  18. Coexpression of nuclear receptors and histone methylation modifying genes in the testis: implications for endocrine disruptor modes of action.

    Directory of Open Access Journals (Sweden)

    Alison M Anderson

    Full Text Available BACKGROUND: Endocrine disruptor chemicals elicit adverse health effects by perturbing nuclear receptor signalling systems. It has been speculated that these compounds may also perturb epigenetic mechanisms and thus contribute to the early origin of adult onset disease. We hypothesised that histone methylation may be a component of the epigenome that is susceptible to perturbation. We used coexpression analysis of publicly available data to investigate the combinatorial actions of nuclear receptors and genes involved in histone methylation in normal testis and when faced with endocrine disruptor compounds. METHODOLOGY/PRINCIPAL FINDINGS: The expression patterns of a set of genes were profiled across testis tissue in human, rat and mouse, plus control and exposed samples from four toxicity experiments in the rat. Our results indicate that histone methylation events are a more general component of nuclear receptor mediated transcriptional regulation in the testis than previously appreciated. Coexpression patterns support the role of a gatekeeper mechanism involving the histone methylation modifiers Kdm1, Prdm2, and Ehmt1 and indicate that this mechanism is a common determinant of transcriptional integrity for genes critical to diverse physiological endpoints relevant to endocrine disruption. Coexpression patterns following exposure to vinclozolin and dibutyl phthalate suggest that coactivity of the demethylase Kdm1 in particular warrants further investigation in relation to endocrine disruptor mode of action. CONCLUSIONS/SIGNIFICANCE: This study provides proof of concept that a bioinformatics approach that profiles genes related to a specific hypothesis across multiple biological settings can provide powerful insight into coregulatory activity that would be difficult to discern at an individual experiment level or by traditional differential expression analysis methods.

  19. Cardiac disorders and mode of action of the Egyptian scorpion venom Androctonus bicolor on isolated toad’s heart

    Directory of Open Access Journals (Sweden)

    Mohamed A. Abdel-Rahman

    2015-10-01

    Full Text Available Scorpion venom is a complex mixture of components with various pharmacological and toxicological effects. It is characterized by the presence of a large number of toxins that specifically interact with ion channels of excitable cells. The Egyptian scorpion Androctonus bicolor belongs to the family of Buthidae and until now no information is available about the effect of its venom on cardiac muscles. Using an in vitro approach, cardiotoxicity and mode of action of A. bicolor venom on isolated toad’s heart were investigated. Direct application of scorpion venom (0.5 μg/ml into isolated toad’s heart induced a remarkable bradycardia concomitant with a protraction in the conduction time (P–R interval. In the meantime, a significant increase in the R-wave amplitude (ventricular contraction was noticed after 5 min of venom perfusion. Various cases of cardiac disorders were recorded such as sinus arrhythmias, ectopic beats and different degrees of heart block. Through using different autonomic and ion channel blockers, the possible mechanism of action of A. bicolor venom on isolated toad’s heart was revealed. The application of both atropine (4 μg/ml and verapamil (5 μg/ml could not alleviate the pronounced negative chronotropic and positive inotropic effects. Meanwhile, a significant decrease in the R-wave amplitude was observed after propranolol (5 μg/ml application. In conclusion, our findings indicate that the venom of A. bicolor directly influenced the cardiac electrical activity of toads through β-adrenergic receptors. The direct effect of this venom on cardiac tissues may significantly contribute in the development of several cardiotoxic effects following scorpion sting.

  20. Insecticidal spectrum and mode of action of the Bacillus thuringiensis Vip3Ca insecticidal protein.

    Science.gov (United States)

    Gomis-Cebolla, Joaquín; Ruiz de Escudero, Iñigo; Vera-Velasco, Natalia Mara; Hernández-Martínez, Patricia; Hernández-Rodríguez, Carmen Sara; Ceballos, Tomás; Palma, Leopoldo; Escriche, Baltasar; Caballero, Primitivo; Ferré, Juan

    2017-01-01

    The Vip3Ca protein, discovered in a screening of Spanish collections of Bacillus thuringiensis, was known to be toxic to Chrysodeixis chalcites, Mamestra brassicae and Trichoplusia ni. In the present study, its activity has been tested with additional insect species and we found that Cydia pomonella is moderately susceptible to this protein. Vip3Ca (of approximately 90kDa) was processed to an approximately 70kDa protein when incubated with midgut juice in all tested species. The kinetics of proteolysis correlated with the susceptibility of the insect species to Vip3Ca. The activation was faster to slower in the following order: M. brassicae (susceptible), Spodoptera littoralis (moderately susceptible), Agrotis ipsilon and Ostrinia nubilalis (slightly susceptible). Processing Vip3Ca by O. nubilalis or M. brassicae midgut juice did not significantly changed its toxicity to either insect species, indicating that the low susceptibility of O. nubilalis is not due to a problem in the midgut processing of the toxin. M. brassicae larvae fed with Vip3Ca showed binding of this toxin to the apical membrane of the midgut epithelial cells. Histopathological inspection showed sloughing of the epithelial cells with further disruption, which suggests that the mode of action of Vip3Ca is similar to that described for Vip3Aa. Biotin-labeled Vip3Ca and Vip3Aa bound specifically to M. brassicae brush border membrane vesicles and both toxins competed for binding sites. This result suggests that insects resistant to Vip3A may also be cross-resistant to Vip3C, which has implications for Insect Resistance Management (IRM).

  1. Mode of Action of the Sesquiterpene Lactones Psilostachyin and Psilostachyin C on Trypanosoma cruzi

    Science.gov (United States)

    Papademetrio, Daniela; Batlle, Alcira; Martino, Virginia S.; Frank, Fernanda M.; Lombardo, María E.

    2016-01-01

    Trypanosoma cruzi is the causative agent of Chagas’ disease, which is a major endemic disease in Latin America and is recognized by the WHO as one of the 17 neglected tropical diseases in the world. Psilostachyin and psilostachyin C, two sesquiterpene lactones isolated from Ambrosia spp., have been demonstrated to have trypanocidal activity. Considering both the potential therapeutic targets present in the parasite, and the several mechanisms of action proposed for sesquiterpene lactones, the aim of this work was to characterize the mode of action of psilostachyin and psilostachyin C on Trypanosoma cruzi and to identify the possible targets for these molecules. Psilostachyin and psilostachyin C were isolated from Ambrosia tenuifolia and Ambrosia scabra, respectively. Interaction of sesquiterpene lactones with hemin, the induction of oxidative stress, the inhibition of cruzipain and trypanothione reductase and their ability to inhibit sterol biosynthesis were evaluated. The induction of cell death by apoptosis was also evaluated by analyzing phosphatidylserine exposure detected using annexin-V/propidium iodide, decreased mitochondrial membrane potential, assessed with Rhodamine 123 and nuclear DNA fragmentation evaluated by the TUNEL assay. Both STLs were capable of interacting with hemin. Psilostachyin increased about 5 times the generation of reactive oxygen species in Trypanosoma cruzi after a 4h treatment, unlike psilostachyin C which induced an increase in reactive oxygen species levels of only 1.5 times. Only psilostachyin C was able to inhibit the biosynthesis of ergosterol, causing an accumulation of squalene. Both sesquiterpene lactones induced parasite death by apoptosis. Upon evaluating the combination of both compounds, and additive trypanocidal effect was observed. Despite their structural similarity, both sesquiterpene lactones exerted their anti-T. cruzi activity through interaction with different targets. Psilostachyin accomplished its

  2. Neurotoxicity and mode of action of N, N-diethyl-meta-toluamide (DEET.

    Directory of Open Access Journals (Sweden)

    Daniel R Swale

    Full Text Available Recent studies suggest that N, N-diethyl-meta-toluamide (DEET is an acetylcholinesterase inhibitor and that this action may result in neurotoxicity and pose a risk to humans from its use as an insect repellent. We investigated the mode of action of DEET neurotoxicity in order to define the specific neuronal targets related to its acute toxicity in insects and mammals. Although toxic to mosquitoes (LD50 ca. 1.5 µg/mg, DEET was a poor acetylcholinesterase inhibitor (<10% inhibition, even at a concentration of 10 mM. IC50 values for DEET against Drosophila melanogaster, Musca domestica, and human acetylcholinesterases were 6-12 mM. Neurophysiological recordings showed that DEET had excitatory effects on the housefly larval central nervous system (EC50: 120 µM, but was over 300-fold less potent than propoxur, a standard anticholinesterase insecticide. Phentolamine, an octopamine receptor antagonist, completely blocked the central neuroexcitation by DEET and octopamine, but was essentially ineffective against hyperexcitation by propoxur and 4-aminopyridine, a potassium channel blocker. DEET was found to illuminate the firefly light organ, a tissue utilizing octopamine as the principal neurotransmitter. Additionally, DEET was shown to increase internal free calcium via the octopamine receptors of Sf21 cells, an effect blocked by phentolamine. DEET also blocked Na(+ and K(+ channels in patch clamped rat cortical neurons, with IC50 values in the micromolar range. These findings suggest DEET is likely targeting octopaminergic synapses to induce neuroexcitation and toxicity in insects, while acetylcholinesterase in both insects and mammals has low (mM sensitivity to DEET. The ion channel blocking action of DEET in neurons may contribute to the numbness experienced after inadvertent application to the lips or mouth of humans.

  3. Dual Mode of Action for Plusbacin A3 in Staphylococcus aureus.

    Science.gov (United States)

    O'Connor, Robert D; Singh, Manmilan; Chang, James; Kim, Sung Joon; VanNieuwenhze, Michael; Schaefer, Jacob

    2017-02-23

    We have used C{F}, N{F}, and N{P} rotational-echo double resonance NMR to determine the location and conformation of (19)F and (15)N double-labeled plusbacin A3 and of double-labeled deslipo-plusbacin A3, each bound to the cell walls of whole cells of Staphyloccocus aureus grown in media containing [1-(13)C]glycine. The (31)P is primarily in wall teichoic acid. Approximately 25% of plusbacin headgroups (the cyclic depsipeptide backbone) are in a closed conformation (N-F separation of 6 Å), while 75% are in a more open conformation (N-F separation of 12 Å). The closed headgroups have no contact with wall teichoic acid, whereas the open headgroups have a strong contact. This places the closed headgroups in hydrophobic regions of the cell wall and the open headgroups in hydrophilic regions. None of the plusbacin tails have contact with the (31)P of either wall teichoic acid or the cell membrane and thus are in hydrophobic regions of the cell wall. In addition, both heads and tails of plusbacin A3 have contact with the glycyl (13)C incorporated in cell-wall peptidoglycan pentaglycyl bridges and with (13)C-labeled purines near the membrane surface. We interpret these results in terms of a dual mode of action for plusbacin A3: first, disruption of the peptidoglycan layer nearest to the membrane surface by closed-conformation plusbacin A3 leading to an inhibition of chain extension by transglycosylation; second, thinning and disruption of the membrane (possibly including disruption of ATP-binding cassette transporters embedded in the membrane) by open-conformation plusbacin A3, thereby leading to release of ATP to the hydrophilic regions of the cell wall and subsequent binding by plusbacin A3.

  4. Modulation of human GABAA receptor function: a novel mode of action of drugs of abuse.

    Science.gov (United States)

    Hondebrink, L; Meulenbelt, J; van Kleef, R G D M; van den Berg, M; Westerink, R H S

    2011-12-01

    Drugs of abuse are known to mainly affect the dopaminergic and serotonergic system, although behavioral studies indicated that the GABA-ergic system also plays a role. We therefore investigated the acute effects of several commonly used drugs of abuse (methamphetamine, amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and meta-chlorophenylpiperazine (mCPP)) on the function of the human α(1)β(2)γ(2) GABA(A) receptor (hGABA(A)-R), expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique. Although none of the tested drugs acted as full agonist on the hGABA(A)-R, some drugs induced differential modulation of hGABA(A)-R function, depending on the degree of receptor occupancy. Methamphetamine did not affect the GABA-evoked current at high receptor occupancy, but induced a minor inhibition at low receptor occupancy. Its metabolite amphetamine slightly potentiated the GABA-evoked current. MDMA and its metabolite MDA both inhibited the current at low receptor occupancy. However, MDMA did not affect the current at high occupancy, whereas MDA induced a potentiation. mCPP induced a strong inhibition (max. ∼ 80%) at low receptor occupancy, but ∼ 25% potentiation at high receptor occupancy. Competitive binding to one of the GABA-binding sites could explain the drug-induced inhibitions observed at low receptor occupancy, whereas an additional interaction with a positive allosteric binding site may play a role in the observed potentiations at high receptor occupancy. This is the first study to identify direct modulation of hGABA(A)-Rs as a novel mode of action for several drugs of abuse. Consequently, hGABA(A)-Rs should be considered as target for psychiatric pharmaceuticals and in developing treatment for drug intoxications.

  5. Some insights into the mode of action of butadiene by examining the genotoxicity of its metabolites.

    Science.gov (United States)

    Kligerman, A D; Hu, Y

    2007-03-20

    1,3-Butadiene (BTD) is an important commodity chemical and air pollutant that has been shown to be a potent carcinogen in mice, and to a lesser extent, a carcinogen in rats. To better assess butadiene's carcinogenic risk to humans, it is important to understand its mode of action and how this relates to differences in responses among species. In a series of in vitro experiments, lymphocytes from rats, mice, and humans were exposed to 3,4-epoxy-1-butene (EB) or 1,2:3,4-diepoxybutane (DEB) for 1h at the G(0) stage of the cell cycle, stimulated to divide, and cultured to assess the ability of these metabolites to induce sister chromatid exchange (SCE) and chromosome aberrations (CAs). EB induced no increases in SCEs or CAs in the cells from the three species. DEB was a potent SCE- and CA-inducer, with the results being similar in each rodent species. The response for SCEs seen in the human cells was more complex, with genetic polymorphism for glutathione-S-transferases (GST) possibly modulating the response. The single cell gel electrophoresis assay was used on genetically engineered V79 cell lines to investigate a possible influence of GST status. Experiments were also conducted to investigate the reason for EB's failure to induce SCEs or CAs in G(0) cells. The results indicate that EB-induced DNA damage was repaired before DNA synthesis in unstimulated lymphocytes, but EB caused a large increase in SCEs if actively cycling cells were treated. Thus, the results indicate that DEB damage is persistent in G(0) cells, and DEB is a much more potent genotoxicant than EB. The carcinogenic effect of butadiene will most likely depend on the degree to which DEB is produced and reaches target tissues, and to a lesser extent on the ability of EB to reach actively dividing or repair deficient cells.

  6. The Two-Peptide (Class-IIb) Bacteriocins: Genetics, Biosynthesis, Structure, and Mode of Action

    Science.gov (United States)

    Nissen-Meyer, Jon; Oppegård, Camilla; Rogne, Per; Haugen, Helen Sophie; Kristiansen, Per Eugen

    The two-peptide (class-IIb) bacteriocins consist of two different peptides, both of which are required to obtain high antimicrobial activity. These bacteriocins kill target-cells by inducing membrane-leakage and they seem to display some specificity with respect to the molecules they transfer across membranes. The genes encoding the two peptides of two-peptide bacteriocins are next to each other on the same operon. In the same or a nearby operon are genes encoding (i) the immunity protein that protects the bacteriocin-producer from its own bacteriocin, (ii) a dedicated ABC-transporter that exports the bacteriocin from cells and cleaves off the N-terminal bacteriocin leader sequence, and (iii) an accessory protein whose exact function has not been fully clarified. Some two-peptide bacteriocins appear to be produced constitutively, whereas the production of other two-peptide bacteriocins is regulated through a three-component regulatory system that consists of a peptide pheromone, a membrane-associated histidine protein kinase, and response regulators. It has recently been proposed that the two peptides of (some) two-peptide bacteriocins may form a membrane-penetrating helix-helix structure involving helix-helix interacting GxxxG-motifs present in all currently characterized two-peptide bacteriocins. It has also been suggested that the helix-helix structure interacts with an integrated membrane (transport) protein, thus inducing a conformational change in the protein, which in turn causes membrane-leakage. This proposed mode-of-action is similar to that of the pediocin-like (class-IIa) bacteriocins and lactococcin A, which bind to a part of the mannose phosphotransferase permease that is embedded in the cell membrane, thereby altering the conformation of the ­permease in a manner that causes membrane-leakage and cell death.

  7. The Interference of Selected Cytotoxic Alkaloids with the Cytoskeleton: An Insight into Their Modes of Action

    Directory of Open Access Journals (Sweden)

    Xiaojuan Wang

    2016-07-01

    Full Text Available Alkaloids, the largest group among the nitrogen-containing secondary metabolites of plants, usually interact with several molecular targets. In this study, we provide evidence that six cytotoxic alkaloids (sanguinarine, chelerythrine, chelidonine, noscapine, protopine, homoharringtonine, which are known to affect neuroreceptors, protein biosynthesis and nucleic acids, also interact with the cellular cytoskeleton, such as microtubules and actin filaments, as well. Sanguinarine, chelerythrine and chelidonine depolymerized the microtubule network in living cancer cells (Hela cells and human osteosarcoma U2OS cells and inhibited tubulin polymerization in vitro with IC50 values of 48.41 ± 3.73, 206.39 ± 4.20 and 34.51 ± 9.47 μM, respectively. However, sanguinarine and chelerythrine did not arrest the cell cycle while 2.5 μM chelidonine arrested the cell cycle in the G2/M phase with 88.27% ± 0.99% of the cells in this phase. Noscapine and protopine apparently affected microtubule structures in living cells without affecting tubulin polymerization in vitro, which led to cell cycle arrest in the G2/M phase, promoting this cell population to 73.42% ± 8.31% and 54.35% ± 11.26% at a concentration of 80 μM and 250.9 μM, respectively. Homoharringtonine did not show any effects on microtubules and cell cycle, while the known microtubule-stabilizing agent paclitaxel was found to inhibit tubulin polymerization in the presence of MAPs in vitro with an IC50 value of 38.19 ± 3.33 μM. Concerning actin filaments, sanguinarine, chelerythrine and chelidonine exhibited a certain effect on the cellular actin filament network by reducing the mass of actin filaments. The interactions of these cytotoxic alkaloids with microtubules and actin filaments present new insights into their molecular modes of action.

  8. Mode of Action of the Sesquiterpene Lactones Psilostachyin and Psilostachyin C on Trypanosoma cruzi.

    Science.gov (United States)

    Sülsen, Valeria P; Puente, Vanesa; Papademetrio, Daniela; Batlle, Alcira; Martino, Virginia S; Frank, Fernanda M; Lombardo, María E

    2016-01-01

    Trypanosoma cruzi is the causative agent of Chagas' disease, which is a major endemic disease in Latin America and is recognized by the WHO as one of the 17 neglected tropical diseases in the world. Psilostachyin and psilostachyin C, two sesquiterpene lactones isolated from Ambrosia spp., have been demonstrated to have trypanocidal activity. Considering both the potential therapeutic targets present in the parasite, and the several mechanisms of action proposed for sesquiterpene lactones, the aim of this work was to characterize the mode of action of psilostachyin and psilostachyin C on Trypanosoma cruzi and to identify the possible targets for these molecules. Psilostachyin and psilostachyin C were isolated from Ambrosia tenuifolia and Ambrosia scabra, respectively. Interaction of sesquiterpene lactones with hemin, the induction of oxidative stress, the inhibition of cruzipain and trypanothione reductase and their ability to inhibit sterol biosynthesis were evaluated. The induction of cell death by apoptosis was also evaluated by analyzing phosphatidylserine exposure detected using annexin-V/propidium iodide, decreased mitochondrial membrane potential, assessed with Rhodamine 123 and nuclear DNA fragmentation evaluated by the TUNEL assay. Both STLs were capable of interacting with hemin. Psilostachyin increased about 5 times the generation of reactive oxygen species in Trypanosoma cruzi after a 4h treatment, unlike psilostachyin C which induced an increase in reactive oxygen species levels of only 1.5 times. Only psilostachyin C was able to inhibit the biosynthesis of ergosterol, causing an accumulation of squalene. Both sesquiterpene lactones induced parasite death by apoptosis. Upon evaluating the combination of both compounds, and additive trypanocidal effect was observed. Despite their structural similarity, both sesquiterpene lactones exerted their anti-T. cruzi activity through interaction with different targets. Psilostachyin accomplished its antiparasitic

  9. Cardiac and Hemodynamic Benefits: Mode of Action of Ivabradine in Heart Failure.

    Science.gov (United States)

    Pereira-Barretto, Antonio Carlos

    2015-10-01

    Heart failure has seen a number of therapeutic advances in recent years. Despite this, heart failure is still related to increasing rates of morbidity, repeated hospitalizations, and mortality. Ivabradine is a recent treatment option for heart failure. It has a mode of action that includes reduction in heart rate, and leads to improvement in outcomes related to heart failure mortality and morbidity, as demonstrated by the results of the SHIFT trial in patients with systolic heart failure, functional classes II and III on the New York Heart Association classification, and left ventricular ejection fraction ≤ 35%. These results are intriguing since many heart failure drugs reduce heart rate without such benefits, or with quite different effects, making it more difficult to understand the novelty of ivabradine in this setting. Many of the drugs used in heart failure modify heart rate, but most have other pathophysiological effects beyond their chronotropic action, which affect their efficacy in preventing morbidity and mortality outcomes. For instance, heart rate reduction at rest or exercise with ivabradine prolongs diastolic perfusion time, improves coronary blood flow, and increases exercise capacity. Another major difference is the increase in stroke volume observed with ivabradine, which may underlie its beneficial cardiac effects. Finally, there is mounting evidence from both preclinical and clinical studies that ivabradine has an anti-remodeling effect, improving left ventricular structures and functions. All together, these mechanisms have a positive impact on the prognosis of ivabradine-treated patients with heart failure, making a compelling argument for use of ivabradine in combination with other treatments.

  10. Modes of action, resistance and toxicity of insecticides targeting nicotinic acetylcholine receptors.

    Science.gov (United States)

    Ihara, Makoto; Buckingham, Steven D; Matsuda, Kazuhiko; Sattelle, David B

    2017-02-06

    Nicotinic acetylcholine receptors (nAChRs) are members of the cys-loop superfamily of ligand-gated ion channels (cys-loop LGICs) and mediate fast cholinergic synaptic transmission in the nervous system of insects. The completion of many insect genome projects has greatly enhanced our understanding of the individual subunits that make up nAChR gene families from an insect genetic model organism (Drosophila melanogaster), crop pests, disease vectors and beneficial (pollinator) species. In addition to considerable insect nAChR subunit diversity, individual subunits can be subject to alternative splicing and RNA editing and these post-transcriptional modifications can add significantly to the diversity of nAChR receptor subtypes. The actions of insecticides targeting nAChRs, notably cartap, neonicotinoids, sulfoximines, flupyradifurone, spinosyns and triflumezopyrim are reviewed. Structural studies obtained using an acetylcholine binding protein (AChBP) co-crystallised with neonicotinoids have yielded important new insights into the requirements for neonicotinoid insecticide - nAChR interactions. The persistent application of insecticides to crop pests leads to the onset of resistance and several examples of resistance to insecticides targeting nAChRs have been documented. Understanding the molecular basis of resistance can inform our understanding of the mechanism of insecticide action. It also provides an important driver for the development of new chemistry, diagnostic tests for resistance and the adoption of application strategies designed to attenuate such problems. Finally, we consider toxicity issues relating to nAChR-active insecticides, with particular reference to beneficial insect species (pollinators) as well as mammalian and avian toxicity. This review is part of the special issue "Insecticide Mode of Action: From Insect to Mammalian Toxicity.".

  11. Evidence for a central mode of action for etoricoxib (COX-2 inhibitor) in patients with painful knee osteoarthritis.

    Science.gov (United States)

    Arendt-Nielsen, Lars; Egsgaard, Line Lindhardt; Petersen, Kristian Kjær

    2016-08-01

    The COX-2 inhibitor etoricoxib modulates the peripheral and central nociceptive mechanisms in animals. This interaction has not been studied in patients with pain. This randomized, double-blind, placebo-controlled, 2-way crossover, 4-week treatment study investigated the pain mechanisms modulated by etoricoxib in patients with painful knee osteoarthritis. Patients were randomized to group A (60 mg/d etoricoxib followed by placebo) or B (placebo followed by 60 mg/d etoricoxib). The quantitative, mechanistic pain biomarkers were pressure pain thresholds, temporal summation (TS), and conditioning pain modulation. Clinical readouts were Brief Pain Inventory, WOMAC, painDETECT questionnaire (PD-Q), and time and pain intensity during walking and stair climbing. Etoricoxib as compared with placebo significantly modulated the pressure pain thresholds (P = 0.012, localized sensitization) at the knee and leg (control site) (P = 0.025, spreading sensitization) and TS assessed from the knee (P = 0.038) and leg (P = 0.045). Conditioning pain modulation was not modulated. The Brief Pain Inventory (pain scores), PD-Q, WOMAC, and walking and stair climbing tests were all significantly improved by etoricoxib. Based on a minimum of 30% or 50% pain alleviation (day 0-day 28), responders and nonresponders were defined. The nonresponders showed a significant association between increased facilitation of TS and increased pain alleviation. None of the other parameters predicted the degree of pain alleviation. Generally, a responder to etoricoxib has the most facilitated TS. In conclusion, etoricoxib (1) modulated central pain modulatory mechanisms and (2) improved pain and function in painful osteoarthritis. Stronger facilitation of TS may indicate a better response to etoricoxib, supporting the central mode-of-action of the drug.

  12. Ruby laser-assisted depilation: The mode of action and potential ways of improved outcome

    Science.gov (United States)

    Topping, Adam Partington

    Aim - To improve efficacy and lessen side effects resulting from normal mode ruby laser (NMRL)-assisted depilation via a greater understanding of its mode of action and the development of novel methods of reducing associated epidermal damage. Employing a thermal imaging camera and ex vivo hair-bearing skin, the targets for the NMRL (pulse duration 900 musec and spot size 7 mm) were defined, the temperatures reached and the heat dissipation rates determined. Production of heat was confined to the hair follicles, with the peak temperatures reached varying considerably between hairs within the same treatment area and also between individuals. Histological assessment for a known indicator of cellular damage (p53 expression) identified the sites and extent of damage, which correlated with the peak temperatures measured. An energy meter was used to detect the penetration of NMRL light through ex vivo skin, which was found to be deeper than previously theorised. The black-haired mouse (C57B1/10) was assessed both macroscopically and histologically and found to be an acceptable animal model of NMRL depilation and associated epidermal damage. Attempts to reduce the epidermal damage by simply stopping the light reaching the epidermis using a chromophore block were assessed. Chromophore did indeed reduce the amount of epidermal damage detected in laser-irradiated ex vivo human skin, whereas in contrast it increased the wounding seen in the much thinner skin of the mouse. Nevertheless the mouse model showed that this technique did not affect the depilation efficacy. An alternative method of reducing epidermal damage using induction of the cells' intrinsic protective mechanisms (heat shock proteins, HSP) was assessed using cultured keratinocytes and the mouse model. Primarily, the sub-lethal temperature optimum for HSP expression in human keratinocytes was determined, then an in vitro model of NMRL-associated epidermal damage was established and the heat pre-treatment assessed

  13. Using Mode of Action to Assess Health Risks from Mixtures of Chemical/Physical Agents

    Energy Technology Data Exchange (ETDEWEB)

    Bull, Richard J.; Lei, Xingye C.; Sasser, Lyle B.

    2003-01-20

    Interactions between tumor promoters with differing mechanisms of action were examined in male B6C3F1 mice treated with mixtures of dichloroacetate (DCA), trichloroacetate (TCA), and tetrachloride (CT), each of which acts by a different mode of action. Mice were initiated by vinyl carbamate (VC), and then promoted by DCA, TCA, CT, or the pair-wised combinations of the three compounds. The effect of each treatment or treatment combination on tumor number/animal and tumor size was individually assessed at 18, 24, 30 or 36 weeks of treatment. Dose-related increases in tumor size were observed with 20 & 50 mg/kg CT, but each produced equal number of tumors at 36 weeks with the main distinction being a decrease in tumor latency at the higher dose. Overall TCA treatment produced dose-related increases in tumor number at 36 weeks of treatment. Thus, the lower doses of CT and TCA treatments apparently affected tumor size rather than number. Results with DCA were not as clear as a true maximum tumor number was not clearly observed within the experimental period. Treatment of mice receiving a high dose of TCA (2 g/L of drinking water) combined with varying doses of DCA (0.1, 0.5 and 2 g/L) produced increased numbers of tumors at 24 weeks and 36 weeks. However, at 36 weeks of treatment DCA produced a dose-related decrease in the size of tumors promoted by TCA. The low dose of TCA (0.1 g/L) decreased the number of tumors produced by a high dose of DCA, however, higher doses of TCA produced the same number as observed with DCA alone. Since these two chemicals produce lesions with differing phenotypes, the combination would have been expected to be additive with respect to number, but this was obviously not the case. These data suggest that the induction of liver cancer from mixtures of solvents may have predictable outcomes. The major conclusion is that these interactions are generally no more than additive. It was most interesting to note that additivity was only observed when

  14. Plant adaptogens. III. Earlier and more recent aspects and concepts on their mode of action.

    Science.gov (United States)

    Panossian, A; Wikman, G; Wagner, H

    1999-10-01

    Stimulus-response coupling systems responsible for defence and adaptation of organism to stressors are multi-target and very complicated pharmacological systems, including the neuroendocrine (stress) and immune system. The mode of action of adaptogens is basically associated with the stress-system (neuroendocrine-immune complex) and can be directed on the various targets of the system involved in regulation (activation and inhibition) of stimulus-response coupling. However, clinical studies performed according to the most modern standards are quite limited. On the other hand there is an extensive amount of clinical experience and also established use in self care etc. These aspects are planned to be dealt within a subsequent article which will be devoted to the application in three areas: self care, adjuvants in medicine and curative action in some diseases. At this stage, nevertheless, it seems possible to define some most important "stress-markers" for evaluation of efficiency of adaptogens in experimental and clinical pharmacological studies. They can be both activating (catecholamines, LT-s, cytokines, NO, etc.--"switch on" system--which activates energetic and other resources of the organism), and deactivating (corticosteroids and PGE2-endogenous mediators of cellular communications, which protect cells and whole organism from overreacting to the activating messengers--"switch off" system) stress-messengers. The balance between the activities of the "switch on" and "switch off" systems reflects the well being of the organism. It could be established on different levels of the homeostasis (heterostasis) with different levels of the sensitivity to stressors (Figure 8). The response of stress system--"reactivity" is different at the various levels of heterostasis and depends on adaptation--capacity of the organism (or a cell) to protect itself. In the process of adaptation to stressor's effects the basal levels mediators of switch on (e.g. NO) and switch of (e

  15. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors.

    Science.gov (United States)

    Nauck, M

    2016-03-01

    Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1), which is partly responsible for augmenting glucose-dependent insulin secretion in response to nutrient intake (the 'incretin effect'). In patients with T2D, pharmacological doses/concentrations of GLP-1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose-dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin-based glucose-lowering medications. Two classes of incretin-based therapies are available: GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors. GLP-1RAs promote GLP-1 receptor (GLP-1R) signalling by providing GLP-1R stimulation through 'incretin mimetics' circulating at pharmacological concentrations, whereas DPP-4 inhibitors prevent the degradation of endogenously released GLP-1. Both agents produce reductions in plasma glucose and, as a result of their glucose-dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non-glycaemic benefits such as weight loss, improvements in β-cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin-based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.

  16. Structure-based discovery of novel US28 small molecule ligands with different modes of action

    DEFF Research Database (Denmark)

    Lückmann, Michael; Amarandi, Roxana-Maria; Papargyri, Natalia

    2017-01-01

    The human cytomegalovirus-encoded G protein-coupled receptor US28 is a constitutively active receptor, which can recognize various chemokines. Despite the recent determination of its 2.9 angstrom crystal structure, potent and US28-specific tool compounds are still scarce. Here, we used structural...

  17. Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action

    Energy Technology Data Exchange (ETDEWEB)

    Scherzberg, Maria-Christina; Kiehl, Andreas; Zivkovic, Aleksandra; Stark, Holger [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Stein, Jürgen [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Department of Internal Medicine, Sachsenhausen Hospital, Frankfurt am Main (Germany); Fürst, Robert [Institute of Pharmaceutical Biology, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Steinhilber, Dieter [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany); Ulrich-Rückert, Sandra, E-mail: sandra.ulrich@em.uni-frankfurt.de [Institute of Pharmaceutical Chemistry, Biozentrum, Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main (Germany)

    2015-08-15

    (Z)-3,5,4′-Trimethoxystilbene (Z-TMS) is a resveratrol analog with increased antiproliferative activity towards a number of cancer cell lines compared to resveratrol, which has been shown to inhibit tubulin polymerization in vitro. The purpose of this study was to investigate if Z-TMS still shows potential for the prevention of metabolic diseases as known for resveratrol. Cell growth inhibition was determined with IC{sub 50} values for Z-TMS between 0.115 μM and 0.473 μM (resveratrol: 110.7 μM to 190.2 μM). Flow cytometric analysis revealed a G{sub 2}/M arrest after Z-TMS treatment, whereas resveratrol caused S phase arrest. Furthermore, Z-TMS was shown to impair microtubule polymerization. Beneficial effects on lipid accumulation were observed for resveratrol, but not for Z-TMS in an in vitro steatosis model. (E)-Resveratrol was confirmed to elevate cAMP levels, and knockdown of AMPK attenuated the antiproliferative activity, while Z-TMS did not show significant effects in these experiments. SIRT1 and AMPK activities were further measured indirectly via induction of the target gene small heterodimer partner (SHP). Thereby, (E)-resveratrol, but not Z-TMS, showed potent induction of SHP mRNA levels in an AMPK- and SIRT1-dependent manner, as confirmed by knockdown experiments. We provide evidence that Z-TMS does not show beneficial metabolic effects, probably due to loss of activity towards resveratrol target genes. Moreover, our data support previous findings that Z-TMS acts as an inhibitor of tubulin polymerization. These findings confirm that the methylation of resveratrol leads to profound changes in the mode of action, which should be taken into consideration when conducting lead structure optimization approaches. - Highlights: • Methylation of resveratrol leads to profound changes in biologic activity. • Z-TMS does not prevent hepatic steatosis, but inhibits tubulin polymerization. • Resveratrol analog Z-TMS does not influence known targets like

  18. Iodine and disinfection: theoretical study on mode of action, efficiency, stability, and analytical aspects in the aqueous system.

    Science.gov (United States)

    Gottardi, W

    1999-05-01

    Although they have been in use for nearly 170 years, the mode of action of iodine-based disinfectants is not yet clearly understood, as is manifested, for example, in diverging judgements about the relevance of the individual iodine species. Although studies based on calculated equilibrium concentrations in pure iodine solutions have already been done, there is a lack of knowledge about iodine solutions in the presence of additional iodide which would be of intrinsic importance for disinfection practice. Therefore, a re-calculation was undertaken considering variations of this parameter in the pH range 0-14. The presented calculations concern fresh iodine solutions not affected by disproportionation (iodate formation) and provide information about the equilibrium concentrations of the species I, I2, I3, I5-, I6(2-), HOI, O1-, HI2O-, IO2- and H2OI+. Additional iodide and the pH value have a very pronounced influence on the individual equilibrium concentrations (several powers of ten); hence, conditions can be indicated where the number of species of virtual importance is drastically reduced. In the most common case with iodine in the presence of additional iodide at pH iodine cation H2OI+, frequently quoted as an active agent in disinfection, is without any relevance under the conditions occurring in practice, as are IO- and HI2O- which become important only at pH > 10. The stability problem (i.e. rate of iodate formation) arising at pH > 6 can be reduced to hypoiodous acid, as manifested in the simple rate law d[IO3]/dt = 0.25 [HOI]3/[H+] which allows an estimation of stability under weakly alkaline conditions. The results of this study allow us to deduce general qualities of aqueous iodine solutions, such as reactivity, stability, and analytical aspects, and to estimate major disinfection-orientated properties such as microbicidal activity, irritation, and incorporation effects. Though the calculations consider primarily preparations devoid of polymeric organic

  19. Systemic insecticides (neonicotinoids and fipronil): trends, uses, mode of action and metabolites.

    Science.gov (United States)

    Simon-Delso, N; Amaral-Rogers, V; Belzunces, L P; Bonmatin, J M; Chagnon, M; Downs, C; Furlan, L; Gibbons, D W; Giorio, C; Girolami, V; Goulson, D; Kreutzweiser, D P; Krupke, C H; Liess, M; Long, E; McField, M; Mineau, P; Mitchell, E A D; Morrissey, C A; Noome, D A; Pisa, L; Settele, J; Stark, J D; Tapparo, A; Van Dyck, H; Van Praagh, J; Van der Sluijs, J P; Whitehorn, P R; Wiemers, M

    2015-01-01

    doing so, they continuously stimulate neurons leading ultimately to death of target invertebrates. Like virtually all insecticides, they can also have lethal and sublethal impacts on non-target organisms, including insect predators and vertebrates. Furthermore, a range of synergistic effects with other stressors have been documented. Here, we review extensively their metabolic pathways, showing how they form both compound-specific and common metabolites which can themselves be toxic. These may result in prolonged toxicity. Considering their wide commercial expansion, mode of action, the systemic properties in plants, persistence and environmental fate, coupled with limited information about the toxicity profiles of these compounds and their metabolites, neonicotinoids and fipronil may entail significant risks to the environment. A global evaluation of the potential collateral effects of their use is therefore timely. The present paper and subsequent chapters in this review of the global literature explore these risks and show a growing body of evidence that persistent, low concentrations of these insecticides pose serious risks of undesirable environmental impacts.

  20. Mode of action and resistance studies unveil new roles for tropodithietic acid as an anticancer agent and the γ-glutamyl cycle as a proton sink.

    Science.gov (United States)

    Wilson, Maxwell Z; Wang, Rurun; Gitai, Zemer; Seyedsayamdost, Mohammad R

    2016-02-09

    While we have come to appreciate the architectural complexity of microbially synthesized secondary metabolites, far less attention has been paid to linking their structural features with possible modes of action. This is certainly the case with tropodithietic acid (TDA), a broad-spectrum antibiotic generated by marine bacteria that engage in dynamic symbioses with microscopic algae. TDA promotes algal health by killing unwanted marine pathogens; however, its mode of action (MoA) and significance for the survival of an algal-bacterial miniecosystem remains unknown. Using cytological profiling, we herein determine the MoA of TDA and surprisingly find that it acts by a mechanism similar to polyether antibiotics, which are structurally highly divergent. We show that like polyether drugs, TDA collapses the proton motive force by a proton antiport mechanism, in which extracellular protons are exchanged for cytoplasmic cations. The α-carboxy-tropone substructure is ideal for this purpose as the proton can be carried on the carboxyl group, whereas the basicity of the tropylium ion facilitates cation export. Based on similarities to polyether anticancer agents we have further examined TDA's cytotoxicity and find it to exhibit potent, broad-spectrum anticancer activities. These results highlight the power of MoA-profiling technologies in repurposing old drugs for new targets. In addition, we identify an operon that confers TDA resistance to the producing marine bacteria. Bioinformatic and biochemical analyses of these genes lead to a previously unknown metabolic link between TDA/acid resistance and the γ-glutamyl cycle. The implications of this resistance mechanism in the context of the algal-bacterial symbiosis are discussed.

  1. Proposed mode of action of benzene-induced leukemia: Interpreting available data and identifying critical data gaps for risk assessment.

    Science.gov (United States)

    Meek, M E Bette; Klaunig, James E

    2010-03-19

    Mode of action is defined as a series of key biological events leading to an observed toxicological effect (for example, metabolism to a toxic entity, cell death, regenerative repair and tumors). It contrasts with mechanism of action, which generally involves a detailed understanding of the molecular basis for an effect. A framework to consider the weight of evidence for hypothesized modes of action in animals and their relevance to humans, has been widely adopted and used by government agencies and international organizations. The framework, developed and refined through its application in case studies for principally non-DNA-reactive carcinogens, has more recently been extended to DNA-reactive carcinogens, non-cancer endpoints and different life stages. In addition to increasing transparency, use of the framework promotes consistency in decision-making concerning adequacy of weight of evidence, facilitates peer input and review and identifies critical research needs. The framework provides an effective tool to facilitate discussion between the research and risk assessment communities on critical data gaps, which if filled, would permit more refined estimates of risk. As a basis for additionally coordinating and focusing research on critical data gaps in a risk assessment context, five key events in the mode of action for benzene-induced leukemia are proposed: (1) benzene metabolism via Cytochrome P450, (2) the interaction of benzene metabolites with target cells in the bone marrow, (3) formation of initiated, mutated target cells, (4) selective proliferation of the mutated cells and (5) production of leukemia. These key events are considered in a framework analysis of human relevance as a basis to consider appropriate next steps in developing research strategies.

  2. Investigations of the mode of action and resistance development of cadazolid, a new antibiotic for treatment of Clostridium difficile infections.

    Science.gov (United States)

    Locher, Hans H; Caspers, Patrick; Bruyère, Thierry; Schroeder, Susanne; Pfaff, Philippe; Knezevic, Andreja; Keck, Wolfgang; Ritz, Daniel

    2014-01-01

    Cadazolid is a new oxazolidinone-type antibiotic currently in clinical development for the treatment of Clostridium difficile-associated diarrhea. Here, we report investigations on the mode of action and the propensity for spontaneous resistance development in C. difficile strains. Macromolecular labeling experiments indicated that cadazolid acts as a potent inhibitor of protein synthesis, while inhibition of DNA synthesis was also observed, albeit only at substantially higher concentrations of the drug. Strong inhibition of protein synthesis was also obtained in strains resistant to linezolid, in agreement with low MICs against such strains. Inhibition of protein synthesis was confirmed in coupled transcription/translation assays using extracts from different C. difficile strains, including strains resistant to linezolid, while inhibitory effects in DNA topoisomerase assays were weak or not detectable under the assay conditions. Spontaneous resistance frequencies of cadazolid were low in all strains tested (generally cadazolid retained potent activity against strains resistant or nonsusceptible to linezolid, fluoroquinolones, and the new antibiotic fidaxomicin. In conclusion, the data presented here indicate that cadazolid acts primarily by inhibition of protein synthesis, with weak inhibition of DNA synthesis as a potential second mode of action, and suggest a low potential for spontaneous resistance development.

  3. Proposed mechanism of antibacterial mode of action of Caesalpinia bonducella seed oil against food-borne pathogens

    Directory of Open Access Journals (Sweden)

    Shruti Shukla

    2016-03-01

    Full Text Available The antibacterial mechanism of action of Caesalpinia bonducella seed oil on membrane permeability of Listeria monocytogenes NCIM 24563 (MIC: 2 mg/mL and Escherichia coli ATCC 25922 (MIC: 4 mg/mL was determined by measuring the extracellular ATP concentration, release of 260-nm absorbing materials, leakage of potassium ions and measurement of relative electrical conductivity of the bacterial cells treated at MIC concentration. Its mode of action on membrane integrity was confirmed by release of extracellular ATP (1.42 and 1.33 pg/mL, loss of 260-nm absorbing materials (4.36 and 4.19 optical density, leakage of potassium ions (950 and 1000 mmol/L and increase in relative electrical conductivity (12.6 and 10.5% against food-borne pathogenic bacteria L. monocytogenes and E. coli, respectively. These findings propose that C. bonducella oil compromised its mode of action on membrane integrity, suggesting its enormous food and pharmacological potential.

  4. Investigating Potential Modes of Actions of Mimusops kummel Fruit Extract and Solvent Fractions for Their Antidiarrheal Activities in Mice.

    Science.gov (United States)

    Molla, Mulugeta; Gemeda, Negero; Abay, Solomon M

    2017-01-01

    Fruits of Mimusops kummel A. DC. (Sapotaceae) are traditionally used for the treatment of diarrhea. The present study aimed at investigating modes of actions of this fruits for antidiarrheal action to guide future drug development process. Fractions of chloroform, n-butanol, and water were obtained from 80% methanol extract, which was prepared by maceration. Antidiarrheal activities and the modes of actions were investigated in mice. In castor oil induced diarrheal model, the extract delayed onset of diarrhea and reduced number and weight of feces at all tested doses significantly. In this model all fractions significantly delayed onset of diarrhea at all tested doses. Charcoal meal test showed that the extract and all the fractions produced a significant antimotility effect at all tested doses. Enteropooling test showed that the extract as well as n-butanol and aqueous fractions at all tested doses produced a significant decline in volume and weight of intestinal contents, whereas chloroform fraction had substantial effect only at high dose. This study demonstrated that the extract and solvent fractions produced antidiarrheal activities due to dual inhibitory effect, intestinal motility, and fluid secretion, with the aqueous fraction being the most active among fractions in three models.

  5. Investigating Potential Modes of Actions of Mimusops kummel Fruit Extract and Solvent Fractions for Their Antidiarrheal Activities in Mice

    Directory of Open Access Journals (Sweden)

    Mulugeta Molla

    2017-01-01

    Full Text Available Background. Fruits of Mimusops kummel A. DC. (Sapotaceae are traditionally used for the treatment of diarrhea. The present study aimed at investigating modes of actions of this fruits for antidiarrheal action to guide future drug development process. Methods. Fractions of chloroform, n-butanol, and water were obtained from 80% methanol extract, which was prepared by maceration. Antidiarrheal activities and the modes of actions were investigated in mice. Results. In castor oil induced diarrheal model, the extract delayed onset of diarrhea and reduced number and weight of feces at all tested doses significantly. In this model all fractions significantly delayed onset of diarrhea at all tested doses. Charcoal meal test showed that the extract and all the fractions produced a significant antimotility effect at all tested doses. Enteropooling test showed that the extract as well as n-butanol and aqueous fractions at all tested doses produced a significant decline in volume and weight of intestinal contents, whereas chloroform fraction had substantial effect only at high dose. Conclusion. This study demonstrated that the extract and solvent fractions produced antidiarrheal activities due to dual inhibitory effect, intestinal motility, and fluid secretion, with the aqueous fraction being the most active among fractions in three models.

  6. Classification, mode of action and production strategy of xylanase and its application for biofuel production from water hyacinth.

