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Sample records for action disruptive selection

  1. Coevolution in action: disruptive selection on egg colour in an avian brood parasite and its host.

    Directory of Open Access Journals (Sweden)

    Canchao Yang

    Full Text Available BACKGROUND: Trait polymorphism can evolve as a consequence of frequency-dependent selection. Coevolutionary interactions between hosts and parasites may lead to selection on both to evolve extreme phenotypes deviating from the norm, through disruptive selection. METHODOLOGY/PRINCIPAL FINDING: Here, we show through detailed field studies and experimental procedures that the ashy-throated parrotbill (Paradoxornis alphonsianus and its avian brood parasite, the common cuckoo (Cuculus canorus, have both evolved egg polymorphism manifested in discrete immaculate white, pale blue, and blue egg phenotypes within a single population. In this host-parasite system the most common egg colours were white and blue, with no significant difference in parasitism rates between hosts laying eggs of either colour. Furthermore, selection on parasites for countering the evolution of host egg types appears to be strong, since ashy-throated parrotbills have evolved rejection abilities for even partially mimetic eggs. CONCLUSIONS/SIGNIFICANCE: The parrotbill-cuckoo system constitutes a clear outcome of disruptive selection on both host and parasite egg phenotypes driven by coevolution, due to the cost of parasitism in the host and by host defences in the parasite. The present study is to our knowledge the first to report the influence of disruptive selection on evolution of discrete phenotypes in both parasite and host traits in an avian brood parasitism system.

  2. Coevolution in Action: Disruptive Selection on Egg Colour in an Avian Brood Parasite and Its Host

    Science.gov (United States)

    Cai, Yan; Shi, Suhua; Takasu, Fugo; Møller, Anders P.; Antonov, Anton; Fossøy, Frode; Moksnes, Arne; Røskaft, Eivin; Stokke, Bård G.

    2010-01-01

    Background Trait polymorphism can evolve as a consequence of frequency-dependent selection. Coevolutionary interactions between hosts and parasites may lead to selection on both to evolve extreme phenotypes deviating from the norm, through disruptive selection. Methodology/Principal finding Here, we show through detailed field studies and experimental procedures that the ashy-throated parrotbill (Paradoxornis alphonsianus) and its avian brood parasite, the common cuckoo (Cuculus canorus), have both evolved egg polymorphism manifested in discrete immaculate white, pale blue, and blue egg phenotypes within a single population. In this host-parasite system the most common egg colours were white and blue, with no significant difference in parasitism rates between hosts laying eggs of either colour. Furthermore, selection on parasites for countering the evolution of host egg types appears to be strong, since ashy-throated parrotbills have evolved rejection abilities for even partially mimetic eggs. Conclusions/Significance The parrotbill-cuckoo system constitutes a clear outcome of disruptive selection on both host and parasite egg phenotypes driven by coevolution, due to the cost of parasitism in the host and by host defences in the parasite. The present study is to our knowledge the first to report the influence of disruptive selection on evolution of discrete phenotypes in both parasite and host traits in an avian brood parasitism system. PMID:20520815

  3. Fisheries-induced disruptive selection.

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    Landi, Pietro; Hui, Cang; Dieckmann, Ulf

    2015-01-21

    Commercial harvesting is recognized to induce adaptive responses of life-history traits in fish populations, in particular by shifting the age and size at maturation through directional selection. In addition to such evolution of a target stock, the corresponding fishery itself may adapt, in terms of fishing policy, technological progress, fleet dynamics, and adaptive harvest. The aim of this study is to assess how the interplay between natural and artificial selection, in the simplest setting in which a fishery and a target stock coevolve, can lead to disruptive selection, which in turn may cause trait diversification. To this end, we build an eco-evolutionary model for a size-structured population, in which both the stock׳s maturation schedule and the fishery׳s harvest rate are adaptive, while fishing may be subject to a selective policy based on fish size and/or maturity stage. Using numerical bifurcation analysis, we study how the potential for disruptive selection changes with fishing policy, fishing mortality, harvest specialization, life-history tradeoffs associated with early maturation, and other demographic and environmental parameters. We report the following findings. First, fisheries-induced disruptive selection is readily caused by commonly used fishing policies, and occurs even for policies that are not specific for fish size or maturity, provided that the harvest is sufficiently adaptive and large individuals are targeted intensively. Second, disruptive selection is more likely in stocks in which the selective pressure for early maturation is naturally strong, provided life-history tradeoffs are sufficiently consequential. Third, when a fish stock is overexploited, fisheries targeting only large individuals might slightly increase sustainable yield by causing trait diversification (even though the resultant yield always remains lower than the maximum sustainable yield that could be obtained under low fishing mortality, without causing disruptive