    Science.gov (United States)

    Uday, Uma Shankar Prasad; Choudhury, Payel; Bandyopadhyay, Tarun Kanti; Bhunia, Biswanath

    2016-01-01

    Xylanases are classified under glycoside hydrolase families which represent one of the largest groups of commercial enzymes. Depolymerizing xylan molecules into monomeric pentose units involves the synergistic action of mainly two key enzymes which are endo-β-xylanase and β-xylosidase. Xylanases are different with respect to their mode of action, substrate specificities, biochemical properties, 3D structure and are widely produced by a spectrum of bacteria and fungi. Currently, large scale production of xylanase can be produced through the application of genetic engineering tool which allow fast identification of novel xylanase genes and their genetic variations makes it an ideal enzymes. Due to depletion of fossil fuel, there is urgent need to find out environment friendly and sustainable energy sources. Therefore, utilisation of cheap lignocellulosic materials along with proper optimisation of process is most important for cost efficient ethanol production. Among, various types of lignocellulosic substances, water hyacinth, a noxious aquatic weed, has been found in many tropical. Therefore, the technological development for biofuel production from water hyacinth is becoming commercially worthwhile. In this review, the classification and mode of action of xylanase including genetic regulation and strategy for robust xylanase production have been critically discussed from recent reports. In addition various strategies for cost effective biofuel production from water hyacinth including chimeric proteins design has also been critically evaluated.

  7. Potential of plant essential oils and their components in animal agriculture – in vitro studies on antibacterial mode of action

    Directory of Open Access Journals (Sweden)

    Corliss A. O'bryan

    2015-09-01

    Full Text Available The broad field of agriculture is currently undergoing major changes in practices, with new catch phrases including organic and sustainable. Consumers are more aware than ever before of the food that they eat and they want food free of toxic chemicals, antibiotics and the like. The antimicrobial activity of essential oils and their components has been recognized for several years. Recent research has demonstrated that many of these essential oils have beneficial effects for livestock, including reduction of foodborne pathogens in these animals. Essential oils as natural antimicrobials offer the opportunity to help maintain the safety of our food supply and minimize consumers’ concerns about consumption of synthetic chemicals. Numerous studies have been made into the mode of action of essential oils and the resulting elucidation of bacterial cell targets have contributed to new perspectives on countering antimicrobial resistance and pathogenicity of these bacteria. In this review, after a brief discussion of the uses essential oils in agriculture as antimicrobials, we give an overview of the current knowledge about the antibacterial mode of action of essential oils and their constituents as determined in vitro.

  8. Inhibition of voltage-gated calcium channels as common mode of action for (mixtures of) distinct classes of insecticides.

    Science.gov (United States)

    Meijer, Marieke; Dingemans, Milou M L; van den Berg, Martin; Westerink, Remco H S

    2014-09-01

    Humans are exposed to distinct structural classes of insecticides with different neurotoxic modes of action. Because calcium homeostasis is essential for proper neuronal function and development, we investigated the effects of insecticides from different classes (pyrethroid: (α-)cypermethrin; organophosphate: chlorpyrifos; organochlorine: endosulfan; neonicotinoid: imidacloprid) and mixtures thereof on the intracellular calcium concentration ([Ca(2+)]i). Effects of acute (20 min) exposure to (mixtures of) insecticides on basal and depolarization-evoked [Ca(2+)]i were studied in vitro with Fura-2-loaded PC12 cells and high resolution single-cell fluorescence microscopy. The data demonstrate that cypermethrin, α-cypermethrin, endosulfan, and chlorpyrifos concentration-dependently decreased depolarization-evoked [Ca(2+)]i, with 50% (IC50) at 78nM, 239nM, 250nM, and 899nM, respectively. Additionally, acute exposure to chlorpyrifos or endosulfan (10μM) induced a modest increase in basal [Ca(2+)]i, amounting to 68 ± 8nM and 53 ± 8nM, respectively. Imidacloprid did not disturb basal or depolarization-evoked [Ca(2+)]i at 10μM. Following exposure to binary mixtures, effects on depolarization-evoked [Ca(2+)]i were within the expected effect additivity range, whereas the effect of the tertiary mixture was less than this expected additivity effect range. These results demonstrate that different types of insecticides inhibit depolarization-evoked [Ca(2+)]i in PC12 cells by inhibiting voltage-gated calcium channels (VGCCs) in vitro at concentrations comparable with human occupational exposure levels. Moreover, the effective concentrations in this study are below those for earlier described modes of action. Because inhibition of VGCCs appears to be a common and potentially additive mode of action of several classes of insecticides, this target should be considered in neurotoxicity risk assessment studies. © The Author 2014. Published by Oxford University Press on behalf

  9. QSAR-analysis and mixture toxicity as diagnostic tools: Influence of degradation on the toxicity and mode of action of diuron in algae and daphnids.

    Science.gov (United States)

    Neuwoehner, Judith; Zilberman, Tobias; Fenner, Kathrin; Escher, Beate I

    2010-04-01

    Even though the environmental occurrence of pesticide transformation products is well established, ecotoxicological data for transformation products are often lacking. Therefore, it remains an open question for regulators how to handle transformation products in the process of authorization and risk assessment. Transformation products may (1) possess a similar mode of toxic action as the parent compound, (2) exhibit unexpected effects towards non-target organisms or (3) contribute to overall mixture toxicity through baseline toxicity even if the specific activity of the parent compound is lost. In the present study, a systematic and integrated approach is presented to differentiate between these three options with the goal of identifying transformation products that significantly add to the risk posed by the parent compound. Quantitative structure-activity relationships (QSAR) and a toxic ratio (TR) analysis were used to evaluate the toxicity and mode of toxic action of the transformation products relative to the parent compound. In addition, mixture toxicity experiments were used as diagnostic tools to underpin the mode of action analysis and to elucidate whether the transformation products possess a similar risk potential as the parent compound. As an illustrative example, the phenylurea herbicide diuron was chosen since a sound basis of ecotoxicological data was available not only for diuron itself but also for most of its transformation products. Effects were investigated using the most sensitive species, algae, and the non-target organism Daphnia magna, for which a previous QSAR-analysis of literature data suggested a specific hazard. In the present study the primary transformation products 1-(3,4-dichlorophenyl)-3-methlyurea (DCPMU), 3-(3-chlorophenyl)-1,1-dimethylurea (MCPDMU), and 1-(3,4-dichlorophenyl)urea (DCPU) were identified as specific toxicants in algae, but as baseline toxicants in daphnids. The subsequent loss of the methylurea group during

  10. Hepatoprotective amide constituents from the fruit of Piper chaba: Structural requirements, mode of action, and new amides.

    Science.gov (United States)

    Matsuda, Hisashi; Ninomiya, Kiyofumi; Morikawa, Toshio; Yasuda, Daisuke; Yamaguchi, Itadaki; Yoshikawa, Masayuki

    2009-10-15

    The 80% aqueous acetone extract from the fruit of Piper chaba (Piperaceae) was found to have hepatoprotective effects on D-galactosamine (D-GalN)/lipopolysaccharide-induced liver injury in mice. From the ethyl acetate-soluble fraction, three new amides, piperchabamides E, G, and H, 33 amides, and four aromatic constituents were isolated. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: (i) the amide moiety is essential for potent activity; and (ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effects at doses of 5 and 10 mg/kg, po and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha.

  11. New strigolactone mimics: structure-activity relationship and mode of action as germinating stimulants for parasitic weeds.

    Science.gov (United States)

    Zwanenburg, Binne; Nayak, Sandip K; Charnikhova, Tatsiana V; Bouwmeester, Harro J

    2013-09-15

    Strigolactones (SLs) are new plant hormones with varies important bio-functions. This Letter deals with germination of seeds of parasitic weeds. Natural SLs have a too complex structure for synthesis. Therefore, there is an active search for SL analogues and mimics with a simpler structure with retention of activity. SL analogues all contain the D-ring connected with an enone moiety through an enol ether unit. A new mechanism for the hydrolysis SL analogues involving bidentate bound water and an α,β-hydrolase with a Ser-His-Asp catalytic triad has been proposed. Newly discovered SL mimics only have the D-ring with an appropriate leaving group at C-5. A mode of action for SL mimics was proposed for which now supporting evidence is provided. As predicted an extra methyl group at C-4 of the D-ring blocks the germination of seeds of parasitic weeds. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Dermcidin-derived peptides show a different mode of action than the cathelicidin LL-37 against Staphylococcus aureus.

    Science.gov (United States)

    Senyürek, Ilknur; Paulmann, Maren; Sinnberg, Tobias; Kalbacher, Hubert; Deeg, Martin; Gutsmann, Thomas; Hermes, Marina; Kohler, Thomas; Götz, Fritz; Wolz, Christiane; Peschel, Andreas; Schittek, Birgit

    2009-06-01

    Dermcidin (DCD) is an antimicrobial peptide which is constitutively expressed in eccrine sweat glands. By postsecretory proteolytic processing in sweat, the DCD protein gives rise to anionic and cationic DCD peptides with a broad spectrum of antimicrobial activity. Many antimicrobial peptides induce membrane permeabilization as part of their killing mechanism, which is accompanied by a loss of the bacterial membrane potential. In this study we show that there is a time-dependent bactericidal activity of anionic and cationic DCD-derived peptides which is followed by bacterial membrane depolarization. However, DCD-derived peptides do not induce pore formation in the membranes of gram-negative and gram-positive bacteria. This is in contrast to the mode of action of the cathelicidin LL-37. Interestingly, LL-37 as well as DCD-derived peptides inhibit bacterial macromolecular synthesis, especially RNA and protein synthesis, without binding to microbial DNA or RNA. Binding studies with components of the cell envelope of gram-positive and gram-negative bacteria and with model membranes indicated that DCD-derived peptides bind to the bacterial envelope but show only a weak binding to lipopolysaccharide (LPS) from gram-negative bacteria or to peptidoglycan, lipoteichoic acid, and wall teichoic acid, isolated from Staphylococcus aureus. In contrast, LL-37 binds strongly in a dose-dependent fashion to these components. Altogether, these data indicate that the mode of action of DCD-derived peptides is different from that of the cathelicidin LL-37 and that components of the bacterial cell envelope play a role in the antimicrobial activity of DCD.

  13. IARC use of oxidative stress as key mode of action characteristic for facilitating cancer classification: Glyphosate case example illustrating a lack of robustness in interpretative implementation.

    Science.gov (United States)

    Bus, James S

    2017-06-01

    The International Agency for Research on Cancer (IARC) has formulated 10 key characteristics of human carcinogens to incorporate mechanistic data into cancer hazard classifications. The analysis used glyphosate as a case example to examine the robustness of IARC's determination of oxidative stress as "strong" evidence supporting a plausible cancer mechanism in humans. The IARC analysis primarily relied on 14 human/mammalian studies; 19 non-mammalian studies were uninformative of human cancer given the broad spectrum of test species and extensive use of formulations and aquatic testing. The mammalian studies had substantial experimental limitations for informing cancer mechanism including use of: single doses and time points; cytotoxic/toxic test doses; tissues not identified as potential cancer targets; glyphosate formulations or mixtures; technically limited oxidative stress biomarkers. The doses were many orders of magnitude higher than human exposures determined in human biomonitoring studies. The glyphosate case example reveals that the IARC evaluation fell substantially short of "strong" supporting evidence of oxidative stress as a plausible human cancer mechanism, and suggests that other IARC monographs relying on the 10 key characteristics approach should be similarly examined for a lack of robust data integration fundamental to reasonable mode of action evaluations. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Understanding the Effectiveness of Natural Compound Mixtures in Cancer through Their Molecular Mode of Action

    Directory of Open Access Journals (Sweden)

    Thazin Nwe Aung

    2017-03-01

    Full Text Available Many approaches to cancer management are often ineffective due to adverse reactions, drug resistance, or inadequate target specificity of single anti-cancer agents. In contrast, a combinatorial approach with the application of two or more anti-cancer agents at their respective effective dosages can achieve a synergistic effect that boosts cytotoxicity to cancer cells. In cancer, aberrant apoptotic pathways allow cells that should be killed to survive with genetic abnormalities, leading to cancer progression. Mutations in apoptotic mechanism arising during the treatment of cancer through cancer progression can consequently lead to chemoresistance. Natural compound mixtures that are believed to have multiple specific targets with minimal acceptable side-effects are now of interest to many researchers due to their cytotoxic and chemosensitizing activities. Synergistic interactions within a drug mixture enhance the search for potential molecular targets in cancer cells. Nonetheless, biased/flawed scientific evidence from natural products can suggest false positive therapeutic benefits during drug screening. In this review, we have taken these factors into consideration when discussing the evidence for these compounds and their synergistic therapeutic benefits in cancer. While there is limited evidence for clinical efficacy for these mixtures, in vitro data suggest that these preparations merit further investigation, both in vitro and in vivo.

  15. [Metamizole (dipyrone): mode of action, drug-drug interactions, and risk of agranulocytosis].

    Science.gov (United States)

    Lampl, C; Likar, R

    2014-12-01

    Metamizole (dipyrone) is a nonsteroidal compound with strong analgesic as well as antipyretic and spasmolytic properties. Based on a small number of cases of agranulocytosis, metamizole was withdrawn from the market in some countries. Other countries restricted its use. This paper discusses the safety aspects of metamizole and compares it with other compounds used for similar indications.

  16. Catalytic Mechanism and Mode of Action of the Periplasmic Alginate Epimerase AlgG

    NARCIS (Netherlands)

    Wolfram, Francis; Kitova, Elena N.; Robinson, Howard; Walvoort, Marthe T. C.; Codee, Jeroen D. C.; Klassen, John S.; Howell, P. Lynne

    2014-01-01

    Background: The alginate epimerase AlgG converts mannuronate to its C5 epimer guluronate at the polymer level. Results: The structure of Pseudomonas syringae AlgG has been determined, and the protein has been functionally characterized. Conclusion: His(319) acts as the catalytic base, whereas

  17. MOAtox: A Comprehensive Mode of Action and Acute Aquatic Toxicity Database for Predictive Model Development

    Science.gov (United States)

    tThe mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity andas an alternative to chemical class-based predictive toxicity modeling. However, the development ofquantitative structure activity relationship (QSAR) and other models has been limite...

  18. Proceedings of the 2006 Toxicology and Risk Assessment Conference: Applying Mode of Action in Risk Assessment

    Science.gov (United States)

    2006-07-01

    identified as causing solvent encephalopathy , low-level exposures are not so well characterized. A fairly large volume of the nervous system is...viability, mitochondrial function, phagocytotic ability, cytokine response, and cell morphology. Preliminary viability results show minimal...to study cell viability based on the mitochondrial function. Size- and dose- dependent MTT reductions were observed with similar LDH leakage. Small

  19. Further evidences for the mode of action of the larvicidal m-pentadecadienyl-phenol isolated from Myracrodruon urundeuva seeds against Aedes aegypti.

    Science.gov (United States)

    Souza, Terezinha M; Menezes, Erika S Bezerra; Oliveira, Rodrigo V; Almeida Filho, Luiz Carlos P; Martins, Jorge M; Moreno, Frederico B; Monteiro-Moreira, Ana Cristina O; Moura, Arlindo A Araripe; Carvalho, Ana F Urano

    2015-12-01

    Nowadays, dengue fever is considered the most important arbovirosis worldwide and its control is still based upon combating the vector Aedes aegypti. Besides monitoring of mosquito populations resistant to conventional insecticides, the search for new environmentally safe insecticides and conduction of molecular studies focusing on the elucidation of mode of action and possible resistance mechanisms are considered the key for a sustainable management of the mosquito vector. Thus, the present work aimed to assess changes in protein expression of 3rd-instar larvae of Ae. aegypti after exposure to the natural insecticide m-pentadecadienyl-phenol. Bidimensional electrophoresis followed by mass spectrometry resulted in identification of 12 proteins differentially expressed between control and treated groups. Larvae exposed to the toxic compound for 24h showed elevated detoxification response (glutathione-S-transferase), increased levels of stress-related proteins (HSP70) as well as evidence of lysosome stabilization to enable survival. Furthermore, expression of proteins involved in protection of peritrophic membrane and metabolism of lipids indicated systemic effect of toxic effects in treated larvae.

  20. Combining cone calorimeter and PCFC to determine the mode of action of flame retardant additives

    OpenAIRE

    LOPEZ CUESTA, José-Marie; Sonnier, Rodolphe; Ferry, Laurent; Longuet, Claire; Laoutid, Fouad; Friedrich, Blandine; Laachachi, Abdelghani

    2011-01-01

    Abstract The flammability of various flame retarded formulations containing different hydrated mineral fillers and/or phosphorous compounds and/or carbon nanotubes has been investigated using both cone calorimeter and PCFC. A method was proposed to evaluate the barrier effect of the flame retardant additives. This method is based on the fact that PCFC is non sensitive to physical flame retardant effects while both chemical and physical phenomena have a great effect on cone calorime...

  1. Cold atmospheric-pressure plasma and bacteria: understanding the mode of action using vibrational microspectroscopy

    Science.gov (United States)

    Kartaschew, Konstantin; Baldus, Sabrina; Mischo, Meike; Bründermann, Erik; Awakowicz, Peter; Havenith, Martina

    2016-09-01

    Cold atmospheric-pressure plasma show promising antimicrobial effects, however the detailed biochemical mechanism of the bacterial inactivation is still unknown. We investigated, for the first time, plasma-treated Gram-positive Bacillus subtilis and Gram-negative Escherichia coli bacteria with Raman and infrared microspectroscopy. A dielectric barrier discharge was used as a plasma source. We were able to detect several plasma-induced chemical modifications, which suggest a pronounced oxidative effect on the cell envelope, cellular proteins and nucleotides as well as a generation of organic nitrates in the treated bacteria. Vibrational microspectroscopy is used as a comprehensive and a powerful tool for the analysis of plasma interactions with whole organisms such as bacteria. Analysis of reaction kinetics of chemical modifications allow a time-dependent insight into the plasma-mediated impact. Investigating possible synergistic effects between the plasma-produced components, our observations strongly indicate that the detected plasma-mediated chemical alterations can be mainly explained by the particle effect of the generated reactive species. By changing the polarity of the applied voltage pulse, and hence the propagation mechanisms of streamers, no significant effect on the spectral results could be detected. This method allows the analysis of the individual impact of each plasma constituent for particular chemical modifications. Our approach shows great potential to contribute to a better understanding of plasma-cell interactions.

  2. Control of Postharvest Bacterial Soft Rot by Gamma Irradiation and its Potential Modes of Action

    Directory of Open Access Journals (Sweden)

    Rae-Dong Jeong

    2016-04-01

    Full Text Available Gamma irradiation was evaluated for its in vitro and in vivo antibacterial activity against a postharvest bacterial pathogen, Erwinia carotovora subsp. carotovora (Ecc. Gamma irradiation in a bacteria cell suspension resulted in a dramatic reduction of the viable counts as well as an increase in the amounts of DNA and protein released from the cells. Gamma irradiation showed complete inactivation of Ecc, especially at a dose of 0.6 kGy. In addition, scanning electron microscopy of irradiated cells revealed severe damage on the surface of most bacterial cells. Along with the morphological changes of cells by gamma irradiation, it also affected the membrane integrity in a dose-dependent manner. The mechanisms by which the gamma irradiation decreased the bacterial soft rot can be directly associated with the disruption of the cell membrane of the bacterial pathogen, along with DNA fragmentation, results in dose-dependent cell inactivation. These findings suggest that gamma irradiation has potential as an antibacterial approach to reduce the severity of the soft rot of paprika.

  3. Mode of Action of Diterpene and Characterization of Related Metabolites from the Soft Coral, Xenia elongata

    Science.gov (United States)

    Andrianasolo, Eric H.; Haramaty, Liti; White, Eileen; Lutz, Richard; Falkowski, Paul

    2014-01-01

    Chemical and biological investigation of the cultured marine soft coral Xenia elongata led to the isolation of two new diterpenes (2, 3). Their structures were elucidated using a combination of NMR and mass spectrometry. Biological evaluations and assessments were determined using the specific apoptosis induction assay based on genetically engineered mammalian cell line D3 deficient in Bak and Bax and derived from a mouse epithelial cell. The diterpenes induce apoptosis in low micromolar concentrations. The results indicate that the previously isolated compound (1) affects cell in a manner similar to that of HSP90 and HDAC inhibitors and in a manner opposite of PI3 kinase/mTOR inhibitors. Compound (3) inhibits selectively HDAC6 in high micromolar concentrations. PMID:24562393

  4. Mode of Action of Diterpene and Characterization of Related Metabolites from the Soft Coral, Xenia elongata

    Directory of Open Access Journals (Sweden)

    Eric H. Andrianasolo

    2014-02-01

    Full Text Available Chemical and biological investigation of the cultured marine soft coral Xenia elongata led to the isolation of two new diterpenes (2, 3. Their structures were elucidated using a combination of NMR and mass spectrometry. Biological evaluations and assessments were determined using the specific apoptosis induction assay based on genetically engineered mammalian cell line D3 deficient in Bak and Bax and derived from a mouse epithelial cell. The diterpenes induce apoptosis in low micromolar concentrations. The results indicate that the previously isolated compound (1 affects cell in a manner similar to that of HSP90 and HDAC inhibitors and in a manner opposite of PI3 kinase/mTOR inhibitors. Compound (3 inhibits selectively HDAC6 in high micromolar concentrations.

  5. Mode of action of dioxin-like versus non-dioxin-like PCBs

    Energy Technology Data Exchange (ETDEWEB)

    Schoeters, G. [VITO (Flemish Institute for Technological Research), Dept. of Environemental Toxicology (Belgium)]|[Antwerp Univ. (Belgium); Birnbaum, L. [United States Environmental Protection Agency, Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory (United States)

    2004-09-15

    Exposure of humans to polychlorinated biphenyls has been associated with different adverse effects such as immune impairment, changes in hormone levels, reproductive and neuropsychological changes and cancer. It is difficult to attribute the observed effects to either dioxin-like, non-dioxin-like PCBs or to both. All known human exposures are mixed, comprising dioxin and non-dioxin like PCB congeners as well as dioxins and furans. The purpose of this work was to evaluate, based on mechanistic data available in the open literature, whether non-dioxin like PCBs (NDL-PCBs) themselves may pose specific health risks. It is clear that dioxin and NDL-PCBs differ in the spectrum of metabolizing enzymes they induce, but the mechanistic links to health of these biochemical changes remain unclear at the moment. NDL-PCBs also cause immunotoxicity and tumor promotion via different mechanisms than do dioxin-like PCBs. We focus on neurotoxicity which has been associated with developmental exposure to PCBs and which is considered as one of the most sensitive adverse health effects.

  6. [Botulism: the agent, mode of action of the botulinum neurotoxins, forms of acquisition, treatment and prevention].

    Science.gov (United States)

    Marvaud, Jean-Christophe; Raffestin, Stéphanie; Popoff, Michel R

    2002-08-01

    The botulinum neurotoxins are produced by anaerobic, spore-forming bacteria belonging to the Clostridium genus. They are synthesised as a single chain protein (150 kDa), which is not or weakly active. The active form results from a proteolysis cleaving the precursor in a light chain (about 50 kDa) and a heavy chain (about 100 kDa), which are linked by a disulfide bridge. The heavy chain is involved in the recognition of a specific neuronal surface receptor and mediates the internalization of the light chain into the cytosol. The light chain is responsible for the intracellular activity. It catalyses the proteolysis of SNARE proteins, which are involved in the exocytosis of synaptic vesicles containing acetylcholine. Hence, the release of acetylcholine at the neuromuscular junction is blocked, leading to a flaccid paralysis. Human botulism, usually type A, B or E, is associated with intoxination, ingestion of preformed toxin in food, with digestive toxi-infection, mainly in newborns (infant botulism), or with wound contamination (wound botulism). The treatment of botulism is usually symptomatic. The specific treatment is based on the serotherapy or on the use of purified specific antibodies. The vaccination against botulism is efficient. However, since the botulinum neurotoxins are widely used for the treatment of numerous dystonias, a generalised vaccination is not conceivable.

  7. The Cyclic Antibacterial Peptide Enterocin AS-48: Isolation, Mode of Action, and Possible Food Applications

    Science.gov (United States)

    Grande Burgos, María José; Pérez Pulido, Rubén; López Aguayo, María del Carmen; Gálvez, Antonio; Lucas, Rosario

    2014-01-01

    Enterocin AS-48 is a circular bacteriocin produced by Enterococcus. It contains a 70 amino acid-residue chain circularized by a head-to-tail peptide bond. The conformation of enterocin AS-48 is arranged into five alpha-helices with a compact globular structure. Enterocin AS-48 has a wide inhibitory spectrum on Gram-positive bacteria. Sensitivity of Gram-negative bacteria increases in combination with outer-membrane permeabilizing treatments. Eukaryotic cells are bacteriocin-resistant. This cationic peptide inserts into bacterial membranes and causes membrane permeabilization, leading ultimately to cell death. Microarray analysis revealed sets of up-regulated and down-regulated genes in Bacillus cereus cells treated with sublethal bacteriocin concentration. Enterocin AS-48 can be purified in two steps or prepared as lyophilized powder from cultures in whey-based substrates. The potential applications of enterocin AS-48 as a food biopreservative have been corroborated against foodborne pathogens and/or toxigenic bacteria (Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus, Escherichia coli, Salmonella enterica) and spoilage bacteria (Alicyclobacillus acidoterrestris, Bacillus spp., Paenibacillus spp., Geobacillus stearothermophilus, Brochothrix thermosphacta, Staphylococcus carnosus, Lactobacillus sakei and other spoilage lactic acid bacteria). The efficacy of enterocin AS-48 in food systems increases greatly in combination with chemical preservatives, essential oils, phenolic compounds, and physico-chemical treatments such as sublethal heat, high-intensity pulsed-electric fields or high hydrostatic pressure. PMID:25493478

  8. Intravenous immunoglobulin in neurology--mode of action and clinical efficacy.

    Science.gov (United States)

    Lünemann, Jan D; Nimmerjahn, Falk; Dalakas, Marinos C

    2015-02-01

    Intravenous immunoglobulin (IVIg)-a preparation of polyclonal serum IgG pooled from thousands of blood donors-has been used for nearly three decades, and is proving to be an efficient anti-inflammatory and immunomodulatory treatment for a growing number of neurological diseases. Evidence from controlled clinical trials has established IVIg as a first-line therapy for Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. IVIg is also an effective rescue therapy in some patients with worsening myasthenia gravis, and is beneficial as a second-line therapy for dermatomyositis and stiff-person syndrome. IVIg has been tested in some neurodegenerative disorders, but a controlled study in Alzheimer disease yielded disappointing results. Despite its widespread use and therapeutic success, the mechanisms of action of IVIg are poorly understood. Several hypotheses, based on the function of either the variable or constant IgG fragments, have been proposed to explain IVIg's immunomodulatory activity. This Review highlights emerging data on the mechanisms of action of IVIg related to its anti-inflammatory activity, especially that involving the cellular Fcγ receptors and Fc glycosylation. We also summarize recent trials in neurological diseases, discuss potential biomarkers of efficacy, offer practical guidelines on administration, and provide a rationale for experimental trials in neuroinflammatory disorders.

  9. The Cyclic Antibacterial Peptide Enterocin AS-48: Isolation, Mode of Action, and Possible Food Applications

    Directory of Open Access Journals (Sweden)

    María José Grande Burgos

    2014-12-01

    Full Text Available Enterocin AS-48 is a circular bacteriocin produced by Enterococcus. It contains a 70 amino acid-residue chain circularized by a head-to-tail peptide bond. The conformation of enterocin AS-48 is arranged into five alpha-helices with a compact globular structure. Enterocin AS-48 has a wide inhibitory spectrum on Gram-positive bacteria. Sensitivity of Gram-negative bacteria increases in combination with outer-membrane permeabilizing treatments. Eukaryotic cells are bacteriocin-resistant. This cationic peptide inserts into bacterial membranes and causes membrane permeabilization, leading ultimately to cell death. Microarray analysis revealed sets of up-regulated and down-regulated genes in Bacillus cereus cells treated with sublethal bacteriocin concentration. Enterocin AS-48 can be purified in two steps or prepared as lyophilized powder from cultures in whey-based substrates. The potential applications of enterocin AS-48 as a food biopreservative have been corroborated against foodborne pathogens and/or toxigenic bacteria (Listeria monocytogenes, Bacillus cereus, Staphylococcus aureus, Escherichia coli, Salmonella enterica and spoilage bacteria (Alicyclobacillus acidoterrestris, Bacillus spp., Paenibacillus spp., Geobacillus stearothermophilus, Brochothrix thermosphacta, Staphylococcus carnosus, Lactobacillus sakei and other spoilage lactic acid bacteria. The efficacy of enterocin AS-48 in food systems increases greatly in combination with chemical preservatives, essential oils, phenolic compounds, and physico-chemical treatments such as sublethal heat, high-intensity pulsed-electric fields or high hydrostatic pressure.

  10. Thiamethoxam induced mouse liver tumors and their relevance to humans. Part 1: mode of action studies in the mouse.

    Science.gov (United States)

    Green, Trevor; Toghill, Alison; Lee, Robert; Waechter, Felix; Weber, Edgar; Noakes, James

    2005-07-01

    Thiamethoxam, a neonicotinoid insecticide, which is not mutagenic either in vitro or in vivo, caused an increased incidence of liver tumors in mice when fed in the diet for 18 months at concentrations in the range 500 to 2500 ppm. A number of dietary studies of up to 50 weeks duration have been conducted in order to identify the mode of action for the development of the liver tumors seen at the end of the cancer bioassay. Both thiamethoxam and its major metabolites have been tested in these studies. Over the duration of a 50-week thiamethoxam dietary feeding study in mice, the earliest change, within one week, is a marked reduction (by up to 40%) in plasma cholesterol. This was followed 10 weeks later by evidence of liver toxicity including single cell necrosis and an increase in apoptosis. After 20 weeks there was a significant increase in hepatic cell replication rates. All of these changes persisted from the time they were first observed until the end of the study at 50 weeks. They occurred in a dose-dependent manner and were only observed at doses (500, 1250, 2500 ppm) where liver tumors were increased in the cancer bioassay. There was a clear no-effect level of 200 ppm. The changes seen in this study are consistent with the development of liver cancer in mice and form the basis of the mode of action. When the major metabolites of thiamethoxam, CGA322704, CGA265307, and CGA330050 were tested in dietary feeding studies of up to 20 weeks duration, only metabolite CGA330050 induced the same changes as those seen in the liver in the thiamethoxam feeding study. It was concluded that thiamethoxam is hepatotoxic and hepatocarcinogenic as a result of its metabolism to CGA330050. Metabolite CGA265307 was also shown to be an inhibitor of inducible nitric oxide synthase and to increase the hepatotoxicity of carbon tetrachloride. It is proposed that CGA265307, through its effects on nitric oxide synthase, exacerbates the toxicity of CGA330050 in thiamethoxam treated mice.

  11. Toxicity, sublethal effects, and potential modes of action of select fungicides on freshwater fish and invertebrates

    Science.gov (United States)

    Elskus, Adria A.

    2012-01-01

    Despite decades of agricultural and urban use of fungicides and widespread detection of these pesticides in surface waters, relatively few data are available on the effects of fungicides on fish and invertebrates in the aquatic environment. Nine fungicides are reviewed in this report: azoxystrobin, boscalid, chlorothalonil, fludioxonil, myclobutanil, fenarimol, pyraclostrobin, pyrimethanil, and zoxamide. These fungicides were identified as emerging chemicals of concern because of their high or increasing global use rates, detection frequency in surface waters, or likely persistence in the environment. A review of the literature revealed significant sublethal effects of fungicides on fish, aquatic invertebrates, and ecosystems, including zooplankton and fish reproduction, fish immune function, zooplankton community composition, metabolic enzymes, and ecosystem processes, such as leaf decomposition in streams, among other biological effects. Some of these effects can occur at fungicide concentrations well below single-species acute lethality values (48- or 96-hour concentration that effects a response in 50 percent of the organisms, that is, effective concentration killing 50 percent of the organisms in 48 or 96 hours) and chronic sublethal values (for example, 21-day no observed adverse effects concentration), indicating that single-species toxicity values may dramatically underestimate the toxic potency of some fungicides. Fungicide modes of toxic action in fungi can sometimes reflect the biochemical and (or) physiological effects of fungicides observed in vertebrates and invertebrates; however, far more studies are needed to explore the potential to predict effects in nontarget organisms based on specific fungicide modes of toxic action. Fungicides can also have additive and (or) synergistic effects when used with other fungicides and insecticides, highlighting the need to study pesticide mixtures that occur in surface waters. For fungicides that partition to

  12. The history, chemistry and modes of action of carmine and related dyes.

    Science.gov (United States)

    Dapson, R W

    2007-08-01

    by heating. Each of the major classes of carmine-based stains is described as are possible mechanisms of attachment to specific substrates. Glycogen binds carmine through hydrogen bonding, and it is here that carmine decomposed by heat could have the greatest detrimental impact. Nuclei and chromosomes are stained via coordination bonds, perhaps supplemented by hydrogen bonds. Finally, acidic mucins react ionically with carmine. Specificity in the latter case may be due to unique polymeric carmine molecules that form in the presence of aluminum chloride.

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

    Science.gov (United States)

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

    2013-12-01

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

  14. Meleagrin, a new FabI inhibitor from Penicillium chryosogenum with at least one additional mode of action.

    Directory of Open Access Journals (Sweden)

    Chang Ji Zheng

    Full Text Available Bacterial enoyl-acyl carrier protein reductase (FabI is a promising novel antibacterial target. We isolated a new class of FabI inhibitor from Penicillium chrysogenum, which produces various antibiotics, the mechanisms of some of them are unknown. The isolated FabI inhibitor was determined to be meleagrin by mass spectroscopy and nuclear magnetic resonance spectral analyses, and its more active and inactive derivatives were chemically prepared. Consistent with their selective inhibition of Staphylococcus aureus FabI, meleagrin and its more active derivatives directly bound to S. aureus FabI in a fluorescence quenching assay, inhibited intracellular fatty acid biosynthesis and growth of S. aureus, and increased the minimum inhibitory concentration for fabI-overexpressing S. aureus. The compounds that were not effective against the FabK isoform, however, inhibited the growth of Streptococcus pneumoniae that contained only the FabK isoform. Additionally no resistant mutant to the compounds was obtained. Importantly, fabK-overexpressing Escherichia coli was not resistant to these compounds, but was resistant to triclosan. These results demonstrate that the compounds inhibited another target in addition to FabI. Thus, meleagrin is a new class of FabI inhibitor with at least one additional mode of action that could have potential for treating multidrug-resistant bacteria.

  15. Jasmine absolute (Jasminum grandiflora L.) and its mode of action on guinea-pig ileum in vitro.

    Science.gov (United States)

    Lis-Balchin, M; Hart, S; Wan Hang Lo, B

    2002-08-01

    Jasmine (Jasminum grandiflorum L.) is used in aromatherapy as a holistic treatment for apathy, hysteria, uterine disorders and childbirth, muscle relaxation and coughs. Its stimulant nature, on inhalation, has been shown both in animals and man. Jasmine has a spasmolytic activity on guinea-pig ileum and rat uterus in vitro. The mechanism of action of the spasmolytic activity, studied in vitro using a guinea-pig ileum smooth muscle preparation, was postsynaptic and not atropine-like. The spasmolytic effect of jasmine absolute was most likely to be mediated through cAMP, and not through cGMP. The mode of action in vitro resembled that of geranium, lavender and peppermint oils. The contradictory effect in vitro and in vivo is probably due to the solely physiological effects of jasmine absolute in vitro (producing a relaxation) compared with that in vivo, where it has a strong psychological input, producing a stimulant effect in man and enhanced movement in animals. Copyright 2002 John Wiley & Sons, Ltd.

  16. The Mode of Action of Cyclo(l-Ala-l-Pro) in Inhibiting Aflatoxin Production of Aspergillus flavus.

    Science.gov (United States)

    Iimura, Kurin; Furukawa, Tomohiro; Yamamoto, Toshiyoshi; Negishi, Lumi; Suzuki, Michio; Sakuda, Shohei

    2017-07-12

    Cyclo(l-Ala-l-Pro) inhibits aflatoxin production in aflatoxigenic fungi without affecting fungal growth. The mode of action of cyclo(l-Ala-l-Pro) in inhibiting aflatoxin production of Aspergillus flavus was investigated. A glutathione S-transferase (GST) of the fungus, designated AfGST, was identified as a binding protein of cyclo(l-Ala-l-Pro) in an experiment performed using cyclo(l-Ala-l-Pro)-immobilized Sepharose beads. Cyclo(l-Ala-l-Pro) specifically bound to recombinant AfGST and inhibited its GST activity. Ethacrynic acid, a known GST inhibitor, inhibited the GST activity of recombinant AfGST and aflatoxin production of the fungus. Ethacrynic acid reduced the expression level of AflR, a key regulatory protein for aflatoxin production, similar to cyclo(l-Ala-l-Pro). These results suggest that cyclo(l-Ala-l-Pro) inhibits aflatoxin production by affecting GST function in A. flavus, and that AfGST inhibitors are possible candidates as selective aflatoxin production inhibitors.

  17. Three toxins, two receptors, one mechanism: Mode of action of Cry1A toxins from Bacillus thuringiensis in Heliothis virescens.

    Science.gov (United States)

    Bretschneider, Anne; Heckel, David G; Pauchet, Yannick

    2016-09-01

    Insecticidal crystal (Cry) proteins from Bacillus thuringiensis (Bt) are highly active against Lepidoptera. However, field-evolved resistance to Bt toxins is on the rise. The 12-cadherin domain protein HevCaLP and the ABC transporter HevABCC2 are both genetically linked to Cry toxin resistance in Heliothis virescens. We investigated their interaction using stably expressing non-lytic clonal Sf9 cell lines expressing either protein or both together. Untransfected Sf9 cells are innately sensitive to Cry1Ca toxin, but not to Cry1A toxins; and quantitative PCR revealed negligible expression of genes involved in Cry1A toxicity such as cadherin, ABCC2, alkaline phosphatase (ALP) and aminopeptidase N (APN). Cry1Aa, Cry1Ab or Cry1Ac caused swelling of Sf9 cells expressing HevABCC2, and caused faster swelling, lysis and up to 86% mortality in cells expressing both proteins. No such effect was observed in control Sf9 cells or in cells expressing only HevCaLP. The results of a mixing experiment demonstrated that both proteins need to be expressed within the same cell for high cytotoxicity, and suggest a novel role for HevCaLP. Binding assays showed that the toxin-receptor interaction is specific. Our findings confirm that HevABCC2 is the central target in Cry1A toxin mode of action, and that HevCaLP plays a supporting role in increasing Cry1A toxicity.

  18. BDE-99 impairs differentiation of human and mouse NPCs into the oligodendroglial lineage by species-specific modes of action.

    Science.gov (United States)

    Dach, Katharina; Bendt, Farina; Huebenthal, Ulrike; Giersiefer, Susanne; Lein, Pamela J; Heuer, Heike; Fritsche, Ellen

    2017-03-20

    Polybrominated diphenyl ethers (PBDEs) are bioaccumulating flame retardants causing developmental neurotoxicity (DNT) in humans and rodents. Their DNT effects are suspected to involve thyroid hormone (TH) signaling disruption. Here, we tested the hypothesis whether disturbance of neural progenitor cell (NPC) differentiation into the oligodendrocyte lineage (O4(+) cells) by BDE-99 involves disruption of TH action in human and mouse (h,m)NPCs. Therefore, we quantified differentiation of NPCs into O4(+) cells and measured their maturation via expression of myelin-associated genes (hMBP, mMog) in presence and absence of TH and/or BDE-99. T3 promoted O4(+) cell differentiation in mouse, but not hNPCs, and induced hMBP/mMog gene expression in both species. BDE-99 reduced generation of human and mouse O4(+) cells, but there is no indication for BDE-99 interfering with cellular TH signaling during O4(+) cell formation. BDE-99 reduced hMBP expression due to oligodendrocyte reduction, but concentrations that did not affect the number of mouse O4(+) cells inhibited TH-induced mMog transcription by a yet unknown mechanism. In addition, ascorbic acid antagonized only the BDE-99-dependent loss of human, not mouse, O4(+) cells by a mechanism probably independent of reactive oxygen species. These data point to species-specific modes of action of BDE-99 on h/mNPC development into the oligodendrocyte lineage.

  19. Cloning, functional characterization, and mode of action of a novel insecticidal pore-forming toxin, sphaericolysin, produced by Bacillus sphaericus.

    Science.gov (United States)

    Nishiwaki, Hisashi; Nakashima, Kenta; Ishida, Chiharu; Kawamura, Tadayuki; Matsuda, Kazuhiko

    2007-05-01

    An insecticidal protein produced by Bacillus sphaericus A3-2 was purified to elucidate its structure and mode of action. The active principle purified from the culture broth of A3-2 was a protein with a molecular mass of 53 kDa that rapidly intoxicated German cockroaches (Blattela germanica) at a dose of about 100 ng when injected. The insecticidal protein sphaericolysin possessed the undecapeptide motif of cholesterol-dependent cytolysins and had a unique N-terminal sequence. The recombinant protein expressed in Escherichia coli was equally as potent as the native protein. Sphaericolysin-induced hemolysis resulted from the protein's pore-forming action. This activity as well as the insecticidal activity was markedly reduced by a Y159A mutation. Also, coapplication of sphaericolysin with cholesterol abolished the insecticidal action, suggesting that cholesterol binding plays an important role in insecticidal activity. Sphaericolysin-lysed neurons dissociated from the thoracic ganglia of the German cockroaches. In addition, sphaericolysin's activity in ganglia was suppressed by the Y159A mutation. The sphaericolysin-induced damage to the cockroach ganglia was greater than the damage to the ganglia of common cutworms (Spodoptera litura), which accounts, at least in part, for the higher sensitivity to sphaericolysin displayed by the cockroaches than that displayed by cutworms.

  20. Efficacy of combined formulations of fungicides with different modes of action in controlling botrytis gray mold disease in chickpea.

    Science.gov (United States)

    Rashid, M H; Hossain, M Ashraf; Kashem, M A; Kumar, Shiv; Rafii, M Y; Latif, M A

    2014-01-01

    Botrytis gray mold (BGM) caused by Botrytis cinerea Pers. Ex. Fr. is an extremely devastating disease of chickpea (Cicer arietinum L.) and has a regional as well as an international perspective. Unfortunately, nonchemical methods for its control are weak and ineffective. In order to identify an effective control measure, six fungicides with different modes of action were evaluated on a BGM susceptible chickpea variety BARIchhola-1 at a high BGM incidence location (Madaripur) in Bangladesh for three years (2008, 2009, and 2010). Among the six fungicides tested, one was protectant [Vondozeb 42SC, a.i. mancozeb (0.2%)], two systemic [Bavistin 50 WP, a.i. carbendazim (0.2%), and Protaf 250EC, propiconazole (0.05%)], and three combination formulations [Acrobat MZ690, dimethomorph 9% + mancozeb 60%, (0.2%); Secure 600 WG, phenomadone + mancozeb (0.2%); and Companion, mancozeb 63% + carbendazim 12% (0.2%)]. The results showed superiority of combination formulations involving both protectant and systemic fungicides over the sole application of either fungicide separately. Among the combination fungicides, Companion was most effective, resulting in the lowest disease severity (3.33 score on 1-9 scale) and the highest increase (38%) of grain yield in chickpea. Therefore, this product could be preferred over the sole application of either solo protectant or systemic fungicides to reduce yield losses and avoid fungicide resistance.

  1. Mode of action of dopamine in inducing hyperglycemia in the fresh water edible crab, Oziothelphusa senex senex.

    Science.gov (United States)

    Swetha, Ch; Sainath, S B; Reddy, P Sreenivasula

    2014-11-01

    The objective of this study was to investigate the mode of action of dopamine in regulating hemolymph sugar level in the fresh water edible crab, Oziothelphusa senex senex. Injection of dopamine produced hyperglycemia in a dose-dependent manner in intact crabs but not in eyestalkless crabs. Administration of dopamine resulted in a significant decrease in total carbohydrates and glycogen levels with a significant increase in glycogen phosphorylase activity levels in hepatopancreas and muscle of intact crabs, indicating dopamine-induced glycogenolysis resulting in hyperglycemia. Bilateral eyestalk ablation resulted in significant increase in the total carbohydrates and glycogen levels with a significant decrease in the activity levels of phosphorylase in the hepatopancreas and muscle of the crabs. Eyestalk ablation resulted in significant decrease in hemolymph hyperglycemic hormone levels. The levels of hyperglycemic hormone in the hemolymph of dopamine injected crabs were significantly higher than in control crabs. However, no significant changes in the levels of hemolymph hyperglycemic hormone and sugar and tissue carbohydrate and phosphorylase activity were observed in dopamine injected eyestalk ablated crabs when compared with eyestalk ablated crabs. These results support an earlier hypothesis in crustaceans that dopamine acts as a neurotransmitter and induces hyperglycemia by triggering the release of hyperglycemic hormone in the crab, O. senex senex. © 2014 Wiley Periodicals, Inc.

  2. Cadmium and naphthalene-induced hyperglycemia in the fiddler crab, Uca pugilator: Differential modes of action on the neutroendocrine system

    Energy Technology Data Exchange (ETDEWEB)

    Reddy, P.S.; Katyayani, R.V.; Fingerman, M. [Tulane Univ., New Orleans, LA (United States)

    1996-03-01

    Hyperglycemia is a typical response of aquatic organisms to heavy metals. In crustaceans, the medulla terminalis X-organ-sinus gland neuroendocrine complex in the eyestalk is the source of the crustacean hyperglycemic hormone (CHH). The role of CHH in pollutant-induced b1ood glucose changes has only recently begun to be studied. Reddy provided evidence that CHH mediates cadmium-induced hyperglycemia in the red swamp crayfish, Procambarus clarkii. In a study of another hormonally-regulated function, color changes, cadmium exposure resulted in pigment in the melanophores of the fiddler crab, Uca pugilator, becoming less dispersed than in unexposed crabs. Earlier studies showed that, like cadmium, both a PCB, Aroclor 1242, and naphthalene induced black pigment aggregation in Uca poor. In general, when crabs are exposed to a pollutant, hydrocarbon or cadmium, they aggregate the pigment in their melanophores, but apparently by different mechanisms. Hydrocarbons appear to inhibit release of black pigment-dispersing hormone (BDPH), whereas cadmium appears to inhibit its synthesis. These apparent different modes of action of cadmium and naphthalene on the color change mechanism led us to compare the impact of these pollutants on the hormonal regulation of blood glucose in Uca pugilator. The present study was performed to determine (1) whether cadmium and naphthalene induce hyperglycemia in Uca pugilator, (2) whether CH has a role, if naphthalene and cadmium do induce hyperglycemia, and (3) the effects, if any, of cadmium and naphthalene on CHH activity in the eyestalk neuroendocrine complex.

  3. Antibacterial Activities and Possible Modes of Action of Acacia nilotica (L. Del. against Multidrug-Resistant Escherichia coli and Salmonella

    Directory of Open Access Journals (Sweden)

    Muhammad Bilal Sadiq

    2017-01-01

    Full Text Available Medicinal plants are frequently used for the treatment of various infectious diseases. The objective of this study was to evaluate the antibacterial activity and mode of action of Acacia nilotica and the antibiogram patterns of foodborne and clinical strains of Escherichia coli and Salmonella. The mechanism of action of acacia extracts against E. coli and Salmonella was elucidated by observing morphological damages including cell integrity and cell membrane permeability, as well as changes in cell structures and growth patterns in kill-time experiments. The clinical isolates of E. coli and Salmonella were found resistant to more of the tested antibiotics, compared to food isolates. Minimum inhibitory concentration and minimum bactericidal concentration of acacia leaf extracts were in the ranges of 1.56–3.12 mg/mL and 3.12–6.25 mg/mL, respectively, whereas pods and bark extracts showed somewhat higher values of 3.12–6.25 mg/mL and 6.25–12.5 mg/mL, respectively, against all tested pathogens. The release of electrolytes and essential cellular constituents (proteins and nucleic acids indicated that acacia extracts damaged the cellular membrane of the pathogens. These changes corresponded to simultaneous reduction in the growth of viable bacteria. This study indicates that A. nilotica can be a potential source of new antimicrobials, effective against antibiotic-resistant strains of pathogens.

  4. Purification, characterization, and mode of action of a rhamnogalacturonan hydrolase from Irpex lacteus, tolerant to an acetylated substrate.

    Science.gov (United States)

    Normand, Jessica; Ralet, Marie-Christine; Thibault, Jean-François; Rogniaux, Hélène; Delavault, Philippe; Bonnin, Estelle

    2010-03-01

    A novel rhamnogalacturonase (RGase) acting on an acetylated substrate was detected in the commercial preparation Driselase, an enzymatic mixture derived from the basidiomycete Irpex lacteus. The activity was isolated by hydrophobic interaction chromatography, gel filtration, and preparative isoelectric focusing, resulting in the isolation of five different rhamnogalacturonan hydrolases exhibiting various isoelectric points from 6.2 to 7.7. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and mass spectrometry analyses after trypsin cleavage of the five fractions revealed that the five rhamnogalacturonases have a molar mass of 55 kDa without any divergences in the identified peptides. The RGase with a pI of 7.2 exhibited a pH optimum between 4.5 and 5 and a temperature optimum between 40 degrees C and 50 degrees C. Its mode of action was analyzed by mass spectrometry of the oligosaccharides produced after hydrolysis of acetylated and nonacetylated rhamnogalacturonan. Oligomers esterified by an acetyl group on the reducing galacturonic acid residue or fully acetylated were detected in the hydrolysate showing that the novel enzyme is able to bind acetylated galacturonic acid in its active site.

  5. Identification of antifungal natural products via Saccharomyces cerevisiae bioassay: insights into macrotetrolide drug spectrum, potency and mode of action.

    Science.gov (United States)

    Tebbets, Brad; Yu, Zhiguo; Stewart, Douglas; Zhao, Li-Xing; Jiang, Yi; Xu, Li-Hua; Andes, David; Shen, Ben; Klein, Bruce

    2013-04-01

    Since current antifungal drugs have not kept pace with the escalating medical demands of fungal infections, new, effective medications are required. However, antifungal drug discovery is hindered by the evolutionary similarity of mammalian and fungal cells, which results in fungal drug targets having human homologs and drug non-selectivity. The group III hybrid histidine kinases (HHKs) are an attractive drug target since they are conserved in fungi and absent in mammals. We used a Saccharomyces cerevisiae reporter strain that conditionally expresses HHK to establish a high-throughput bioassay to screen microbial extracts natural products for antifungals. We identified macrotetrolides, a group of related ionophores thought to exhibit restricted antifungal activity. In addition to confirming the use of this bioassay for the discovery of antifungal natural products, we demonstrated broader, more potent fungistatic activity of the macrotetrolides against multiple Candida spp., Cryptococcus spp., and Candida albicans in biofilms. Macrotetrolides were also active in an animal model of C. albicans biofilm, but were found to have inconsistent activity against fluconazole-resistant C. albicans, with most isolates resistant to this natural product. The macrotetrolides do not directly target HHKs, but their selective activity against S. cerevisiae grown in galactose (regardless of Drk1 expression) revealed potential new insight into the role of ion transport in the mode of action of these promising antifungal compounds. Thus, this simple, high-throughput bioassay permitted us to screen microbial extracts, identify natural products as antifungal drugs, and expand our understanding of the activity of macrotetrolides.

  6. Bacillus thuringiensis insecticidal three-domain Cry toxins: mode of action, insect resistance and consequences for crop protection.

    Science.gov (United States)

    Pardo-López, Liliana; Soberón, Mario; Bravo, Alejandra

    2013-01-01

    Bacillus thuringiensis bacteria are insect pathogens that produce different Cry and Cyt toxins to kill their hosts. Here we review the group of three-domain Cry (3d-Cry) toxins. Expression of these 3d-Cry toxins in transgenic crops has contributed to efficient control of insect pests and a reduction in the use of chemical insecticides. The mode of action of 3d-Cry toxins involves sequential interactions with several insect midgut proteins that facilitate the formation of an oligomeric structure and induce its insertion into the membrane, forming a pore that kills midgut cells. We review recent progress in our understanding of the mechanism of action of these Cry toxins and focus our attention on the different mechanisms of resistance that insects have evolved to counter their action, such as mutations in cadherin, APN and ABC transporter genes. Activity of Cry1AMod toxins, which are able to form toxin oligomers in the absence of receptors, against different resistant populations, including those affected in the ABC transporter and the role of dominant negative mutants as antitoxins, supports the hypothesis that toxin oligomerization is a limiting step in the Cry insecticidal activity. Knowledge of the action of 3d-Cry toxin and the resistance mechanisms to these toxins will set the basis for a rational design of novel toxins to overcome insect resistance, extending the useful lifespan of Cry toxins in insect control programs.

  7. Mode of Action and Specificity of Bacillus thuringiensis Toxins in the Control of Caterpillars and Stink Bugs in Soybean Culture.

    Science.gov (United States)

    Schünemann, Rogério; Knaak, Neiva; Fiuza, Lidia Mariana

    2014-01-01

    The bacterium Bacillus thuringiensis (Bt) produces delta-endotoxins that possess toxic properties and can be used as biopesticides, as well as a source of genes for the construction of transgenic plants resistant to insects. In Brazil, the introduction of Bt soybean with insecticidal properties to the velvetbean caterpillar, the main insect pest of soybean, has been seen a promising tool in the management of these agroecosystems. However, the increase in stink bug populations in this culture, in various regions of the country, which are not susceptible to the existing genetically modified plants, requires application of chemicals that damage the environment. Little is known about the actual toxicity of Bt to Hemiptera, since these insects present sucking mouthparts, which hamper toxicity assays with artificial diets containing toxins of this bacterium. In recent studies of cytotoxicity with the gut of different hemipterans, susceptibility in the mechanism of action of delta-endotoxins has been demonstrated, which can generate promising subsidies for the control of these insect pests in soybean. This paper aims to review the studies related to the selection, application and mode of action of Bt in the biological control of the major pest of soybean, Anticarsia gemmatalis, and an analysis of advances in research on the use of Bt for control hemipterans.

  8. Efficacy of Combined Formulations of Fungicides with Different Modes of Action in Controlling Botrytis Gray Mold Disease in Chickpea

    Directory of Open Access Journals (Sweden)

    M. H. Rashid

    2014-01-01

    Full Text Available Botrytis gray mold (BGM caused by Botrytis cinerea Pers. Ex. Fr. is an extremely devastating disease of chickpea (Cicer arietinum L. and has a regional as well as an international perspective. Unfortunately, nonchemical methods for its control are weak and ineffective. In order to identify an effective control measure, six fungicides with different modes of action were evaluated on a BGM susceptible chickpea variety BARIchhola-1 at a high BGM incidence location (Madaripur in Bangladesh for three years (2008, 2009, and 2010. Among the six fungicides tested, one was protectant [Vondozeb 42SC, a.i. mancozeb (0.2%], two systemic [Bavistin 50 WP, a.i. carbendazim (0.2%, and Protaf 250EC, propiconazole (0.05%], and three combination formulations [Acrobat MZ690, dimethomorph 9% + mancozeb 60%, (0.2%; Secure 600 WG, phenomadone + mancozeb (0.2%; and Companion, mancozeb 63% + carbendazim 12% (0.2%]. The results showed superiority of combination formulations involving both protectant and systemic fungicides over the sole application of either fungicide separately. Among the combination fungicides, Companion was most effective, resulting in the lowest disease severity (3.33 score on 1–9 scale and the highest increase (38% of grain yield in chickpea. Therefore, this product could be preferred over the sole application of either solo protectant or systemic fungicides to reduce yield losses and avoid fungicide resistance.

  9. Unraveling the role of fermentation in the mode of action of acetolactate synthase inhibitors by metabolic profiling.

    Science.gov (United States)

    Zabalza, Ana; Orcaray, Luis; Igal, María; Schauer, Nicolas; Fernie, Alisdair R; Geigenberger, Peter; van Dongen, Joost T; Royuela, Mercedes

    2011-09-01

    Herbicides that inhibit branched chain amino acid biosynthesis induce aerobic fermentation. The role of fermentation in the mode of action of these herbicides is not known, nor is the importance of this physiological response in the growth inhibition and the lethality caused by them. Metabolic profiling was used to compare the effects of the herbicide imazethapyr (IM) on pea plants with two other treatments that also induce fermentation: hypoxia and the exogenous supply pyruvate for seven days. While hypoxic roots did not show internal anoxia, feeding pyruvate or applying IM to the roots led to internal anoxia, probably related to the respiratory burst detected. The three treatments induced ethanol fermentation, but fermentation induced following herbicide treatment was earlier than that following pyruvate supply and was not associated with a decrease in the energy status. No striking changes were detected in the metabolic profiling of hypoxic roots, indicating that metabolism was only slightly impaired. Feeding pyruvate resulted in marked succinate accumulation and a general amino acid accumulation. IM-treated roots showed a general accumulation of glycolytic metabolites upstream of pyruvate, a decrease in some TCA intermediates and an increase in the free amino acid pool sizes. All treatments caused GABA and putrescine accumulation. Our results indicate that IM supply impairs carbon/nitrogen metabolism and this impaired metabolism is likely to be related to the growth arrest detected. As growth is arrested, carbohydrates and glycolytic intermediates accumulate and energy becomes more available.

  10. Developmental Triclosan Exposure Decreases Maternal,Fetal, and Early Neonatal Thyroxine: Dynamic and Kinetic Data Support for a Mode-of-Action

    Science.gov (United States)

    This work tests the mode-of-action (MOA) hypothesis that perinatal triclosan (TCS) exposure decreases circulating thyroxine (T4) concentrations via activation of pregnane X and/or constitutive androstane receptors (PXR, CAR), resulting in up-regulation of hepatic catabolism and e...

  11. Use of Electroencephalography (EEG) to Assess CNS Changes Produced by Pesticides with different Modes of Action: Effects of Permethrin, Deltamethrin, Fipronil, Imidacloprid, Carbaryl, and Triadimefon

    Science.gov (United States)

    The electroencephalogram (EEG) is an apical measure, capable of detecting changes in brain neuronal activity produced by internal or external stimuli. We assessed whether pesticides with different modes of action produced different changes in the EEG of adult male Long-Evans rats...

  12. Use of Electroencephalography (EEG) to Assess CNS Changes Produced by Pesticides with different Modes of Action: Effects of Permethrin, Deltamethrin, Fipronil, Imidacloprid, Carbaryl, and Triadimefon

    Science.gov (United States)

    The electroencephalogram (EEG) is an apical measure, capable of detecting changes in brain neuronal activity produced by internal or external stimuli. We assessed whether pesticides with different modes of action produced different changes in the EEG of adult male Long-Evans rats...

  13. DIFFICULTY OF MODE OF ACTION DETERMINATION FOR TRICHLOROETHYLENE: AN EXAMPLE OF COMPLEX INTERACTIONS OF METABOLITES AND OTHER CHEMICAL EXPOSURES (Journal Article)

    Science.gov (United States)

    The mode(s) of action (MOA) of a pollutant for adverse health effects may be dependent on the mixture of metabolites resulting from exposure to a single agent and may also be affected by co-exposure to pollutants that have similar targets or affected pathways. Trichloroethylene ...

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

    Science.gov (United States)

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

  15. Mode of action of human pharmaceuticals in fish: the effects of the 5-alpha-reductase inhibitor, dutasteride, on reproduction as a case study.

    Science.gov (United States)

    Margiotta-Casaluci, Luigi; Hannah, Robert E; Sumpter, John P

    2013-03-15

    In recent years, a growing number of human pharmaceuticals have been detected in the aquatic environment, generally at low concentrations (sub-ng/L-low μg/L). In most cases, these compounds are characterised by highly specific modes of action, and the evolutionary conservation of drug targets in wildlife species suggests the possibility that pharmaceuticals present in the environment may cause toxicological effects by acting through the same targets as they do in humans. Our research addressed the question of whether or not dutasteride, a pharmaceutical used to treat benign prostatic hyperplasia, may cause adverse effects in a teleost fish, the fathead minnow (Pimephales promelas), by inhibiting the activity of both isoforms of 5α-reductase (5αR), the enzyme that converts testosterone into dihydrotestosterone (DHT). Mammalian pharmacological and toxicological information were used to guide the experimental design and the selection of relevant endpoints, according to the so-called "read-across approach", suggesting that dutasteride may affect male fertility and steroid hormone dynamics. Therefore, a 21-day reproduction study was conducted to determine the effects of dutasteride (10, 32 and 100 μg/L) on fish reproduction. Exposure to dutasteride significantly reduced fecundity of fish and affected several aspects of reproductive endocrine functions in both males and females. However, none of the observed adverse effects occurred at concentrations of exposure lower than 32 μg/L; this, together with the low volume of drug prescribed every year (10.34 kg in the UK in 2011), and the extremely low predicted environmental concentration (0.03 ng/L), suggest that, at present, the potential presence of dutasteride in the environment does not represent a threat to wild fish populations.

  16. Evaluating genotoxicity data to identify a mode of action and its application in estimating cancer risk at low doses: A case study involving carbon tetrachloride.

    Science.gov (United States)

    Eastmond, David A

    2008-03-01

    In the new USEPA cancer risk assessment guidelines, mode of action (MoA) information, combined with a determination of whether or not a chemical is mutagenic, plays an important role in determining whether a linear or nonlinear approach should be used to estimate cancer risks at low doses. In this article, carbon tetrachloride (CT) is used as an example to illustrate how mixed genotoxicity data can be evaluated and used to identify a likely MoA. CT is essentially negative in inducing gene mutations in Salmonella, but is consistently positive in inducing recombination and aneuploidy in fungi. Negative or equivocal results were seen in most in vitro and in vivo studies in mammals, including mutation studies in transgenic mice. However, DNA adducts, primarily those derived from oxidation- and lipid-peroxidation-derived products as well as DNA double-strand breaks and micronucleated cells, have been seen repeatedly in the liver of CT-treated animals. On the basis of the weight of evidence, CT should not be considered a directly mutagenic agent. Mutagenic as well as other genotoxic effects, as they occur, will most likely be generated through indirect mechanisms resulting from oxidative and lipid peroxidative damage and/or damage occurring during necrosis or apoptosis. As key events in this process are expected to occur in a nonlinear fashion, the expected relationship between CT dose and carcinogenic response in the liver is likely to be nonlinear with a steep dose response. This conclusion is consistent with rodent cancer bioassay results in which steep nonlinear dose responses have been seen.

  17. Mode-of-Action Uncertainty for Dual-Mode Carcinogens:Lower Bounds for Naphthalene-Induced Nasal Tumors in Rats Implied byPBPK and 2-Stage Stochastic Cancer Risk Models

    Energy Technology Data Exchange (ETDEWEB)

    Bogen, K T

    2007-01-30

    As reflected in the 2005 USEPA Guidelines for Cancer Risk Assessment, some chemical carcinogens may have a site-specific mode of action (MOA) that is dual, involving mutation in addition to cell-killing induced hyperplasia. Although genotoxicity may contribute to increased risk at all doses, the Guidelines imply that for dual MOA (DMOA) carcinogens, judgment be used to compare and assess results obtained using separate ''linear'' (genotoxic) vs. ''nonlinear'' (nongenotoxic) approaches to low-level risk extrapolation. However, the Guidelines allow the latter approach to be used only when evidence is sufficient to parameterize a biologically based model that reliably extrapolates risk to low levels of concern. The Guidelines thus effectively prevent MOA uncertainty from being characterized and addressed when data are insufficient to parameterize such a model, but otherwise clearly support a DMOA. A bounding factor approach--similar to that used in reference dose procedures for classic toxicity endpoints--can address MOA uncertainty in a way that avoids explicit modeling of low-dose risk as a function of administered or internal dose. Even when a ''nonlinear'' toxicokinetic model cannot be fully validated, implications of DMOA uncertainty on low-dose risk may be bounded with reasonable confidence when target tumor types happen to be extremely rare. This concept was illustrated for the rodent carcinogen naphthalene. Bioassay data, supplemental toxicokinetic data, and related physiologically based pharmacokinetic and 2-stage stochastic carcinogenesis modeling results all clearly indicate that naphthalene is a DMOA carcinogen. Plausibility bounds on rat-tumor-type specific DMOA-related uncertainty were obtained using a 2-stage model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2- and 1,4-naphthoquinone. Resulting

  18. Synergistic anti-candidal activity and mode of action of Mentha piperita essential oil and its major components.

    Science.gov (United States)

    Samber, Neha; Khan, Amber; Varma, Ajit; Manzoor, Nikhat

    2015-01-01

    Mentha piperita L. (Lamiaceae) has been used in folk medicine since antiquity. Its essential oil (mint EO) and major bioactive components have antimicrobial properties but their mechanism of action is still not clear. The present work aims to elucidate M. piperita's anti-Candida activity and mode of action. Chemical constituents of mint EO were identified by GC-MS by injecting 0.1 ml sample in a splitless mode. MIC was determined by the broth dilution method. Synergy with fluconazole (FLC) was evaluated by checkerboard assay and FICI. Mid log phase cells harvested from YPD media were used for proton extrusion measurement and the rate of glucose-induced H(+) efflux gives PM-ATPase activity. Cell membrane integrity was estimated by total ergosterol content and scanning microscopy at respective MIC and sub-MIC values. In vitro hemolytic activity was performed to rule out possible cytotoxicity of the test compounds. The MIC value of mint EO, carvone, menthol, and menthone was 225, 248, 500, and 4200 µg/ml, respectively. At their respective MICs, these compounds showed 47, 42, 35, and 29% decrease in PM-ATPase activity besides showing synergy with FLC. In case of FLC-resistant strains, the decrease in H(+) efflux was by 52, 48, 32, and 30%, a trend similar to the susceptible cases. Exposed Candida cells showed a 100% decrease in the ergosterol content, cell membrane breakage, and alterations in morphology. Our studies suggest that mint EO and its lead compounds exert antifungal activity by reducing ergosterol levels, inhibiting PM-ATPase leading to intracellular acidification, and ultimately cell death. Our results suggest that mint EO and its constituents are potential antifungal agents and need to be further investigated.

  19. Mode of action and variability in efficacy of plant essential oils showing toxicity against the poultry red mite, Dermanyssus gallinae.

    Science.gov (United States)

    George, D R; Smith, T J; Shiel, R S; Sparagano, O A E; Guy, J H

    2009-05-12

    This paper describes a series of experiments to examine the mode of action and toxicity of three plant essential oils (thyme, manuka and pennyroyal) to the poultry red mite, Dermanyssus gallinae (De Geer), a serious ectoparasitic pest of laying hens. All three oils were found to be toxic to D. gallinae in laboratory tests with LC(50), LC(90) and LC(99) values below 0.05, 0.20 and 0.30mg/cm(3), respectively, suggesting that these products may make for effective acaricides against this pest. Further experiments demonstrated that when mites were exposed to only the vapour phase of the essential oil without contact with the oil itself, mortality was consistently higher in closed arenas than in arenas open to the surrounding environment, or in control arenas. This suggests that all three essential oils were toxic to D. gallinae by fumigant action. In addition, in an experiment where mites were allowed contact with the essential oil in either open or closed arenas, mortality was always reduced in the open arenas where this was comparable to control mortality for thyme and pennyroyal essential oil treatments. This supports the findings of the previous experiment and also suggests that, with the possible exception of manuka, the selected essential oils were not toxic to D. gallinae on contact. Statistical comparisons were made between the toxicity of the selected essential oils to D. gallinae in the current work and in a previous study conducted in the same laboratory. The results demonstrated considerable variation in LC(50), LC(90) and LC(99) values. Since both the essential oils and the mites were obtained from identical sources in the two studies, it is hypothesized that this variation resulted from the use of different 'batches' of essential oil, which could have varied in chemistry and hence acaricidal activity.

  20. Anticancer drug mithramycin interacts with core histones: An additional mode of action of the DNA groove binder

    Directory of Open Access Journals (Sweden)

    Amrita Banerjee

    2014-01-01

    Full Text Available Mithramycin (MTR is a clinically approved DNA-binding antitumor antibiotic currently in Phase 2 clinical trials at National Institutes of Health for treatment of osteosarcoma. In view of the resurgence in the studies of this generic antibiotic as a human medicine, we have examined the binding properties of MTR with the integral component of chromatin – histone proteins – as a part of our broad objective to classify DNA-binding molecules in terms of their ability to bind chromosomal DNA alone (single binding mode or both histones and chromosomal DNA (dual binding mode. The present report shows that besides DNA, MTR also binds to core histones present in chromatin and thus possesses the property of dual binding in the chromatin context. In contrast to the MTR–DNA interaction, association of MTR with histones does not require obligatory presence of bivalent metal ion like Mg2+. As a consequence of its ability to interact with core histones, MTR inhibits histone H3 acetylation at lysine 18, an important signature of active chromatin, in vitro and ex vivo. Reanalysis of microarray data of Ewing sarcoma cell lines shows that upon MTR treatment there is a significant down regulation of genes, possibly implicating a repression of H3K18Ac-enriched genes apart from DNA-binding transcription factors. Association of MTR with core histones and its ability to alter post-translational modification of histone H3 clearly indicates an additional mode of action of this anticancer drug that could be implicated in novel therapeutic strategies.

  1. Mutant analysis in Arabidopsis provides insight into the molecular mode of action of the auxinic herbicide dicamba.

    Directory of Open Access Journals (Sweden)

    Cynthia Gleason

    Full Text Available Herbicides that mimic the natural auxin indole-3-acetic acid are widely used in weed control. One common auxin-like herbicide is dicamba, but despite its wide use, plant gene responses to dicamba have never been extensively studied. To further understand dicamba's mode of action, we utilized Arabidopsis auxin-insensitive mutants and compared their sensitivity to dicamba and the widely-studied auxinic herbicide 2,4-dichlorophenoxyacetic acid (2,4-D. The mutant axr4-2, which has disrupted auxin transport into cells, was resistant to 2,4-D but susceptible to dicamba. By comparing dicamba resistance in auxin signalling F-box receptor mutants (tir1-1, afb1, afb2, afb3, and afb5, only tir1-1 and afb5 were resistant to dicamba, and this resistance was additive in the double tir1-1/afb5 mutant. Interestingly, tir1-1 but not afb5 was resistant to 2,4-D. Whole genome analysis of dicamba-induced gene expression showed that 10 hours after application, dicamba stimulated many stress-responsive and signalling genes, including those involved in biosynthesis or signalling of auxin, ethylene, and abscisic acid (ABA, with TIR1 and AFB5 required for the dicamba-responsiveness of some genes. Research into dicamba-regulated gene expression and the selectivity of auxin receptors has provided molecular insight into dicamba-regulated signalling and could help in the development of novel herbicide resistance in crop plants.

  2. Mechanistic insights into mode of action of potent natural antagonists of BACE-1 for checking Alzheimer’s plaque pathology

    Energy Technology Data Exchange (ETDEWEB)

    Dhanjal, Jaspreet Kaur [School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067 (India); Goyal, Sukriti [Apaji Institute of Mathematics and Applied Computer Technology, Banasthali University, Tonk 304022, Rajasthan (India); Sharma, Sudhanshu [Department of Biotechnology, Delhi Technological University, New Delhi 110042 (India); Hamid, Rabia [Department of Biochemistry, University of Kashmir, Srinagar 190006 (India); Grover, Abhinav, E-mail: abhinavgr@gmail.com [School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067 (India)

    2014-01-17

    Highlights: •Accumulation of Aβ plaques is one of the major pathology associated with Alzheimer’s disease. •Inhibition of β-Secretase or BACE-1 offers a viable prospect to check the growth of these plaques. •A large virtual dataset of natural compounds was screened against BACE-1. •Top two hits were analyzed for thermodynamic and structural stability using MD simulations. •Their detailed binding mode of actions were elucidated. -- Abstract: Alzheimer’s is a neurodegenerative disorder resulting in memory loss and decline in cognitive abilities. Accumulation of extracellular beta amyloidal plaques is one of the major pathology associated with this disease. β-Secretase or BACE-1 performs the initial and rate limiting step of amyloidic pathway in which 37–43 amino acid long peptides are generated which aggregate to form plaques. Inhibition of this enzyme offers a viable prospect to check the growth of these plaques. Numerous efforts have been made in recent years for the generation of BACE-1 inhibitors but many of them failed during the preclinical or clinical trials due to drug related or drug induced toxicity. In the present work, we have used computational methods to screen a large dataset of natural compounds to search for small molecules having BACE-1 inhibitory activity with low toxicity to normal cells. Molecular dynamics simulations were performed to analyze molecular interactions between the screened compounds and the active residues of the enzyme. Herein, we report two natural compounds of inhibitory nature active against β-secretase enzyme of amyloidic pathway and are potent lead molecules against Alzheimer’s disease.

  3. Antifungal activity, mode of action and anti-biofilm effects of Laurus nobilis Linnaeus essential oil against Candida spp.

    Science.gov (United States)

    Peixoto, Larissa Rangel; Rosalen, Pedro Luiz; Ferreira, Gabriela Lacet Silva; Freires, Irlan Almeida; de Carvalho, Fabíola Galbiatti; Castellano, Lúcio Roberto; de Castro, Ricardo Dias

    2017-01-01

    The present study demonstrated the antifungal potential of the chemically characterized essential oil (EO) of Laurus nobilis L. (bay laurel) against Candida spp. biofilm adhesion and formation, and further established its mode of action on C. albicans. L. nobilis EO was obtained and tested for its minimum inhibitory and fungicidal concentrations (MIC/MFC) against Candida spp., as well as for interaction with cell wall biosynthesis and membrane ionic permeability. Then we evaluated its effects on the adhesion, formation, and reduction of 48hC. albicans biofilms. The EO phytochemical profile was determined by gas chromatography coupled to mass spectrometry (GC/MS). The MIC and MFC values of the EO ranged from (250 to 500) μg/mL. The MIC values increased in the presence of sorbitol (osmotic protector) and ergosterol, which indicates that the EO may affect cell wall biosynthesis and membrane ionic permeability, respectively. At 2 MIC the EO disrupted initial adhesion of C. albicans biofilms (p0.05). When applied for 1min, every 8h, for 24h and 48h, the EO reduced the amount of C. albicans mature biofilm with no difference in relation to nystatin (p>0.05). The phytochemical analysis identified isoeugenol as the major compound (53.49%) in the sample. L. nobilis EO has antifungal activity probably due to monoterpenes and sesquiterpenes in its composition. This EO may affect cell wall biosynthesis and membrane permeability, and showed deleterious effects against C. albicans biofilms. Copyright © 2016. Published by Elsevier Ltd.

  4. A Microplate Growth Inhibition Assay for Screening Bacteriocins against Listeria monocytogenes to Differentiate Their Mode-of-Action.

    Science.gov (United States)

    Vijayakumar, Paul Priyesh; Muriana, Peter M

    2015-06-11

    Lactic acid bacteria (LAB) have historically been used in food fermentations to preserve foods and are generally-recognized-as-safe (GRAS) by the FDA for use as food ingredients. In addition to lactic acid; some strains also produce bacteriocins that have been proposed for use as food preservatives. In this study we examined the inhibition of Listeria monocytogenes 39-2 by neutralized and non-neutralized bacteriocin preparations (Bac+ preps) produced by Lactobacillus curvatus FS47; Lb. curvatus Beef3; Pediococcus acidilactici Bac3; Lactococcus lactis FLS1; Enterococcus faecium FS56-1; and Enterococcus thailandicus FS92. Activity differences between non-neutralized and neutralized Bac+ preps in agar spot assays could not readily be attributed to acid because a bacteriocin-negative control strain was not inhibitory to Listeria in these assays. When neutralized and non-neutralized Bac+ preps were used in microplate growth inhibition assays against L. monocytogenes 39-2 we observed some differences attributed to acid inhibition. A microplate growth inhibition assay was used to compare inhibitory reactions of wild-type and bacteriocin-resistant variants of L. monocytogenes to differentiate bacteriocins with different modes-of-action (MOA) whereby curvaticins FS47 and Beef3, and pediocin Bac3 were categorized to be in MOA1; enterocins FS92 and FS56-1 in MOA2; and lacticin FLS1 in MOA3. The microplate bacteriocin MOA assay establishes a platform to evaluate the best combination of bacteriocin preparations for use in food applications as biopreservatives against L. monocytogenes.

  5. The mode of action of isocyanide in three aquatic organisms, Balanus amphitrite, Bugula neritina and Danio rerio.

    Directory of Open Access Journals (Sweden)

    Yi-Fan Zhang

    Full Text Available Isocyanide is a potential antifouling compound in marine environments. In this study, we investigated its mode of action in three aquatic organisms. Two of them, the bryozoan Bugula neritina and the barnacle Balanus amphitrite, are major marine fouling invertebrates, and the other organism is the non-target species zebrafish Danio rerio. In the swimming larvae of B. neritina, isocyanide did not affect the total attachment rate (≤50 µg ml(-1, but it did change the attachment site by increasing the percentage of attachment on the bottom of the container rather than on the wall or air-water inter-surface. Isocyanide binds several proteins in B. neritina as identified via SDS-PAGE-LC-MS/MS: 1 a 30 kD protein band containing two proteins similar to voltage dependent anion channels (VDAC, which control the direct coupling of the mitochondrial matrix to the energy maintenance of the cytosol and the release of apoptogenic factors from mitochondria of mammalian cells; and 2 an unknown 39 kD protein. In B. amphitrite cyprids, the isocyanide binding protein were 1 a protein similar to NADH-ubiquinone oxidoreductase, which is the "entry enzyme" of oxidative phosphorylation in mitochondria; and 2 cytochrome P450. In Danio rerio embryos, isocyanide caused "wavy" notochords, hydrocephalus, pericardial edema, poor blood circulation, and defects in pigmentation and hematopoiesis, which phenocopied copper deficiency. This is the first report on isocyanide binding proteins in fouling organisms, as well as the first description of its phenotype and potential toxicology in zebrafish.

  6. The dual role of serotonin in defense and the mode of action of antidepressants on generalized anxiety and panic disorders.

    Science.gov (United States)

    Graeff, Frederico G; Zangrossi, Hélio

    2010-09-01

    Antidepressants are widely used to treat several anxiety disorders, among which generalized anxiety disorder (GAD) and panic disorder (PD). Serotonin (5-HT) is believed to play a key role in the mode of action of these agents, a major question being which pathways and receptor subtypes are involved in each type of anxiety disorder. The dual role of 5-HT in defense hypothesis assumes that 5-HT facilitates defensive responses to potential threat, like inhibitory avoidance, related to anxiety, whereas it inhibits defensive responses to proximal danger, like one-way escape, related to panic. The former action would be exerted at the forebrain, chiefly the amygdala and medial prefrontal cortex (PFC), while the latter would be exerted at the dorsal periaqueductal gray (DPAG) matter of the midbrain. The present review is focused on studies designed to test this hypothesis, performed in animal models of anxiety and panic, as well as in human experimental anxiety tests. The reviewed results suggest that chronic, but not acute, administration of antidepressants suppress panic attacks by increasing the release of 5-HT and enhancing the responsivity of post-synaptic 5-HT1A and 5-HT2A receptors in the DPAG. The attenuation of generalized anxiety, also caused by the same drug treatment, would be due to the desensitization of 5-HT2C receptors and, less certainly, to increased stimulation of 5-HT1A receptors in forebrain structures. This action would result in less activation of the amygdala, medial PFC and insula by warning signals, as shown by the reviewed results obtained with functional neuroimaging in healthy volunteers and patients with anxiety disorders.

  7. A novel mode-of-action mediated by the fetal muscle nicotinic acetylcholine receptor resulting in developmental toxicity in rats.

    Science.gov (United States)

    Rasoulpour, Reza J; Ellis-Hutchings, Robert G; Terry, Claire; Millar, Neil S; Zablotny, Carol L; Gibb, Alasdair; Marshall, Valerie; Collins, Toby; Carney, Edward W; Billington, Richard

    2012-06-01

    Sulfoxaflor (X11422208), a novel agricultural molecule, induced fetal effects (forelimb flexure, hindlimb rotation, and bent clavicle) and neonatal death in rats at high doses (≥ 400 ppm in diet); however, no such effects occurred in rabbit dietary studies despite achieving similar maternal and fetal plasma exposure levels. Mode-of-action (MoA) studies were conducted to test the hypothesis that the effects in rats had a single MoA induced by sulfoxaflor agonism on the fetal rat muscle nicotinic acetylcholine receptor (nAChR). The studies included cross-fostering and critical windows of exposure studies in rats, fetal ((α1)(2)β1γδ) and adult ((α1)(2)β1δε) rat and human muscle nAChR in vitro agonism experiments, and neonatal rat phrenic nerve-hemidiaphragm contracture studies. The weight of evidence from these studies supported a novel MoA where sulfoxaflor is an agonist to the fetal, but not adult, rat muscle nAChR and that prolonged agonism on this receptor in fetal/neonatal rats causes sustained striated muscle contracture resulting in concomitant reduction in muscle responsiveness to physiological nerve stimulation. Fetal effects were inducible with as little as 1 day of exposure at the end of gestation, but were rapidly reversible after birth, consistent with a pharmacological MoA. With respect to human relevance, sulfoxaflor was shown to have no agonism on human fetal or adult muscle nAChRs. Taken together, the data support the hypothesis that the developmental effects of sulfoxaflor in rats are mediated via sustained agonism on the fetal muscle nAChR during late fetal development and are considered not relevant to humans.

  8. The Mode of Action of Isocyanide in Three Aquatic Organisms, Balanus amphitrite, Bugula neritina and Danio rerio

    KAUST Repository

    Zhang, Yi-Fan

    2012-09-18

    Isocyanide is a potential antifouling compound in marine environments. In this study, we investigated its mode of action in three aquatic organisms. Two of them, the bryozoan Bugula neritina and the barnacle Balanus amphitrite, are major marine fouling invertebrates, and the other organism is the non-target species zebrafish Danio rerio. In the swimming larvae of B. neritina, isocyanide did not affect the total attachment rate (≤50 µg ml^(−1)), but it did change the attachment site by increasing the percentage of attachment on the bottom of the container rather than on the wall or air-water inter-surface. Isocyanide binds several proteins in B. neritina as identified via SDS-PAGE-LC-MS/MS: 1) a 30 kD protein band containing two proteins similar to voltage dependent anion channels (VDAC), which control the direct coupling of the mitochondrial matrix to the energy maintenance of the cytosol and the release of apoptogenic factors from mitochondria of mammalian cells; and 2) an unknown 39 kD protein. In B. amphitrite cyprids, the isocyanide binding protein were 1) a protein similar to NADH-ubiquinone oxidoreductase, which is the “entry enzyme” of oxidative phosphorylation in mitochondria; and 2) cytochrome P450. In Danio rerio embryos, isocyanide caused “wavy” notochords, hydrocephalus, pericardial edema, poor blood circulation, and defects in pigmentation and hematopoiesis, which phenocopied copper deficiency. This is the first report on isocyanide binding proteins in fouling organisms, as well as the first description of its phenotype and potential toxicology in zebrafish.

  9. New insights into the structure and mode of action of Mo-CBP3, an antifungal chitin-binding protein of Moringa oleifera seeds.

    Directory of Open Access Journals (Sweden)

    Adelina B Batista

    Full Text Available Mo-CBP3 is a chitin-binding protein purified from Moringa oleifera Lam. seeds that displays inhibitory activity against phytopathogenic fungi. This study investigated the structural properties and the antifungal mode of action of this protein. To this end, circular dichroism spectroscopy, antifungal assays, measurements of the production of reactive oxygen species and microscopic analyses were utilized. Mo-CBP3 is composed of 30.3% α-helices, 16.3% β-sheets, 22.3% turns and 30.4% unordered forms. The Mo-CBP3 structure is highly stable and retains its antifungal activity regardless of temperature and pH. Fusarium solani was used as a model organism for studying the mechanisms by which this protein acts as an antifungal agent. Mo-CBP3 significantly inhibited spore germination and mycelial growth at 0.05 mg.mL-1. Mo-CBP3 has both fungistatic and fungicidal effects, depending on the concentration used. Binding of Mo-CBP3 to the fungal cell surface is achieved, at least in part, via electrostatic interactions, as salt was able to reduce its inhibitory effect. Mo-CBP3 induced the production of ROS and caused disorganization of both the cytoplasm and the plasma membrane in F. solani cells. Based on its high stability and specific toxicity, with broad-spectrum efficacy against important phytopathogenic fungi at low inhibitory concentrations but not to human cells, Mo-CBP3 has great potential for the development of new antifungal drugs or transgenic crops with enhanced resistance to phytopathogens.

  10. Mode of action analysis for the synthetic pyrethroid metofluthrin-induced rat liver tumors: evidence for hepatic CYP2B induction and hepatocyte proliferation.

    Science.gov (United States)

    Deguchi, Yoshihito; Yamada, Tomoya; Hirose, Yukihiro; Nagahori, Hirohisa; Kushida, Masahiko; Sumida, Kayo; Sukata, Tokuo; Tomigahara, Yoshitaka; Nishioka, Kazuhiko; Uwagawa, Satoshi; Kawamura, Satoshi; Okuno, Yasuyoshi

    2009-03-01

    Two-year treatment with high doses of Metofluthrin produced hepatocellular tumors in both sexes of Wistar rats. To understand the mode of action (MOA) by which the tumors are produced, a series of studies examined the effects of Metofluthrin on hepatic microsomal cytochrome P450 (CYP) content, hepatocellular proliferation, hepatic gap junctional intercellular communication (GJIC), oxidative stress and apoptosis was conducted after one or two weeks of treatment. The global gene expression profile indicated that most genes with upregulated expression with Metofluthrin were metabolic enzymes that were also upregulated with phenobarbital. Metofluthrin induced CYP2B and increased liver weights associated with centrilobular hepatocyte hypertrophy (increased smooth endoplasmic reticulum [SER]), and induction of increased hepatocellular DNA replication. CYP2B1 mRNA induction by Metofluthrin was not observed in CAR knockdown rat hepatocytes using the RNA interference technique, demonstrating that Metofluthrin induces CYP2B1 through CAR activation. Metofluthrin also suppressed hepatic GJIC and induced oxidative stress and increased antioxidant enzymes, but showed no alteration in apoptosis. The above parameters related to the key events in Metofluthrin-induced liver tumors were observed at or below tumorigenic dose levels. All of these effects were reversible upon cessation of treatment. Metofluthrin did not cause cytotoxicity or peroxisome proliferation. Thus, it is highly likely that the MOA for Metofluthrin-induced liver tumors in rats is through CYP induction and increased hepatocyte proliferation, similar to that seen for phenobarbital. Based on analysis with the International Life Sciences Institute/Risk Science Institute MOA framework, it is reasonable to conclude that Metofluthrin will not have any hepatocarcinogenic activity in humans, at least at expected levels of exposure.

  11. New insights into the structure and mode of action of Mo-CBP3, an antifungal chitin-binding protein of Moringa oleifera seeds.

    Science.gov (United States)

    Batista, Adelina B; Oliveira, José T A; Gifoni, Juliana M; Pereira, Mirella L; Almeida, Marina G G; Gomes, Valdirene M; Da Cunha, Maura; Ribeiro, Suzanna F F; Dias, Germana B; Beltramini, Leila M; Lopes, José Luiz S; Grangeiro, Thalles B; Vasconcelos, Ilka M

    2014-01-01

    Mo-CBP3 is a chitin-binding protein purified from Moringa oleifera Lam. seeds that displays inhibitory activity against phytopathogenic fungi. This study investigated the structural properties and the antifungal mode of action of this protein. To this end, circular dichroism spectroscopy, antifungal assays, measurements of the production of reactive oxygen species and microscopic analyses were utilized. Mo-CBP3 is composed of 30.3% α-helices, 16.3% β-sheets, 22.3% turns and 30.4% unordered forms. The Mo-CBP3 structure is highly stable and retains its antifungal activity regardless of temperature and pH. Fusarium solani was used as a model organism for studying the mechanisms by which this protein acts as an antifungal agent. Mo-CBP3 significantly inhibited spore germination and mycelial growth at 0.05 mg.mL-1. Mo-CBP3 has both fungistatic and fungicidal effects, depending on the concentration used. Binding of Mo-CBP3 to the fungal cell surface is achieved, at least in part, via electrostatic interactions, as salt was able to reduce its inhibitory effect. Mo-CBP3 induced the production of ROS and caused disorganization of both the cytoplasm and the plasma membrane in F. solani cells. Based on its high stability and specific toxicity, with broad-spectrum efficacy against important phytopathogenic fungi at low inhibitory concentrations but not to human cells, Mo-CBP3 has great potential for the development of new antifungal drugs or transgenic crops with enhanced resistance to phytopathogens.

  12. Control of postharvest soft rot caused by Erwinia carotovora of vegetables by a strain of Bacillus amyloliquefaciens and its potential modes of action.

    Science.gov (United States)

    Zhao, Yancun; Li, Pengxia; Huang, Kaihong; Wang, Yuning; Hu, Huali; Sun, Ya

    2013-03-01

    Erwinia carotovora subsp. carotovora (Ecc), the causal agent of bacterial soft rot, is one of the destructive pathogens of postharvest vegetables. In this study, a bacterial isolate (BGP20) from the vegetable farm soil showed strong antagonistic activity against Ecc in vitro, and its twofold cell-free culture filtrate showed excellent biocontrol effect in controlling the postharvest bacterial soft rot of potatoes at 25 °C. The anti-Ecc metabolites produced by the isolate BGP20 had a high resistance to high temperature, UV-light and protease K. Based on the colonial morphology, cellular morphology, sporulation, and partial nucleotide sequences of 16S rRNA and gyrB gene, the isolate BGP20 was identified as Bacillus amyloliquefaciens subsp. plantarum. Further in vivo assays showed that the BGP20 cell culture was more effective in controlling the postharvest bacterial soft rot of green peppers and Chinese cabbages than its twofold cell-free culture filtrate. In contrast, the biocontrol effect and safety of the BGP20 cell culture were very poor on potatoes. In the wounds of potatoes treated with both the antagonist BGP20 and the pathogen Ecc, the viable count of Ecc was 31,746 times that of BGP20 at 48 h of incubation at 25 °C. But in the wounds of green peppers, the viable count of BGP20 increased 182.3 times within 48 h, and that of Ecc increased only 51.3 %. In addition, the treatment with both BGP20 and Ecc induced higher activity of phenylalanine ammonia-lyase (PAL) than others in potatoes. But the same treatment did not induce an increase of PAL activity in green peppers. In conclusion, the present study demonstrated that the isolate BGP20 is a promising candidate in biological control of postharvest bacterial soft rot of vegetables, but its main mode of action is different among various vegetables.

  13. Toxicity ranking and toxic mode of action evaluation of commonly used agricultural adjuvants on the basis of bacterial gene expression profiles.

    Directory of Open Access Journals (Sweden)

    Ingrid Nobels

    used agricultural adjuvants based on toxicity and toxic mode of action data.

  14. Determining the mode of action of anti-mycobacterial C17 diyne natural products using expression profiling: evidence for fatty acid biosynthesis inhibition

    OpenAIRE

    Li, Haoxin; Cowie, Andrew; JOHNSON, JOHN A.; Webster, Duncan; Martyniuk, Christopher J.; Gray, Christopher A.

    2016-01-01

    Background The treatment of microbial infections is becoming increasingly challenging because of limited therapeutic options and the growing number of pathogenic strains that are resistant to current antibiotics. There is an urgent need to identify molecules with novel modes of action to facilitate the development of new and more effective therapeutic agents. The anti-mycobacterial activity of the C17 diyne natural products falcarinol and panaxydol has been described previously; however, thei...

  15. Structure-Activity Relationships of the Antimicrobial Peptide Arasin 1 — And Mode of Action Studies of the N-Terminal, Proline-Rich Region

    Science.gov (United States)

    Paulsen, Victoria S.; Blencke, Hans-Matti; Benincasa, Monica; Haug, Tor; Eksteen, Jacobus J.; Styrvold, Olaf B.; Scocchi, Marco; Stensvåg, Klara

    2013-01-01

    Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH2 terminus of the peptide and the fragment arasin 1(1–23) was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1–23) were shown to be non-toxic to human red blood cells and arasin 1(1–23) was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1–23) was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC), arasin 1(1–23) was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1–23) has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1–23) involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC. PMID:23326415

  16. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Directory of Open Access Journals (Sweden)

    Victoria S Paulsen

    Full Text Available Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2 terminus of the peptide and the fragment arasin 1(1-23 was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23 were shown to be non-toxic to human red blood cells and arasin 1(1-23 was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23 was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC, arasin 1(1-23 was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23 has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23 involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  17. Structure-activity relationships of the antimicrobial peptide arasin 1 - and mode of action studies of the N-terminal, proline-rich region.