  4. Introduction. Modelling natural action selection.

    Science.gov (United States)

    Prescott, Tony J; Bryson, Joanna J; Seth, Anil K

    2007-09-29

    Action selection is the task of resolving conflicts between competing behavioural alternatives. This theme issue is dedicated to advancing our understanding of the behavioural patterns and neural substrates supporting action selection in animals, including humans. The scope of problems investigated includes: (i) whether biological action selection is optimal (and, if so, what is optimized), (ii) the neural substrates for action selection in the vertebrate brain, (iii) the role of perceptual selection in decision-making, and (iv) the interaction of group and individual action selection. A second aim of this issue is to advance methodological practice with respect to modelling natural action section. A wide variety of computational modelling techniques are therefore employed ranging from formal mathematical approaches through to computational neuroscience, connectionism and agent-based modelling. The research described has broad implications for both natural and artificial sciences. One example, highlighted here, is its application to medical science where models of the neural substrates for action selection are contributing to the understanding of brain disorders such as Parkinson's disease, schizophrenia and attention deficit/hyperactivity disorder.

  5. Rapid actions of xenoestrogens disrupt normal estrogenic signaling.

    Science.gov (United States)

    Watson, Cheryl S; Hu, Guangzhen; Paulucci-Holthauzen, Adriana A

    2014-03-01

    Some chemicals used in consumer products or manufacturing (e.g. plastics, surfactants, pesticides, resins) have estrogenic activities; these xenoestrogens (XEs) chemically resemble physiological estrogens and are one of the major categories of synthesized compounds that disrupt endocrine actions. Potent rapid actions of XEs via nongenomic mechanisms contribute significantly to their disruptive effects on functional endpoints (e.g. cell proliferation/death, transport, peptide release). Membrane-initiated hormonal signaling in our pituitary cell model is predominantly driven by mERα with mERβ and GPR30 participation. We visualized ERα on plasma membranes using many techniques in the past (impeded ligands, antibodies to ERα) and now add observations of epitope proximity with other membrane signaling proteins. We have demonstrated a range of rapid signals/protein activations by XEs including: calcium channels, cAMP/PKA, MAPKs, G proteins, caspases, and transcription factors. XEs can cause disruptions of the oscillating temporal patterns of nongenomic signaling elicited by endogenous estrogens. Concentration effects of XEs are nonmonotonic (a trait shared with natural hormones), making it difficult to design efficient (single concentration) toxicology tests to monitor their harmful effects. A plastics monomer, bisphenol A, modified by waste treatment (chlorination) and other processes causes dephosphorylation of extracellular-regulated kinases, in contrast to having no effects as it does in genomic signaling. Mixtures of XEs, commonly found in contaminated environments, disrupt the signaling actions of physiological estrogens even more severely than do single XEs. Understanding the features of XEs that drive these disruptive mechanisms will allow us to redesign useful chemicals that exclude estrogenic or anti-estrogenic activities.

  6. Mate choice, sexual selection, and endocrine-disrupting chemicals.

    Science.gov (United States)

    Gore, Andrea C; Holley, Amanda M; Crews, David

    2017-09-11

    Humans have disproportionately affected the habitat and survival of species through environmental contamination. Important among these anthropogenic influences is the proliferation of organic chemicals, some of which perturb hormone systems, the latter referred to as endocrine-disrupting chemicals (EDCs). EDCs are widespread in the environment and affect all levels of reproduction, including development of reproductive organs, hormone release and regulation through the life cycle, the development of secondary sexual characteristics, and the maturation and maintenance of adult physiology and behavior. However, what is not well-known is how the confluence of EDC actions on the manifestation of morphological and behavioral sexual traits influences mate choice, a process that requires the reciprocal evaluation of and/or acceptance of a sexual partner. Moreover, the outcomes of EDC-induced perturbations are likely to influence sexual selection; yet this has rarely been directly tested. Here, we provide background on the development and manifestation of sexual traits, reproductive competence, and the neurobiology of sexual behavior, and evidence for their perturbation by EDCs. Selection acts on individuals, with the consequences manifest in populations, and we discuss the implications for EDC contamination of these processes, and the future of species. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Endocrine disruption of oestrogen action and female reproductive tract cancers.