    Science.gov (United States)

    Paulsen, Victoria S; Blencke, Hans-Matti; Benincasa, Monica; Haug, Tor; Eksteen, Jacobus J; Styrvold, Olaf B; Scocchi, Marco; Stensvåg, Klara

    2013-01-01

    Arasin 1 is a 37 amino acid long proline-rich antimicrobial peptide isolated from the spider crab, Hyas araneus. In this work the active region of arasin 1 was identified through structure-activity studies using different peptide fragments derived from the arasin 1 sequence. The pharmacophore was found to be located in the proline/arginine-rich NH(2) terminus of the peptide and the fragment arasin 1(1-23) was almost equally active to the full length peptide. Arasin 1 and its active fragment arasin 1(1-23) were shown to be non-toxic to human red blood cells and arasin 1(1-23) was able to bind chitin, a component of fungal cell walls and the crustacean shell. The mode of action of the fully active N-terminal arasin 1(1-23) was explored through killing kinetic and membrane permeabilization studies. At the minimal inhibitory concentration (MIC), arasin 1(1-23) was not bactericidal and had no membrane disruptive effect. In contrast, at concentrations of 5×MIC and above it was bactericidal and interfered with membrane integrity. We conclude that arasin 1(1-23) has a different mode of action than lytic peptides, like cecropin P1. Thus, we suggest a dual mode of action for arasin 1(1-23) involving membrane disruption at peptide concentrations above MIC, and an alternative mechanism of action, possibly involving intracellular targets, at MIC.

  18. The Mode of Action of the Bacillus thuringiensis Vegetative Insecticidal Protein Vip3A Differs from That of Cry1Ab δ-Endotoxin

    OpenAIRE

    Lee, Mi Kyong; Walters, Frederick S.; Hart, Hope; Palekar, Narendra; Chen, Jeng-Shong

    2003-01-01

    The Vip3A protein, secreted by Bacillus spp. during the vegetative stage of growth, represents a new family of insecticidal proteins. In our investigation of the mode of action of Vip3A, the 88-kDa Vip3A full-length toxin (Vip3A-F) was proteolytically activated to an approximately 62-kDa core toxin either by trypsin (Vip3A-T) or lepidopteran gut juice extracts (Vip3A-G). Biotinylated Vip3A-G demonstrated competitive binding to lepidopteran midgut brush border membrane vesicles (BBMV). Further...

  19. Transaction based approach

    Science.gov (United States)

    Hunka, Frantisek; Matula, Jiri

    2017-07-01

    Transaction based approach is utilized in some methodologies in business process modeling. Essential parts of these transactions are human beings. The notion of agent or actor role is usually used for them. The paper on a particular example describes possibilities of Design Engineering Methodology for Organizations (DEMO) and Resource-Event-Agent (REA) methodology. Whereas the DEMO methodology can be regarded as a generic methodology having its foundation in the theory of Enterprise Ontology the REA methodology is regarded as the domain specific methodology and has its origin in accountancy systems. The results of these approaches is that the DEMO methodology captures everything that happens in the reality with a good empirical evidence whereas the REA methodology captures only changes connected with economic events. Economic events represent either change of the property rights to economic resource or consumption or production of economic resources. This results from the essence of economic events and their connection to economic resources.

  20. Partial Purification and Characterization of the Mode of Action of Enterocin S37: A Bacteriocin Produced by Enterococcus faecalis S37 Isolated from Poultry Feces

    Directory of Open Access Journals (Sweden)

    Y. Belguesmia

    2010-01-01

    Full Text Available The aim of this research was to purify and characterize the mode of action of enterocin S37, a bacteriocin produced by Enterococcus faecalis S37, a strain recently isolated from the chicken feces. Enterocin S37 has a molecular weight comprised between 4 and 5 kDa. It remained active after 1 h at 80oC and at pH values ranging from 4.0 to 9.0. Furthermore, cell-free supernatant of Enterococcus faecalis S37 and purified enterocin S37 were active against Gram-positive bacteria including Listeria monocytogenes EGDe, L. innocua F, Enterococcus faecalis JH2-2, and Lactobacillus brevis F145. The purification of enterocin S37 was performed by ammonium sulfate precipitation followed up by hydrophobic-interaction chromatography procedures. Treatment of enterocin S37 with proteinase K, -chymotrypsin, and papain confirmed its proteinaceous nature, while its treatment with lysozyme and lipase resulted in no alteration of activity. Enterocin S37 is hydrophobic, anti-Listeria and likely acting by depletion of intracellular K+ ions upon action on KATP channels. This study contributed to gain more insights into the mode of action of enterocins.

  1. Biological control of the cucurbit powdery mildew pathogen Podosphaera xanthii by means of the epiphytic fungus Pseudozyma aphidis and parasitism as a mode of action.

    Science.gov (United States)

    Gafni, Aviva; Calderon, Claudia E; Harris, Raviv; Buxdorf, Kobi; Dafa-Berger, Avis; Zeilinger-Reichert, Einat; Levy, Maggie

    2015-01-01

    Epiphytic yeasts, which colonize plant surfaces, may possess activity that can be harnessed to help plants defend themselves against various pathogens. Due to their unique characteristics, epiphytic yeasts belonging to the genus Pseudozyma hold great potential for use as biocontrol agents. We identified a unique, biologically active isolate of the epiphytic yeast Pseudozyma aphidis that is capable of inhibiting Botrytis cinerea via a dual mode of action, namely induced resistance and antibiosis. Here, we show that strain L12 of P. aphidis can reduce the severity of powdery mildew caused by Podosphaera xanthii on cucumber plants with an efficacy of 75%. Confocal and scanning electron microscopy analyses demonstrated P. aphidis proliferation on infected tissue and its production of long hyphae that parasitize the powdery mildew hyphae and spores as an ectoparasite. We also show that crude extract of P. aphidis metabolites can inhibit P. xanthii spore germination in planta. Our results suggest that in addition to its antibiosis as mode of action, P. aphidis may also act as an ectoparasite on P. xanthii. These results indicate that P. aphidis strain L12 has the potential to control powdery mildew.

  2. Biological control of the cucurbit powdery mildew pathogen Podosphaera xanthii by means of the epiphytic fungus Pseudozyma aphidis and parasitism as a mode of action

    Directory of Open Access Journals (Sweden)

    Aviva eGafni

    2015-03-01

    Full Text Available Epiphytic yeasts, which colonize plant surfaces, may possess activity that can be harnessed to help plants defend themselves against various pathogens. Due to their unique characteristics, epiphytic yeasts belonging to the genus Pseudozyma hold great potential for use as biocontrol agents. We identified a unique, biologically active isolate of the epiphytic yeast Pseudozyma aphidis that is capable of inhibiting Botrytis cinerea via a dual mode of action, namely induced resistance and antibiosis. Here, we show that strain L12 of P. aphidis can reduce the severity of powdery mildew caused by Podosphaera xanthii on cucumber plants with an efficacy of 75%. Confocal and scanning electron microscopy analyses demonstrated P. aphidis proliferation on infected tissue and its production of long hyphae that parasitize the powdery mildew hyphae and spores as an ectoparasite. We also show that crude extract of P. aphidis metabolites can inhibit P. xanthii spore germination in planta. Our results suggest that in addition to its antibiosis mode of action, P. aphidis may also act as an ectoparasite on P. xanthii. These results indicate that P. aphidis strain L12 has the potential to control powdery mildew.

  3. Mode of Action: Oxalate Crystal-Induced Renal Tubule Degeneration and Glycolic Acid-Induced Dysmorphogenesis—Renal and Developmental Effects of Ethylene Glycol

    Energy Technology Data Exchange (ETDEWEB)

    Corley, Rick A.; Meek, M E.; Carney, E W.

    2005-10-01

    Ethylene glycol can cause both renal and developmental toxicity, with metabolism playing a key role in the mode of action (MOA) for each form of toxicity. Renal toxicity is ascribed to the terminal metabolite oxalic acid, which precipitates in the kidney in the form of calcium oxalate crystals and is believed to cause physical damage to the renal tubules. The human relevance of the renal toxicity of ethylene glycol is indicated by the similarity between animals and humans of metabolic pathways, the observation of renal oxalate crystals in toxicity studies in experimental animals and human poisonings, and cases of human kidney and bladder stones related to dietary oxalates and oxalate precursors. High-dose gavage exposures to ethylene glycol also cause axial skeletal defects in rodents (but not rabbits), with the intermediary metabolite, glycolic acid, identified as the causative agent. However, the mechanism by which glycolic acid perturbs development has not been investigated sufficiently to develop a plausible hypothesis of mode of action, nor have any cases of ethylene glycol-induced developmental effects been reported in humans. Given this, and the variations in sensitivity between animal species in response, the relevance to humans of ethylene glycol-induced developmental toxicity in animals is unknown at this time.

  4. The economic importance of acaricides in the control of phytophagous mites and an update on recent acaricide mode of action research.

    Science.gov (United States)

    Van Leeuwen, Thomas; Tirry, Luc; Yamamoto, Atsushi; Nauen, Ralf; Dermauw, Wannes

    2015-06-01

    Acaricides are one of the cornerstones of an efficient control program for phytophagous mites. An analysis of the global acaricide market reveals that spider mites such as Tetranychus urticae, Panonychus citri and Panonychus ulmi are by far the most economically important species, representing more than 80% of the market. Other relevant mite groups are false spider mites (mainly Brevipalpus), rust and gall mites and tarsonemid mites. Acaricides are most frequently used in vegetables and fruits (74% of the market), including grape vines and citrus. However, their use is increasing in major crops where spider mites are becoming more important, such as soybean, cotton and corn. As revealed by a detailed case study of the Japanese market, major shifts in acaricide use are partially driven by resistance development and the commercial availability of compounds with novel mode of action. The importance of the latter cannot be underestimated, although some compounds are successfully used for more than 30 years. A review of recent developments in mode of action research is presented, as such knowledge is important for devising resistance management programs. This includes spirocyclic keto-enols as inhibitors of acetyl-CoA carboxylase, the carbazate bifenazate as a mitochondrial complex III inhibitor, a novel class of complex II inhibitors, and the mite growth inhibitors hexythiazox, clofentezine and etoxazole that interact with chitin synthase I.

  5. Partial Purification and Characterization of the Mode of Action of Enterocin S37: A Bacteriocin Produced by Enterococcus faecalis S37 Isolated from Poultry Feces

    Science.gov (United States)

    Belguesmia, Y.; Choiset, Y.; Prévost, H.; Dalgalarrondo, M.; Chobert, J.-M.; Drider, D.

    2010-01-01

    The aim of this research was to purify and characterize the mode of action of enterocin S37, a bacteriocin produced by Enterococcus faecalis S37, a strain recently isolated from the chicken feces. Enterocin S37 has a molecular weight comprised between 4 and 5 kDa. It remained active after 1 h at 80oC and at pH values ranging from 4.0 to 9.0. Furthermore, cell-free supernatant of Enterococcus faecalis S37 and purified enterocin S37 were active against Gram-positive bacteria including Listeria monocytogenes EGDe, L. innocua F, Enterococcus faecalis JH2-2, and Lactobacillus brevis F145. The purification of enterocin S37 was performed by ammonium sulfate precipitation followed up by hydrophobic-interaction chromatography procedures. Treatment of enterocin S37 with proteinase K, α-chymotrypsin, and papain confirmed its proteinaceous nature, while its treatment with lysozyme and lipase resulted in no alteration of activity. Enterocin S37 is hydrophobic, anti-Listeria and likely acting by depletion of intracellular K+ ions upon action on KATP channels. This study contributed to gain more insights into the mode of action of enterocins. PMID:20811593

  6. Assessment of the mode of action of polyhexamethylene biguanide against Listeria innocua by Fourier transformed infrared spectroscopy and fluorescence anisotropy analysis.

    Science.gov (United States)

    Chadeau, Elise; Dumas, Emilie; Adt, Isabelle; Degraeve, Pascal; Noël, Claude; Girodet, Christophe; Oulahal, Nadia

    2012-12-01

    Polyhexamethylene biguanide (PHMB) is a cationic biocide. The antibacterial mode of action of PHMB (at concentrations not exceeding its minimal inhibitory concentration) upon Listeria innocua LRGIA 01 was investigated by Fourier transformed infrared spectroscopy and fluorescence anisotropy analysis. Fourier transformed infrared spectra of bacteria treated with or without PHMB presented some differences in the lipids region: the CH(2)/CH(3) (2924 cm(-1)/2960 cm(-1)) band areas ratio significantly increased in the presence of PHMB. Since this ratio generally reflects membrane phospholipids and membrane microenvironment of the cells, these results suggest that PHMB molecules interact with membrane phospholipids and, thus, affect membrane fluidity and conformation. To assess the hypothesis of PHMB interaction with L. innocua membrane phospholipids and to clarify the PHMB mode of action, we performed fluorescence anisotropy experiments. Two probes, 1,6-diphenyl-1,3,5-hexatriene (DPH) and its derivative 1-[4-(trimethyl-amino)-phenyl]-6-phenylhexa-1,3,5-triene (TMA-DPH), were used. DPH and TMA-DPH incorporate inside and at the surface of the cytoplasmic membrane, respectively. When PHMB was added, an increase of TMA-DPH fluorescence anisotropy was observed, but no changes of DPH fluorescence anisotropy occurred. These results are consistent with the hypothesis that PHMB molecules perturb L. innocua LRGIA 01 cytoplasmic membrane by interacting with the first layer of the membrane lipid bilayer.

  7. Use of mode of action data to inform a dose-response assessment for bladder cancer following exposure to inorganic arsenic.

    Science.gov (United States)

    Gentry, P R; Yager, J W; Clewell, R A; Clewell, H J

    2014-10-01

    In the recent National Research Council report on conducting a dose-response assessment for inorganic arsenic, the committee remarked that mode of action data should be used, to the extent possible, to extrapolate below the observed range for epidemiological studies to inform the shape of the dose-response curve. Recent in vitro mode of action studies focused on understanding the development of bladder cancer following exposure to inorganic arsenic provide data to inform the dose-response curve. These in vitro data, combined with results of bladder cancer epidemiology studies, inform the dose-response curve in the low-dose region, and include values for both pharmacokinetic and pharmacodynamic variability. Integration of these data provides evidence of a range of concentrations of arsenic for which no effect on the bladder would be expected. Specifically, integration of these results suggest that arsenic exposures in the range of 7-43 ppb in drinking water are exceedingly unlikely to elicit changes leading to key events in the development of cancer or noncancer effects in bladder tissue. These findings are consistent with the lack of evidence for bladder cancer following chronic ingestion of arsenic water concentrations <100 ppb in epidemiological studies.

  8. The first toxicological study of the antiozonant and research tool ethylene diurea (EDU) using a Lemna minor L. bioassay: Hints to its mode of action.

    Science.gov (United States)

    Agathokleous, Eugenios; Mouzaki-Paxinou, Akrivi-Chara; Saitanis, Costas J; Paoletti, Elena; Manning, William J

    2016-06-01

    The antiozonant and research tool ethylene diurea (EDU) is widely studied as a phytoprotectant against the widespread pollutant ground-surface ozone. Although it has been extensively used, its potential toxicity in the absence of ozone is unknown and its mode of action is unclear. The purpose of this research was to toxicologically assess EDU and to further investigate its mode of action using Lemna minor L. as a model organism. Application of EDU concentrations greater than 593 mg L(-1) (practically 600 mg L(-1)) resulted in adverse inhibition of colony growth. As no-observed-toxic-effects concentration (NOEL) we recommend a concentration of 296 mg L(-1) (practically 300 mg L(-1)). A hormetic response was detected, i.e. stimulatory effects of low EDU concentrations, which may indicate overcompensation in response to disruption in homeostasis. Growth inhibition and suppressed biomass were associated with impacted chlorophyll a fluorescence (ΦPSII, qP and ETR). Furthermore, EDU increased mesophyll thickness, as indicated by frond succulence index. Applications of concentrations ≥593 mg L(-1) to uncontrolled environments should be avoided due to potential toxicity to sensitive organisms and the environment.

  9. Use of electroencephalography (EEG) to assess CNS changes produced by pesticides with different modes of action: Effects of permethrin, deltamethrin, fipronil, imidacloprid, carbaryl, and triadimefon

    Energy Technology Data Exchange (ETDEWEB)

    Freeborn, Danielle L., E-mail: Freeborn.danielle@epa.gov; McDaniel, Katherine L., E-mail: McDaniel.kathy@epa.gov; Moser, Virginia C., E-mail: Moser.ginger@epa.gov; Herr, David W., E-mail: Herr.david@epa.gov

    2015-01-15

    The electroencephalogram (EEG) is an apical measure, capable of detecting changes in brain neuronal activity produced by internal or external stimuli. We assessed whether pesticides with different modes of action produced different changes in the EEG of adult male Long–Evans rats. The EEG was recorded using two montages (visual cortex referenced to the cerebellum and to the frontal cortex) in unrestrained rats at the time of peak behavioral effects. Pesticides included: permethrin and deltamethrin (Type I and Type II pyrethroids; 2 h), fipronil (single and repeated doses; phenylpyrazole; 6 h), imidacloprid (neonicotinoid; 2 h), carbaryl (carbamate; 0.5 h), and triadimefon (triazole; 1 h), using dosages that produced approximately an ED{sub 30} or an ED{sub 50}–ED{sub 80} change in motor activity. Permethrin (43, 100 mg/kg) increased amplitudes or areas (delta, alpha, or gamma bands) in the EEG. Deltamethrin (2.5, 5.5 mg/kg) reduced the amplitudes or areas of the delta, theta, alpha, beta, and gamma bands, but the changes were not dose-related. A single treatment with fipronil (25, 50 mg/kg, but not 5, 10 mg/kg) decreased gamma band area. Additional changes in the delta, theta, and gamma bands were observed when fipronil (5, 10 mg/kg) was administered for 14 days. Imidacloprid (50, 100 mg/kg) did not alter the EEG. Carbaryl (10, 50 mg/kg) decreased theta area, and decreased delta and increased beta frequency. Triadimefon (75, 150 mg/kg) produced minimal changes in the EEG. The results show that the EEG is affected differently by approximately equipotent doses of pesticides with different modes of action. - Highlights: • Pesticides with different modes of action have different effects on in vivo rodent EEG. • The EEG was also changed differently after single vs. repeated treatment with fipronil. • The data suggest that EEG may be used as an apical measure for detecting chemical effects on the central nervous system.

  10. Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action?

    Science.gov (United States)

    Dalhoff, A

    2015-04-01

    This review summarizes evidence that commercially available fluoroquinolones used for the treatment of bacterial infections are active against other non-bacterial infectious agents as well. Any of these fluoroquinolones exerts, in parallel to its antibacterial action, antiviral, antifungal, and antiparasitic actions at clinically achievable concentrations. This broad range of anti-infective activities is due to one common mode of action, i.e., the inhibition of type II topoisomerases or inhibition of viral helicases, thus maintaining the selective toxicity of fluoroquinolones inhibiting microbial topoisomerases at low concentrations but mammalian topoisomerases at much higher concentrations. Evidence suggests that standard doses of the fluoroquinolones studied are clinically effective against viral and parasitic infections, whereas higher doses administered topically were active against Candida spp. causing ophthalmological infections. Well-designed clinical studies should be performed to substantiate these findings.

  11. Use of the antiozonant ethylenediurea (EDU) in Italy: verification of the effects of ambient ozone on crop plants and trees and investigation of EDU's mode of action.

    Science.gov (United States)

    Paoletti, Elena; Contran, Nicla; Manning, William J; Ferrara, Anna M

    2009-05-01

    Twenty-four experiments where EDU was used to protect plants from ozone (O(3)) in Italy are reviewed. Doses of 150 and 450 ppm EDU at 2-3 week intervals were successfully applied to alleviate O(3)-caused visible injury and growth reductions in crop and forest species respectively. EDU was mainly applied as soil drench to crops and by stem injection or infusion into trees. Visible injury was delayed and reduced but not completely. In investigations on mode of action, EDU was quickly (8 days), as it cannot move via phloem. EDU did not enter cells, suggesting it does not directly affect cell metabolism. EDU delayed senescence, did not affect photosynthesis and foliar nitrogen content, and stimulated antioxidant responses to O(3) exposure. Preliminary results suggest developing an effective soil application method for forest trees is warranted.

  12. Significando o risco sanitário: modos de atuação sobre o risco na vigilância sanitária / Meaning the health risk: modes of action on the risk in health surveillance

    Directory of Open Access Journals (Sweden)

    Ana Valesca Fernandes GIlson Silva

    2014-05-01

    intervention there are processes that mixture the rationality, subjectivity, authority, control, experience, the formal knowledge acquired. The act of the HS professional consists of knowledge, acquired experience, socio-cultural contexts, and interactions that define and redefine the modes of action. The actions are based on the meanings of the risk that moves in the planes of objectivity and subjectivity and, the legislation is an important instrument of decision and persuasion. Although there is an offset to the use of the knowledge and experience, it is the legal framework that prints what should or should not be controlled.

  13. Comparative Systems Biology Analysis To Study the Mode of Action of the Isothiocyanate Compound Iberin on Pseudomonas aeruginosa

    DEFF Research Database (Denmark)

    Tan, Sean Yang-Yi; Liu, Yang; Chua, Song Lin;

    2014-01-01

    Pseudomonas aeruginosa. In this study, we used a comparative systems biology approach to unravel the molecular mechanisms of the effects of iberin on QS and virulence factor expression of P. aeruginosa. Our study shows that the two systems biology methods used (i.e., RNA sequencing and proteomics) complement...

  14. 新颖杀螨剂Pyflubumide的合成和作用机制%The Synthesis and Mode of Action of Novel Acaricide Pyflubumidera

    Institute of Scientific and Technical Information of China (English)

    邓建玲

    2015-01-01

    Pyflubumide是新颖的杀螨剂,具有独特的化学结构,其苯胺部分上有甲氧基取代的六氟异丙基基团.其结构与琥珀酸脱氢酶抑制剂型杀菌剂相似.主要介绍了pyflubumide的发现过程、合成和构效关系;以及作用机制.Pyflubumide在蛛螨体内很快脱酰代谢为NH-物,后者与腈吡螨酯的OH-物作用于线粒体复合体Ⅱ的同一酶,但其结合点和/或结合方式不同,应属于不同的类别.%Pyflubumide is a novel acaricide with a unique chemical structure that contains a methoxy-substituted hexafluoroisopropyl group on the anilino moiety. Its structure is similar to that of succinate-dehydrogenase inhibitor(SDHI) fungicides. This paper introduces the discovery, synthesis and structure-activity relationship of pyflubumide, and its mode of action. Pyflubumide is quickly metabolized to its NH-form in the homogenate of spider mites and NH-form acts on the same enzyme with OH-form of cyenopyrafen. But the two compounds act the different binding sites on mitochondrial complexⅡand/or with the different manners of binding, and should be classified into different groups in terms of their mode of action.

  15. Probable neuro sexual mode of action of Casimiroa edulis seed extract versus [correction of verses] sildenafil citrate (Viagra(tm)) on mating behavior in normal male rats.

    Science.gov (United States)

    Ali, Syed Tabrez; Rakkah, Nabeeh I

    2008-01-01

    The present study deals with the aphrodisiac actions of the aqueous extract of the seeds of the hypotensive plant Casimiroa edulis on the sexual behavior of normal male rats. In this investigation 30 healthy male Wister strain white albino rats showing the brisk sexual activity age 15 weeks, weighing 400-450 grams were included. Female rats were artificially brought into estrous by hormonal treatment. Receptivity was checked by exposing them to the male rats and the most receptive females were selected for the stud The mating responses including Mounting Frequency (MF), Intromission Frequency (IF), Mounting Latency (ML), Intromission Latency (IL), Ejaculatory Latency in first and second series (EL1 and EL2) and Post Ejaculatory Interval (PEI) were recorded after treating the animals with 250 mg/kg casimiroa edulis extract (test reference) and 5 mg/kg sildenafil citrate (standard reference) respectively orally per day for 7 days. Both the groups exhibited a significant increase in Mounting Frequency, Intromission Frequency, and first and second ejaculatory latencies, where as Mounting and Intromission latencies and the Post Ejaculatory Interval showed a significant reduction than the controls. Although a similar pattern of mating behavior was observed among the test and the standard groups, however in all the cases as expected, sildenafil produced greater activity than the casimiroa edulis extract. These results suggest the possibility of a similar mode of action of casimiroa edulis and sildenafil citrate on mating behavior in these animals. Our work reported in this research thus provide preliminary evidence that the aqueous seed extract of casimiroa edulis possesses alphrodisiac activity and may be used as an alternative drug therapy to restore sexual functions probably via a neurogenic mode of action.

  16. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    Science.gov (United States)

    Currie, Richard A.; Peffer, Richard C.; Goetz, Amber K.; Omiecinski, Curtis J.; Goodman, Jay I.

    2014-01-01

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA. PMID:24675475

  17. Coriandrum sativum L. (Coriander essential oil: antifungal activity and mode of action on Candida spp., and molecular targets affected in human whole-genome expression.

    Directory of Open Access Journals (Sweden)

    Irlan de Almeida Freires

    Full Text Available Oral candidiasis is an opportunistic fungal infection of the oral cavity with increasingly worldwide prevalence and incidence rates. Novel specifically-targeted strategies to manage this ailment have been proposed using essential oils (EO known to have antifungal properties. In this study, we aim to investigate the antifungal activity and mode of action of the EO from Coriandrum sativum L. (coriander leaves on Candida spp. In addition, we detected the molecular targets affected in whole-genome expression in human cells. The EO phytochemical profile indicates monoterpenes and sesquiterpenes as major components, which are likely to negatively impact the viability of yeast cells. There seems to be a synergistic activity of the EO chemical compounds as their isolation into fractions led to a decreased antimicrobial effect. C. sativum EO may bind to membrane ergosterol, increasing ionic permeability and causing membrane damage leading to cell death, but it does not act on cell wall biosynthesis-related pathways. This mode of action is illustrated by photomicrographs showing disruption in biofilm integrity caused by the EO at varied concentrations. The EO also inhibited Candida biofilm adherence to a polystyrene substrate at low concentrations, and decreased the proteolytic activity of Candida albicans at minimum inhibitory concentration. Finally, the EO and its selected active fraction had low cytotoxicity on human cells, with putative mechanisms affecting gene expression in pathways involving chemokines and MAP-kinase (proliferation/apoptosis, as well as adhesion proteins. These findings highlight the potential antifungal activity of the EO from C. sativum leaves and suggest avenues for future translational toxicological research.

  18. Coriandrum sativum L. (Coriander) essential oil: antifungal activity and mode of action on Candida spp., and molecular targets affected in human whole-genome expression.

    Science.gov (United States)

    Freires, Irlan de Almeida; Murata, Ramiro Mendonça; Furletti, Vivian Fernandes; Sartoratto, Adilson; Alencar, Severino Matias de; Figueira, Glyn Mara; de Oliveira Rodrigues, Janaina Aparecida; Duarte, Marta Cristina Teixeira; Rosalen, Pedro Luiz

    2014-01-01

    Oral candidiasis is an opportunistic fungal infection of the oral cavity with increasingly worldwide prevalence and incidence rates. Novel specifically-targeted strategies to manage this ailment have been proposed using essential oils (EO) known to have antifungal properties. In this study, we aim to investigate the antifungal activity and mode of action of the EO from Coriandrum sativum L. (coriander) leaves on Candida spp. In addition, we detected the molecular targets affected in whole-genome expression in human cells. The EO phytochemical profile indicates monoterpenes and sesquiterpenes as major components, which are likely to negatively impact the viability of yeast cells. There seems to be a synergistic activity of the EO chemical compounds as their isolation into fractions led to a decreased antimicrobial effect. C. sativum EO may bind to membrane ergosterol, increasing ionic permeability and causing membrane damage leading to cell death, but it does not act on cell wall biosynthesis-related pathways. This mode of action is illustrated by photomicrographs showing disruption in biofilm integrity caused by the EO at varied concentrations. The EO also inhibited Candida biofilm adherence to a polystyrene substrate at low concentrations, and decreased the proteolytic activity of Candida albicans at minimum inhibitory concentration. Finally, the EO and its selected active fraction had low cytotoxicity on human cells, with putative mechanisms affecting gene expression in pathways involving chemokines and MAP-kinase (proliferation/apoptosis), as well as adhesion proteins. These findings highlight the potential antifungal activity of the EO from C. sativum leaves and suggest avenues for future translational toxicological research.

  19. Antimicrobial growth promoter use in livestock: a requirement to understand their modes of action to develop effective alternatives.

    Science.gov (United States)

    Brown, Kirsty; Uwiera, Richard R E; Kalmokoff, Martin L; Brooks, Steve P J; Inglis, G Douglas

    2017-01-01

    Antimicrobial agents (AMAs) have been used in agriculture since the 1950s as growth-promoting agents [antimicrobial growth promoters (AGPs)]. They have provided benefits to the agricultural industry by increasing production efficiencies and maximising livestock health, yet the potential risks surrounding resistance to AMAs in medically important pathogenic bacteria have enhanced public and government scrutiny regarding AMA use in agriculture. Although it is recognised that AGP administration can select for resistance to AMAs in enteric bacteria of livestock, conclusive evidence showing a link between resistant bacteria from livestock and human health is lacking (e.g. transmission of resistant zoonotic pathogens). Livestock production output must be increased significantly due to the increase in global population, and thus the identification of non-AMA alternatives to AGP use is required. One strategy employed to identify alternatives to AGPs is an observational empirical methodology, but this approach has failed to deliver effective alternatives. A second approach is aimed at understanding the mechanisms involved in AGP function and developing alternatives that mimic the physiological responses to AGPs. New evidence indicates that AGP function is more complex than merely affecting enteric bacterial populations, and AGPs likely function by directly or indirectly modulating host responses such as the immune system. As such, a more comprehensive understanding of the mechanisms associated with AMA function as AGPs will facilitate the development of effective alternatives. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  20. Bacteriocins from Lactobacillus plantarum - production, genetic organization and mode of action: produção, organização genética e modo de ação.

    Science.gov (United States)

    Todorov, Svetoslav D

    2009-04-01

    Bacteriocins are biologically active proteins or protein complexes that display a bactericidal mode of action towards usually closely related species. Numerous strains of bacteriocin producing Lactobacillus plantarum have been isolated in the last two decades from different ecological niches including meat, fish, fruits, vegetables, and milk and cereal products. Several of these plantaricins have been characterized and the aminoacid sequence determined. Different aspects of the mode of action, fermentation optimization and genetic organization of the bacteriocin operon have been studied. However, numerous of bacteriocins produced by different Lactobacillus plantarum strains have not been fully characterized. In this article, a brief overview of the classification, genetics, characterization, including mode of action and production optimization for bacteriocins from Lactic Acid Bacteria in general, and where appropriate, with focus on bacteriocins produced by Lactobacillus plantarum, is presented.

  1. MOAtox: A comprehensive mode of action and acute aquatic toxicity database for predictive model development (SETAC abstract)

    Science.gov (United States)

    The mode of toxic action (MOA) has been recognized as a key determinant of chemical toxicity and as an alternative to chemical class-based predictive toxicity modeling. However, the development of quantitative structure activity relationship (QSAR) and other models has been limit...

  2. Acute toxicities of pharmaceuticals toward green algae. mode of action, biopharmaceutical drug disposition classification system and quantile regression models.

    Science.gov (United States)

    Villain, Jonathan; Minguez, Laetitia; Halm-Lemeille, Marie-Pierre; Durrieu, Gilles; Bureau, Ronan

    2016-02-01

    The acute toxicities of 36 pharmaceuticals towards green algae were estimated from a set of quantile regression models representing the first global quantitative structure-activity relationships. The selection of these pharmaceuticals was based on their predicted environmental concentrations. An agreement between the estimated values and the observed acute toxicity values was found for several families of pharmaceuticals, in particular, for antidepressants. A recent classification (BDDCS) of drugs based on ADME properties (Absorption, Distribution, Metabolism and Excretion) was clearly correlated with the acute ecotoxicities towards algae. Over-estimation of toxicity from our QSAR models was observed for classes 2, 3 and 4 whereas our model results were in agreement for the class 1 pharmaceuticals. Clarithromycin, a class 3 antibiotic characterized by weak metabolism and high solubility, was the most toxic to algae (molecular stability and presence in surface water).

  3. Intracellular Diagnostics: Hunting for the Mode of Action of Redox-Modulating Selenium Compounds in Selected Model Systems

    Directory of Open Access Journals (Sweden)

    Dominika Mániková

    2014-08-01

    Full Text Available Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the “redox link” which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks.

  4. Modes of action of ADP-ribosylated elongation factor 2 in inhibiting the polypeptide elongation cycle: a modeling study.

    Directory of Open Access Journals (Sweden)

    Kevin C Chen

    Full Text Available Despite the fact that ADP-ribosylation of eukaryotic elongation factor 2 (EF2 leads to inhibition of protein synthesis, the mechanism by which ADP-ribosylated EF2 (ADPR•EF2 causes this inhibition remains controversial. Here, we applied modeling approaches to investigate the consequences of various modes of ADPR•EF2 inhibitory actions on the two coupled processes, the polypeptide chain elongation and ADP-ribosylation of EF2. Modeling of experimental data indicates that ADPR•EF2 fully blocks the late-phase translocation of tRNAs; but the impairment in the translocation upstream process, mainly the GTP-dependent factor binding with the pretranslocation ribosome and/or the guanine nucleotide exchange in EF2, is responsible for the overall inhibition kinetics. The reduced ADPR•EF2-ribosome association spares the ribosome to bind and shield native EF2 against toxin attack, thereby deferring the inhibition of protein synthesis inhibition and inactivation of EF2. Minimum association with the ribosome also keeps ADPR•EF2 in an accessible state for toxins to catalyze the reverse reaction when nicotinamide becomes available. Our work underscores the importance of unveiling the interactions between ADPR•EF2 and the ribosome, and argues against that toxins inhibit protein synthesis through converting native EF2 to a competitive inhibitor to actively disable the ribosome.

  5. The role of blood cell membrane lipids on the mode of action of HIV-1 fusion inhibitor sifuvirtide

    Energy Technology Data Exchange (ETDEWEB)

    Matos, Pedro M.; Freitas, Teresa; Castanho, Miguel A.R.B. [Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisbon, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal); Santos, Nuno C., E-mail: nsantos@fm.ul.pt [Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisbon, Av. Prof. Egas Moniz, 1649-028 Lisboa (Portugal)

    2010-12-17

    Research highlights: {yields} Sifuvirtide interacts with erythrocyte and lymphocyte membrane in a concentration dependent manner by decreasing its dipole potential. {yields} Dipole potential variations in lipid vesicles show sifuvirtide's lipid selectivity towards saturated phosphatidylcholines. {yields} This peptide-membrane interaction may direct the drug towards raft-like membrane domains where the receptors used by HIV are located, facilitating its inhibitory action. -- Abstract: Sifuvirtide is a gp41 based peptide that inhibits HIV-1 fusion with the host cells and is currently under clinical trials. Previous studies showed that sifuvirtide partitions preferably to saturated phosphatidylcholine lipid membranes, instead of fluid-phase lipid vesicles. We extended the study to the interaction of the peptide with circulating blood cells, by using the dipole potential sensitive probe di-8-ANEPPS. Sifuvirtide decreased the dipole potential of erythrocyte and lymphocyte membranes in a concentration dependent manner, demonstrating its interaction. Also, the lipid selectivity of the peptide towards more rigid phosphatidylcholines was confirmed based on the dipole potential variations. Overall, the interaction of the peptide with the cell membranes is a contribution of different lipid preferences that presumably directs the peptide towards raft-like domains where the receptors are located, facilitating the reach of the peptide to its molecular target, the gp41 in its pre-fusion conformation.

  6. Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping.

    Science.gov (United States)

    McKinney, David C; Eyermann, Charles J; Gu, Rong-Fang; Hu, Jun; Kazmirski, Steven L; Lahiri, Sushmita D; McKenzie, Andrew R; Shapiro, Adam B; Breault, Gloria

    2016-07-01

    Fatty acid biosynthesis is essential to bacterial growth in Gram-negative pathogens. Several small molecules identified through a combination of high-throughput and fragment screening were cocrystallized with FabH (β-ketoacyl-acyl carrier protein synthase III) from Escherichia coli and Streptococcus pneumoniae. Structure-based drug design was used to merge several scaffolds to provide a new class of inhibitors. After optimization for Gram-negative enzyme inhibitory potency, several compounds demonstrated antimicrobial activity against an efflux-negative strain of Haemophilus influenzae. Mutants resistant to these compounds had mutations in the FabH gene near the catalytic triad, validating FabH as a target for antimicrobial drug discovery.

  7. Effects of chronic exposure to sodium arsenite on hypothalamo-pituitary-testicular activities in adult rats: possible an estrogenic mode of action

    Directory of Open Access Journals (Sweden)

    Jana Subarna

    2006-02-01

    Full Text Available Abstract Background Inorganic arsenic is a major water pollutant and a known human carcinogen that has a suppressive influence on spermatogenesis and androgenesis in male reproductive system. However, the actual molecular events resulting in male reproductive dysfunctions from exposure to arsenic remain unclear. In this context, we evaluated the mode of action of chronic oral exposure of sodium arsenite on hypothalamo-pituitary- testicular activities in mature male albino rats. Methods The effect of chronic oral exposure to sodium arsenite (5 mg/kg body weight/day via drinking water without or with hCG (5 I.U./kg body weight/day and oestradiol (25 micrograms oestradiol 3-benzoate suspended in 0.25 ml olive oil/rat/day co-treatments for 6 days a week for 4 weeks (about the duration of two spermatogenic cycle was evaluated in adult male rats. Changes in paired testicular weights, quantitative study of different varieties of germ cells at stage VII of spermatogenic cycle, epididymal sperm count, circulatory concentrations of hormones (LH, FSH, testosterone and corticosterone, testicular activities of delta 5, 3beta-hydroxysteroid dehydrogenase (delta 5, 3beta-HSD, 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD, sorbitol dehydrogenase (SDH, acid phosphatase (ACP, alkaline phosphatase (ALP, and lactate dehydrogenase (LDH, as well as the levels of biogenic amines (dopamine, noradrenaline and 5-hydroxytryptamine (5-HT in the hypothalamus and pituitary were monitored in this study. Hormones were assayed by radioimmuno- assay or enzyme- linked immunosorbent assay and the enzymes were estimated after spectrophotometry as well as the biogenic amines by HPLC electrochemistry. Results Sodium arsenite treatment resulted in: decreased paired testicular weights; epididymal sperm count; plasma LH, FSH, testosterone and testicular testosterone concentrations; and increased plasma concentration of corticosterone. Testicular enzymes such as delta 5, 3 beta

  8. Medicinal Chemistry of the Anti-Diabetic Effects of Momordica Charantia: Active Constituents and Modes of Actions

    Science.gov (United States)

    Singh, Jaipaul; Cumming, Emmanuel; Manoharan, Gunasekar; Kalasz, Huba; Adeghate, Ernest

    2011-01-01

    Diabetes mellitus (DM) is one of the oldest known human disease currently affecting more than 200 million people worldwide. Diabetes mellitus is derived from two Greek words meaning siphon and sugar. In DM, patients have high blood level of glucose and this passes out with urine. This is because the endocrine pancreas does not produce either or not enough insulin or the insulin which is produced is not exerting its biochemical effect (or insulin resistance) effectively. Insulin is a major metabolic hormone which has numerous functions in the body and one main role is to stimulate glucose uptake into body’s cells where it is utilized to provide energy. The disease is classified into type 1 and type 2 DM. Type 1 DM develops when the insulin producing β cells have been destroyed and are unable to produce insulin. This is very common in children and is treated with insulin. Type 2 DM (T2DM) develops when the body is unable to produce an adequate amount of insulin or the insulin which is provided does not work efficiently. This is due to life style habits including unhealthy diet, obesity, lack of exercise and hereditary and environmental factors. Some symptoms of DM include excess urination, constant thirst, lethargy, weight loss, itching, decreased digestive enzyme secretion, slow wound healing and other related symptoms. If left untreated, DM can result in severe long-term complications such as kidney and heart failure, stroke, blindness, nerve damage, exocrine glands insufficiency and other forms of complications. T2DM can be treated and controlled by prescribed drugs, regular exercise, diet (including some plant-based food) and general change in life style habits. This review is concerned with the role of plant-based medicine to treat DM. One such plant is Momordica charantia which is grown in tropical countries worldwide and it has been used as a traditional herbal medicine for thousands of years although its origin in unknown. This review examines the

  9. Tetrahydrobiopterin, its mode of action on phenylalanine hydroxylase, and importance of genotypes for pharmacological therapy of phenylketonuria.

    Science.gov (United States)

    Heintz, Caroline; Cotton, Richard G H; Blau, Nenad

    2013-07-01

    In about 20%-30% of phenylketonuria (PKU) patients (all phenotypes of PAH deficiency), Phe levels may be controlled through phenylalanine hydroxylase cofactor tetrahydrobiopterin therapy. These patients can be diagnosed by an oral tetrahydrobiopterin challenge and are characterized by mutations coding for proteins with substantial residual PAH activity. They can be treated with a commercially available synthetic form of tetrahydrobiopterin, either as a monotherapy or as adjunct to the diet. This review article summarizes molecular and metabolic bases of PKU and the importance of the tetrahydrobiopterin loading test used for PKU patients. On the basis of in vitro residual PAH activity, more than 1,200 genotypes from patients challenged with tetrahydrobiopterin were categorized as predictive for tetrahydrobiopterin responsiveness or non-responsiveness and correlated with the loading test, phenotype, and residual in vitro PAH activity. The coexpression of two distinct PAH mutant alleles revealed possible dominance effects (positive or negative) by one of the mutations on residual activity as result of interallelic complementation. The treatment of the transfected cells with tetrahydrobiopterin showed an increase in residual PAH activity with several mutations coexpressed.

  10. Exploring the mode of action of dithranol therapy for psoriasis: a metabolomic analysis using HaCaT cells.

    Science.gov (United States)

    Hollywood, Katherine A; Winder, Catherine L; Dunn, Warwick B; Xu, Yun; Broadhurst, David; Griffiths, Christopher E M; Goodacre, Royston

    2015-08-01

    Psoriasis is a common, immune-mediated inflammatory skin disease characterized by red, heavily scaled plaques. The disease affects over one million people in the UK and causes significant physical, psychological and societal impact. There is limited understanding regarding the exact pathogenesis of the disease although it is believed to be a consequence of genetic predisposition and environmental triggers. Treatments vary from topical therapies, such as dithranol, for disease of limited extent (biologic therapies for severe psoriasis. Dithranol (also known as anthralin) is a topical therapy for psoriasis believed to work by inhibiting keratinocyte proliferation. To date there have been no metabolomic-based investigations into psoriasis. The HaCaT cell line is a model system for the epidermal keratinocyte proliferation characteristic of psoriasis and was thus chosen for study. Dithranol was applied at therapeutically relevant doses to HaCaT cells. Following the optimisation of enzyme inactivation and metabolite extraction, gas chromatography-mass spectrometry was employed for metabolomics as this addresses central metabolism. Cells were challenged with 0-0.5 μg mL(-1) in 0.1 μg mL(-1) steps and this quantitative perturbation generated data that were highly amenable to correlation analysis. Thus, we used a combination of traditional principal components analysis, hierarchical cluster analysis, along with correlation networks. All methods highlighted distinct metabolite groups, which had different metabolite trajectories with respect to drug concentration and the interpretation of these data established that cellular metabolism had been altered significantly and provided further clarification of the proposed mechanism of action of the drug.

  11. The mode of action of the Bacillus thuringiensis vegetative insecticidal protein Vip3A differs from that of Cry1Ab delta-endotoxin.

    Science.gov (United States)

    Lee, Mi Kyong; Walters, Frederick S; Hart, Hope; Palekar, Narendra; Chen, Jeng-Shong

    2003-08-01

    The Vip3A protein, secreted by Bacillus spp. during the vegetative stage of growth, represents a new family of insecticidal proteins. In our investigation of the mode of action of Vip3A, the 88-kDa Vip3A full-length toxin (Vip3A-F) was proteolytically activated to an approximately 62-kDa core toxin either by trypsin (Vip3A-T) or lepidopteran gut juice extracts (Vip3A-G). Biotinylated Vip3A-G demonstrated competitive binding to lepidopteran midgut brush border membrane vesicles (BBMV). Furthermore, in ligand blotting experiments with BBMV from the tobacco hornworm, Manduca sexta (Linnaeus), activated Cry1Ab bound to 120-kDa aminopeptidase N (APN)-like and 250-kDa cadherin-like molecules, whereas Vip3A-G bound to 80-kDa and 100-kDa molecules which are distinct from the known Cry1Ab receptors. In addition, separate blotting experiments with Vip3A-G did not show binding to isolated Cry1A receptors, such as M. sexta APN protein, or a cadherin Cry1Ab ecto-binding domain. In voltage clamping assays with dissected midgut from the susceptible insect, M. sexta, Vip3A-G clearly formed pores, whereas Vip3A-F was incapable of pore formation. In the same assay, Vip3A-G was incapable of forming pores with larvae of the nonsusceptible insect, monarch butterfly, Danaus plexippus (Linnaeus). In planar lipid bilayers, both Vip3A-G and Vip3A-T formed stable ion channels in the absence of any receptors, supporting pore formation as an inherent property of Vip3A. Both Cry1Ab and Vip3A channels were voltage independent and highly cation selective; however, they differed considerably in their principal conductance state and cation specificity. The mode of action of Vip3A supports its use as a novel insecticidal agent.

  12. Pharmacokinetics and pharmacodynamics of orally administered acetylenic tricyclic bis(cyanoenone), a highly potent Nrf2 activator with a reversible covalent mode of action

    Energy Technology Data Exchange (ETDEWEB)

    Kostov, Rumen V.; Knatko, Elena V.; McLaughlin, Lesley A.; Henderson, Colin J. [Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY, Scotland (United Kingdom); Zheng, Suqing [Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, 11794 (United States); Huang, Jeffrey T.-J. [Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY, Scotland (United Kingdom); Honda, Tadashi [Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY, 11794 (United States); Dinkova-Kostova, Albena T., E-mail: a.dinkovakostova@dundee.ac.uk [Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, DD1 9SY, Scotland (United Kingdom); Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States); Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205 (United States)

    2015-09-25

    The acetylenic tricyclic bis(cyanoenone) TBE-31 is a highly potent cysteine targeting compound with a reversible covalent mode of action; its best-characterized target being Kelch-like ECH-associated protein-1 (Keap1), the cellular sensor for oxidants and electrophiles. TBE-31 reacts with cysteines of Keap1, impairing its ability to target nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) for degradation. Consequently, Nrf2 accumulates and orchestrates cytoprotective gene expression. In this study we investigated the pharmacokinetic and pharmacodynamic properties of TBE-31 in C57BL/6 mice. After a single oral dose of 10 μmol/kg (∼200 nmol/animal), the concentration of TBE-31 in blood exhibited two peaks, at 22.3 nM and at 15.5 nM, 40 min and 4 h after dosing, respectively, as determined by a quantitative stable isotope dilution LC-MS/MS method. The AUC{sub 0–24h} was 195.5 h/nmol/l, the terminal elimination half-life was 10.2 h, and the k{sub el} was 0.068 h{sup −1}. To assess the pharmacodynamics of Nrf2 activation by TBE-31, we determined the enzyme activity of its prototypic target, NAD(P)H:quinone oxidoreductase 1 (NQO1) and found it elevated by 2.4- and 1.5-fold in liver and heart, respectively. Continuous feeding for 18 days with diet delivering the same daily doses of TBE-31 under conditions of concurrent treatment with the immunosuppressive agent azathioprine had a similar effect on Nrf2 activation without any indications of toxicity. Together with previous reports showing the cytoprotective effects of TBE-31 in animal models of carcinogenesis, our results demonstrate the high potency, efficacy and suitability for chronic administration of cysteine targeting reversible covalent drugs. - Highlights: • TBE-31 is a cysteine targeting compound with a reversible covalent mode of action. • After a single oral dose, the blood concentration of TBE-31 exhibits two peaks. • Oral TBE-31 is a potent activator of Nrf2-dependent enzymes in

  13. Antibacterial Mode of Action of the Essential Oil Obtained from Chamaecyparis obtusa Sawdust on the Membrane Integrity of Selected Foodborne Pathogens

    Directory of Open Access Journals (Sweden)

    Vivek K. Bajpai

    2014-01-01

    Full Text Available The present study examines the possible antibacterial mechanism of action of the essential oil obtained from Chamaecyparis obtusa (COEO sawdust against foodborne pathogenic bacteria. The COEO was obtained by microwave-assisted hydrodistillation of C. obtusa sawdust. The minimum inhibitory concentration (MIC and minimum bactericidal concentration (MBC values of COEO against the tested foodborne pathogens including Bacillus cereus ATCC 13061, Listeria monocytogenes ATCC 7644, Staphylococcus aureus ATCC 12600, Salmonella Typhimurium ATCC 43174 and Escherichia coli ATCC 43889 were found in the range from 62.5 to 500 μg/mL and from 125 to 1000 μg/mL, respectively. At the MIC concentrations, the COEO had potential inhibitory effect on the cell viability of the tested bacteria. In addition, the scanning electron microscopic analysis confirmed the inhibitory effect of COEO by revealing significant morphological alterations or rupture of the cell membranes of B. cereus ATCC 13061 and E. coli ATCC 43889. Moreover, the mode of action of COEO on the cell membrane of both Gram-positive B. cereus ATCC 13061 and Gram-negative E. coli ATCC 43889 bacteria was confirmed by marked release of extracellular adenosine 5’-triphosphate (ATP and cellular material that absorbs at 260 nm, and by efflux of potassium ions. These findings suggest that COEO holds a broad-spectrum antibacterial efficacy, confirming its influence on the membrane integrity and morphological characteristics of tested foodborne pathogens.

  14. Evaluation of Antifungal Activity and Mode of Action of New Coumarin Derivative, 7-Hydroxy-6-nitro-2H-1-benzopyran-2-one, against Aspergillus spp.

    Directory of Open Access Journals (Sweden)

    Felipe Queiroga Sarmento Guerra

    2015-01-01

    Full Text Available Aspergillus spp. produce a wide variety of diseases. For the treatment of such infections, the azoles and Amphotericin B are used in various formulations. The treatment of fungal diseases is often ineffective, because of increases in azole resistance and their several associated adverse effects. To overcome these problems, natural products and their derivatives are interesting alternatives. The aim of this study was to examine the effects of coumarin derivative, 7-hydroxy-6-nitro-2H-1-benzopyran-2-one (Cou-NO2, both alone and with antifungal drugs. Its mode of action against Aspergillus spp. Cou-NO2 was tested to evaluate its effects on mycelia growth and germination of fungal conidia of Aspergillus spp. We also investigated possible Cou-NO2 action on cell walls (0.8 M sorbitol and on Cou-NO2 to ergosterol binding in the cell membrane. The study shows that Cou-NO2 is capable of inhibiting both the mycelia growth and germination of conidia for the species tested, and that its action affects the structure of the fungal cell wall. At subinhibitory concentration, Cou-NO2 enhanced the in vitro effects of azoles. Moreover, in combination with azoles (voriconazole and itraconazole Cou-NO2 displays an additive effect. Thus, our study supports the use of coumarin derivative 7-hydroxy-6-nitro-2H-1-benzopyran-2-one as an antifungal agent against Aspergillus species.

  15. Antimicrobial activity of cationic antimicrobial peptides against gram-positives: Current progress made in understanding the mode of action and the response of bacteria

    Directory of Open Access Journals (Sweden)

    Soraya Omardien

    2016-10-01

    Full Text Available Antimicrobial peptides (AMPs have been proposed as a novel class of antimicrobials that could aid the fight against antibiotic resistant bacteria. The mode of action of AMPs as acting on the bacterial cytoplasmic membrane has often been presented as an enigma and there are doubts whether the membrane is the sole target of AMPs. Progress has been made in clarifying the possible targets of these peptides, which is reported in this review with as focus gram-positive vegetative cells and spores. Numerical estimates are discussed to evaluate the possibility that targets, other than the membrane, could play a role in susceptibility to AMPs. Concerns about possible resistance that bacteria might develop to AMPs are addressed. Proteomics, transcriptomics and other molecular techniques are reviewed in the context of explaining the response of bacteria to the presence of AMPs and to predict what resistance strategies might be. Emergent mechanisms are cell envelope stress responses as well as enzymes able to degrade and/or specifically bind (and thus inactivate AMPs. Further studies are needed to address the broadness of the AMP resistance and stress responses observed.

  16. In Vitro Evaluation of CBR-2092, a Novel Rifamycin-Quinolone Hybrid Antibiotic: Studies of the Mode of Action in Staphylococcus aureus▿

    Science.gov (United States)

    Robertson, Gregory T.; Bonventre, Eric J.; Doyle, Timothy B.; Du, Qun; Duncan, Leonard; Morris, Timothy W.; Roche, Eric D.; Yan, Dalai; Lynch, A. Simon

    2008-01-01

    Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent S. aureus infections. PMID:18443108

  17. Bioefficacy and mode-of-action of some limonoids of salannin group from Azadirachta indica A. Juss and their role in a multicomponent system against lepidopteran larvae

    Indian Academy of Sciences (India)

    Opender Koul; Gurmeet Singh; Rajwinder Singh; Jasbir Singh; W M Daniewski; Stanislaw Berlozecki

    2004-12-01

    Biological activities of the salannin type of limonoids isolated from Azadirachta indica A. Juss were assessed using the gram pod borer Helicoverpa armigera (Hubner) and the tobacco armyworm Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae). Inhibition of larval growth was concomitant with reduced feeding by neonate and third instar larvae. All three compounds exhibited strong antifeedant activity in a choice leaf disc bioassay with 2.0, 2.3 and 2.8 g/cm2 of 3-O-acetyl salannol, salannol and salannin, respectively deterring feeding by 50% in S. litura larvae. In nutritional assays, all three compounds reduced growth and consumption when fed to larvae without any effect on efficiency of conversion of ingested food (ECI), suggesting antifeedant activity alone. No toxicity was observed nor was there any significant affect on nutritional indices following topical application, further suggesting specific action as feeding deterrents. When relative growth rates were plotted against relative consumption rates, growth efficiency of the H. armigera fed diet containing 3-O-acetyl salannol, salannol or salannin did not differ from that of starved control larvae (used as calibration curve), further confirming the specific antifeedant action of salannin type of limonoids. Where the three compounds were co-administered, no enhancement in activity was observed. Non-azadirachtin limonoids having structural similarities and explicitly similar modes of action, like feeding deterrence in the present case, have no potentiating effect in any combination.

  18. Evaluation of Antifungal Activity and Mode of Action of New Coumarin Derivative, 7-Hydroxy-6-nitro-2H-1-benzopyran-2-one, against Aspergillus spp.

    Science.gov (United States)

    Guerra, Felipe Queiroga Sarmento; de Araújo, Rodrigo Santos Aquino; de Sousa, Janiere Pereira; Pereira, Fillipe de Oliveira; Mendonça-Junior, Francisco J B; Barbosa-Filho, José M; de Oliveira Lima, Edeltrudes

    2015-01-01

    Aspergillus spp. produce a wide variety of diseases. For the treatment of such infections, the azoles and Amphotericin B are used in various formulations. The treatment of fungal diseases is often ineffective, because of increases in azole resistance and their several associated adverse effects. To overcome these problems, natural products and their derivatives are interesting alternatives. The aim of this study was to examine the effects of coumarin derivative, 7-hydroxy-6-nitro-2H-1-benzopyran-2-one (Cou-NO2), both alone and with antifungal drugs. Its mode of action against Aspergillus spp. Cou-NO2 was tested to evaluate its effects on mycelia growth and germination of fungal conidia of Aspergillus spp. We also investigated possible Cou-NO2 action on cell walls (0.8 M sorbitol) and on Cou-NO2 to ergosterol binding in the cell membrane. The study shows that Cou-NO2 is capable of inhibiting both the mycelia growth and germination of conidia for the species tested, and that its action affects the structure of the fungal cell wall. At subinhibitory concentration, Cou-NO2 enhanced the in vitro effects of azoles. Moreover, in combination with azoles (voriconazole and itraconazole) Cou-NO2 displays an additive effect. Thus, our study supports the use of coumarin derivative 7-hydroxy-6-nitro-2H-1-benzopyran-2-one as an antifungal agent against Aspergillus species.

  19. How the mode of action affects evidence of planning and movement kinematics in aging: End-state comfort in older adults.

    Science.gov (United States)

    Scharoun, Sara M; Gonzalez, Dave A; Roy, Eric A; Bryden, Pamela J

    2016-05-01

    Motor deficits are commonly observed with age; however, it has been argued that older adults are more adept when acting in natural tasks and do not differ from young adults in these contexts. This study assessed end-state comfort and movement kinematics in a familiar task to examine this further. Left- and right-handed older adults picked up a glass (upright or overturned) as if to pour water in four modes of action (pantomime, pantomime with image/cup as a guide, actual grasping). With increasing age, a longer deceleration phase (in pantomime without a stimulus) and less end-state comfort (in pantomime without a stimulus and image as a guide) was displayed as the amount of contextual information available to guide movement decreased. Changes in movement strategies likely reflect an increased reliance on feedback control and demonstration of a more cautious movement. A secondary aim of this study was to assess hand preference and performance, considering conflicting reports of manual asymmetries with age. Performance differences in the Grooved Pegboard place task indicate left handers may display a shift towards right handedness in some, but not all cases. Summarizing, this study supports age-related differences in planning and control processes in a familiar task, and changes in manual asymmetries with age in left handers.

  20. Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Merilin Al Sharif

    2014-01-01

    Full Text Available Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD concepts: (i PPARγ activation in hepatocytes and (ii PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.

  1. Consensus diagnoses and mode of action for the formation of gastric tumors in rats treated with the chloroacetanilide herbicides alachlor and butachlor.

    Science.gov (United States)

    Furukawa, Satoshi; Harada, Takanori; Thake, Daryl; Iatropoulos, Michael J; Sherman, James H

    2014-01-01

    A panel of pathologists (Panel) was formed to evaluate the pathogenesis and human relevance of tumors that developed in the fundic region of rat stomachs in carcinogenicity and mechanistic studies with alachlor and butachlor. The Panel evaluated stomach sections stained with hematoxylin and eosin, neuron-specific enolase, and chromogranin A to determine the presence and relative proportion of enterochromaffin-like (ECL) cells in the tumors and concluded all tumors were derived from ECL cells. Biochemical and pathological data demonstrated the tumor formation involved a nongenotoxic threshold mode of action (MOA) initially characterized by profound atrophy of the glandular fundic mucosa that affected gastric glands, but not surface epithelium. This resulted in a substantial loss of parietal cells and a compensatory mucosal cell proliferation. The loss of parietal cells caused a marked increase in gastric pH (hypochlorhydria), leading to sustained and profound hypergastrinemia. The mucosal atrophy, together with the increased gastrin, stimulated cell growth in one or more ECL cell populations, resulting in neoplasia. ECL cell autocrine and paracrine effects led to dedifferentiation of ECL cell tumors. The Panel concluded the tumors develop via a threshold-dependent nongenotoxic MOA, under conditions not relevant to humans.

  2. Mode of Action Temu Kunci (Kaempferia pandurata Essential Oil on E. coli K1.1 Cell Determined by Leakage of Material Cell and Salt Tolerance Assays

    Directory of Open Access Journals (Sweden)

    MIKSUSANTI

    2008-06-01

    Full Text Available The essential oil of Kaempferia pandurata consist of terpen and oxygenated terpen that exhibits broad-spectrum antimicrobial activity. It’s mode of action against the gram-negative bacterium E. coli K1.1 has been investigated using a range of treatments. The mode action of the essential oil were analyzed by it’s ability to leakage E. coli K1.1 cell, to change permeability of the cell, and to alter salt tolerance of the cell. Ion leakage from the cell were analyzed by atomic absorption spectrophotometer. Salt tolerance assays was conducted by investigating the ability of E. coli K1.1 treated with temu kunci essential oil to grow on NA supplemented with NaCl. Protein and acid nucleic leakage were analyzed by UV spectrophotometer. There were inorganic compound leakage (potassium, calcium ion and organic compound leakage (nucleic acid, protein from cytoplasmic membrane, after exposing this organism to essential oil of Kaempferia pandurata. The more concentration of oil added, the more leakage was observed due to the loss of absorbing material such as nucleic acid (260 nm and protein (280 nm, the loss of potassium and calcium ion, and loss of the salt tolerance of E. coli K1.1.

  3. In vitro evaluation of CBR-2092, a novel rifamycin-quinolone hybrid antibiotic: studies of the mode of action in Staphylococcus aureus.

    Science.gov (United States)

    Robertson, Gregory T; Bonventre, Eric J; Doyle, Timothy B; Du, Qun; Duncan, Leonard; Morris, Timothy W; Roche, Eric D; Yan, Dalai; Lynch, A Simon

    2008-07-01

    Rifamycins have proven efficacy in the treatment of persistent bacterial infections. However, the frequency with which bacteria develop resistance to rifamycin agents restricts their clinical use to antibiotic combination regimens. In a program directed toward the synthesis of rifamycins with a lower propensity to elicit resistance development, a series of compounds were prepared that covalently combine rifamycin and quinolone pharmacophores to form stable hybrid antibacterial agents. We describe mode-of-action studies with Staphylococcus aureus of CBR-2092, a novel hybrid that combines the rifamycin SV and 4H-4-oxo-quinolizine pharmacophores. In biochemical studies, CBR-2092 exhibited rifampin-like potency as an inhibitor of RNA polymerase, was an equipotent (balanced) inhibitor of DNA gyrase and DNA topoisomerase IV, and retained activity against a prevalent quinolone-resistant variant. Macromolecular biosynthesis studies confirmed that CBR-2092 has rifampin-like effects on RNA synthesis in rifampin-susceptible strains and quinolone-like effects on DNA synthesis in rifampin-resistant strains. Studies of mutant strains that exhibited reduced susceptibility to CBR-2092 further substantiated RNA polymerase as the primary cellular target of CBR-2092, with DNA gyrase and DNA topoisomerase IV being secondary and tertiary targets, respectively, in strains exhibiting preexisting rifampin resistance. In contrast to quinolone comparator agents, no strains with altered susceptibility to CBR-2092 were found to exhibit changes consistent with altered efflux properties. The combined data indicate that CBR-2092 may have potential utility in monotherapy for the treatment of persistent S. aureus infections.

  4. Microwave synthesis of ZnO@mSiO₂ for detailed antifungal mode of action study: understanding the insights into oxidative stress.

    Science.gov (United States)

    Mitra, Shouvik; Patra, Prasun; Pradhan, Saheli; Debnath, Nitai; Dey, Kushal Kumar; Sarkar, Sampad; Chattopadhyay, Dhrubajyoti; Goswami, Arunava

    2015-04-15

    A simple chemical method has been devised for deliberate incorporation of zinc oxide nanoparticles (ZNPs) within mesoporous nanosilica (mSiO2) matrix to yield zinc oxide nanoparticles embedded in mesoporous nanosilica (ZnO@mSiO2). ZnO@mSiO2 inhibited the growth of four strains of fungi in a dose dependant manner. A series of biochemical assays revealed generation of oxidative stress from ZnO@mSiO2 for such biocidal response. We proposed transient superoxide and its subsequent conversion to H2O2 played a pivotal role behind such biocidal response as revealed from our systematic evaluation. This resulted morphological alteration of fungi through increase in number of facets, in correlation we found up-regulation in oxidative stress related genes. Bioavailability within the fungal sample was confirmed from microscopic, spectroscopic, biophysical techniques. Protein carbonylation of fungal species was the chemical outcome of such above mentioned stress and quantified by high performance liquid chromatography (HPLC) via subsequent hydrazone derivatization. Several in vitro and in vivo evaluations revealed the biocompatibility of ZnO@mSiO2. Altogether this report claims a new biocidal agent with a detailed mode of action focusing on the origin and quantification of oxidative stress through biophysical and biochemical techniques for the first time for real time applications.

  5. Diclofenac can exhibit estrogenic modes of action in male Xenopus laevis, and affects the hypothalamus-pituitary-gonad axis and mating vocalizations.

    Science.gov (United States)

    Efosa, Norah Johanna; Kleiner, Wibke; Kloas, Werner; Hoffmann, Frauke

    2017-04-01

    Diclofenac (DCF) is a non-steroidal analgesic and antiphlogistic. Due to its tremendous use, DCF can be found in the environment, especially in sewage, but also surface waters, ground and drinking water. Previous studies indicated that DCF can modulate the reproductive physiology of fish by altering the expression of important key enzymes of the hypothalamus-pituitary-gonad-axis (HPG-axis) and might act as an estrogenic endocrine disrupting chemical (EDC). Other studies, however, demonstrated that DCF does not exhibit any estrogenicity. Thus, in the present study we investigated whether an exposure to DCF can affect reproductive behavior and physiology of adult male X. laevis by analyzing DCF effects on the mate calling behavior of the frogs and on gene expression patterns of key biomarkers of the HPG-axis. In addition, plasma sex steroid levels were determined to gain detailed insights into the mechanisms of DCF action. We could demonstrate that DCF can act as EDC by exhibiting slight estrogenic modes of action. In addition, pharmacological impacts on gonadal steroidogenesis could be revealed leading to imbalances in sex steroid levels and ratios. DCF furthermore altered the calling behavior of exposed males, potentially reducing the mating and reproductive success of the frogs, possibly leading to severe population effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. MODE OF ACTION OF LANTANA CAMARA EXTRACTS ON ENZYMES ASPARTATE AMINO TRANSFERASE AND ALANINE AMINO TRANSFERASE ACTIVITY IN TARGET AND NONTARGET ORGANISMS

    Directory of Open Access Journals (Sweden)

    DIVYA RAJAN

    2013-01-01

    Full Text Available The plant Lantana camara on the basis of study conducted found to show effective larvicidal activity. The presentstudy deals with the mode of action of Lantana camara extract on enzymes, Aspartate Amino Transferase andAlanine Amino Transferase activity in target and non-target organisms. The major transaminase system of the bodysuch as AsAT and AlAT were significantly inhibited by the plant extract. A significant decrease in the activity ofabove two enzyme systems were observed from the fourth h of incubation onwards. The transaminase system ofmosquito larvae was more sensitive to Lantana camara extract than that of vertebrate system such as Anabastestudineus and Rana hexadactyla which are the non-target organisms seen in the aquatic habitat. The majortransaminase systems of the body such as AsAT and AlAT were inhibited in a dose dependent manner under bothinvitro and invivo conditions. The change of pH from alkaline (normal larvae to acidic (intoxicated larvae, mayalso be sufficient for inhibiting or blocking most of the enzymatic reactions leading to the death of the organisms.The results of this experiment indicated that the shrub Lantana camara could be studied further in detail and itsbenificial effects to the control of vector bron diseases could be utilised for healthy environments

  7. Mode of action and in vitro susceptibility of mastitis pathogens to macedocin ST91KM and preparation of a teat seal containing the bacteriocin

    Directory of Open Access Journals (Sweden)

    Renee Pieterse

    2010-03-01

    Full Text Available Mastitis is considered to be the most economically costly disease affecting the dairy industry. Regular dosage of animals with antibiotics, including use of prophylactic concentrations, may select for resistant strains. The purpose of this study was to determine the mode of action of a new bacteriocin (macedocin ST91KM, to evaluate the antimicrobial resistance of mastitis pathogens to antibiotics commonly used in treatment remedies, and to introduce the possible use of an alternative antimicrobial agent. The bacteriocin macedocin ST91KM, produced by Streptococcus gallolyticus subsp. macedonicus ST91KM, is bactericidal to Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis and Staphylococcus aureus associated with mastitis infections, including strains resistant to methicillin and oxacillin. Sensitive cells were deformed and secreted nucleotides, K+ and β-galactosidase when exposed to macedocin ST91KM. Adsorption of the peptide to target cells decreased in the presence of solvents, suggesting that receptors on the cell surfaces have lipid moieties. No adsorption was recorded in the presence of MgCl2, KI and Na2CO3, suggesting that ionic strength plays an important role. A teat seal preparation containing macedocin ST91KM effectively released the peptide and inhibited the growth of S. agalactiae. Macedocin ST91KM could form the basis for alternative dry cow therapy to prevent mastitis infections in dairy cows as it is effective against pathogens that display resistance to conventional antibiotic therapy.

  8. Antimicrobial Activity of Cationic Antimicrobial Peptides against Gram-Positives: Current Progress Made in Understanding the Mode of Action and the Response of Bacteria

    Science.gov (United States)

    Omardien, Soraya; Brul, Stanley; Zaat, Sebastian A. J.

    2016-01-01

    Antimicrobial peptides (AMPs) have been proposed as a novel class of antimicrobials that could aid the fight against antibiotic resistant bacteria. The mode of action of AMPs as acting on the bacterial cytoplasmic membrane has often been presented as an enigma and there are doubts whether the membrane is the sole target of AMPs. Progress has been made in clarifying the possible targets of these peptides, which is reported in this review with as focus gram-positive vegetative cells and spores. Numerical estimates are discussed to evaluate the possibility that targets, other than the membrane, could play a role in susceptibility to AMPs. Concerns about possible resistance that bacteria might develop to AMPs are addressed. Proteomics, transcriptomics, and other molecular techniques are reviewed in the context of explaining the response of bacteria to the presence of AMPs and to predict what resistance strategies might be. Emergent mechanisms are cell envelope stress responses as well as enzymes able to degrade and/or specifically bind (and thus inactivate) AMPs. Further studies are needed to address the broadness of the AMP resistance and stress responses observed.

  9. Sources and modes of action of invasive knotweed allelopathy: the effects of leaf litter and trained soil on the germination and growth of native plants

    Directory of Open Access Journals (Sweden)

    Madalin Parepa

    2012-05-01

    Full Text Available Invasive knotweeds, native to Eastern Asia, are among the most dominant plant invaders of European and North American temperate ecosystems. Recent studies indicate that one cause of this dominance might be allelopathy, but the possible sources and modes of action of this allelopathy are insufficiently understood. Here, we asked whether the invasive knotweed Fallopia × bohemica can exert allelopathic effects on native plants also through its leaf litter, or through persistent soil contaminants, and whether these affect the germination or growth of native plants. In a germination experiment with nine native species neither litter leachate, an aqueous extract of knotweed leaves added to the soil, nor trained soil with a history of Fallopia pre-cultivation suppressed the germination or early growth of natives. A mesocosm study with experimental native communities showed that the presence of F. × bohemica, although not a dominant in these communities, caused significant shifts of life-history strategy in two dominant natives, and that similar effects could be elicited through litter leachates or trained soil alone. However, there were hardly any effects on the biomass of natives. Our study indicates that knotweed allelopathy acts on the growth rather than germination of natives, and that soil contamination through persistent allelochemicals may not be a significant problem in habitat restoration. It also shows that allelopathic effects can sometimes be subtle changes in life-history and allocation patterns of the affected species.

  10. Plant bioassay to assess the effects of allelochemicals on the metabolome of the target species Aegilops geniculata by an NMR-based approach.

    Science.gov (United States)

    D'Abrosca, Brigida; Scognamiglio, Monica; Fiumano, Vittorio; Esposito, Assunta; Choi, Young Hae; Verpoorte, Robert; Fiorentino, Antonio

    2013-09-01

    A metabolomic-based approach for the study of allelopathic interactions in the Mediterranean area is proposed using Aegilops geniculata Roth (Poaceae), a Mediterranean herbaceous plant, as test species. Its metabolome has been elucidated by 1D and 2D NMR experiments. Hydroponic plant cultures of A. geniculata were treated with specific compounds of known allelopathic potential: catechol, coumarin, p-coumaric acid, p-hydroxybenzoic acid, ferulic acid and juglone. The metabolic variations due to the presence of allelochemicals have been analyzed and measured. All of the compounds showed the strongest effects at the highest concentration, with coumarin and juglone as the most active compounds, causing an increase of several metabolites. The metabolome changes in test plants confirmed the allelochemicals' reported modes of action. The results demonstrated that the proposed method is a promising tool. It can be applied to plant extracts, making it possible to evidence the metabolites responsible for the activity, as well as their mechanisms of action.

  11. A Biologically-Based Computational Approach to Drug Repurposing for Anthrax Infection

    Directory of Open Access Journals (Sweden)

    Jane P. F. Bai

    2017-03-01

    Full Text Available Developing drugs to treat the toxic effects of lethal toxin (LT and edema toxin (ET produced by B. anthracis is of global interest. We utilized a computational approach to score 474 drugs/compounds for their ability to reverse the toxic effects of anthrax toxins. For each toxin or drug/compound, we constructed an activity network by using its differentially expressed genes, molecular targets, and protein interactions. Gene expression profiles of drugs were obtained from the Connectivity Map and those of anthrax toxins in human alveolar macrophages were obtained from the Gene Expression Omnibus. Drug rankings were based on the ability of a drug/compound’s mode of action in the form of a signaling network to reverse the effects of anthrax toxins; literature reports were used to verify the top 10 and bottom 10 drugs/compounds identified. Simvastatin and bepridil with reported in vitro potency for protecting cells from LT and ET toxicities were computationally ranked fourth and eighth. The other top 10 drugs were fenofibrate, dihydroergotamine, cotinine, amantadine, mephenytoin, sotalol, ifosfamide, and mefloquine; literature mining revealed their potential protective effects from LT and ET toxicities. These drugs are worthy of investigation for their therapeutic benefits and might be used in combination with antibiotics for treating B. anthracis infection.

  12. Contractility of isolated bovine ventricular myocytes is enhanced by intracellular injection of cardioactive glycosides. Evidence for an intracellular mode of action.

    Science.gov (United States)

    Isenberg, G

    1984-01-01

    The contractions of isolated bovine left ventricular myocytes were evaluated by optically measuring the extent of unloaded shortening (ES), the maximal rate of shortening (MRS) and the maximal rate of re-lengthening (MRL). Ouabain, digoxin or digitoxin were intracellularly injected by 2 sec long pressure pulses via the microelectrodes. Their i.c. concentration was estimated to be 2-5 nM. Within 1-4 min after the injection, ES, MRS and MRL increased by more than 2-fold. The contractility renormalized within the following 20 min. Injection of solutions without glycosides did not increase the contractility. An interaction of the injected glycoside with the e.c. ouabain receptor could be largely excluded because a) the amount of the released glycoside was too small for e.c. effects, b) 500 nM e.c. antidigoxin, c) 20 mM [K]o or d) covalent binding of digoxin to HSA did not prevent the increase in contractility due to the i.c. injections. Since contractility also increased when the injections were performed at Na-free conditions, [Na]i-load is not necessary for the effect of i.e. glycosides. The increased contractility due to the injected glycosides was not observed when the contractility prior to the injection was already potentiated, e.g. by greater than 3.6 mM [Ca]o or by stimulation at frequencies greater than 1.25 Hz. The results are interpreted by the hypothesis that the i.c. glycosides facilitate the release of activator calcium from the SR. The possible i.c. modes of action are discussed as well as the idea that e.c. applied glycosides internalize and mediate inotropy via the i.e. mechanism.

  13. A medium-term gpt delta rat model as an in vivo system for analysis of renal carcinogenesis and the underlying mode of action.

    Science.gov (United States)

    Matsushita, Kohei; Ishii, Yuji; Takasu, Shinji; Kuroda, Ken; Kijima, Aki; Tsuchiya, Takuma; Kawaguchi, Hiroaki; Miyoshi, Noriaki; Nohmi, Takehiko; Ogawa, Kumiko; Nishikawa, Akiyoshi; Umemura, Takashi

    2015-01-01

    The kidney is a major target site of chemical carcinogenesis. However, a reliable in vivo assay for rapid identification of renal carcinogens has not been established. The purpose of this study was to develop a new medium-term gpt delta rat model (the GNP model) to facilitate identification of renal carcinogens. In this model, we carried out an in vivo mutation assay using unilaterally nephrectomized kidney tissue and a tumor-promoting assay using residual kidney tissue, with diethylnitrosamine (DEN) as the renal tumor initiator. To clarify the optimal time of DEN injection after nephrectomy, time-dependent changes in bromodeoxyuridine-labeling indices in the tubular epithelium of nephrectomized rats were examined. The optimal dose of DEN injection and sufficient duration of subsequent nitrilotriacetic acid treatment were determined for detection of renal preneoplastic lesions. The standard protocol for the GNP model was determined as follows. Six-week-old female gpt delta rats were treated with test chemicals for 4 weeks, followed by a 2-week washout period, and 40 mg/kg DEN was administered intraperitoneally to initiate renal carcinogenesis. Unilateral nephrectomy was performed 48 h before DEN injection, followed by gpt assays using excised kidney tissues. One week after DEN injection, rats were further exposed to test chemicals for 12 weeks, and histopathological analysis of renal preneoplastic lesions was performed as an indicator of tumor-promoting activity in residual kidney tissue. Validation studies using aristolochic acid, potassium dibasic phosphate, phenylbutazone, and d-limonene indicated the reliability of the GNP model for predicting renal carcinogens and the underlying mode of action.

  14. Toxicity assessment of four insecticides with different modes of action on pupae and adults of Eriopis connexa (Coleoptera: Coccinellidae), a relevant predator of the Neotropical Region.

    Science.gov (United States)

    Fogel, Marilina Noelia; Schneider, Marcela Inés; Rimoldi, Federico; Ladux, Lorena Sabrina; Desneux, Nicolas; Ronco, Alicia Estela

    2016-08-01

    Pesticides can be toxic to nontarget organisms including the natural enemies of agricultural pests, thus reducing the biodiversity of agroecosystems. The lethal and sublethal effects of four insecticides with different modes of action-pyriproxyfen, teflubenzuron, acetamiprid, and cypermethrin-were evaluated on pupae and adults of Eriopis connexa, an effective predator in horticultural crops. Pupal survival was reduced by pyriproxyfen (26 %) and cypermethrin (41 %). Malformations in adults emerged from treated pupae were observed after acetamiprid (82.7 and 100 % for 100 and 200 mg a.i./l, respectively), pyriproxyfen (48.6 %), and cypermethrin (13.3 %) treatments. A longer mean oviposition time was also observed in adults emerged from pupae treated with cypermethrin. Moreover, the latter insecticide as well as teflubenzuron did not reduce reproductive parameters, whereas females emerged from pyriproxyfen-treated pupae were not be able to lay eggs even when females showed large abdomens. Upon exposure of adults, survival was reduced to approximately 90 % by acetamiprid, but no reduction occurred with pyriproxyfen, teflubenzuron, or cypermethrin though the fecundity at fifth oviposition time of the female survivors was reduced. Pyriproxyfen decreased the hatching at all the oviposition times tested, whereas fertility was reduced in the fourth and fifth ovipositions by teflubenzuron and in the first and third ovipositions by cypermethrin. In conclusion, all four insecticides tested exhibited lethal or sublethal effects, or both, on E. connexa. The neurotoxic insecticides were more harmful than the insect-growth regulators, and pupae were more susceptible than adults. The toxicity of insecticides on the conservation of predators in agroecosystems of the Neotropical Region is discussed.

  15. FTIR Metabolomic Fingerprint Reveals Different Modes of Action Exerted by Structural Variants of N-Alkyltropinium Bromide Surfactants on Escherichia coli and Listeria innocua Cells

    Science.gov (United States)

    Corte, Laura; Tiecco, Matteo; Roscini, Luca; De Vincenzi, Sergio; Colabella, Claudia; Germani, Raimondo; Tascini, Carlo; Cardinali, Gianluigi

    2015-01-01

    Surfactants are extremely important agents to clean and sanitize various environments. Their biocidal activity is a key factor determined by the interactions between amphiphile structure and the target microbial cells. The object of this study was to analyze the interactions between four structural variants of N-alkyltropinium bromide surfactants with the Gram negative Escherichia coli and the Gram positive Listeria innocua bacteria. Microbiological and conductometric methods with a previously described FTIR bioassay were used to assess the metabolomic damage exerted by these compounds. All surfactants tested showed more biocidal activity in L. innocua than in E. coli. N-tetradecyltropinium bromide was the most effective compound against both species, while all the other variants had a reduced efficacy as biocides, mainly against E. coli cells. In general, the most prominent metabolomic response was observed for the constituents of the cell envelope in the fatty acids (W1) and amides (W2) regions and at the wavenumbers referred to peptidoglycan (W2 and W3 regions). This response was particularly strong and negative in L. innocua, when cells were challenged by N-tetradecyltropinium bromide, and by the variant with a smaller head and a 12C tail (N-dodecylquinuclidinium bromide). Tail length was critical for microbial inhibition especially when acting against E. coli, maybe due the complex nature of Gram negative cell envelope. Statistical analysis allowed us to correlate the induced mortality with the metabolomic cell response, highlighting two different modes of action. In general, gaining insights in the interactions between fine structural properties of surfactants and the microbial diversity can allow tailoring these compounds for the various operative conditions. PMID:25588017

  16. Editor's Highlight: Mode of Action Analysis for Rat Hepatocellular Tumors Produced by the Synthetic Pyrethroid Momfluorothrin: Evidence for Activation of the Constitutive Androstane Receptor and Mitogenicity in Rat Hepatocytes.

    Science.gov (United States)

    Okuda, Yu; Kushida, Masahiko; Sumida, Kayo; Nagahori, Hirohisa; Nakamura, Yoshimasa; Higuchi, Hashihiro; Kawamura, Satoshi; Lake, Brian G; Cohen, Samuel M; Yamada, Tomoya

    2017-08-01

    High dietary levels of momfluorothrin, a nongenotoxic synthetic pyrethroid, induced hepatocellular tumors in male and female Wistar rats in a 2-year bioassay. The mode of action (MOA) for rat hepatocellular tumors was postulated to occur via activation of the constitutive androstane receptor (CAR), as momfluorothrin is a close structural analogue of the pyrethroid metofluthrin, which is known to produce rat liver tumors through a CAR-mediated MOA. To elucidate the MOA for rat hepatocellular tumor formation by momfluorothrin, this study was conducted to examine effects on key and associative events of the CAR-mediated MOA for phenobarbital based on the International Programme on Chemical Safety framework. A 2-week in vivo study in Wistar rats revealed that momfluorothrin induced CYP2B activities, increased liver weights, produced hepatocyte hypertrophy and increased hepatocyte replicative DNA synthesis. These effects correlated with the dose-response relationship for liver tumor formation and also showed reversibility upon cessation of treatment. Moreover, momfluorothrin did not increase CYP2B1/2 mRNA expression and hepatocyte replicative DNA synthesis in CAR knockout rats. Using cultured Wistar rat hepatocytes and the RNA interference technique, knockdown of CAR resulted in a suppression of induction of CYP2B1/2 mRNA levels by momfluorothrin. Alternative MOAs for liver tumor formation were excluded. A global gene expression profile analysis of the liver of male Wistar rats treated with momfluorothrin for 2 weeks also showed similarity to the prototypic CAR activator phenobarbital. Overall, these data strongly support that the postulated MOA for momfluorothrin-induced rat hepatocellular tumors as being mediated by CAR activation. © 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.

  17. Cytotoxicity and modes of action of four Cameroonian dietary spices ethno-medically used to treat cancers: Echinops giganteus, Xylopia aethiopica, Imperata cylindrica and Piper capense.

    Science.gov (United States)

    Kuete, Victor; Sandjo, Louis P; Wiench, Benjamin; Efferth, Thomas

    2013-08-26

    Echinops giganteus, Imperata cylindrica, Piper capense and Xylopia aethiopica are four medicinal spices used in Cameroon to treat cancers. The above plants previously displayed cytotoxicity against leukemia CCRF-CEM and CEM/ADR5000 cell lines as well as human pancreatic MiaPaCa-2 cells. The present study aims at emphasizing the study of the cytotoxicity and the modes of action of the above plants on a panel of ten cancer cell lines including various sensitive and drug-resistant phenotypes. The study has been extended to the isolation of the bioactive constituents from Echinops giganteus. The cytotoxicity of the extracts was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with the four extracts. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS). The four tested extracts inhibited the proliferation of all tested cancer cell lines including sensitive and drug-resistant phenotypes. Collateral sensitivity of cancer cells to the extract of Echinops giganteus was generally better than to doxorubicin. The recorded IC50 ranges were 3.29 µg/mL [against human knockout clones HCT116 (p53(-/-)) colon cancer cells] to 14.32 µg/mL (against human liver hepatocellular carcinoma HepG2 cells) for the crude extract from Echinops giganteus, 4.17 µg/mL (against breast cancer cells transduced with control vector MDA-MB231 cells) to 19.45 µg/mL (against MDA-MB-231 BCRP cells) for that of Piper capense, 4.11 µg/mL (against leukemia CCRF-CEM cells) to 30.60 µg/mL (against leukemia HL60AR cells) for Xylopia aethiopica, 3.28 µg/mL [against HCT116 (p53(-/-)) cells] to 33.43 µg/mL (against HepG2 cells) for Imperata cylindica and 0.11 µg/mL (against CCRF-CEM cells) to 132.47 µg/mL (against HL60AR cells) for doxorubicin. The four

  18. Repeated inhalation exposure of rats to an anionic high molecular weight polymer aerosol: application of prediction models to better understand pulmonary effects and modes of action.

    Science.gov (United States)

    Pauluhn, Jürgen

    2014-08-01

    Opposed to the wealth of information available for kinetic lung overload-related effects of poorly-soluble, low-toxicity particles (PSP), only limited information is available on biodegradable high molecular weight (HMW) organic polymers (molecular weight >20,000 Da). It is hypothesized that such types of polymers may exert a somewhat similar volume displacement-related mode of action in alveolar macrophages as PSP; however, with a differing biokinetics of the material retained in the lung. This polyurethane polymer was examined in single and 2-/13-week repeated exposure rat inhalation bioassays. The design of studies was adapted to that commonly applied for PSP. Rats were nose-only exposed for 6h/day for the respective study duration, followed by 1-, 2- and 4-week postexposure periods in the single, 2- and 13-week studies, respectively. While the findings in bronchoalveolar lavage (BAL) and histopathology were consistent with those typical of PSP, they appear to be superimposed by pulmonary phospholipidosis and a much faster reversibility of pulmonary inflammation. Kinetic modeling designed to estimate the accumulated lung burden of biopersistent PSP was also suitable to simulate the overload-dependent outcomes of this biodegradable polymer as long as the faster than normal elimination kinetics was observed and an additional 'void space volume' was added to adjust for the phagocytosed additional fraction of pulmonary phospholipids. The changes observed following repeated inhalation exposure appear to be consistent with a retention-related etiopathology (kinetic overload). In summary, this study did not reveal evidence of any polymer-specific pulmonary irritation or parenchymal injury. Taking all findings into account, 7 mg polymer/m(3) (exposure 6h/day, 5-days/week on 13 consecutive weeks) constitutes the point of departure for lower respiratory tract findings that represent a transitional state from effects attributable to an overload-dependent pulmonary

  19. Comparative analysis of pharmaceuticals versus industrial chemicals acute aquatic toxicity classification according to the United Nations classification system for chemicals. Assessment of the (Q)SAR predictability of pharmaceuticals acute aquatic toxicity and their predominant acute toxic mode-of-action

    DEFF Research Database (Denmark)

    Sanderson, Hans; Thomsen, Marianne

    2009-01-01

    a comprehensive database based on OECD's standardized measured ecotoxicological data and to evaluate if there is generally cause of greater concern with regards to pharmaceutical aquatic toxicological profiles relative to industrial chemicals. Comparisons were based upon aquatic ecotoxicity classification under......Pharmaceuticals have been reported to be ubiquitously present in surface waters prompting concerns of effects of these bioactive substances. Meanwhile, there is a general scarcity of publicly available ecotoxicological data concerning pharmaceuticals. The aim of this paper was to compile...... the United Nations Global Harmonized System for classification and labeling of chemicals (GHS). Moreover, we statistically explored whether the predominant mode-of-action (MOA) for pharmaceuticals is narcosis. We found 275 pharmaceuticals with 569 acute aquatic effect data; 23 pharmaceuticals had chronic...

  20. Form-based Approaches vs. Task-Based Approaches

    Directory of Open Access Journals (Sweden)

    Zahra Talebi

    2015-07-01

    Full Text Available This study aimed at investigating whether task-based approaches bear any superiority to that of more traditional ones evident in presentation-practice- and production phase .to fulfill the purpose of the study, the participants within the age range of 11-19, took part in the study. Following a pretest, treatment, and a posttest, the obtained data was analyzed using analysis of covariance (ANCOVA to examine the effects of the variables. The results of the analysis showed that participants in the PPP group did significantly better in the grammar recognition of the posttest than that of the task group. However, their counterparts in the task group gained better scores in the writing section of the test .this research study provided evidence in support of task proponents' claim in the merit of task-based activity in raising learners' implicit knowledge claiming to play the primary role in spontaneous speech.Keywords: Task-based language teaching, PPP model, focus on form, focus on meaning

  1. The Mode of Action of D-Pinitol and It's Formulation on Sphaerotheca fuliginea%D-松醇原药及其水剂对黄瓜白粉病的作用方式

    Institute of Scientific and Technical Information of China (English)

    王丹丹; 陈佳; 陈义娟; 张红艳; 贾福丽; 白羡钦; 代光辉

    2012-01-01

    .07%. [Conclusions] The present results indicated that D-pinitol TC and D-pinitol AS have good control effect on S. Fuliginea, especially at the 3rd day after treatment. D-Pinitol TC showed best control at 2000 mg/L, and D-pinitol 20% AS diluted to the concentration of 3.3% also exhibited excellent fungicidal activity against 5. Fuliginea. Additionally D-pinitol AS further relieve the degree of disease based on reducing D-pinitol TC dose, which provides the feasibility basis for development of D-pinitol AS. Besides, the determination of mode of action of D-pinitol TC and D-pinitol AS on S. Fuliginea also provides reference for further study.

  2. Ontology Partitioning: Clustering Based Approach

    Directory of Open Access Journals (Sweden)

    Soraya Setti Ahmed

    2015-05-01

    Full Text Available The semantic web goal is to share and integrate data across different domains and organizations. The knowledge representations of semantic data are made possible by ontology. As the usage of semantic web increases, construction of the semantic web ontologies is also increased. Moreover, due to the monolithic nature of the ontology various semantic web operations like query answering, data sharing, data matching, data reuse and data integration become more complicated as the size of ontology increases. Partitioning the ontology is the key solution to handle this scalability issue. In this work, we propose a revision and an enhancement of K-means clustering algorithm based on a new semantic similarity measure for partitioning given ontology into high quality modules. The results show that our approach produces meaningful clusters than the traditional algorithm of K-means.

  3. Metabonomic strategy for the investigation of the mode of action of the phytotoxin (5S,8R,13S,16R)-(-)-pyrenophorol using 1H nuclear magnetic resonance fingerprinting.

    Science.gov (United States)

    Aliferis, Konstantinos A; Chrysayi-Tokousbalides, Maria

    2006-03-08

    The biochemical mode of action of (5S,8R,13S,16R)-(-)-pyrenophorol isolated from a Drechslera avenae pathotype was investigated by using metabolic fingerprinting. (1)H NMR spectra of crude leaf extracts from untreated Avena sterilis seedlings and A. sterilis seedlings treated with pyrenophorol were compared with those obtained from treatments with the herbicides diuron, glyphosate, mesotrione, norflurazon, oxadiazon, and paraquat. Multivariate analysis was carried out to group treatments according to the mode of action of the phytotoxic substances applied. Analysis results revealed that none of the herbicide treatments fitted the pyrenophorol model and indicate that the effect of the phytotoxin on A. sterilis differs than those caused by glyphosate, mesotrione, norflurazon, oxadiazon, paraquat, and diuron, which inhibit 5-enolpyruvylshikimate-3-phosphate synthase, 4-hydroxyphenyl-pyruvate-dioxygenase, phytoene desaturase, protoporphyrinogen oxidase, photosystem I, and photosystem II, respectively. The method applied, combined with appropriate data preprocessing and analysis, was found to be rapid for the screening of phytotoxic substances for metabolic effects.

  4. Materiality in a Practice-Based Approach

    Science.gov (United States)

    Svabo, Connie

    2009-01-01

    Purpose: The paper aims to provide an overview of the vocabulary for materiality which is used by practice-based approaches to organizational knowing. Design/methodology/approach: The overview is theoretically generated and is based on the anthology Knowing in Organizations: A Practice-based Approach edited by Nicolini, Gherardi and Yanow. The…

  5. Dynamics and Modes of Action of Xylanases fromPenicillium corylophilum on Xylan%顶青霉木聚糖酶的水解动力学与水解模式

    Institute of Scientific and Technical Information of China (English)

    杨瑞金; 许时婴; 王璋

    2001-01-01

    从顶青霉(Penicillium corylophilum)培养液中分离纯化得到的3种木聚糖酶组分(Part A, Part B 和 Part C),对其水解动力学和水解模式的研究结果表明,3种木聚糖酶的动力学常数(桦木木聚糖为底物)分别为:Part A,Km=1.00 mg/mL,Vmax=0.159 U/mL;Part B, Km=1.59 mg/mL, Vmax=0.274 U/mL;Part C,Km=0.85 mg/mL,Vmax=0.200 U/mL. 3种木聚糖酶的水解模式相同,主要从一端(非还原端)水解得到木三糖和木二糖,并且得到木三糖的速度大于得到木二糖的速度;水解会产生木四糖,但木四糖会很快进一步水解成木二糖,木四糖水解成木糖和木三糖的可能性极小;木三糖会进一步水解成木糖和木二糖,但速度不快;木二糖不会进一步水解。粗酶水解玉米芯木聚糖时,阿拉伯糖侧链的水解与木聚糖主链的水解同步进行,粗酶中含有水解阿拉伯糖基侧链的阿拉伯糖苷酶活力.%Dynamics and mode of acting on xylan of three parts of xylanases (Part A, Part B and Part C) separated and purified from a culture filtrate of Penicillium corylophilum No. P-3-31 were investigated. The Km and Vmax of the three purified enzymes with birchwood xylan as a substrate were 1.00 mg/mL and 0.159 U/mL for Part A ( pH 4.0, 50 ℃) , 1.59 mg/mL and 0.274 U/mL for Part B (pH 4.0,50 ℃) and 0.85 mg/mL and 0.200 U/mL for Part C (pH 5.5,50 ℃). Based on the dynamic studies, it was deduced that three purified enzymes had the same mode of action on xylan. Xylotriose and xylobiose were main hydrolysates of long-chain xylan by these enzymes. Xylooligosaccharides upwards from xylotetraose were immediately hydrolyzed, and xylotetraose was mainly hydrolyzed to xylobiose. Xylotriose was slowly hydrolyzed, but xylobiose was unable to be further hydrolyzed by these enzymes. The studies on the hydrolysis dynamics of xylan from corncob with crude enzyme showed that the hydrolysis of arabinose side-chain was almost

  6. Transgenic approaches to western corn rootworm control.

    Science.gov (United States)

    Narva, Kenneth E; Siegfried, Blair D; Storer, Nicholas P

    2013-01-01

    The western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae) is a significant corn pest throughout the United States corn belt. Rootworm larvae feed on corn roots causing yield losses and control expenditures that are estimated to exceed US$1 billion annually. Traditional management practices to control rootworms such as chemical insecticides or crop rotation have suffered reduced effectiveness due to the development of physiological and behavioral resistance. Transgenic maize expressing insecticidal proteins are very successful in protecting against rootworm damage and preserving corn yield potential. However, the high rate of grower adoption and early reliance on hybrids expressing a single mode of action and low-dose traits threatens the durability of commercialized transgenic rootworm technology for rootworm control. A summary of current transgenic approaches for rootworm control and the corresponding insect resistance management practices is included. An overview of potential new modes of action based on insecticidal proteins, and especially RNAi targeting mRNA coding for essential insect proteins is provided.

  7. Toxicity testing in the 21 century: defining new risk assessment approaches based on perturbation of intracellular toxicity pathways.

    Directory of Open Access Journals (Sweden)

    Sudin Bhattacharya

    Full Text Available The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC report Toxicity Testing in the 21(st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a "toxicity pathways" (the innate cellular pathways that may be perturbed by chemicals and (b the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU. EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair.

  8. Bacteriocins from Lactobacillus plantarum production, genetic organization and mode of action: produção, organização genética e modo de ação Bacteriocinas de Lactobacillus plantarum

    Directory of Open Access Journals (Sweden)

    Svetoslav D. Todorov

    2009-06-01

    Full Text Available Bacteriocins are biologically active proteins or protein complexes that display a bactericidal mode of action towards usually closely related species. Numerous strains of bacteriocin producing Lactobacillus plantarum have been isolated in the last two decades from different ecological niches including meat, fish, fruits, vegetables, and milk and cereal products. Several of these plantaricins have been characterized and the aminoacid sequence determined. Different aspects of the mode of action, fermentation optimization and genetic organization of the bacteriocin operon have been studied. However, numerous of bacteriocins produced by different Lactobacillus plantarum strains have not been fully characterized. In this article, a brief overview of the classification, genetics, characterization, including mode of action and production optimization for bacteriocins from Lactic Acid Bacteria in general, and where appropriate, with focus on bacteriocins produced by Lactobacillus plantarum, is presented.Bacteriocinas são proteínas ou complexos protéicos biologicamente ativos que apresentam atividade bactericida contra espécies relacionadas. Nas ultimas duas décadas, várias cepas de Lactobacillus plantarum produtoras de bacteriocinas foram isoladas de diferentes nichos ecológicos como carnes, peixes, frutas, vegetais e produtos lácteos e de cereais. Várias plantaricinas foram caracterizadas e suas seqüências de aminoácidos determinadas. Diferentes aspectos do modo de ação, otimização da fermentação e organização genética já foram estudados. Entretanto, muitas bacteriocinas produzidas por diferentes cepas de Lactobacillus plantarum ainda não foram completamente caracterizadas.Nesse artigo, apresenta-se uma breve revisão sobre a classificação, genética, caracterização, modo de ação, e otimização da produção de bacteriocinas de bactérias láticas em geral, e, quando apropriado, de bacteriocinas de Lactobacillus plantarum.

  9. Multiple exposures to indoor contaminants: Derivation of benchmark doses and relative potency factors based on male reprotoxic effects.

    Science.gov (United States)

    Fournier, K; Tebby, C; Zeman, F; Glorennec, P; Zmirou-Navier, D; Bonvallot, N

    2016-02-01

    Semi-Volatile Organic Compounds (SVOCs) are commonly present in dwellings and several are suspected of having effects on male reproductive function mediated by an endocrine disruption mode of action. To improve knowledge of the health impact of these compounds, cumulative toxicity indicators are needed. This work derives Benchmark Doses (BMD) and Relative Potency Factors (RPF) for SVOCs acting on the male reproductive system through the same mode of action. We included SVOCs fulfilling the following conditions: detection frequency (>10%) in French dwellings, availability of data on the mechanism/mode of action for male reproductive toxicity, and availability of comparable dose-response relationships. Of 58 SVOCs selected, 18 induce a decrease in serum testosterone levels. Six have sufficient and comparable data to derive BMDs based on 10 or 50% of the response. The SVOCs inducing the largest decrease in serum testosterone concentration are: for 10%, bisphenol A (BMD10 = 7.72E-07 mg/kg bw/d; RPF10 = 7,033,679); for 50%, benzo[a]pyrene (BMD50 = 0.030 mg/kg bw/d; RPF50 = 1630), and the one inducing the smallest one is benzyl butyl phthalate (RPF10 and RPF50 = 0.095). This approach encompasses contaminants from diverse chemical families acting through similar modes of action, and makes possible a cumulative risk assessment in indoor environments. The main limitation remains the lack of comparable toxicological data.

  10. A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

    Science.gov (United States)

    Vasaturo, Michele; Fiengo, Lorenzo; de Tommasi, Nunziatina; Sabatino, Lina; Ziccardi, Pamela; Colantuoni, Vittorio; Bruno, Maurizio; Cerchia, Carmen; Novellino, Ettore; Lupo, Angelo; Lavecchia, Antonio; Piaz, Fabrizio Dal

    2017-01-01

    Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPARγ, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the β-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPARγ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPARγ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPARγ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPARγ ligands with reduced undesired harmful side effects.

  11. A compound-based proteomic approach discloses 15-ketoatractyligenin methyl ester as a new PPARγ partial agonist with anti-proliferative ability

    Science.gov (United States)

    Vasaturo, Michele; Fiengo, Lorenzo; De Tommasi, Nunziatina; Sabatino, Lina; Ziccardi, Pamela; Colantuoni, Vittorio; Bruno, Maurizio; Cerchia, Carmen; Novellino, Ettore; Lupo, Angelo; Lavecchia, Antonio; Piaz, Fabrizio Dal

    2017-01-01

    Proteomics based approaches are emerging as useful tools to identify the targets of bioactive compounds and elucidate their molecular mechanisms of action. Here, we applied a chemical proteomic strategy to identify the peroxisome proliferator-activated receptor γ (PPARγ) as a molecular target of the pro-apoptotic agent 15-ketoatractyligenin methyl ester (compound 1). We demonstrated that compound 1 interacts with PPARγ, forms a covalent bond with the thiol group of C285 and occupies the sub-pocket between helix H3 and the β-sheet of the ligand-binding domain (LBD) of the receptor by Surface Plasmon Resonance (SPR), mass spectrometry-based studies and docking experiments. 1 displayed partial agonism of PPARγ in cell-based transactivation assays and was found to inhibit the AKT pathway, as well as its downstream targets. Consistently, a selective PPARγ antagonist (GW9662) greatly reduced the anti-proliferative and pro-apoptotic effects of 1, providing the molecular basis of its action. Collectively, we identified 1 as a novel PPARγ partial agonist and elucidated its mode of action, paving the way for therapeutic strategies aimed at tailoring novel PPARγ ligands with reduced undesired harmful side effects. PMID:28117438

  12. Model based feature fusion approach

    NARCIS (Netherlands)

    Schwering, P.B.W.

    2001-01-01

    In recent years different sensor data fusion approaches have been analyzed and evaluated in the field of mine detection. In various studies comparisons have been made between different techniques. Although claims can be made for advantages for using certain techniques, until now there has been no si

  13. Synthesis and evaluation of new NIR-fluorescent probes for cathepsin B: ICT versus FRET as a turn-ON mode-of-action.

    Science.gov (United States)

    Kisin-Finfer, Einat; Ferber, Shiran; Blau, Rachel; Satchi-Fainaro, Ronit; Shabat, Doron

    2014-06-01

    Recent years have seen tremendous progress in the design and study of molecular imaging geared towards biological and biomedical applications. The expression or activity of specific enzymes including proteases can be monitored by cutting edge molecular imaging techniques. Cathepsin B plays key roles in tumor progression via controlled degradation of extracellular matrix. Consequently, this protease has been attracting significant attention in cancer research, and many imaging probes targeting its activity have been developed. Here, we describe the design, synthesis and evaluation of two novel near infrared (NIR) fluorescent probes for detection of cathepsin B activity with different turn-ON mechanisms. One probe is based on an ICT activation mechanism of a donor-two-acceptor π-electron dye system, while the other is based on the FRET mechanism obtained by a fluorescent dye and a quencher. The two probes exhibit significant fluorescent turn-ON response upon cleavage by cathepsin B. The NIR fluorescence of the ICT probe in its OFF state was significantly lower than that of the FRET-based probe. This effect results in a higher signal-to-noise ratio and consequently increased sensitivity and better image contrast.

  14. A peripherally restricted P2Y12 receptor antagonist altered rat tumor incidences with no human relevance: Mode of action consistent with dopamine agonism

    Directory of Open Access Journals (Sweden)

    David A. Brott

    2014-01-01

    Discussion: Similar to Ticagrelor, centrally active dopamine agonists induce the same altered tumor incidence patterns that according to literature do not translate into the clinical setting, with a MOA involving decreased prolactin secretion. The Ticagrelor MOA data and literature suggest that altered dopamine levels in the hypophyseal part of the hypothalamus–hypophyseal axis (by Ticagrelor will result in similar altered tumor incidences in rat that do not translate into the clinical setting, based on qualitative species differences. In conclusion Ticagrelor increased uterine tumors in the rat carcinogenesis study by a MOA consistent with reduced dopamine inhibition of prolactin, which is not a patient safety risk.

  15. Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

    Science.gov (United States)

    Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

    2017-03-01

    Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Labeling of Oxidizable Proteins with a Photoactivatable Analog of the Antitumor Agent DMXAA: Evidence for Redox Signaling in Its Mode of Action

    Directory of Open Access Journals (Sweden)

    Romy Brauer

    2010-09-01

    Full Text Available The signaling pathway(s and molecular target(s for 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a tumor vascular disrupting agent in late stages of clinical development, are still undefined. As an approach toward identifying potential targets for DMXAA, a tritiated azido-analog of DMXAA was used to probe for cellular binding proteins. More than 20 cytosolic proteins from murine splenocytes, RAW 264.7 cells, and the HECPP immortalized endothelial cells were photoaffinity-labeled. Although no protein domain, fold, or binding site for a specific ligand was found to be shared by all the candidate proteins, essentially all were noted to be oxidizable proteins, implicating a role for redox signaling in the action of DMXAA. Consistent with this hypothesis, DMXAA caused an increase in concentrations of reactive oxygen species (ROS in RAW264.7 cells during the first 2 hours. This increase in ROS was suppressed in the presence of the antioxidant, N-acetyl-L-cysteine, which also suppressed DMXAA-induced cytokine production in the RAW 264.7 cells with no effects on cell viability. Short interfering RNA (siRNA-mediated knockdown of one of the photoaffinity-labeled proteins, superoxide dismutase 1, an ROS scavenger, resulted in an increase in tumor necrosis factor-α production by RAW 264.7 cells in response to DMXAA compared with negative or positive controls transfected with nontargeting or lamin A/C-targeting siRNA molecules, respectively. The results from these lines of study all suggest that redox signaling plays a central role in cytokine induction by DMXAA.

  17. Structure-Activity Relationship and Mode of Action of a Frog Secreted Antibacterial Peptide B1CTcu5 Using Synthetically and Modularly Modified or Deleted (SMMD) Peptides.

    Science.gov (United States)

    Abraham, Parvin; Sundaram, Anand; R, Asha; V, Reshmy; George, Sanil; Kumar, K Santhosh

    2015-01-01

    All life forms are equipped with rapidly acting, evolutionally conserved components of an innate immune defense system that consists of a group of unique and diverse molecules known as host defense peptides (HDPs). A Systematic and Modular Modification and Deletion (SMMD) approach was followed to analyse the structural requirement of B1CTcu5, a brevinin antibacterial peptide amide identified from the skin secretion of frog Clinotarsus curtipes, India, to show antibacterial activity and to explore the active core region. Seventeen SMMD-B1CTcu5 analogs were designed and synthesised by C and N-terminal amino acid substitution or deletion. Enhancement in cationicity by N-terminal Lys/Arg substitution or hydrophobicity by Trp substitution produced no drastic change in bactericidal nature against selected bacterial strains except S. aureus. But the sequential removal of N-terminal amino acids had a negative effect on bactericidal potency. Analog B1CTcu5-LIAG obtained by the removal of four N-terminal amino acids displayed bactericidal effect comparable to, or in excess of, the parent peptide with reduced hemolytic character. Its higher activity was well correlated with the improved inner membrane permeabilisation capacity. This region may act as the active core of B1CTcu5. Presence of C-terminal disulphide bond was not a necessary condition to display antibacterial activity but helped to promote hemolytic nature. Removal of the C-terminal rana box region drastically reduced antibacterial and hemolytic activity of the peptide, showing that this region is important for membrane targeting. The bactericidal potency of the D-peptide (DB1CTcu5) helped to rule out the stereospecific interaction with the bacterial membrane. Our data suggests that both the C and N-terminal regions are necessary for bactericidal activity, even though the active core region is located near the N-terminal of B1CTcu5. A judicious modification at the N-terminal region may produce a short SMMD analog

  18. Anti-methicillin Resistant Staphylococcus aureus Compound Isolation from Halophilic Bacillus amyloliquefaciens MHB1 and Determination of Its Mode of Action Using Electron Microscope and Flow Cytometry Analysis.

    Science.gov (United States)

    Jeyanthi, Venkadapathi; Velusamy, Palaniyandi

    2016-06-01

    The aim of this study was to purify, characterize and evaluate the antibacterial activity of bioactive compound against methicillin-resistant Staphylococcus aureus (MRSA). The anti-MRSA compound was produced by a halophilic bacterial strain designated as MHB1. The MHB1 strain exhibited 99 % similarity to Bacillus amyloliquefaciens based on 16S rRNA gene analysis. The culture conditions of Bacillus amyloliquefaciens MHB1 were optimized using nutritional and environmental parameters for enhanced anti-MRSA compound production. The pure bioactive compound was isolated using silica gel column chromatography and Semi-preparative High-performance liquid chromatography (Semi-preparative HPLC). The Thin layer chromatography, Fourier transform infrared spectroscopy and proton NMR ((1)H NMR) analysis indicated the phenolic nature of the compound. The molecular mass of the purified compound was 507 Da as revealed by Liquid chromatography-mass spectrometry (LC-MS) analysis. The compound inhibited the growth of MRSA with minimum inhibitory concentration (MIC) of 62.5 µg mL(-1). MRSA bacteria exposed to 4× MIC of the compound and the cell viability was determined using flow cytometric analysis. Scanning electron microscope and Transmission electron microscope analysis was used to determine the ultrastructural changes in bacteria. This is the first report on isolation of anti-MRSA compound from halophilic B. amyloliquefaciens MHB1 and could act as a promising biocontrol agent.

  19. Inhibition of cellular efflux pumps involved in multi xenobiotic resistance (MXR) in echinoid larvae as a possible mode of action for increased ecotoxicological risk of mixtures.

    Science.gov (United States)

    Anselmo, Henrique M R; van den Berg, Johannes H J; Rietjens, Ivonne M C M; Murk, Albertinka J

    2012-11-01

    In marine organisms the multi xenobiotic resistance (MXR) mechanism via e.g. P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) is an important first line of defense against contaminants by pumping contaminants out of the cells. If compounds would impair the MXR mechanism, this could result in increased intracellular levels of other compounds, thereby potentiating their toxicity. A calcein-AM based larval cellular efflux pump inhibition assay (CEPIA) was developed for echinoid (Psammechinus miliaris) larvae and applied for several contaminants. The larval CEPIA revealed that triclosan (TCS) and the nanoparticles P-85(®) (P-85) were 124 and 155× more potent inhibitors (IC(50) 0.5 ± 0.05 and 0.4 ± 0.1 μM, respectively) of efflux pumps than the model inhibitor Verapamil (VER). PFOS (heptadecafluorooctane sulfonic acid) and pentachlorophenol also were more potent than VER, 24 and 5×, respectively. Bisphenol A and o,p'-dichlorodiphenyltrichloroethane (o,p'-DDT) inhibited efflux pumps with a potency 3× greater than VER. In a 48 h early life stage bioassay with P. miliaris, exposure to a non-lethal concentration of the inhibitors TCS, VER, the model MRP inhibitor MK-571, the nanoparticles P-85 and the model P-gp inhibitor PSC-833, increased the toxicity of the toxic model substrate for efflux pumps vinblastine by a factor of 2, 4, 4, 8 and 16, respectively. Our findings show that several contaminants accumulating in the marine environment inhibit cellular efflux pumps, which could potentiate toxic effects of efflux pumps substrates.

  20. Fragment-based approaches to enzyme inhibition

    OpenAIRE

    Ciulli, Alessio; Abell, Chris

    2007-01-01

    Fragment-based approaches have provided a new paradigm for small-molecule drug discovery. The methodology is complementary to high-throughput screening approaches, starting from fragments of low molecular complexity and high ligand efficiency, and building up to more potent inhibitors. The approach, which depends heavily on a number of biophysical techniques, is now being taken up by more groups in both industry and academia. This article describes key aspects of the process and highlights re...

  1. A programmable approach to revising knowledge bases

    Institute of Scientific and Technical Information of China (English)

    LUAN Shangmin; DAI Guozhong; LI Wei

    2005-01-01

    This paper presents a programmable approach to revising knowledge bases consisting of clauses. Some theorems and lemmas are shown in order to give procedures for generating maximally consistent subsets. Then a complete procedure and an incomplete procedure for generating the maximal consistent subsets are presented, and the correctness of the procedures is also shown. Furthermore, a way to implement knowledge base revision is presented, and a prototype system is introduced. Compared with related works, the main characteristic of our approach is that the approach can be implemented by a computer program.

  2. Azelaic acid: Properties and mode of action.

    Science.gov (United States)

    Sieber, M A; Hegel, J K E

    2014-01-01

    Acne is a common skin disorder that can be problematic for adults as well as for adolescents. It has several key pathophysiological features such as follicular hyperkeratosis, elevated Propionibacterium acnes proliferation, and reactive inflammation, all of which should be targeted for an optimal outcome. Azelaic acid (AzA) has profound anti-inflammatory, antioxidative effects, and is bactericidal against a range of Gram-negative and Gram-positive microorganisms as well, including antibiotic-resistant bacterial strains. In addition, AzA's antikeratinizing effects are inhibitory toward comedones. AzA is effective overall in targeting multiple causes of acne and has been proven to be well tolerated in numerous clinical trials.

  3. GHB for cataplexy: Possible mode of action.

    Science.gov (United States)

    Szabadi, Elemer

    2015-06-01

    The sleep disorder narcolepsy is caused by the loss of orexinergic neurones in the lateral hypothalamus. A troublesome symptom of narcolepsy is cataplexy, the sudden loss of muscle tone in response to strong emotions. It can be alleviated by antidepressants and sodium oxybate (γ-hydroxybutyric acid (GHB)). It is likely that the noradrenergic nucleus locus coeruleus (LC) is involved since it is essential for the maintenance of muscle tone, and ceases to fire during cataplectic attacks. Furthermore, alpha-2 adrenoceptors proliferate in the LC in cataplexy, probably due to 'heterologous denervation supersensitivity' resulting from the loss/weakening of the orexinergic input to the LC. This would lead to the sensitization of the autoinhibition mechanism of LC neurones mediated by inhibitory alpha-2 adrenoceptors ('autoreceptors'). Thus the excitatory input from the amygdala to the LC, activated by an emotional stimulus, would lead to the 'switching off' of LC activity via the supersensitive auto-inhibition mechanism. GHB is an agonist at both γ-aminobutyric acid (GABA) GABA (B) and GHB receptors that may be a subtype of an extrasynaptic GABA(A) receptor. GHB may prevent a cataplectic attack by dampening the tone of LC neurones via the stimulation of inhibitory extrasynaptic GABA receptors in the LC, and thus increasing the threshold for autoinhibition.

  4. Lactococcal bacteriocins : mode of action and immunity

    NARCIS (Netherlands)

    Venema, Koen; Venema, Gerard; Kok, Jan

    1995-01-01

    Bacteriocins are antimicrobial peptides produced by bacteria. Some of those synthesized by Lactococcus lactis have been characterized in great detail recently. The lactococcal bacteriocins are hydrophobic cationic peptides, which form pores in the cytoplasmic membrane of sensitive cells.

  5. LACTOCOCCAL BACTERIOCINS - MODE OF ACTION AND IMMUNITY

    NARCIS (Netherlands)

    VENEMA, K; KOK, J; Venema, Gerhardus

    1995-01-01

    Bacteriocins are antimicrobial peptides produced by bacteria. Some of those synthesized by Lactococcus lactis have been characterized in great detail recently. The lactococcal bacteriocins are hydrophobic cationic peptides, which form pores in the cytoplasmic membrane of sensitive cells.

  6. Lactococcins : Mode of action, immunity and secretion

    NARCIS (Netherlands)

    Venema, K; Kok, J; Venema, Gerhardus

    1995-01-01

    Lactococcus lactis subsp. cremoris 9B4 produces three small (around 5kDa), heat-stable, non-lanthionine containing, membrane active bacteriocins. Amino acid uptake experiments and proton motive force measurements have indicated that these peptides most probably form pores in the cytoplasmic membrane

  7. The mode of action of immunological adjuvants.

    Science.gov (United States)

    Allison, A C

    1998-01-01

    Adjuvants augment immune responses to antigens and influence the balance between cell-mediated and humoral responses, as well as the isotypes of antibodies formed. New adjuvant formulations include antigen-carrying vehicles and small molecules with immunomodulating activity. Widely used two-phase vehicles comprise liposomes and microfluidized squalene or squalane emulsions. These are believed to target antigens to antigen-presenting cells, including dendritic cells (DC), follicular dendritic cells (FDC) and B-lymphocytes. Activation of complement generates C3d, which binds CR2 (CD21) on FDC and B-lymphocytes, thereby stimulating the proliferation of the latter and the generation of B-memory. Targeting of antigens to DC may favour cell-mediated immunity. Immunomodulating agents induce the production of cytokine cascades. In a primary cascade at injection sites TNF-alpha, GM-CSF and IL-1 are produced. TNF-alpha promotes migration of DC to lymphoid tissues, while GM-CSF and IL-1 accelerate the maturation of DC into efficient antigen-presenting cells for T-lymphocytes. In a secondary cytokine cascade in draining lymph nodes, DC produce IL-12, which induces Th1 responses with the production of IFN-gamma. The cytokines elicit cell-mediated immune responses and the formation of antibodies of protective isotypes, such as IgG2a in the mouse and IgG1 in humans. Antibodies of these isotypes activate complement and collaborate with antibody-dependent effector cells in protective immune responses.

  8. mode of action (Part 2 of 4)

    African Journals Online (AJOL)

    Inlrodiu lion. Probiotic preparations are usually defined as live microbial dietary adjuvants which by improving nutritional and .... used in the treatment of oral pathogens, should be .... relapsing Clostridium difficile colitis with Lactobacillus. GG.

  9. [Mode of action of terrazoleon Mucor mucedo].

    Science.gov (United States)

    Lyr, H; Casperson, G; Laussmann, B

    1977-01-01

    It is assumed that the fungistatic effect of terrazol in Mucor mucedo is induced by a liberation of phospholipases within within the mitochondria and perhaps at other membranes. In isolated mitochondria a rapid formation of lysolecithin can be demonstrated at low concentrations of terrazol. This would explain the lytic symptoms in mitochondria visible by electron microscopy. Lipid peroxidation could not be demonstrated. The only antidots at present known for the growth inhibiting effect of terrazol and on its ultrastructural effects are impure saccharose, which seems to contain an unknown factor, and procain hydrochloride or to a lesser extent lidocain, which are well-known inhibitors of phospholipases. The pathological thickening of the cell wall induced by terazol seems to be an unspecific side effect reflecting a diminished phosphorylating activity of the mitochondria.

  10. Nanoscaled boehmites' modes of action in a polymer and its carbon fiber reinforced plastic under compression load; Wirkungsweisen nanoskaliger Boehmite in einem Polymer und seinem Kohlenstofffaserverbund unter Druckbelastung

    Energy Technology Data Exchange (ETDEWEB)

    Arlt, Christine

    2011-07-01

    Increasing ecological awareness as well as quality and safety demands, which are present, for instance, in the aerospace and automotive sectors, lead to the need to use more sophisticated and more effective materials. For that purpose, laminates of carbon fiber reinforced plastic (CFRP), which are manufactured by injection technology, are reinforced with boehmite particles. This doping strengthens the laminates, whose original properties are weaker than prepregs. Besides the shear strength, compression strength and the damage tolerance, the mode of action of the nanoparticles in resin and in CRFP is also analyzed. It thereby reveals that the hydroxyl groups and even more a taurine modification of the boehmites' surface after the elementary polymer morphology. Consequently a new flow and reaction comportment, lower glass transition temperatures and shrinkage, as well as a changed mechanical behavior occur. Due to a structural upgrading of the matrix (higher shear stiffness, reduced residual stress), a better fiber-matrix adhesion, and differing crack paths, the boehmite nanoparticles move the degradation barrier of the material to higher loadings, thus resulting in considerably upgraded new CFRP. (orig.)

  11. Teaching writing through genre-based approach

    Directory of Open Access Journals (Sweden)

    Luu, Tuan Trong

    2011-01-01

    Full Text Available This research is an endeavour to examine the impact of genre-based approach on students’ writing performance as well as students’ attitudes towards the implementation of genre-based approach in writing learning. Research findings reveal that most of the students gained the control over the key features of the required recount genre in terms of social purposes, language features and schematic structure. The necessity and usefulness of the application of teaching-learning cycle into learning the recount genre was predominantly recognized among students

  12. A computational approach to mechanistic and predictive toxicology of pesticides

    DEFF Research Database (Denmark)

    Kongsbak, Kristine Grønning; Vinggaard, Anne Marie; Hadrup, Niels

    2014-01-01

    Emerging challenges of managing and interpreting large amounts of complex biological data have given rise to the growing field of computational biology. We investigated the applicability of an integrated systems toxicology approach on five selected pesticides to get an overview of their modes...... of action in humans, to group them according to their modes of action, and to hypothesize on their potential effects on human health. We extracted human proteins associated to prochloraz, tebuconazole, epoxiconazole, procymidone, and mancozeb and enriched each protein set by using a high confidence human...... protein interactome. Then, we explored modes of action of the chemicals, by integrating protein-disease information to the resulting protein networks. The dominating human adverse effects affected were reproductive disorders followed by adrenal diseases. Our results indicated that prochloraz, tebuconazole...

  13. Determination of antiprotozoal drug mechanisms by metabolomics approaches.

    Science.gov (United States)

    Creek, Darren J; Barrett, Michael P

    2014-01-01

    The discovery, development and optimal utilization of pharmaceuticals can be greatly enhanced by knowledge of their modes of action. However, many drugs currently on the market act by unknown mechanisms. Untargeted metabolomics offers the potential to discover modes of action for drugs that perturb cellular metabolism. Development of high resolution LC-MS methods and improved data analysis software now allows rapid detection of drug-induced changes to cellular metabolism in an untargeted manner. Several studies have demonstrated the ability of untargeted metabolomics to provide unbiased target discovery for antimicrobial drugs, in particular for antiprotozoal agents. Furthermore, the utilization of targeted metabolomics techniques has enabled validation of existing hypotheses regarding antiprotozoal drug mechanisms. Metabolomics approaches are likely to assist with optimization of new drug candidates by identification of drug targets, and by allowing detailed characterization of modes of action and resistance of existing and novel antiprotozoal drugs.

  14. N(4)-tolyl-2-acetylpyridine thiosemicarbazones and their platinum(II,IV) and gold(III) complexes: cytotoxicity against human glioma cells and studies on the mode of action.

    Science.gov (United States)

    Ferraz, Karina S O; Da Silva, Jeferson G; Costa, Flávia M; Mendes, Bruno M; Rodrigues, Bernardo L; dos Santos, Raquel G; Beraldo, Heloisa

    2013-10-01

    Complexes [Au(2Ac4oT)Cl][AuCl2] (1), [Au(Hpy2Ac4mT)Cl2]Cl·H2O (2), [Au(Hpy2Ac4pT)Cl2]Cl (3), [Pt(H2Ac4oT)Cl]Cl (4), [Pt(2Ac4mT)Cl]·H2O (5), [Pt(2Ac4pT)Cl] (6) and [Pt(L)Cl2OH], L = 2Ac4mT (7), 2Ac4oT (8), 2Ac4pT (9) were prepared with N(4)-ortho- (H2Ac4oT), N(4)-meta- (H2Ac4mT) and N(4)-para- (H2Ac4pT) tolyl-2-acetylpyridine thiosemicarbazone. The cytotoxic activities of all compounds were assayed against U-87 and T-98 human malignant glioma cell lines. Upon coordination cytotoxicity improved in 2, 5 and 8. In general, the gold(III) complexes were more cytotoxic than those with platinum(II,IV). Several of these compounds proved to be more active than cisplatin and auranofin used as controls. The gold(III) complexes probably act by inhibiting the activity of thioredoxin reductase enzyme whereas the mode of action of the platinum(II,IV) complexes involves binding to DNA. Cells treated with the studied compounds presented morphological changes such as cell shrinkage and blebs formation, which indicate cell death by apoptosis induction.

  15. 天然化合物丁香酚抗烟草花叶病毒病作用机制初探%Mode of Action of Natural Compound Eugenol on Tobacco Mosaic Virus Disease

    Institute of Scientific and Technical Information of China (English)

    王春梅; 苏杭; 陈浩; 石志琦; 范永坚

    2012-01-01

    [Aims] The aim of this research was to study mode of action of eugenol on tobacco mosaic virus disease. [Methods] The preventive and therapeutic effect of Eugenol on tobacco mosaic virus disease was determined. The influence of eugenol on TMV virions was observed with electron microscope. The effect of ugenol on polymerization of TMV coat protein was also determined. [Results] The results showed that eugenol had a better preventive and therapeutic effect. The TMV virions treated with Eugenol showed ruptures and abnormality. Eugenol had an inhibition effect on polymerization of TMV coat protein. [Conclusions] Eugenol as a newly reported antiviral compound could be used to control plant virus diseases.%[目的]初步研究丁香酚对植物病毒病的作用机制.[方法]利用盆栽法测定了丁香酚对烟草花叶病毒病的预防和治疗效果;电镜法观察了丁香酚对病毒粒子的影响;体外混合法测定了丁香酚对烟草花叶病毒外壳蛋白体外聚合的影响.[结果]丁香酚对烟草花叶病毒病具有较好的预防和治疗效果;丁香酚与病毒混合处理后,病毒粒子有断裂现象;丁香酚对TMV外壳蛋白体外聚合有一定的抑制作用.[结论]丁香酚可以作为新型抗病毒剂用于防治作物病毒病.

  16. Comparison of the effects of hexavalent chromium in the alimentary canal of F344 rats and B6C3F1 mice following exposure in drinking water: implications for carcinogenic modes of action.

    Science.gov (United States)

    Thompson, Chad M; Proctor, Deborah M; Suh, Mina; Haws, Laurie C; Hébert, Charles D; Mann, Jill F; Shertzer, Howard G; Hixon, J Gregory; Harris, Mark A

    2012-01-01

    Exposure to high concentrations of hexavalent chromium (Cr[VI]) in drinking water is reported to induce oral mucosa tumors in F344 rats and intestinal tumors in B6C3F1 mice. To investigate the modes of action underlying these tumors, 90-day drinking water studies (with interim necropsy at day 8) were conducted with concentrations of 0.1-182 mg/l Cr(VI), administered as 0.3-520 mg/l sodium dichromate dihydrate. Blood and tissue samples were analyzed for chromium content, oxidative stress, iron levels, and gross and microscopic lesions. Results for the F344 rats are described herein and compared with results from B6C3F1 mice published previously. After 90 days of exposure, total chromium concentrations in the rat and mouse oral mucosae were comparable, yet significant dose-dependent decreases in the reduced-to-oxidized glutathione ratio (GSH/GSSG) were observed only in rats. In the duodenum, changes in GSH/GSSG were only observed in mice. Levels of 8-hydroxydeoxyguanosine were not increased in the oral or duodenal mucosae of either species. Glutathione levels were increased in the duodenum but decreased in the jejunum of both species, indicating potential differential responses in the intestinal segments. Histiocytic infiltration was observed in the duodenum of both species, yet duodenal cytokines were repressed in mice but increased in rats. Serum and bone marrow iron levels were more decreased in rats than mice. Collectively, these data suggest that Cr(VI)-induced carcinogenesis in the rodent alimentary canal involves oxidative stress; however, differences in histopathology, cytokines, and iron status suggest potential contributions from other factors as well.

  17. Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways.

    Science.gov (United States)

    Kakehashi, Anna; Hagiwara, Akihiro; Imai, Norio; Nagano, Kasuke; Nishimaki, Fukumi; Banton, Marcy; Wei, Min; Fukushima, Shoji; Wanibuchi, Hideki

    2013-12-01

    To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000 mg/kg body weight twice a day by gavage for 1 and 2 weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500 ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulation of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans.

  18. In silico prediction of toxicity of phenols to Tetrahymena pyriformis by using genetic algorithm and decision tree-based modeling approach.

    Science.gov (United States)

    Abbasitabar, Fatemeh; Zare-Shahabadi, Vahid

    2017-04-01

    Risk assessment of chemicals is an important issue in environmental protection; however, there is a huge lack of experimental data for a large number of end-points. The experimental determination of toxicity of chemicals involves high costs and time-consuming process. In silico tools such as quantitative structure-toxicity relationship (QSTR) models, which are constructed on the basis of computational molecular descriptors, can predict missing data for toxic end-points for existing or even not yet synthesized chemicals. Phenol derivatives are known to be aquatic pollutants. With this background, we aimed to develop an accurate and reliable QSTR model for the prediction of toxicity of 206 phenols to Tetrahymena pyriformis. A multiple linear regression (MLR)-based QSTR was obtained using a powerful descriptor selection tool named Memorized_ACO algorithm. Statistical parameters of the model were 0.72 and 0.68 for Rtraining(2) and Rtest(2), respectively. To develop a high-quality QSTR model, classification and regression tree (CART) was employed. Two approaches were considered: (1) phenols were classified into different modes of action using CART and (2) the phenols in the training set were partitioned to several subsets by a tree in such a manner that in each subset, a high-quality MLR could be developed. For the first approach, the statistical parameters of the resultant QSTR model were improved to 0.83 and 0.75 for Rtraining(2) and Rtest(2), respectively. Genetic algorithm was employed in the second approach to obtain an optimal tree, and it was shown that the final QSTR model provided excellent prediction accuracy for the training and test sets (Rtraining(2) and Rtest(2) were 0.91 and 0.93, respectively). The mean absolute error for the test set was computed as 0.1615.

  19. Ugi-based approaches to quinoxaline libraries.

    Science.gov (United States)

    Azuaje, Jhonny; El Maatougui, Abdelaziz; García-Mera, Xerardo; Sotelo, Eddy

    2014-08-11

    An expedient and concise Ugi-based unified approach for the rapid assembly of quinoxaline frameworks has been developed. This convergent and versatile method uses readily available commercial reagents, does not require advanced intermediates, and exhibits excellent bond-forming efficiency, thus exemplifying the operationally simple synthesis of quinoxaline libraries.

  20. Immune based computer virus detection approaches

    Institute of Scientific and Technical Information of China (English)

    TAN Ying; ZHANG Pengtao

    2013-01-01

    The computer virus is considered one of the most horrifying threats to the security of computer systems worldwide.The rapid development of evasion techniques used in virus causes the signature based computer virus detection techniques to be ineffective.Many novel computer virus detection approaches have been proposed in the past to cope with the ineffectiveness,mainly classified into three categories:static,dynamic and heuristics techniques.As the natural similarities between the biological immune system (BIS),computer security system (CSS),and the artificial immune system (AIS) were all developed as a new prototype in the community of anti-virus research.The immune mechanisms in the BIS provide the opportunities to construct computer virus detection models that are robust and adaptive with the ability to detect unseen viruses.In this paper,a variety of classic computer virus detection approaches were introduced and reviewed based on the background knowledge of the computer virus history.Next,a variety of immune based computer virus detection approaches were also discussed in detail.Promising experimental results suggest that the immune based computer virus detection approaches were able to detect new variants and unseen viruses at lower false positive rates,which have paved a new way for the anti-virus research.

  1. Ecosystem based approaches to climate adaptation

    DEFF Research Database (Denmark)

    Zandersen, Marianne; Jensen, Anne; Termansen, Mette

    This report analyses the prospects and barriers of applying ecosystem based approaches systematically to climate adaptation in urban areas, taking the case of green roofs in Copenhagen Municipality. It looks at planning aspects of green roofs in Copenhagen as well as citizen views and preferences...

  2. Advanced Approach of Multiagent Based Buoy Communication

    Directory of Open Access Journals (Sweden)

    Gediminas Gricius

    2015-01-01

    Full Text Available Usually, a hydrometeorological information system is faced with great data flows, but the data levels are often excessive, depending on the observed region of the water. The paper presents advanced buoy communication technologies based on multiagent interaction and data exchange between several monitoring system nodes. The proposed management of buoy communication is based on a clustering algorithm, which enables the performance of the hydrometeorological information system to be enhanced. The experiment is based on the design and analysis of the inexpensive but reliable Baltic Sea autonomous monitoring network (buoys, which would be able to continuously monitor and collect temperature, waviness, and other required data. The proposed approach of multiagent based buoy communication enables all the data from the costal-based station to be monitored with limited transition speed by setting different tasks for the agent-based buoy system according to the clustering information.

  3. Advanced Approach of Multiagent Based Buoy Communication

    Science.gov (United States)

    Gricius, Gediminas; Drungilas, Darius; Andziulis, Arunas; Dzemydiene, Dale; Voznak, Miroslav; Kurmis, Mindaugas; Jakovlev, Sergej

    2015-01-01

    Usually, a hydrometeorological information system is faced with great data flows, but the data levels are often excessive, depending on the observed region of the water. The paper presents advanced buoy communication technologies based on multiagent interaction and data exchange between several monitoring system nodes. The proposed management of buoy communication is based on a clustering algorithm, which enables the performance of the hydrometeorological information system to be enhanced. The experiment is based on the design and analysis of the inexpensive but reliable Baltic Sea autonomous monitoring network (buoys), which would be able to continuously monitor and collect temperature, waviness, and other required data. The proposed approach of multiagent based buoy communication enables all the data from the costal-based station to be monitored with limited transition speed by setting different tasks for the agent-based buoy system according to the clustering information. PMID:26345197

  4. Surgical approaches for tongue base schwannoma.

    Science.gov (United States)

    Ying, Binbin; Zhu, Songsong; Qiao, Yang; Ye, Weimin; Maimaiti, Abdikerimjian; Hu, Jingzhou; Zhang, Yong

    2013-01-01

    Schwannomas (neurilemmomas) are benign nerve sheath tumor originating from Schwann cells. They are well circumscribed and rarely infiltrate and metastasize. Schwannomas of the head and neck commonly occur in the tongue followed by the palate, floor of mouth, buccal mucosa, and mandible. Tongue base schwannomas could extend to the pharyngeal cavity or the floor of the mouse, and it is difficult to differentiate between tumors of the lingual, hypoglossal, and glossopharyngeal nerves.Surgical treatment of tongue base schwannomas is difficult because of limited operative exposure. Although mandibulotomy with lip splitting could obtain good exposure, surgeons might strike a balance between exposure obtaining and morbidity following because there are intricate neurovascular anatomical relationships in this region, and mandibulotomy with lip splitting would cause significant morbidity. Surgical approach options are important for tongue base schwannoma removal. From March 2008 to March 2010, 8 patients were clinically and pathologically diagnosed with tongue base schwannomas in our department, and all underwent surgical treatment. In our experience, transoral approach was used for tongue base schwannomas extending to the floor of the mouse and suprahyroid pharyngotomy approach for those extending to the pharyngeal cavity. Follow-up was made until now. One patient who experienced transoral excision still experienced numbness in the region of the lateral tongue tip, and the other 7 patients had no postoperative long-term complications.

  5. Managing projects a team-based approach

    CERN Document Server

    Brown, Karen A

    2010-01-01

    Students today are likely to be assigned to project teams or to be project managers almost immediately in their first job. Managing Projects: A Team-Based Approach was written for a wide range of stakeholders, including project managers, project team members, support personnel, functional mangers who provide resources for projects, project customers (and customer representatives), project sponsors, project subcontractors, and anyone who plays a role in the project delivery process. The need for project management is on the rise as product life cycles compress, demand for IT systems increases, and business takes on an increasingly global character. This book adds to the project management knowledge base in a way that fills an unmet need—it shows how teams can apply many of the standard project management tools, as well as several tools that are relatively new to the field. Managing Projects: A Team-Based Approach offers the academic rigor found in most textbooks along with the practical attributes often foun...

  6. An Approach to Programming Based on Concepts

    CERN Document Server

    Savinov, Alexandr

    2007-01-01

    In this paper we describe a new approach to programming which generalizes object-oriented programming. It is based on using a new programming construct, called concept, which generalizes classes. Concept is defined as a pair of two classes: one reference class and one object class. Each concept has a parent concept which is specified using inclusion relation generalizing inheritance. We describe several important mechanisms such as reference resolution, context stack, dual methods and life-cycle management, inheritance and polymorphism. This approach to programming is positioned as a new programming paradigm and therefore we formulate its main principles and rules.

  7. A network approach based on cliques

    Science.gov (United States)

    Fadigas, I. S.; Pereira, H. B. B.

    2013-05-01

    The characterization of complex networks is a procedure that is currently found in several research studies. Nevertheless, few studies present a discussion on networks in which the basic element is a clique. In this paper, we propose an approach based on a network of cliques. This approach consists not only of a set of new indices to capture the properties of a network of cliques but also of a method to characterize complex networks of cliques (i.e., some of the parameters are proposed to characterize the small-world phenomenon in networks of cliques). The results obtained are consistent with results from classical methods used to characterize complex networks.

  8. Studying the effects of genistein on gene expression of fish embryos as an alternative testing approach for endocrine disruption.

    Science.gov (United States)

    Schiller, Viktoria; Wichmann, Arne; Kriehuber, Ralf; Muth-Köhne, Elke; Giesy, John P; Hecker, Markus; Fenske, Martina

    2013-01-01

    Assessment of endocrine disruption currently relies on testing strategies involving adult vertebrates. In order to minimize the use of animal tests according to the 3Rs principle of replacement, reduction and refinement, we propose a transcriptomics and fish embryo based approach as an alternative to identify and analyze an estrogenic activity of environmental chemicals. For this purpose, the suitability of 48 h and 7 days post-fertilization zebrafish and medaka embryos to test for estrogenic disruption was evaluated. The embryos were exposed to the phytoestrogen genistein and subsequently analyzed by microarrays and quantitative real-time PCR. The functional analysis showed that the genes affected related to multiple metabolic and signaling pathways in the early fish embryo, which reflect the known components of genistein's mode of actions, like apoptosis, estrogenic response, hox gene expression and steroid hormone synthesis. Moreover, the transcriptomic data also suggested a thyroidal mode of action and disruption of the nervous system development. The parallel testing of two fish species provided complementary data on the effects of genistein at gene expression level and facilitated the separation of common from species-dependent effects. Overall, the study demonstrated that combining fish embryo testing with transcriptomics can deliver abundant information about the mechanistic effects of endocrine disrupting chemicals, rendering this strategy a promising alternative approach to test for endocrine disruption in a whole organism in-vitro scale system. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Trait-based approaches to zooplankton communities

    DEFF Research Database (Denmark)

    Lichtman, E.; Ohman, M.D.; Kiørboe, Thomas

    2013-01-01

    Zooplankton are major primary consumers and predators in most aquatic ecosystems. They exhibit tremendous diversity of traits, ecological strategies and, consequently, impacts on other trophic levels and the cycling of materials and energy. An adequate representation of this diversity in community...... and ecosystem models is necessary to generate realistic predictions on the functioning of aquatic ecosystems but remains extremely challenging. We propose that the use of trait-based approaches is a promising way to reduce complexity while retaining realism in developing novel descriptions of zooplankton...... traits, such as body size and motility, transcend several functions and are major determinants of zooplankton ecological strategies. Future developments of trait-based approaches to zooplankton should assemble a comprehensive matrix of key traits for diverse groups and explore it for general patterns...

  10. Materiality in a practice-based approach

    DEFF Research Database (Denmark)

    Svabo, Connie

    2009-01-01

    The paper provides an overview of the vocabulary for materiality which is used by practice-based approaches to organizational knowing. Common terms for materiality are 'artifact' and 'object'. The interaction between social and material realities is grasped as several processes: object-oriented a......The paper provides an overview of the vocabulary for materiality which is used by practice-based approaches to organizational knowing. Common terms for materiality are 'artifact' and 'object'. The interaction between social and material realities is grasped as several processes: object......-oriented activity, symbolization, embodiment, performance, alignment and mediation. Material artifacts both stabilize and destabilize organizational action. They may ensure coordination, communication, and control, but they may also create disturbance and conflict....

  11. An Approach to Programming Based on Concepts

    OpenAIRE

    Savinov, Alexandr

    2007-01-01

    In this paper we describe a new approach to programming which generalizes object-oriented programming. It is based on using a new programming construct, called concept, which generalizes classes. Concept is defined as a pair of two classes: one reference class and one object class. Each concept has a parent concept which is specified using inclusion relation generalizing inheritance. We describe several important mechanisms such as reference resolution, context stack, dual methods and life-cy...

  12. Stem cell-based approaches in dentistry

    OpenAIRE

    Mitsiadis, T A; Orsini, G.; Jimenez-Rojo, L

    2015-01-01

    Repair of dental pulp and periodontal lesions remains a major clinical challenge. Classical dental treatments require the use of specialised tissue-adapted materials with still questionable efficacy and durability. Stem cell-based therapeutic approaches could offer an attractive alternative in dentistry since they can promise physiologically improved structural and functional outcomes. These therapies necessitate a sufficient number of specific stem cell populations for implantation. Dental m...

  13. Tourism Planning: A Case Based Approach

    Directory of Open Access Journals (Sweden)

    Muhammad Khalid Khan

    2014-06-01

    Full Text Available This study is an attempt to investigate the tourism marketing and attraction strategies adopted by various countries. A case study based approach is adopted in this study. On the basis of investigation of tourism development strategies adopted by various countries, suggestions are also made at the end. These suggestions are aimed to increase visitors our tourists’ base in a country. These suggestions can be used by any country to increase visitors or tourists. Future directions are also given at the end.

  14. Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: Evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Kakehashi, Anna, E-mail: anna@med.osaka-cu.ac.jp [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Hagiwara, Akihiro; Imai, Norio [DIMS Institute of Medical Science, Inc., 64 Goura, Nishiazai, Azai-cho, Ichinomiya, Aichi 491-0113 (Japan); Nagano, Kasuke [Nagano Toxicologic-Pathology Consulting, Ochiai, Hadano, Kanagawa 257-0025 (Japan); Nishimaki, Fukumi [Biofuel Assessment Group, New Fuels Dept., Japan Petroleum Energy Center (JPEC), 4-3-9 Toranomon, Minato-ku, Tokyo 105-0001 (Japan); Banton, Marcy [Toxicology and Risk Assessment, LyondellBasell Industries, LyondellBasell Corporate HSE/Product Safety, One Houston Center, Suite 700, 1221 McKinney Street, Houston, TX 770 10 (United States); Wei, Min [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Fukushima, Shoji [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Japan Bioassay Research Center, Japan Industrial Safety and Health Association, 2445 Hirasawa, Hadano, Kanagawa 257-0011 (Japan); Wanibuchi, Hideki [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

    2013-12-01

    To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000 mg/kg body weight twice a day by gavage for 1 and 2 weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500 ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulation of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans. - Highlights: • We focus on MOA and human relevance of hepatotumorigenicity in rats for ETBE. • ETBE was administered to F344 rats for 1 and 2 weeks. • Oxidative stress formation, proliferation and apoptosis in the liver are analyzed. • ETBE-induced changes of gene and protein expression in the liver are examined. • The effects are compared with those induced by non-genotoxic carcinogen PB.

  15. Matched filter based iterative adaptive approach

    Science.gov (United States)

    Nepal, Ramesh; Zhang, Yan Rockee; Li, Zhengzheng; Blake, William

    2016-05-01

    Matched Filter sidelobes from diversified LPI waveform design and sensor resolution are two important considerations in radars and active sensors in general. Matched Filter sidelobes can potentially mask weaker targets, and low sensor resolution not only causes a high margin of error but also limits sensing in target-rich environment/ sector. The improvement in those factors, in part, concern with the transmitted waveform and consequently pulse compression techniques. An adaptive pulse compression algorithm is hence desired that can mitigate the aforementioned limitations. A new Matched Filter based Iterative Adaptive Approach, MF-IAA, as an extension to traditional Iterative Adaptive Approach, IAA, has been developed. MF-IAA takes its input as the Matched Filter output. The motivation here is to facilitate implementation of Iterative Adaptive Approach without disrupting the processing chain of traditional Matched Filter. Similar to IAA, MF-IAA is a user parameter free, iterative, weighted least square based spectral identification algorithm. This work focuses on the implementation of MF-IAA. The feasibility of MF-IAA is studied using a realistic airborne radar simulator as well as actual measured airborne radar data. The performance of MF-IAA is measured with different test waveforms, and different Signal-to-Noise (SNR) levels. In addition, Range-Doppler super-resolution using MF-IAA is investigated. Sidelobe reduction as well as super-resolution enhancement is validated. The robustness of MF-IAA with respect to different LPI waveforms and SNR levels is also demonstrated.

  16. Cosine-Based Clustering Algorithm Approach

    Directory of Open Access Journals (Sweden)

    Mohammed A. H. Lubbad

    2012-02-01

    Full Text Available Due to many applications need the management of spatial data; clustering large spatial databases is an important problem which tries to find the densely populated regions in the feature space to be used in data mining, knowledge discovery, or efficient information retrieval. A good clustering approach should be efficient and detect clusters of arbitrary shapes. It must be insensitive to the outliers (noise and the order of input data. In this paper Cosine Cluster is proposed based on cosine transformation, which satisfies all the above requirements. Using multi-resolution property of cosine transforms, arbitrary shape clusters can be effectively identified at different degrees of accuracy. Cosine Cluster is also approved to be highly efficient in terms of time complexity. Experimental results on very large data sets are presented, which show the efficiency and effectiveness of the proposed approach compared to other recent clustering methods.

  17. RISK BASED TESTING A Fuzzy Approach

    Directory of Open Access Journals (Sweden)

    Ochin Sharma

    2011-10-01

    Full Text Available Earlier Testers used to concentrate on only functionality, usability or performance sort of testing. Many of these derived by the customer’s desire or need. Same thing was with the risk based testing. If an application used to be real time based or crucial in terms or national security or economic then it was considered to be a risk based testing candidate. But business of individual has equalimportance for the people. Hence now risked based scenario and testing is a must do strategy. But based on the various factors how will you decide when an event or activity is under risk and should be treated on priority based. In real time projects many activities cannot be decided as ‘Yes’ or ‘No’ criteria. For example in a project if any one person is left out of 10 members’ team. It cannot be treated as crucial, but if 5 members left within short span of time. This 50% breakdown in work force definitely be consider as critical, so here we can wave a red (priority signal. So fuzzy approach can be consider as an important deal with respect of risk management

  18. Solving Operator Equation Based on Expansion Approach

    Directory of Open Access Journals (Sweden)

    A. Aminataei

    2014-01-01

    Full Text Available To date, researchers usually use spectral and pseudospectral methods for only numerical approximation of ordinary and partial differential equations and also based on polynomial basis. But the principal importance of this paper is to develop the expansion approach based on general basis functions (in particular case polynomial basis for solving general operator equations, wherein the particular cases of our development are integral equations, ordinary differential equations, difference equations, partial differential equations, and fractional differential equations. In other words, this paper presents the expansion approach for solving general operator equations in the form Lu+Nu=g(x,x∈Γ, with respect to boundary condition Bu=λ, where L, N and B are linear, nonlinear, and boundary operators, respectively, related to a suitable Hilbert space, Γ is the domain of approximation, λ is an arbitrary constant, and g(x∈L2(Γ is an arbitrary function. Also the other importance of this paper is to introduce the general version of pseudospectral method based on general interpolation problem. Finally some experiments show the accuracy of our development and the error analysis is presented in L2(Γ norm.

  19. Creative teaching an evidence-based approach

    CERN Document Server

    Sale, Dennis

    2015-01-01

    This book contains an evidence-based pedagogic guide to enable any motivated teaching/training professional to be able to teach effectively and creatively. It firstly summarises the extensive research field on human psychological functioning relating to learning and how this can be fully utilised in the design and facilitation of quality learning experiences. It then demonstrates what creativity actually 'looks like' in terms of teaching practices, modelling the underpinning processes of creative learning design and how to apply these in lesson planning. The book, having established an evidence-based and pedagogically driven approach to creative learning design, extensively focuses on key challenges facing teaching professionals today. These include utilising information technologies in blended learning formats, differentiating instruction, and developing self-directed learners who can think well. The main purpose of the book is to demystify what it means to teach creatively, explicitly demonstrating the pr...

  20. Classifier Assignment by Corpus-based Approach

    CERN Document Server

    Sornlertlamvanich, V; Meknavin, S; Sornlertlamvanich, Virach; Pantachat, Wantanee; Meknavin, Surapant

    1994-01-01

    This paper presents an algorithm for selecting an appropriate classifier word for a noun. In Thai language, it frequently happens that there is fluctuation in the choice of classifier for a given concrete noun, both from the point of view of the whole spe ech community and individual speakers. Basically, there is no exect rule for classifier selection. As far as we can do in the rule-based approach is to give a default rule to pick up a corresponding classifier of each noun. Registration of classifier for each noun is limited to the type of unit classifier because other types are open due to the meaning of representation. We propose a corpus-based method (Biber, 1993; Nagao, 1993; Smadja, 1993) which generates Noun Classifier Associations (NCA) to overcome the problems in classifier assignment and semantic construction of noun phrase. The NCA is created statistically from a large corpus and recomposed under concept hierarchy constraints and frequency of occurrences.

  1. Market-based approaches to tree valuation

    Science.gov (United States)

    Geoffrey H. Donovan; David T. Butry

    2008-01-01

    A recent four-part series in Arborist News outlined different appraisal processes used to value urban trees. The final article in the series described the three generally accepted approaches to tree valuation: the sales comparison approach, the cost approach, and the income capitalization approach. The author, D. Logan Nelson, noted that the sales comparison approach...

  2. Peptide Based Radiopharmaceuticals: Specific Construct Approach

    Energy Technology Data Exchange (ETDEWEB)

    Som, P; Rhodes, B A; Sharma, S S

    1997-10-21

    The objective of this project was to develop receptor based peptides for diagnostic imaging and therapy. A series of peptides related to cell adhesion molecules (CAM) and immune regulation were designed for radiolabeling with 99mTc and evaluated in animal models as potential diagnostic imaging agents for various disease conditions such as thrombus (clot), acute kidney failure, and inflection/inflammation imaging. The peptides for this project were designed by the industrial partner, Palatin Technologies, (formerly Rhomed, Inc.) using various peptide design approaches including a newly developed rational computer assisted drug design (CADD) approach termed MIDAS (Metal ion Induced Distinctive Array of Structures). In this approach, the biological function domain and the 99mTc complexing domain are fused together so that structurally these domains are indistinguishable. This approach allows construction of conformationally rigid metallo-peptide molecules (similar to cyclic peptides) that are metabolically stable in-vivo. All the newly designed peptides were screened in various in vitro receptor binding and functional assays to identify a lead compound. The lead compounds were formulated in a one-step 99mTc labeling kit form which were studied by BNL for detailed in-vivo imaging using various animals models of human disease. Two main peptides usingMIDAS approach evolved and were investigated: RGD peptide for acute renal failure and an immunomodulatory peptide derived from tuftsin (RMT-1) for infection/inflammation imaging. Various RGD based metallopeptides were designed, synthesized and assayed for their efficacy in inhibiting ADP-induced human platelet aggregation. Most of these peptides displayed biological activity in the 1-100 µM range. Based on previous work by others, RGD-I and RGD-II were evaluated in animal models of acute renal failure. These earlier studies showed that after acute ischemic injury the renal cortex displays

  3. New approaches in diffraction based optical metrology

    Science.gov (United States)

    Ebert, M.; Vanoppen, P.; Jak, M.; v. d. Zouw, G.; Cramer, H.; Nooitgedagt, T.; v. d. Laan, H.

    2016-03-01

    Requirements for on-product overlay, focus and CD uniformity continue to tighten in order to support the demands of 10nm and 7nm nodes. This results in the need for simultaneously accurate, robust and dense metrology data as input for closed-loop control solutions thereby enabling wafer-level control and high order corrections. In addition the use of opaque materials and stringent design rules drive the need for expansion of the available measurement wavelengths and metrology target design space. Diffraction based optical metrology has been established as the leading methodology for integrated as well as standalone optical metrology for overlay, focus and CD monitoring and control in state of the art chip manufacturing. We are presenting the new approaches to diffraction based optical metrology designed to meet the processing diffraction based metrology signals. In this paper we will present the new detection principle and its impact on key performance characteristics of overlay and focus measurements. We will also describe the wide range of applications of a newly introduced increased measurement spot size, enabling significant improvements to accuracy and process robustness of overlay and focus measurements. With the YS350E the optical CD measurement capability is also extended, to 10x10μm2 targets. We will discuss the performance and value of small targets in after-develop and after-etch applications.

  4. Age Classification Based On Integrated Approach

    Directory of Open Access Journals (Sweden)

    Pullela. SVVSR Kumar

    2014-05-01

    Full Text Available The present paper presents a new age classification method by integrating the features derived from Grey Level Co-occurrence Matrix (GLCM with a new structural approach derived from four distinct LBP's (4-DLBP on a 3 x 3 image. The present paper derived four distinct patterns called Left Diagonal (LD, Right diagonal (RD, vertical centre (VC and horizontal centre (HC LBP's. For all the LBP's the central pixel value of the 3 x 3 neighbourhood is significant. That is the reason in the present research LBP values are evaluated by comparing all 9 pixels of the 3 x 3 neighbourhood with the average value of the neighbourhood. The four distinct LBP's are grouped into two distinct LBP's. Based on these two distinct LBP's GLCM is computed and features are evaluated to classify the human age into four age groups i.e: Child (0-15, Young adult (16-30, Middle aged adult (31-50 and senior adult (>50. The co-occurrence features extracted from the 4-DLBP provides complete texture information about an image which is useful for classification. The proposed 4-DLBP reduces the size of the LBP from 6561 to 79 in the case of original texture spectrum and 2020 to 79 in the case of Fuzzy Texture approach.

  5. Toxidrome-based Approach to Common Poisonings

    Directory of Open Access Journals (Sweden)

    Bruno Mégarbane

    2014-03-01

    Full Text Available Poisoning remains a major cause of hospital admission into the emergency department and intensive care unit. Proper diagnosis is the cornerstone for optimal management of poisoned patients. Since the definitive analytical confirmation of the nature of the toxicant involved in the poisoning cannot be rapidly obtained in the majority of healthcare facilities, diagnosis relies on the medical history and the rigorous clinical examination of the patients well as results of the routine biological tests and the electrocardiogram. Identification of the toxidromes addresses not only the correct diagnosis but also rules out other differential diagnoses. Despite no definitive predictive value, this clinical approach facilitates making decision on empirical treatments and emergent antidotes. Pharmacodynamic tests using specific antidotes including naloxone for opioids and flumazenil for benzodiazepines and its analogues are also helpful to assess the final diagnosis in comatose patients. The objective of this article is to review the toxidrome-based approach to common poisonings before toxicological analysis enables the confirmation of the initially suspected toxic etiology.

  6. Linear systems a measurement based approach

    CERN Document Server

    Bhattacharyya, S P; Mohsenizadeh, D N

    2014-01-01

    This brief presents recent results obtained on the analysis, synthesis and design of systems described by linear equations. It is well known that linear equations arise in most branches of science and engineering as well as social, biological and economic systems. The novelty of this approach is that no models of the system are assumed to be available, nor are they required. Instead, a few measurements made on the system can be processed strategically to directly extract design values that meet specifications without constructing a model of the system, implicitly or explicitly. These new concepts are illustrated by applying them to linear DC and AC circuits, mechanical, civil and hydraulic systems, signal flow block diagrams and control systems. These applications are preliminary and suggest many open problems. The results presented in this brief are the latest effort in this direction and the authors hope these will lead to attractive alternatives to model-based design of engineering and other systems.

  7. Sepsis management: An evidence-based approach.

    Science.gov (United States)

    Baig, Muhammad Akbar; Shahzad, Hira; Jamil, Bushra; Hussain, Erfan

    2016-03-01

    The Surviving Sepsis Campaign (SSC) guidelines have outlined an early goal directed therapy (EGDT) which demonstrates a standardized approach to ensure prompt and effective management of sepsis. Having said that, there are barriers associated with the application of evidence-based practice, which often lead to an overall poorer adherence to guidelines. Considering the global burden of disease, data from low- to middle-income countries is scarce. Asia is the largest continent but most Asian countries do not have a well-developed healthcare system and compliance rates to resuscitation and management bundles are as low as 7.6% and 3.5%, respectively. Intensive care units are not adequately equipped and financial concerns limit implementation of expensive treatment strategies. Healthcare policy-makers should be notified in order to alleviate financial restrictions and ensure delivery of standard care to septic patients.

  8. Wavelet based approach for facial expression recognition

    Directory of Open Access Journals (Sweden)

    Zaenal Abidin

    2015-03-01

    Full Text Available Facial expression recognition is one of the most active fields of research. Many facial expression recognition methods have been developed and implemented. Neural networks (NNs have capability to undertake such pattern recognition tasks. The key factor of the use of NN is based on its characteristics. It is capable in conducting learning and generalizing, non-linear mapping, and parallel computation. Backpropagation neural networks (BPNNs are the approach methods that mostly used. In this study, BPNNs were used as classifier to categorize facial expression images into seven-class of expressions which are anger, disgust, fear, happiness, sadness, neutral and surprise. For the purpose of feature extraction tasks, three discrete wavelet transforms were used to decompose images, namely Haar wavelet, Daubechies (4 wavelet and Coiflet (1 wavelet. To analyze the proposed method, a facial expression recognition system was built. The proposed method was tested on static images from JAFFE database.

  9. Nanotechnology-based approaches in anticancer research.

    Science.gov (United States)

    Jabir, Nasimudeen R; Tabrez, Shams; Ashraf, Ghulam Md; Shakil, Shazi; Damanhouri, Ghazi A; Kamal, Mohammad A

    2012-01-01

    Cancer is a highly complex disease to understand, because it entails multiple cellular physiological systems. The most common cancer treatments are restricted to chemotherapy, radiation and surgery. Moreover, the early recognition and treatment of cancer remains a technological bottleneck. There is an urgent need to develop new and innovative technologies that could help to delineate tumor margins, identify residual tumor cells and micrometastases, and determine whether a tumor has been completely removed or not. Nanotechnology has witnessed significant progress in the past few decades, and its effect is widespread nowadays in every field. Nanoparticles can be modified in numerous ways to prolong circulation, enhance drug localization, increase drug efficacy, and potentially decrease chances of multidrug resistance by the use of nanotechnology. Recently, research in the field of cancer nanotechnology has made remarkable advances. The present review summarizes the application of various nanotechnology-based approaches towards the diagnostics and therapeutics of cancer.

  10. A Rule-Based Approach To Prepositional Phrase Attachment Disambiguation

    CERN Document Server

    Brill, E; Brill, Eric; Resnik, Philip

    1994-01-01

    In this paper, we describe a new corpus-based approach to prepositional phrase attachment disambiguation, and present results comparing performance of this algorithm with other corpus-based approaches to this problem.

  11. The Significance of Temperature Based Approach Over the Energy Based Approaches in the Buildings Thermal Assessment

    Science.gov (United States)

    Albatayneh, Aiman; Alterman, Dariusz; Page, Adrian; Moghtaderi, Behdad

    2017-05-01

    The design of low energy buildings requires accurate thermal simulation software to assess the heating and cooling loads. Such designs should sustain thermal comfort for occupants and promote less energy usage over the life time of any building. One of the house energy rating used in Australia is AccuRate, star rating tool to assess and compare the thermal performance of various buildings where the heating and cooling loads are calculated based on fixed operational temperatures between 20 °C to 25 °C to sustain thermal comfort for the occupants. However, these fixed settings for the time and temperatures considerably increase the heating and cooling loads. On the other hand the adaptive thermal model applies a broader range of weather conditions, interacts with the occupants and promotes low energy solutions to maintain thermal comfort. This can be achieved by natural ventilation (opening window/doors), suitable clothes, shading and low energy heating/cooling solutions for the occupied spaces (rooms). These activities will save significant amount of operating energy what can to be taken into account to predict energy consumption for a building. Most of the buildings thermal assessment tools depend on energy-based approaches to predict the thermal performance of any building e.g. AccuRate in Australia. This approach encourages the use of energy to maintain thermal comfort. This paper describes the advantages of a temperature-based approach to assess the building's thermal performance (using an adaptive thermal comfort model) over energy based approach (AccuRate Software used in Australia). The temperature-based approach was validated and compared with the energy-based approach using four full scale housing test modules located in Newcastle, Australia (Cavity Brick (CB), Insulated Cavity Brick (InsCB), Insulated Brick Veneer (InsBV) and Insulated Reverse Brick Veneer (InsRBV)) subjected to a range of seasonal conditions in a moderate climate. The time required for

  12. Evaluating face trustworthiness: a model based approach.

    Science.gov (United States)

    Todorov, Alexander; Baron, Sean G; Oosterhof, Nikolaas N

    2008-06-01

    Judgments of trustworthiness from faces determine basic approach/avoidance responses and approximate the valence evaluation of faces that runs across multiple person judgments. Here, based on trustworthiness judgments and using a computer model for face representation, we built a model for representing face trustworthiness (study 1). Using this model, we generated novel faces with an increased range of trustworthiness and used these faces as stimuli in a functional Magnetic Resonance Imaging study (study 2). Although participants did not engage in explicit evaluation of the faces, the amygdala response changed as a function of face trustworthiness. An area in the right amygdala showed a negative linear response-as the untrustworthiness of faces increased so did the amygdala response. Areas in the left and right putamen, the latter area extended into the anterior insula, showed a similar negative linear response. The response in the left amygdala was quadratic--strongest for faces on both extremes of the trustworthiness dimension. The medial prefrontal cortex and precuneus also showed a quadratic response, but their response was strongest to faces in the middle range of the trustworthiness dimension.

  13. Concurrency-based approaches to parallel programming

    Science.gov (United States)

    Kale, L.V.; Chrisochoides, N.; Kohl, J.; Yelick, K.

    1995-01-01

    The inevitable transition to parallel programming can be facilitated by appropriate tools, including languages and libraries. After describing the needs of applications developers, this paper presents three specific approaches aimed at development of efficient and reusable parallel software for irregular and dynamic-structured problems. A salient feature of all three approaches in their exploitation of concurrency within a processor. Benefits of individual approaches such as these can be leveraged by an interoperability environment which permits modules written using different approaches to co-exist in single applications.

  14. IPTV inter-destination synchronization: A network-based approach

    NARCIS (Netherlands)

    Stokking, H.M.; Deventer, M.O. van; Niamut, O.A.; Walraven, F.A.; Mekuria, R.N.

    2010-01-01

    This paper introduces a novel network-based approach to inter-destination media synchronization. The approach meets the need for synchronization in advanced TV concepts like social TV and offers high scalability, unlike conventional end-point based approaches. The solution for interdestination media

  15. A discourse based approach in text-based machine translation

    CERN Document Server

    Ullah, Sana; Kwak, Kyung Sup

    2009-01-01

    This paper presents a theoretical research based approach to ellipsis resolution in machine translation. Moreover, the formula of discourse is applied in order to resolve ellipses. The validity of the discourse formula is analyzed by applying it to the real world text i.e. newspaper fragments. The source text is converted into mono-sentential discourses where complex discourses require further dissection either directly into primitive discourses or first into compound discourses and later into primitive ones. The procedure of dissection needs further improvement i.e. discovering as many primitive discourse forms as possible [1]. This work is further improvement to the concepts presented by Khan (Khan, 1995). Likewise, an attempt has been made to investigate new primitive discourses i.e. patterns from the given text.

  16. A Constructivist Approach to Rule Bases

    NARCIS (Netherlands)

    Sileno, G.; Boer, A.; van Engers, T.; Loiseau, S.; Filipe, J.; Duval, B.; van den Herik, J.

    2015-01-01

    The paper presents a set of algorithms for the conversion of rule bases between priority-based and constraint-based representations. Inspired by research in precedential reasoning in law, such algorithms can be used for the analysis of a rule base, and for the study of the impact of the introduction

  17. Model Mapping Approach Based on Ontology Semantics

    Directory of Open Access Journals (Sweden)

    Jinkui Hou

    2013-09-01

    Full Text Available The mapping relations between different models are the foundation for model transformation in model-driven software development. On the basis of ontology semantics, model mappings between different levels are classified by using structural semantics of modeling languages. The general definition process for mapping relations is explored, and the principles of structure mapping are proposed subsequently. The approach is further illustrated by the mapping relations from class model of object oriented modeling language to the C programming codes. The application research shows that the approach provides a theoretical guidance for the realization of model mapping, and thus can make an effective support to model-driven software development

  18. Predicting Liaison: an Example-Based Approach

    NARCIS (Netherlands)

    Greefhorst, A.P.M.; Bosch, A.P.J. van den

    2016-01-01

    Predicting liaison in French is a non-trivial problem to model. We compare a memory-based machine-learning algorithm with a rule-based baseline. The memory-based learner is trained to predict whether liaison occurs between two words on the basis of lexical, orthographic, morphosyntactic, and

  19. Abstract algebra an inquiry based approach

    CERN Document Server

    Hodge, Jonathan K; Sundstrom, Ted

    2013-01-01

    ""This book arose from the authors' approach to teaching abstract algebra. They place an emphasis on active learning and on developing students' intuition through their investigation of examples. … The text is organized in such a way that it is possible to begin with either rings or groups.""-Florentina Chirtes, Zentralblatt MATH 1295

  20. An eigenvector based approach to neutrino mixing

    CERN Document Server

    Sierra, D Aristizabal; Houet, E

    2013-01-01

    We propose a model-independent analysis of the neutrino mass matrix through an expansion in terms of the eigenvectors defining the lepton mixing matrix, which we show can be parametrized as small perturbations of the tribimaximal mixing eigenvectors. This approach proves to be powerful and convenient for some aspects of lepton mixing, in particular when studying the sensitivity of the mass matrix elements to departures from their tribimaximal form. In terms of the eigenvector decomposition, the neutrino mass matrix can be understood as originating from a tribimaximal dominant structure with small departures determined by data. By implementing this approach to cases when the neutrino masses originate from different mechanisms, we show that the experimentally observed structure arises very naturally. We thus claim that the observed deviations from the tribimaximal mixing pattern might be interpreted as a possible hint of a ``hybrid'' nature of the neutrino mass matrix.

  1. Supraorbital eyebrow approach to skull base lesions

    Directory of Open Access Journals (Sweden)

    Fernandes Yvens Barbosa

    2002-01-01

    Full Text Available We report our experience with a supraorbital eyebrow minicraniotomy. This technique is suitable to lesions situated in the region of the anterior fossa, suprasellar cisterns, parasellar region and Sylvian fissure. A 50 mm incision in the eyebrow and a supraorbital minicraniotomy is performed. Sixteem patients harboring different lesions were operated on with good postoperative and cosmetic results. We conclude that this approach is safe and useful in selected cases.

  2. Parallel Graph Transformation based on Merged Approach

    Directory of Open Access Journals (Sweden)

    Asmaa Aouat

    2013-01-01

    Full Text Available Graph transformation is one of the key concepts in graph grammar. In order to accelerate the graph transformation, the concept of parallel graph transformation has been proposed by different tools such as AGG tool. The theory of parallel graph transformation used by AGG just allows clarifying the concepts of conflict and dependency between the transformation rules. This work proposes an approach of parallel graph transformations which enables dependent transformation rules to be executed in parallel.

  3. Evaluating a Pivot-Based Approach for Bilingual Lexicon Extraction

    Directory of Open Access Journals (Sweden)

    Jae-Hoon Kim

    2015-01-01

    Full Text Available A pivot-based approach for bilingual lexicon extraction is based on the similarity of context vectors represented by words in a pivot language like English. In this paper, in order to show validity and usability of the pivot-based approach, we evaluate the approach in company with two different methods for estimating context vectors: one estimates them from two parallel corpora based on word association between source words (resp., target words and pivot words and the other estimates them from two parallel corpora based on word alignment tools for statistical machine translation. Empirical results on two language pairs (e.g., Korean-Spanish and Korean-French have shown that the pivot-based approach is very promising for resource-poor languages and this approach observes its validity and usability. Furthermore, for words with low frequency, our method is also well performed.

  4. A systematic approach for component-based software development

    NARCIS (Netherlands)

    Guareis de farias, Cléver; van Sinderen, Marten J.; Ferreira Pires, Luis

    2000-01-01

    Component-based software development enables the construction of software artefacts by assembling prefabricated, configurable and independently evolving building blocks, called software components. This paper presents an approach for the development of component-based software artefacts. This

  5. A polyhedral approach to computing border bases

    CERN Document Server

    Braun, Gábor

    2009-01-01

    Border bases can be considered to be the natural extension of Gr\\"obner bases that have several advantages. Unfortunately, to date the classical border basis algorithm relies on (degree-compatible) term orderings and implicitly on reduced Gr\\"obner bases. We adapt the classical border basis algorithm to allow for calculating border bases for arbitrary degree-compatible order ideals, which is \\emph{independent} from term orderings. Moreover, the algorithm also supports calculating degree-compatible order ideals with \\emph{preference} on contained elements, even though finding a preferred order ideal is NP-hard. Effectively we retain degree-compatibility only to successively extend our computation degree-by-degree. The adaptation is based on our polyhedral characterization: order ideals that support a border basis correspond one-to-one to integral points of the order ideal polytope. This establishes a crucial connection between the ideal and the combinatorial structure of the associated factor spaces.

  6. Antirandom Testing: A Distance-Based Approach

    Directory of Open Access Journals (Sweden)

    Shen Hui Wu

    2008-01-01

    Full Text Available Random testing requires each test to be selected randomly regardless of the tests previously applied. This paper introduces the concept of antirandom testing where each test applied is chosen such that its total distance from all previous tests is maximum. This spans the test vector space to the maximum extent possible for a given number of vectors. An algorithm for generating antirandom tests is presented. Compared with traditional pseudorandom testing, antirandom testing is found to be very effective when a high-fault coverage needs to be achieved with a limited number of test vectors. The superiority of the new approach is even more significant for testing bridging faults.

  7. Thinning based Antialiasing Approach for Visual Saliency of Digital Images

    NARCIS (Netherlands)

    Rukundo, O.

    2015-01-01

    A thinning based approach for spatial antialiasing (TAA) has been proposed for visual saliency of digital images. This TAA approach is based on edge-matting and digital compositing strategies. Prior to edgematting the image edges are detected using ant colony optimization (ACO) algorithm and then th

  8. Thinning based Antialiasing Approach for Visual Saliency of Digital Images

    NARCIS (Netherlands)

    Rukundo, O.

    2015-01-01

    A thinning based approach for spatial antialiasing (TAA) has been proposed for visual saliency of digital images. This TAA approach is based on edge-matting and digital compositing strategies. Prior to edgematting the image edges are detected using ant colony optimization (ACO) algorithm and then

  9. A Strength-Based Approach to Teacher Professional Development

    Science.gov (United States)

    Zwart, Rosanne C.; Korthagen, Fred A. J.; Attema-Noordewier, Saskia

    2015-01-01

    Based on positive psychology, self-determination theory and a perspective on teacher quality, this study proposes and examines a strength-based approach to teacher professional development. A mixed method pre-test/post-test design was adopted to study perceived outcomes of the approach for 93 teachers of six primary schools in the Netherlands and…

  10. A strength-based approach to teacher professional development

    NARCIS (Netherlands)

    Zwart, Rosanne C.; Korthagen, Fred A J; Attema-Noordewier, Saskia

    2014-01-01

    Based on positive psychology, self-determination theory and a perspective on teacher quality, this study proposes and examines a strength-based approach to teacher professional development. A mixed method pre-test/post-test design was adopted to study perceived outcomes of the approach for 93 teache

  11. A strength-based approach to teacher professional development

    NARCIS (Netherlands)

    Zwart, Rosanne; Korthagen, Fred A J; Attema-Noordewier, Saskia

    2015-01-01

    Based on positive psychology, self-determination theory and a perspective on teacher quality, this study proposes and examines a strength-based approach to teacher professional development. A mixed method pre-test/post-test design was adopted to study perceived outcomes of the approach for 93 teache

  12. A strength-based approach to teacher professional development

    NARCIS (Netherlands)

    Zwart, Rosanne C.; Korthagen, Fred A J; Attema-Noordewier, Saskia

    2014-01-01

    Based on positive psychology, self-determination theory and a perspective on teacher quality, this study proposes and examines a strength-based approach to teacher professional development. A mixed method pre-test/post-test design was adopted to study perceived outcomes of the approach for 93 teache

  13. A Task-Based Approach to Materials Development

    Science.gov (United States)

    Nunan, David

    2010-01-01

    The purpose of this chapter is to present a task-based approach to materials development. In the first part of the chapter, I sketch out the evolution of task based language teaching, drawing on a distinction between synthetic and analytical approaches to syllabus design first articulated by Wilkins (1976).

  14. A Task-based Approach to Materials Development

    OpenAIRE

    2010-01-01

    The purpose of this chapter is to present a task-based approach to materials development. In the first part of the chapter, I sketch out the evolution of task based language teaching, drawing on a distinction between synthetic and analytical approaches to syllabus design first articulated by Wilkins (1976).

  15. A Task-based Approach to Materials Development

    Directory of Open Access Journals (Sweden)

    David Nunan

    2010-07-01

    Full Text Available The purpose of this chapter is to present a task-based approach to materials development. In the first part of the chapter, I sketch out the evolution of task based language teaching, drawing on a distinction between synthetic and analytical approaches to syllabus design first articulated by Wilkins (1976.

  16. Knowledge-Based Approaches: Two cases of applicability

    DEFF Research Database (Denmark)

    Andersen, Tom

    1997-01-01

    Basic issues of the term: A knowledge-based approach (KBA) are discussed. Two cases of applicable to KBA are presented, and its concluded that KBA is more than just IT.......Basic issues of the term: A knowledge-based approach (KBA) are discussed. Two cases of applicable to KBA are presented, and its concluded that KBA is more than just IT....

  17. EFL Reading Instruction: Communicative Task-Based Approach

    Science.gov (United States)

    Sidek, Harison Mohd

    2012-01-01

    The purpose of this study was to examine the overarching framework of EFL (English as a Foreign Language) reading instructional approach reflected in an EFL secondary school curriculum in Malaysia. Based on such analysis, a comparison was made if Communicative Task-Based Language is the overarching instructional approach for the Malaysian EFL…

  18. A strength-based approach to teacher professional development

    NARCIS (Netherlands)

    Zwart, Rosanne|info:eu-repo/dai/nl/298981823; Korthagen, Fred A J|info:eu-repo/dai/nl/06936432X; Attema-Noordewier, Saskia

    2015-01-01

    Based on positive psychology, self-determination theory and a perspective on teacher quality, this study proposes and examines a strength-based approach to teacher professional development. A mixed method pre-test/post-test design was adopted to study perceived outcomes of the approach for 93 teache

  19. Morphological Pattern Based Approach for Trademark Retrieval

    Directory of Open Access Journals (Sweden)

    Ranjeet Kumar

    2011-01-01

    Full Text Available In the current scenario of the economic developments in the world market and growth in the international trade practices, Trademark registration is becoming a critical issue. The number of company and brand is increasing day by day and they all demand a trademark registration for same trade both in the home country as well as in foreign markets. In this paper we propose an invariant approach to break the character and shape of the trademark (logo or design to capture the shape and related attributes therein to build an efficient trademark retrieval tool. We create the input image in a negative image format for ignoring the background and objects reverse intensities values. The paper illustrates the morphological opening approach for removing the very small objects which can be acting as a noise. The paper also proposes how the extracted images from the trademark database will be matched further for similar input trademarks on the basis of trademark retrieval process from the database.

  20. Construction of the first compendium of chemical-genetic profiles in the fission yeast Schizosaccharomyces pombe and comparative compendium approach

    Energy Technology Data Exchange (ETDEWEB)

    Han, Sangjo [Bioinformatics Lab, Healthcare Group, SK Telecom, 9-1, Sunae-dong, Pundang-gu, Sungnam-si, Kyunggi-do 463-784 (Korea, Republic of); Lee, Minho [Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701 (Korea, Republic of); Chang, Hyeshik [Department of Biological Science, Seoul National University, 599 Gwanakro, Gwanak-gu, Seoul 151-747 (Korea, Republic of); Nam, Miyoung [Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764 (Korea, Republic of); Park, Han-Oh [Bioneer Corp., 8-11 Munpyeongseo-ro, Daedeok-gu, Daejeon 306-220 (Korea, Republic of); Kwak, Youn-Sig [Department of Applied Biology, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam 660-701 (Korea, Republic of); Ha, Hye-jeong [Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-Gu, Daejeon 305-806 (Korea, Republic of); Kim, Dongsup [Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon 305-701 (Korea, Republic of); Hwang, Sung-Ook [Department of Obstetrics and Gynecology, Inha University Hospital, 7-206 Sinheung-dong, Jung-gu, Incheon 400-711 (Korea, Republic of); Hoe, Kwang-Lae [Department of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 305-764 (Korea, Republic of); Kim, Dong-Uk [Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-Gu, Daejeon 305-806 (Korea, Republic of)

    2013-07-12

    Highlights: •The first compendium of chemical-genetic profiles form fission yeast was generated. •The first HTS of drug mode-of-action in fission yeast was performed. •The first comparative chemical genetic analysis between two yeasts was conducted. -- Abstract: Genome-wide chemical genetic profiles in Saccharomyces cerevisiae since the budding yeast deletion library construction have been successfully used to reveal unknown mode-of-actions of drugs. Here, we introduce comparative approach to infer drug target proteins more accurately using two compendiums of chemical-genetic profiles from the budding yeast S. cerevisiae and the fission yeast Schizosaccharomyces pombe. For the first time, we established DNA-chip based growth defect measurement of genome-wide deletion strains of S. pombe, and then applied 47 drugs to the pooled heterozygous deletion strains to generate chemical-genetic profiles in S. pombe. In our approach, putative drug targets were inferred from strains hypersensitive to given drugs by analyzing S. pombe and S. cerevisiae compendiums. Notably, many evidences in the literature revealed that the inferred target genes of fungicide and bactericide identified by such comparative approach are in fact the direct targets. Furthermore, by filtering out the genes with no essentiality, the multi-drug sensitivity genes, and the genes with less eukaryotic conservation, we created a set of drug target gene candidates that are expected to be directly affected by a given drug in human cells. Our study demonstrated that it is highly beneficial to construct the multiple compendiums of chemical genetic profiles using many different species. The fission yeast chemical-genetic compendium is available at (http://pombe.kaist.ac.kr/compendium)

  1. Supplier selection an MCDA-based approach

    CERN Document Server

    Mukherjee, Krishnendu

    2017-01-01

    The purpose of this book is to present a comprehensive review of the latest research and development trends at the international level for modeling and optimization of the supplier selection process for different industrial sectors. It is targeted to serve two audiences: the MBA and PhD student interested in procurement, and the practitioner who wishes to gain a deeper understanding of procurement analysis with multi-criteria based decision tools to avoid upstream risks to get better supply chain visibility. The book is expected to serve as a ready reference for supplier selection criteria and various multi-criteria based supplier’s evaluation methods for forward, reverse and mass customized supply chain. This book encompasses several criteria, methods for supplier selection in a systematic way based on extensive literature review from 1998 to 2012. It provides several case studies and some useful links which can serve as a starting point for interested researchers. In the appendix several computer code wri...

  2. Web Based ‘C’ IDE: Approach

    Directory of Open Access Journals (Sweden)

    Sravanthi Emani

    2012-03-01

    Full Text Available A Web based environment has been designed to execute C programs without explicitly installing any compilers on the machine, thus addressing the concerns of portability and accessibility. Theenvironment runs on a Linux server, uses password authentication and provides each user with separate project directories to store all his programs. These can be accessed and modified by the respective useronly. The entered code can be compiled and executed easily without using licensed software for the same. This saves installation time as well as memory of the client machine. The configuration of the machineneed not be an issue as the system is web based and thus platform independent.

  3. Evolutionary algorithm based configuration interaction approach

    CERN Document Server

    Chakraborty, Rahul

    2016-01-01

    A stochastic configuration interaction method based on evolutionary algorithm is designed as an affordable approximation to full configuration interaction (FCI). The algorithm comprises of initiation, propagation and termination steps, where the propagation step is performed with cloning, mutation and cross-over, taking inspiration from genetic algorithm. We have tested its accuracy in 1D Hubbard problem and a molecular system (symmetric bond breaking of water molecule). We have tested two different fitness functions based on energy of the determinants and the CI coefficients of determinants. We find that the absolute value of CI coefficients is a more suitable fitness function when combined with a fixed selection scheme.

  4. A New Text Location Approach Based Wavelet

    Institute of Scientific and Technical Information of China (English)

    Weihua Li; Zhen Fang; Shuozhong Wang

    2002-01-01

    With the advancement of content-based retrieval technology, the importance of semantics for text information contained in images attracts many researchers. An algorithm which will automatically locate the textual regions in the input image will facilitate the retrieving task, and the optical character recognizer can then be applied to only those regions of the image which contain text. In this paper a new text location method based wavelet is described, which can be used to locate textual regions from complex image and video frame. Experimental results show that the textual regions in image can be located effectively and quickly.

  5. Face Recognition Based on Nonlinear Feature Approach

    Directory of Open Access Journals (Sweden)

    Eimad E.A. Abusham

    2008-01-01

    Full Text Available Feature extraction techniques are widely used to reduce the complexity high dimensional data. Nonlinear feature extraction via Locally Linear Embedding (LLE has attracted much attention due to their high performance. In this paper, we proposed a novel approach for face recognition to address the challenging task of recognition using integration of nonlinear dimensional reduction Locally Linear Embedding integrated with Local Fisher Discriminant Analysis (LFDA to improve the discriminating power of the extracted features by maximize between-class while within-class local structure is preserved. Extensive experimentation performed on the CMU-PIE database indicates that the proposed methodology outperforms Benchmark methods such as Principal Component Analysis (PCA, Fisher Discrimination Analysis (FDA. The results showed that 95% of recognition rate could be obtained using our proposed method.

  6. A model-based multisensor data fusion knowledge management approach

    Science.gov (United States)

    Straub, Jeremy

    2014-06-01

    A variety of approaches exist for combining data from multiple sensors. The model-based approach combines data based on its support for or refutation of elements of the model which in turn can be used to evaluate an experimental thesis. This paper presents a collection of algorithms for mapping various types of sensor data onto a thesis-based model and evaluating the truth or falsity of the thesis, based on the model. The use of this approach for autonomously arriving at findings and for prioritizing data are considered. Techniques for updating the model (instead of arriving at a true/false assertion) are also discussed.

  7. Case-based approaches for knowledge application and organisational learning

    DEFF Research Database (Denmark)

    Wang, Chengbo; Johansen, John; Luxhøj, James T.

    2005-01-01

    . These practices and activity patterns are based on learning and applying the knowledge internal and external to an organisation. To ensure their smooth formulation process, there are two important techniques designed – an expert adaptation approach and an expert evaluation approach. These two approaches provide...... structured processes to execute the organisational learning and knowledge application, which intend to guide the practitioners during the process of manufacturing competence development and improvement. They are based on Case-Based Reasoning (CBR) methodology and rely on cases as the primary knowledge supply....... This paper aims to present the two approaches; introduce two types of tests on these approaches to verify their functionality: role-play testing and real world application testing; and summarises the applicability of the two approaches....

  8. Algebraic Verification Method for SEREs Properties via Groebner Bases Approaches

    Directory of Open Access Journals (Sweden)

    Ning Zhou

    2013-01-01

    Full Text Available This work presents an efficient solution using computer algebra system to perform linear temporal properties verification for synchronous digital systems. The method is essentially based on both Groebner bases approaches and symbolic simulation. A mechanism for constructing canonical polynomial set based symbolic representations for both circuit descriptions and assertions is studied. We then present a complete checking algorithm framework based on these algebraic representations by using Groebner bases. The computational experience result in this work shows that the algebraic approach is a quite competitive checking method and will be a useful supplement to the existent verification methods based on simulation.

  9. SLAM - Based Approach to Dynamic Ship Positioning

    Directory of Open Access Journals (Sweden)

    Krzysztof Wrobel

    2014-03-01

    Full Text Available Dynamically positioned vessels, used by offshore industry, use not only satellite navigation but also different positioning systems, often referred to as reference' systems. Most of them use multiple technical devices located outside the vessel which creates some problems with their accessibility and performance. In this paper, a basic concept of reference system independent from any external device is presented, basing on hydroacoustics and Simultaneous Localization and Mapping (SLAM method. Theoretical analysis of its operability is also performed.

  10. A Monocular Vision Based Approach to Flocking

    Science.gov (United States)

    2006-03-01

    The bird represented with the green triangle desires to move away from its neighbors to avoid overcrowding . The bird reacts the most strongly to the... brightness gradients [35], neural networks [18, 19], and other vision-based methods [6, 26, 33]. For the purposes of this thesis effort, it is assumed that...Once started, however, maneuver waves spread through the flock at a mean speed of less than 15 milliseconds [43]. 2.5.3 Too Perfect. In nature, a bird

  11. Media approach to gender-based violence

    Directory of Open Access Journals (Sweden)

    Mršević Zorica

    2012-01-01

    Full Text Available The author grounds her research and the latter analysis on continually conducted daily press-clipping of seven main printed daily newspapers and two main electronic media in Serbia, within the three years period (2009 - 2011. An analysis of media reports on gender based violence, with particular focus on the most frequent domestic violence cases within the two years period, 2010 to 2011 is presented. As the best of media reports on gender based violence, the author stressed out its „whistle blower“ role - media are the main source of information on cases, dimensions and forms of gender based violence. Also the worse moments of media reporting in the mentioned period are presented - when the violence was justified or when reality is deformed by presenting these cases as romantic love stories. For example, in 2010 the worst was reporting on the „Pajčin/Kapisoda“ case, while in 2011 it was the „Ponjiger“ case. In the end, the author also warned on the worrysome fact of sudden dissapearance of media reports on partners’ murdering their wives after the last such report published in mid-october 2011, which could mean that now we have a new problem of diminished freedom of media.

  12. Nanotechnology-Based Approach in Tuberculosis Treatment

    Science.gov (United States)

    Neyaz, Md. Kausar; Das, Shilpi

    2017-01-01

    Tuberculosis, commonly known as TB, is the second most fatal infectious disease after AIDS, caused by bacterium called Mycobacterium tuberculosis. Prolonged treatment, high pill burden, low compliance, and stiff administration schedules are factors that are responsible for emergence of MDR and XDR cases of tuberculosis. Till date, only BCG vaccine is available which is ineffective against adult pulmonary TB, which is the most common form of disease. Various unique antibodies have been developed to overcome drug resistance, reduce the treatment regimen, and elevate the compliance to treatment. Therefore, we need an effective and robust system to subdue technological drawbacks and improve the effectiveness of therapeutic drugs which still remains a major challenge for pharmaceutical technology. Nanoparticle-based ideology has shown convincing treatment and promising outcomes for chronic infectious diseases. Different types of nanocarriers have been evaluated as promising drug delivery systems for various administration routes. Controlled and sustained release of drugs is one of the advantages of nanoparticle-based antituberculosis drugs over free drug. It also reduces the dosage frequency and resolves the difficulty of low poor compliance. This paper reviews various nanotechnology-based therapies which can be used for the treatment of TB. PMID:28210505

  13. One Piece Orbitozygomatic Approach Based on the Sphenoid Ridge Keyhole

    DEFF Research Database (Denmark)

    Spiriev, Toma; Poulsgaard, Lars; Fugleholm, Kaare

    2016-01-01

    The one-piece orbitozygomatic (OZ) approach is traditionally based on the McCarty keyhole. Here, we present the use of the sphenoid ridge keyhole and its possible advantages as a keyhole for the one-piece OZ approach. Using transillumination technique the osteology of the sphenoid ridge was exami......The one-piece orbitozygomatic (OZ) approach is traditionally based on the McCarty keyhole. Here, we present the use of the sphenoid ridge keyhole and its possible advantages as a keyhole for the one-piece OZ approach. Using transillumination technique the osteology of the sphenoid ridge...

  14. Model-based experimental design for assessing effects of mixtures of chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Baas, Jan, E-mail: jan.baas@falw.vu.n [Vrije Universiteit of Amsterdam, Dept of Theoretical Biology, De Boelelaan 1085, 1081 HV Amsterdam (Netherlands); Stefanowicz, Anna M., E-mail: anna.stefanowicz@uj.edu.p [Institute of Environmental Sciences, Jagiellonian University, Gronostajowa 7, 30-387 Krakow (Poland); Klimek, Beata, E-mail: beata.klimek@uj.edu.p [Institute of Environmental Sciences, Jagiellonian University, Gronostajowa 7, 30-387 Krakow (Poland); Laskowski, Ryszard, E-mail: ryszard.laskowski@uj.edu.p [Institute of Environmental Sciences, Jagiellonian University, Gronostajowa 7, 30-387 Krakow (Poland); Kooijman, Sebastiaan A.L.M., E-mail: bas@bio.vu.n [Vrije Universiteit of Amsterdam, Dept of Theoretical Biology, De Boelelaan 1085, 1081 HV Amsterdam (Netherlands)

    2010-01-15

    We exposed flour beetles (Tribolium castaneum) to a mixture of four poly aromatic hydrocarbons (PAHs). The experimental setup was chosen such that the emphasis was on assessing partial effects. We interpreted the effects of the mixture by a process-based model, with a threshold concentration for effects on survival. The behavior of the threshold concentration was one of the key features of this research. We showed that the threshold concentration is shared by toxicants with the same mode of action, which gives a mechanistic explanation for the observation that toxic effects in mixtures may occur in concentration ranges where the individual components do not show effects. Our approach gives reliable predictions of partial effects on survival and allows for a reduction of experimental effort in assessing effects of mixtures, extrapolations to other mixtures, other points in time, or in a wider perspective to other organisms. - We show a mechanistic approach to assess effects of mixtures in low concentrations.

  15. A New Text Location Approach Based Wavelet

    Institute of Scientific and Technical Information of China (English)

    Weihua Li; Zhen Fang; Shuozhong Wang

    2002-01-01

    With the advancement of content-based retrieval technology, the importance of semantics for text information contained in images attracts many researchers. An algorithm which will automatically locate the textual regions in the input image will facilitate the retrieving task, and the optical character recognizer can then be applied to only those regions of the image which contain text. In this paper a new text location method is described, which can be used to locate textual regions from complex image and video frame. Experimental results show that the textual regions in image can be located effectively and quickly.

  16. Workflow-based approaches to neuroimaging analysis.

    Science.gov (United States)

    Fissell, Kate

    2007-01-01

    Analysis of functional and structural magnetic resonance imaging (MRI) brain images requires a complex sequence of data processing steps to proceed from raw image data to the final statistical tests. Neuroimaging researchers have begun to apply workflow-based computing techniques to automate data analysis tasks. This chapter discusses eight major components of workflow management systems (WFMSs): the workflow description language, editor, task modules, data access, verification, client, engine, and provenance, and their implementation in the Fiswidgets neuroimaging workflow system. Neuroinformatics challenges involved in applying workflow techniques in the domain of neuroimaging are discussed.

  17. Ethics education for health professionals: a values based approach.

    Science.gov (United States)

    Godbold, Rosemary; Lees, Amanda

    2013-11-01

    It is now widely accepted that ethics is an essential part of educating health professionals. Despite a clear mandate to educators, there are differing approaches, in particular, how and where ethics is positioned in training programmes, underpinning philosophies and optimal modes of assessment. This paper explores varying practices and argues for a values based approach to ethics education. It then explores the possibility of using a web-based technology, the Values Exchange, to facilitate a values based approach. It uses the findings of a small scale study to signal the potential of the Values Exchange for engaging, meaningful and applied ethics education.

  18. Ameliorated GA approach for base station planning

    Science.gov (United States)

    Wang, Andong; Sun, Hongyue; Wu, Xiaomin

    2011-10-01

    In this paper, we aim at locating base station (BS) rationally to satisfy the most customs by using the least BSs. An ameliorated GA is proposed to search for the optimum solution. In the algorithm, we mesh the area to be planned according to least overlap length derived from coverage radius, bring into isometric grid encoding method to represent BS distribution as well as its number and develop select, crossover and mutation operators to serve our unique necessity. We also construct our comprehensive object function after synthesizing coverage ratio, overlap ratio, population and geographical conditions. Finally, after importing an electronic map of the area to be planned, a recommended strategy draft would be exported correspondingly. We eventually import HongKong, China to simulate and yield a satisfactory solution.

  19. An Event Based Approach To Situational Representation

    CERN Document Server

    Ashish, Naveen; Mehrotra, Sharad; Venkatasubramanian, Nalini

    2009-01-01

    Many application domains require representing interrelated real-world activities and/or evolving physical phenomena. In the crisis response domain, for instance, one may be interested in representing the state of the unfolding crisis (e.g., forest fire), the progress of the response activities such as evacuation and traffic control, and the state of the crisis site(s). Such a situation representation can then be used to support a multitude of applications including situation monitoring, analysis, and planning. In this paper, we make a case for an event based representation of situations where events are defined to be domain-specific significant occurrences in space and time. We argue that events offer a unifying and powerful abstraction to building situational awareness applications. We identify challenges in building an Event Management System (EMS) for which traditional data and knowledge management systems prove to be limited and suggest possible directions and technologies to address the challenges.

  20. Dictionary based Approach to Edge Detection

    CERN Document Server

    Chandra, Nitish

    2015-01-01

    Edge detection is a very essential part of image processing, as quality and accuracy of detection determines the success of further processing. We have developed a new self learning technique for edge detection using dictionary comprised of eigenfilters constructed using features of the input image. The dictionary based method eliminates the need of pre or post processing of the image and accounts for noise, blurriness, class of image and variation of illumination during the detection process itself. Since, this method depends on the characteristics of the image, the new technique can detect edges more accurately and capture greater detail than existing algorithms such as Sobel, Prewitt Laplacian of Gaussian, Canny method etc which use generic filters and operators. We have demonstrated its application on various classes of images such as text, face, barcodes, traffic and cell images. An application of this technique to cell counting in a microscopic image is also presented.

  1. Similarity-Based Approaches to Natural Language Processing

    CERN Document Server

    Lee, L

    1997-01-01

    This thesis presents two similarity-based approaches to sparse data problems. The first approach is to build soft, hierarchical clusters: soft, because each event belongs to each cluster with some probability; hierarchical, because cluster centroids are iteratively split to model finer distinctions. Our second approach is a nearest-neighbor approach: instead of calculating a centroid for each class, as in the hierarchical clustering approach, we in essence build a cluster around each word. We compare several such nearest-neighbor approaches on a word sense disambiguation task and find that as a whole, their performance is far superior to that of standard methods. In another set of experiments, we show that using estimation techniques based on the nearest-neighbor model enables us to achieve perplexity reductions of more than 20 percent over standard techniques in the prediction of low-frequency events, and statistically significant speech recognition error-rate reduction.

  2. [Management of large marine ecosystem based on ecosystem approach].

    Science.gov (United States)

    Chu, Jian-song

    2011-09-01

    Large marine ecosystem (LME) is a large area of ocean characterized by distinct oceanology and ecology. Its natural characteristics require management based on ecosystem approach. A series of international treaties and regulations definitely or indirectly support that it should adopt ecosystem approach to manage LME to achieve the sustainable utilization of marine resources. In practices, some countries such as Canada, Australia, and U.S.A. have adopted ecosystem-based approach to manage their oceans, and some international organizations such as global environment fund committee have carried out a number of LME programs based on ecosystem approach. Aiming at the sustainable development of their fisheries, the regional organizations such as Caribbean Community have established regional fisheries mechanism. However, the adoption of ecosystem approach to manage LME is not only a scientific and legal issue, but also a political matter largely depending on the political will and the mutual cooperation degree of related countries.

  3. Information theory based approaches to cellular signaling.

    Science.gov (United States)

    Waltermann, Christian; Klipp, Edda

    2011-10-01

    Cells interact with their environment and they have to react adequately to internal and external changes such changes in nutrient composition, physical properties like temperature or osmolarity and other stresses. More specifically, they must be able to evaluate whether the external change is significant or just in the range of noise. Based on multiple external parameters they have to compute an optimal response. Cellular signaling pathways are considered as the major means of information perception and transmission in cells. Here, we review different attempts to quantify information processing on the level of individual cells. We refer to Shannon entropy, mutual information, and informal measures of signaling pathway cross-talk and specificity. Information theory in systems biology has been successfully applied to identification of optimal pathway structures, mutual information and entropy as system response in sensitivity analysis, and quantification of input and output information. While the study of information transmission within the framework of information theory in technical systems is an advanced field with high impact in engineering and telecommunication, its application to biological objects and processes is still restricted to specific fields such as neuroscience, structural and molecular biology. However, in systems biology dealing with a holistic understanding of biochemical systems and cellular signaling only recently a number of examples for the application of information theory have emerged. This article is part of a Special Issue entitled Systems Biology of Microorganisms. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Enuresis in children: a case based approach.

    Science.gov (United States)

    Baird, Drew C; Seehusen, Dean A; Bode, David V

    2014-10-15

    Enuresis is defined as intermittent urinary incontinence during sleep in a child at least five years of age. Approximately 5% to 10% of all seven-year-olds have enuresis, and an estimated 5 to 7 million children in the United States have enuresis. The pathophysiology of primary nocturnal enuresis involves the inability to awaken from sleep in response to a full bladder, coupled with excessive nighttime urine production or a decreased functional capacity of the bladder. Initial evaluation should include a history, physical examination, and urinalysis. Several conditions, such as constipation, obstructive sleep apnea, diabetes mellitus, diabetes insipidus, chronic kidney disease, and psychiatric disorders, are associated with enuresis. If identified, these conditions should be evaluated and treated. Treatment of primary monosymptomatic enuresis (i.e., the only symptom is nocturnal bed-wetting in a child who has never been dry) begins with counseling the child and parents on effective behavioral modifications. First-line treatments for enuresis include bed alarm therapy and desmopressin. The choice of therapy is based on the child's age and nighttime voiding patterns, and the desires of the child and family. Referral to a pediatric urologist is indicated for children with primary enuresis refractory to standard and combination therapies, and for children with some secondary causes of enuresis, including urinary tract malformations, recurrent urinary tract infections, or neurologic disorders.

  5. Cognitive neuroscience of creativity: EEG based approaches.

    Science.gov (United States)

    Srinivasan, Narayanan

    2007-05-01

    Cognitive neuroscience of creativity has been extensively studied using non-invasive electrical recordings from the scalp called electroencephalograms (EEGs) and event related potentials (ERPs). The paper discusses major aspects of performing research using EEG/ERP based experiments including the recording of the signals, removing noise, estimating ERP signals, and signal analysis for better understanding of the neural correlates of processes involved in creativity. Important factors to be kept in mind to record clean EEG signal in creativity research are discussed. The recorded EEG signal can be corrupted by various sources of noise and methodologies to handle the presence of unwanted artifacts and filtering noise are presented followed by methods to estimate ERPs from the EEG signals from multiple trials. The EEG and ERP signals are further analyzed using various techniques including spectral analysis, coherence analysis, and non-linear signal analysis. These analysis techniques provide a way to understand the spatial activations and temporal development of large scale electrical activity in the brain during creative tasks. The use of this methodology will further enhance our understanding the processes neural and cognitive processes involved in creativity.

  6. Content-based, Task-based, and Participatory Approaches (I)

    Institute of Scientific and Technical Information of China (English)

    Diane Larsen-Freeman

    2012-01-01

    1. Introduction In this chapter we will be investigating three more approaches that make communication central: content-based instruction, task-based instruction, and the participatory approach. The approaches we examine in this chapter do not begin with functions, or approaches we examine in this chapter don't begin with functions, or indeed, any other language items. Instead, they give priority to process over predetermined linguistic content. In these approaches rather than "learning to use English",

  7. Poverty reduction Approaches in Kenya: Assessing the Usefulness of the Right Based Approach in Kenya

    Directory of Open Access Journals (Sweden)

    Wambua Leonard Munyao, Ph.D

    2013-06-01

    Full Text Available While billions of dollars have been spent in development projects in least developed countries, poverty continues to increase. This study proposes human-rights based approach to poverty eradication. To this end, the study seeks to assess the key determinants of use of rights- based approaches to poverty reduction and it’s usefulness in Kenya with special reference to NGOs in Kibera. The study further high lights some of the basic skills of implementing the rights based approach to poverty reduction. The attempts to establish the proportion of NGOs applying rights based approach to poverty reduction in Kibera Division as well. The review of relevant literature has been undertaken and a field study done. The study is informed by a qualitative human rights framework.

  8. Simulation-Based Constructivist Approach for Education Leaders

    Science.gov (United States)

    Shapira-Lishchinsky, Orly

    2015-01-01

    The purpose of this study was to reflect the leadership strategies that may arise using a constructivist approach based on organizational learning. This approach involved the use of simulations that focused on ethical tensions in school principals' daily experiences, and the development of codes of ethical conduct to reduce these tensions. The…

  9. A Semantics-Based Approach to Retrieving Biomedical Information

    DEFF Research Database (Denmark)

    Andreasen, Troels; Bulskov, Henrik; Zambach, Sine

    2011-01-01

    This paper describes an approach to representing, organising, and accessing conceptual content of biomedical texts using a formal ontology. The ontology is based on UMLS resources supplemented with domain ontologies developed in the project. The approach introduces the notion of ‘generative...

  10. Emotion Detection on Twitter Data using Knowledge Base Approach

    National Research Council Canada - National Science Library

    Srinivasu Badugu; Matla Suhasini

    2017-01-01

    ... will help us better to interpret millions of individuals. This paper describes a Rule Based approach, which detects the emotion or mood of the tweet and classifies the twitter message under appropriate emotional category...

  11. A New Detection Approach Based on the Maximum Entropy Model

    Institute of Scientific and Technical Information of China (English)

    DONG Xiaomei; XIANG Guang; YU Ge; LI Xiaohua

    2006-01-01

    The maximum entropy model was introduced and a new intrusion detection approach based on the maximum entropy model was proposed. The vector space model was adopted for data presentation. The minimal entropy partitioning method was utilized for attribute discretization. Experiments on the KDD CUP 1999 standard data set were designed and the experimental results were shown. The receiver operating characteristic(ROC) curve analysis approach was utilized to analyze the experimental results. The analysis results show that the proposed approach is comparable to those based on support vector machine(SVM) and outperforms those based on C4.5 and Naive Bayes classifiers. According to the overall evaluation result, the proposed approach is a little better than those based on SVM.

  12. Stochastic learning and optimization a sensitivity-based approach

    CERN Document Server

    Cao, Xi-Ren

    2007-01-01

    Performance optimization is vital in the design and operation of modern engineering systems. This book provides a unified framework based on a sensitivity point of view. It introduces new approaches and proposes new research topics.

  13. Pattern-based approach for logical traffic isolation forensic modelling

    CSIR Research Space (South Africa)

    Dlamini, I

    2009-08-01

    Full Text Available The use of design patterns usually changes the approach of software design and makes software development relatively easy. This paper extends work on a forensic model for Logical Traffic Isolation (LTI) based on Differentiated Services (Diff...

  14. An improved Hough transform-based fingerprint alignment approach

    CSIR Research Space (South Africa)

    Mlambo, CS

    2014-11-01

    Full Text Available An improved Hough Transform based fingerprint alignment approach is presented, which improves computing time and memory usage with accurate alignment parameter (rotation and translation) results. This is achieved by studying the strengths...

  15. Model Construct Based Enterprise Model Architecture and Its Modeling Approach

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    In order to support enterprise integration, a kind of model construct based enterprise model architecture and its modeling approach are studied in this paper. First, the structural makeup and internal relationships of enterprise model architecture are discussed. Then, the concept of reusable model construct (MC) which belongs to the control view and can help to derive other views is proposed. The modeling approach based on model construct consists of three steps, reference model architecture synthesis, enterprise model customization, system design and implementation. According to MC based modeling approach a case study with the background of one-kind-product machinery manufacturing enterprises is illustrated. It is shown that proposal model construct based enterprise model architecture and modeling approach are practical and efficient.

  16. Evaluating a Focus-Based Approach to Anaphora Resolution

    CERN Document Server

    Azzam, S; Gaizauskas, R J; Azzam, Saliha; Humphreys, Kevin; Gaizauskas, Robert

    1998-01-01

    We present an approach to anaphora resolution based on a focusing algorithm, and implemented within an existing MUC (Message Understanding Conference) Information Extraction system, allowing quantitative evaluation against a substantial corpus of annotated real-world texts. Extensions to the basic focusing mechanism can be easily tested, resulting in refinements to the mechanism and resolution rules. Results are compared with the results of a simpler heuristic-based approach.

  17. An ecosystem-based fisheries assessment and forecasting approach

    OpenAIRE

    Zhang, Chang Ik

    2009-01-01

    A comprehensive ecosystem-based approach is required to holistically assess, forecast and manage fisheries resources and their associated habitats by considering ecological interactions of target species with predators, competitors, and prey species, interactions between fishes and their habitats, and the effects of fishing on these processes. A pragmatic ecosystem-based approach was developed for the assessment of fisheries resources involving three management objectives: sustainability, bio...

  18. A Cell-Based Approach to Early Pancreatic Cancer Detection

    Science.gov (United States)

    2016-10-01

    Award Number: W81XWH-15-1-0457 TITLE: A Cell-Based Approach to Early Pancreatic Cancer Detection PRINCIPAL INVESTIGATOR: Dr. Ben Stanger...SUBTITLE 5a. CONTRACT NUMBER A Cell-Based Approach to Early Pancreatic Cancer Detection 5b. GRANT NUMBER W81XWH-15-1-0457 5c. PROGRAM ELEMENT NUMBER 6...pancreatic cancer patients. 15. SUBJECT TERMS Pancreatic cancer , metastasis, circulating tumor cells 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION

  19. A Programmable Approach to Maintenance of a Finite Knowledge Base

    Institute of Scientific and Technical Information of China (English)

    LUAN ShangMin(栾尚敏); DAI GuoZhong(戴国忠); LI Wei(李未)

    2003-01-01

    In this paper, we present a programmable method of revising a finite clause set. We first present a procedure whose formal parameters are a consistent clause set Γ and a clause A and whose output is a set of minimal subsets of Γ which are inconsistent with A. The maximal consistent subsets can be generated from all minimal inconsistent subsets. We develop a prototype system based on the above procedure, and discuss the implementation of knowledge base maintenance. At last, we compare the approach presented in this paper with other related approaches. The main characteristic of the approach is that it can be implemented by a computer program.

  20. Content-based, Task-based, and Participatory Approaches (II)

    Institute of Scientific and Technical Information of China (English)

    Diane Larsen-Freeman

    2012-01-01

    4. Participatory Approach Although it originated in the early sixties with the work of Paulo Freire, and therefore antedates modern versions of content-based and task-based approaches, it was not until the 1980s that the participatory approach started being widely discussed in the language teaching literature.

  1. Integrating Ontological Data Sources Using Viewpoints-Based Approach

    Directory of Open Access Journals (Sweden)

    Bouchra Boulkroun

    2016-12-01

    Full Text Available Within the development of Internet and intranets, information integration from various data sources becomes increasingly important and more challenging issue. Recently, the trend in data integration has favored the semantic integration using ontologies. However, the existing ontology-based approaches do not support the aspect of data multi-representations, which is important in the development of multi-user applications. The motivation of this paper is to address a novel semantic integration approach based on ontologies and viewpoints paradigms. This contribution combines the advantages of existing ontology-based integration approaches while avoiding their drawbacks. The proposed integration approach is evaluated using query processing. Profiles are introduced to offer answers to users according to their viewpoints and choices.

  2. Local fractal dimension based approaches for colonic polyp classification.

    Science.gov (United States)

    Häfner, Michael; Tamaki, Toru; Tanaka, Shinji; Uhl, Andreas; Wimmer, Georg; Yoshida, Shigeto

    2015-12-01

    This work introduces texture analysis methods that are based on computing the local fractal dimension (LFD; or also called the local density function) and applies them for colonic polyp classification. The methods are tested on 8 HD-endoscopic image databases, where each database is acquired using different imaging modalities (Pentax's i-Scan technology combined with or without staining the mucosa) and on a zoom-endoscopic image database using narrow band imaging. In this paper, we present three novel extensions to a LFD based approach. These extensions additionally extract shape and/or gradient information of the image to enhance the discriminativity of the original approach. To compare the results of the LFD based approaches with the results of other approaches, five state of the art approaches for colonic polyp classification are applied to the employed databases. Experiments show that LFD based approaches are well suited for colonic polyp classification, especially the three proposed extensions. The three proposed extensions are the best performing methods or at least among the best performing methods for each of the employed databases. The methods are additionally tested by means of a public texture image database, the UIUCtex database. With this database, the viewpoint invariance of the methods is assessed, an important features for the employed endoscopic image databases. Results imply that most of the LFD based methods are more viewpoint invariant than the other methods. However, the shape, size and orientation adapted LFD approaches (which are especially designed to enhance the viewpoint invariance) are in general not more viewpoint invariant than the other LFD based approaches.

  3. A Comparison of Filter-based Approaches for Model-based Prognostics

    Data.gov (United States)

    National Aeronautics and Space Administration — Model-based prognostics approaches use domain knowledge about a system and its failure modes through the use of physics-based models. Model-based prognosis is...

  4. Knowledge-based biomedical word sense disambiguation: comparison of approaches

    Directory of Open Access Journals (Sweden)

    Aronson Alan R

    2010-11-01

    Full Text Available Abstract Background Word sense disambiguation (WSD algorithms attempt to select the proper sense of ambiguous terms in text. Resources like the UMLS provide a reference thesaurus to be used to annotate the biomedical literature. Statistical learning approaches have produced good results, but the size of the UMLS makes the production of training data infeasible to cover all the domain. Methods We present research on existing WSD approaches based on knowledge bases, which complement the studies performed on statistical learning. We compare four approaches which rely on the UMLS Metathesaurus as the source of knowledge. The first approach compares the overlap of the context of the ambiguous word to the candidate senses based on a representation built out of the definitions, synonyms and related terms. The second approach collects training data for each of the candidate senses to perform WSD based on queries built using monosemous synonyms and related terms. These queries are used to retrieve MEDLINE citations. Then, a machine learning approach is trained on this corpus. The third approach is a graph-based method which exploits the structure of the Metathesaurus network of relations to perform unsupervised WSD. This approach ranks nodes in the graph according to their relative structural importance. The last approach uses the semantic types assigned to the concepts in the Metathesaurus to perform WSD. The context of the ambiguous word and semantic types of the candidate concepts are mapped to Journal Descriptors. These mappings are compared to decide among the candidate concepts. Results are provided estimating accuracy of the different methods on the WSD test collection available from the NLM. Conclusions We have found that the last approach achieves better results compared to the other methods. The graph-based approach, using the structure of the Metathesaurus network to estimate the relevance of the Metathesaurus concepts, does not perform well

  5. A SEMINAR-DISCUSSION-BASED APPROACH TOWARD LINGUISTICS

    Institute of Scientific and Technical Information of China (English)

    郎勇

    2002-01-01

    In this article, based on the experience of many years of teaching Linguistics courses to undergraduates, postgraduates and in-service teacher trainees, we argue that taking a seminar-discussion-based approach is a better way to achieve students' full involvement and understanding.

  6. Assessing a New Approach to Class-Based Affirmative Action

    Science.gov (United States)

    Gaertner, Matthew N.

    2011-01-01

    In November, 2008, Colorado and Nebraska voted on amendments that sought to end race-based affirmative action at public universities. In anticipation of the vote, Colorado's flagship public institution--The University of Colorado at Boulder (CU)--explored statistical approaches to support class-based affirmative action. This paper details CU's…

  7. Integration of Task-Based Approaches in a TESOL Course

    Science.gov (United States)

    Chien, Chin-Wen

    2014-01-01

    Under task-based language teaching (TBLT), language learners engage in purposeful, problem-oriented, and outcome-driven tasks that are comparable to real-world activities. This qualitative case study discusses the integration of a task-based approach into a TESOL course in a language teacher education program in Taiwan with regard to 39…

  8. Component-Based Approach in Learning Management System Development

    Science.gov (United States)

    Zaitseva, Larisa; Bule, Jekaterina; Makarov, Sergey

    2013-01-01

    The paper describes component-based approach (CBA) for learning management system development. Learning object as components of e-learning courses and their metadata is considered. The architecture of learning management system based on CBA being developed in Riga Technical University, namely its architecture, elements and possibilities are…

  9. Implementing Project Based Learning Approach to Graphic Design Course

    Science.gov (United States)

    Riyanti, Menul Teguh; Erwin, Tuti Nuriah; Suriani, S. H.

    2017-01-01

    The purpose of this study was to develop a learning model based Commercial Graphic Design Drafting project-based learning approach, was chosen as a strategy in the learning product development research. University students as the target audience of this model are the students of the fifth semester Visual Communications Design Studies Program…

  10. System identification based approach to dynamic weighing revisited

    Science.gov (United States)

    Niedźwiecki, Maciej; Meller, Michał; Pietrzak, Przemysław

    2016-12-01

    Dynamic weighing, i.e., weighing of objects in motion, without stopping them on the weighing platform, allows one to increase the rate of operation of automatic weighing systems, used in industrial production processes, without compromising their accuracy. Since the classical identification-based approach to dynamic weighing, based on the second-order mass-spring-damper model of the weighing system, does not yield satisfactory results when applied to conveyor belt type checkweighers, several extensions of this technique are examined. Experiments confirm that when appropriately modified the identification-based approach becomes a reliable tool for dynamic mass measurement in checkweighers.

  11. A Brief Introduction of Task-based Approach

    Institute of Scientific and Technical Information of China (English)

    王丹

    2012-01-01

    The task-based language teaching approach is one of the syllabus models that have been proposed in the last twenty years or so. Task-based syllabus represent a particular realization of communicative language teaching. Task-based teaching/learning helps develop students’ communicative competence, enabling them to communicate effectively in real communicating world and engage in interaction. The most active element in the process of the task-based teaching is the learner’ creativity. By exploiting this kind of creativity, learning can be made significantly more efficient and more interesting. It is well-known that the task-based teaching/learning have a rich potential for promoting successful second language learning than the traditional teaching/learning. Task-based approach is reflected not only in China but also in some other countries, such as America, Canada, Singapore, Hong Kong and son on.

  12. Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian Influenza virus (H5N1, H7N7 and swine-origin H1N1 (S-OIV

    Directory of Open Access Journals (Sweden)

    Schoop Roland

    2009-11-01

    Full Text Available Abstract Background Influenza virus (IV infections are a major threat to human welfare and animal health worldwide. Anti-viral therapy includes vaccines and a few anti-viral drugs. However vaccines are not always available in time, as demonstrated by the emergence of the new 2009 H1N1-type pandemic strain of swine origin (S-OIV in April 2009, and the acquisition of resistance to neuraminidase inhibitors such as Tamiflu® (oseltamivir is a potential problem. Therefore the prospects for the control of IV by existing anti-viral drugs are limited. As an alternative approach to the common anti-virals we studied in more detail a commercial standardized extract of the widely used herb Echinacea purpurea (Echinaforce®, EF in order to elucidate the nature of its anti-IV activity. Results Human H1N1-type IV, highly pathogenic avian IV (HPAIV of the H5- and H7-types, as well as swine origin IV (S-OIV, H1N1, were all inactivated in cell culture assays by the EF preparation at concentrations ranging from the recommended dose for oral consumption to several orders of magnitude lower. Detailed studies with the H5N1 HPAIV strain indicated that direct contact between EF and virus was required, prior to infection, in order to obtain maximum inhibition in virus replication. Hemagglutination assays showed that the extract inhibited the receptor binding activity of the virus, suggesting that the extract interferes with the viral entry into cells. In sequential passage studies under treatment in cell culture with the H5N1 virus no EF-resistant variants emerged, in contrast to Tamiflu®, which produced resistant viruses upon passaging. Furthermore, the Tamiflu®-resistant virus was just as susceptible to EF as the wild type virus. Conclusion As a result of these investigations, we believe that this standard Echinacea preparation, used at the recommended dose for oral consumption, could be a useful, readily available and affordable addition to existing control options

  13. Anti-viral properties and mode of action of standardized Echinacea purpurea extract against highly pathogenic avian influenza virus (H5N1, H7N7) and swine-origin H1N1 (S-OIV).

    Science.gov (United States)

    Pleschka, Stephan; Stein, Michael; Schoop, Roland; Hudson, James B

    2009-11-13

    Influenza virus (IV) infections are a major threat to human welfare and animal health worldwide. Anti-viral therapy includes vaccines and a few anti-viral drugs. However vaccines are not always available in time, as demonstrated by the emergence of the new 2009 H1N1-type pandemic strain of swine origin (S-OIV) in April 2009, and the acquisition of resistance to neuraminidase inhibitors such as Tamiflu (oseltamivir) is a potential problem. Therefore the prospects for the control of IV by existing anti-viral drugs are limited. As an alternative approach to the common anti-virals we studied in more detail a commercial standardized extract of the widely used herb Echinacea purpurea (Echinaforce, EF) in order to elucidate the nature of its anti-IV activity. Human H1N1-type IV, highly pathogenic avian IV (HPAIV) of the H5- and H7-types, as well as swine origin IV (S-OIV, H1N1), were all inactivated in cell culture assays by the EF preparation at concentrations ranging from the recommended dose for oral consumption to several orders of magnitude lower. Detailed studies with the H5N1 HPAIV strain indicated that direct contact between EF and virus was required, prior to infection, in order to obtain maximum inhibition in virus replication. Hemagglutination assays showed that the extract inhibited the receptor binding activity of the virus, suggesting that the extract interferes with the viral entry into cells. In sequential passage studies under treatment in cell culture with the H5N1 virus no EF-resistant variants emerged, in contrast to Tamiflu, which produced resistant viruses upon passaging. Furthermore, the Tamiflu-resistant virus was just as susceptible to EF as the wild type virus. As a result of these investigations, we believe that this standard Echinacea preparation, used at the recommended dose for oral consumption, could be a useful, readily available and affordable addition to existing control options for IV replication and dissemination.

  14. An Integrated Approach for Creating Service-Based Interactive Applications

    Science.gov (United States)

    Feldmann, Marius; Janeiro, Jordan; Nestler, Tobias; Hübsch, Gerald; Jugel, Uwe; Preussner, André; Schill, Alexander

    While the implementation of business logic and business processes based on service-oriented architectures is well-understood and covered by existing development approaches, integrated concepts that empower users to exploit the Internet of Services to create complex interactive applications are missing. In this paper, we present an integrated approach that fills this gap. Our approach builds upon service annotations that add meta-information related to user interface generation, service dependencies, and service composition to existing service descriptions. Services can be composed visually to complex interactive applications based on these annotations without the need to write any code. The application code is generated completely from the service composition description. Our approach is able to support heterogeneous target environments ranging from client/server architectures to mobile platforms.

  15. Analysis of Kernel Approach in Fuzzy-Based Image Classifications

    Directory of Open Access Journals (Sweden)

    Mragank Singhal

    2013-03-01

    Full Text Available This paper presents a framework of kernel approach in the field of fuzzy based image classification in remote sensing. The goal of image classification is to separate images according to their visual content into two or more disjoint classes. Fuzzy logic is relatively young theory. Major advantage of this theory is that it allows the natural description, in linguistic terms, of problems that should be solved rather than in terms of relationships between precise numerical values. This paper describes how remote sensing data with uncertainty are handled with fuzzy based classification using Kernel approach for land use/land cover maps generation. The introduction to fuzzification using Kernel approach provides the basis for the development of more robust approaches to the remote sensing classification problem. The kernel explicitly defines a similarity measure between two samples and implicitly represents the mapping of the input space to the feature space.

  16. THE DEVELOPMENT OF THE PROCESS-BASED APPROACH TO MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Urij V. Lyandau

    2013-01-01

    Full Text Available This article considers the timeline of the approaches to management of the industrial processes and organizations in general.The Adam Smith’s idea of specialization, the Henry Ford’s conveyor and Frederick Taylor’s scientific approach created functional corporations, in which specialized departments consisted of specialized workers. Such organizational chart was optimized for every department’s tasks, which are necessary to perform.During the life cycle evolution of industrial and then informational ages external conditions of production has changed. In consequence, there was born the necessity to change key factors of the management paradigm. These changes are the transfer from the functional management to the process-based approach. The functional management was the basic type of management in many organizations during the 20th century. Only in the end of 1990 companies started to integrate the process-based approach. This conversion was born cause of special conditions that the informational age created.

  17. Two approaches to synthesis based on the domain theory

    DEFF Research Database (Denmark)

    Hansen, Claus Thorp; Andreasen, Mogens Myrup

    2002-01-01

    . The functional reasoning within each domain and between the domains seems to be ruled by the function-means law (Hubka´s law). On the basis of the domain theory and the function-means law we present two formal approaches to the synthesis of mechanical artefacts, namely a design-process-oriented approach...... and an artefact-oriented approach. The design-process-oriented synthesis approach can be seen as a basic design step for composite mechanical artefacts. The artefact-oriented approach has been utilised for the development of computer-based design support systems.......The domain theory is described in this chapter. By a strict distinction between the structural characteristics and the behavioural properties of a mechanical artefact, each domain, i.e. transformation-, organ-, and part domain, becomes a productive view for design of mechanical artefacts...

  18. An Eavesdropping Detecting Approach Based on Mode-Mode Correlation

    Institute of Scientific and Technical Information of China (English)

    XIONG Jin; ZENG Gui-Hua; ZHOU Nan-Run

    2005-01-01

    @@ We find that second-order coherence as well as a Hanbury-Brown-Twiss intensity interferometer may provide an optimal approach for eavesdropping detection in the quantum key distribution based on two-mode squeezed'vacuum states. With this approach, eavesdropping can be easily detected without sacrificing extra secret bits as the test key. In addition, the efficiency of the quantum key distribution protocol is enhanced greatly.

  19. LMI Approach to Observer-based FD Systems Designing

    Institute of Scientific and Technical Information of China (English)

    钟麦英; 汤兵勇; 丁·史蒂芬·先春

    2001-01-01

    Increasing the robustness to the unknown uncertainty and simultaneously enhancing the sensibility to the faults is one of the important issues considered in the fault detection development. Considering the L2-gain of residual system, this paper deals the observer-based fault detection problem. By using of H∞ control theory,an LMI approach to design fault detection observer is given. A numerical example is used to illustrate the effectiveness of the proposed approach.

  20. A Moving Human Tracking Approach Based on Semantic Interaction

    Institute of Scientific and Technical Information of China (English)

    ZHOU Ning; FANG Bao-hong; SUN Fu-liang

    2007-01-01

    In order to deal with partical occlusion, a semantic interaction based moving human tracking approach is put forward. Firstly human is modeled as moving blobs which are described as blob descriptions. Then moving blobs are updated and verified by projecting these descriptions. The approach exploits improved fast gauss transform and chooses source and target samples to reduce compute cost. Multi-moving human can be tracked simply and part occlusion can be done well.

  1. RESEARCH ON NEGOTIATION-BASED PARTNER SELECTION APPROACH

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    The key problem in the construction of virtual enterprises (VEs) is how to select appropriate partners. The negotiation-based approach is proposed to support partner selection in the construction of VEs . The negotiation model is discussed from three main aspects respectively, i.e., negotiation protocol, negotiation goal and negotiation decision-making model. And the generic mathematical description of the negotiation model is formally presented. Finally, a simple example is used to validate the approach's availability.

  2. A Smart Approach for GPT Cryptosystem Based on Rank Codes

    CERN Document Server

    Rashwan, Haitham; Honary, Bahram

    2010-01-01

    The concept of Public- key cryptosystem was innovated by McEliece's cryptosystem. The public key cryptosystem based on rank codes was presented in 1991 by Gabidulin -Paramonov-Trejtakov(GPT). The use of rank codes in cryptographic applications is advantageous since it is practically impossible to utilize combinatoric decoding. This has enabled using public keys of a smaller size. Respective structural attacks against this system were proposed by Gibson and recently by Overbeck. Overbeck's attacks break many versions of the GPT cryptosystem and are turned out to be either polynomial or exponential depending on parameters of the cryptosystem. In this paper, we introduce a new approach, called the Smart approach, which is based on a proper choice of the distortion matrix X. The Smart approach allows for withstanding all known attacks even if the column scrambler matrix P over the base field Fq.

  3. A discrete Lagrangian based direct approach to macroscopic modelling

    Science.gov (United States)

    Sarkar, Saikat; Nowruzpour, Mohsen; Reddy, J. N.; Srinivasa, A. R.

    2017-01-01

    A direct discrete Lagrangian based approach, designed at a length scale of interest, to characterize the response of a body is proposed. The main idea is to understand the dynamics of a deformable body via a Lagrangian corresponding to a coupled interaction of rigid particles in the reduced dimension. We argue that the usual practice of describing the laws of a deformable body in the continuum limit is redundant, because for most of the practical problems, analytical solutions are not available. Since continuum limit is not taken, the framework automatically relaxes the requirement of differentiability of field variables. The discrete Lagrangian based approach is illustrated by deriving an equivalent of the Euler-Bernoulli beam model. A few test examples are solved, which demonstrate that the derived non-local model predicts lower deflections in comparison to classical Euler-Bernoulli beam solutions. We have also included crack propagation in thin structures for isotropic and anisotropic cases using the Lagrangian based approach.

  4. Mindfulness-based approaches: are they all the same?

    Science.gov (United States)

    Chiesa, Alberto; Malinowski, Peter

    2011-04-01

    Mindfulness-based approaches are increasingly employed as interventions for treating a variety of psychological, psychiatric and physical problems. Such approaches include ancient Buddhist mindfulness meditations such as Vipassana and Zen meditations, modern group-based standardized meditations, such as mindfulness-based stress reduction and mindfulness-based cognitive therapy, and further psychological interventions, such as dialectical behavioral therapy and acceptance and commitment therapy. We review commonalities and differences of these interventions regarding philosophical background, main techniques, aims, outcomes, neurobiology and psychological mechanisms. In sum, the currently applied mindfulness-based interventions show large differences in the way mindfulness is conceptualized and practiced. The decision to consider such practices as unitary or as distinct phenomena will probably influence the direction of future research.

  5. User-based and Cognitive Approaches to Knowledge Organization

    DEFF Research Database (Denmark)

    Hjørland, Birger

    2013-01-01

    In the 1970s and 1980s, forms of user-based and cognitive approaches to knowledge organization came to the forefront as part of the overall development in library and information science and in the broader society. The specific nature of userbased approaches is their basis in the empirical studies......’s PageRank are not based on the empirical studies of users. In knowledge organization, the Book House System is one example of a system based on user studies. In cognitive science the important WordNet database is claimed to be based on psychological research. This article considers such examples....... The role of the user is often confused with the role of subjectivity. Knowledge organization systems cannot be objective and must therefore, by implication, be based on some kind of subjectivity. This subjectivity should, however, be derived from collective views in discourse communities rather than...

  6. An Open Science Approach to Gis-Based Paleoenvironment Data

    Science.gov (United States)

    Willmes, C.; Becker, D.; Verheul, J.; Yener, Y.; Zickel, M.; Bolten, A.; Bubenzer, O.; Bareth, G.

    2016-06-01

    Paleoenvironmental studies and according information (data) are abundantly published and available in the scientific record. However, GIS-based paleoenvironmental information and datasets are comparably rare. Here, we present an Open Science approach for creating GIS-based data and maps of paleoenvironments, and Open Access publishing them in a web based Spatial Data Infrastructure (SDI), for access by the archaeology and paleoenvironment communities. We introduce an approach to gather and create GIS datasets from published non-GIS based facts and information (data), such as analogous maps, textual information or figures in scientific publications. These collected and created geo-datasets and maps are then published, including a Digital Object Identifier (DOI) to facilitate scholarly reuse and citation of the data, in a web based Open Access Research Data Management Infrastructure. The geo-datasets are additionally published in an Open Geospatial Consortium (OGC) standards compliant SDI, and available for GIS integration via OGC Open Web Services (OWS).

  7. A Market-Based Approach to Multi-factory Scheduling

    Science.gov (United States)

    Vytelingum, Perukrishnen; Rogers, Alex; MacBeth, Douglas K.; Dutta, Partha; Stranjak, Armin; Jennings, Nicholas R.

    In this paper, we report on the design of a novel market-based approach for decentralised scheduling across multiple factories. Specifically, because of the limitations of scheduling in a centralised manner - which requires a center to have complete and perfect information for optimality and the truthful revelation of potentially commercially private preferences to that center - we advocate an informationally decentralised approach that is both agile and dynamic. In particular, this work adopts a market-based approach for decentralised scheduling by considering the different stakeholders representing different factories as self-interested, profit-motivated economic agents that trade resources for the scheduling of jobs. The overall schedule of these jobs is then an emergent behaviour of the strategic interaction of these trading agents bidding for resources in a market based on limited information and their own preferences. Using a simple (zero-intelligence) bidding strategy, we empirically demonstrate that our market-based approach achieves a lower bound efficiency of 84%. This represents a trade-off between a reasonable level of efficiency (compared to a centralised approach) and the desirable benefits of a decentralised solution.

  8. Ellipse Fitting Based Approach for Extended Object Tracking

    Directory of Open Access Journals (Sweden)

    Borui Li

    2014-01-01

    Full Text Available With the increase of sensors’ resolution, traditional object tracking technology, which ignores object’s physical extension, gradually becomes inappropriate. Extended object tracking (EOT technology is able to obtain more information about the object through jointly estimating both centroid’s dynamic state and physical extension of the object. Random matrix based approach is a promising method for EOT. It uses ellipse/ellipsoid to describe the physical extension of the object. In order to reduce the physical extension estimation error when object maneuvers, the relationship between ellipse/ellipsoid and symmetrical positive definite matrix is analyzed at first. On this basis, ellipse/ellipsoid fitting based approach (EFA for EOT is proposed based on the measurement model and centroid’s dynamic model of random matrix based EOT approach. Simulation results show that EFA is effective. The physical extension estimation error of EFA is lower than those of random matrix based approaches when object maneuvers. Besides, the estimation error of centroid’s dynamic state of EFA is also lower.

  9. The Process - based Approach in English Writing Class%The Process-based Approach in English Writing Class

    Institute of Scientific and Technical Information of China (English)

    秦梅

    2007-01-01

    English writing is gaining high attention and emphasis in our college syllabus. It is a complicated process of written communication. In the process, the four basic skills-speaking, reading, listening and writing are organically integrated together. This paper is about the processbased approach in English writing class and its aim to emphasize the importance of process -based approach to writing. There are four parts in this paper. I start with a brief introduction to the importance of writing. Next, I will introduce my practice in English writing class. Then I will comment on the process approach and then make a little revision.

  10. A multiparameter chaos control method based on OGY approach

    Energy Technology Data Exchange (ETDEWEB)

    Souza de Paula, Aline [Universidade Federal do Rio de Janeiro, COPPE - Department of Mechanical Engineering, 21.941.972 - Rio de Janeiro - RJ, P.O. Box 68.503 (Brazil)], E-mail: alinesp@ufrj.br; Amorim Savi, Marcelo [Universidade Federal do Rio de Janeiro, COPPE - Department of Mechanical Engineering, 21.941.972 - Rio de Janeiro - RJ, P.O. Box 68.503 (Brazil)], E-mail: savi@mecanica.ufrj.br

    2009-05-15

    Chaos control is based on the richness of responses of chaotic behavior and may be understood as the use of tiny perturbations for the stabilization of a UPO embedded in a chaotic attractor. Since one of these UPO can provide better performance than others in a particular situation the use of chaos control can make this kind of behavior to be desirable in a variety of applications. The OGY method is a discrete technique that considers small perturbations promoted in the neighborhood