    Science.gov (United States)

    Gibson, Douglas A; Saunders, Philippa T K

    2014-04-01

    Endocrine disrupting chemicals (EDC) are ubiquitous and persistent compounds that have the capacity to interfere with normal endocrine homoeostasis. The female reproductive tract is exquisitely sensitive to the action of sex steroids, and oestrogens play a key role in normal reproductive function. Malignancies of the female reproductive tract are the fourth most common cancer in women, with endometrial cancer accounting for most cases. Established risk factors for development of endometrial cancer include high BMI and exposure to oestrogens or synthetic compounds such as tamoxifen. Studies on cell and animal models have provided evidence that many EDC can bind oestrogen receptors and highlighted early life exposure as a window of risk for adverse lifelong effects on the reproductive system. The most robust evidence for a link between early life exposure to EDC and adverse reproductive health has come from studies on women who were exposed in utero to diethylstilbestrol. Demonstration that EDC can alter expression of members of the HOX gene cluster highlights one pathway that might be vulnerable to their actions. In summary, evidence for a direct link between EDC exposure and cancers of the reproductive system is currently incomplete. It will be challenging to attribute causality to any single EDC when exposure and development of malignancy may be separated by many years and influenced by lifestyle factors such as diet (a source of phytoestrogens) and adiposity. This review considers some of the evidence collected to date.

  8. Dynamic Nigrostriatal Dopamine Biases Action Selection.

    Science.gov (United States)

    Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

    2017-03-22

    Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Production control and supplier selection under demand disruptions

    Directory of Open Access Journals (Sweden)

    Xianzhe Chen

    2010-12-01

    Full Text Available This paper investigates the effects of demand disruptions on production control and supplier selection in a three-echelon supply chain system. The customer demand is modeled as a jump-diffusion process in a continuous-time setting. A two-number production-inventory policy is implemented in the production control model for the manufacturer. The objective is to minimize the long-term average total cost consisting of backlog cost, holding cost, switching cost, and ordering cost. The simulated annealing method is applied to search the optimal critical switching values. Furthermore, an improved analytical hierarchy process (AHP is proposed to select the best supplier, based on quantitative factors such as the optimal long-term total cost obtained through the simulated annealing method under demand disruptions and qualitative factors such as quality and service. Numerical studies are conducted to demonstrate the effects of demand disruptions in the face of various risk scenarios. Managerial insights from simulation results are provided as well. Our approaches can be implemented as the “stress test” for companies in front of various supply chain disruption scenarios.

  10. Mechanisms underlying selecting objects for action

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    Melanie eWulff

    2015-04-01

    Full Text Available We assessed the factors which affect the selection of objects for action, focusing on the role of action knowledge and its modulation by distracters. 14 neuropsychological patients and 10 healthy aged-matched controls selected pairs of objects commonly used together among distracters in two contexts: with real objects and with pictures of the same objects presented sequentially on a computer screen. Across both tasks, semantically related distracters led to slower responses and more errors than unrelated distracters and the object actively used for action was selected prior to the object that would be passively held during the action. We identified a sub-group of patients (N=6 whose accuracy was 2SD below the controls performances in the real object task. Interestingly, these impaired patients were more affected by the presence of unrelated distracters during both tasks than intact patients and healthy controls. Note the impaired had lesions to left parietal, right anterior temporal and bilateral pre-motor regions. We conclude that: (1 motor procedures guide object selection for action, (2 semantic knowledge affects action-based selection, (3 impaired action decision is associated with the inability to ignore distracting information and (4 lesions to either the dorsal or ventral visual stream can lead to deficits in making action decisions. Overall, the data indicate that impairments in everyday tasks can be evaluated using a simulated computer task. The implications for rehabilitation are discussed.

  11. Endocrine-Disrupting Chemicals: Associated Disorders and Mechanisms of Action

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    Sam De Coster

    2012-01-01

    Full Text Available The incidence and/or prevalence of health problems associated with endocrine-disruption have increased. Many chemicals have endocrine-disrupting properties, including bisphenol A, some organochlorines, polybrominated flame retardants, perfluorinated substances, alkylphenols, phthalates, pesticides, polycyclic aromatic hydrocarbons, alkylphenols, solvents, and some household products including some cleaning products, air fresheners, hair dyes, cosmetics, and sunscreens. Even some metals were shown to have endocrine-disrupting properties. Many observations suggesting that endocrine disruptors do contribute to cancer, diabetes, obesity, the metabolic syndrome, and infertility are listed in this paper. An overview is presented of mechanisms contributing to endocrine disruption. Endocrine disruptors can act through classical nuclear receptors, but also through estrogen-related receptors, membrane-bound estrogen-receptors, and interaction with targets in the cytosol resulting in activation of the Src/Ras/Erk pathway or modulation of nitric oxide. In addition, changes in metabolism of endogenous hormones, cross-talk between genomic and nongenomic pathways, cross talk with estrogen receptors after binding on other receptors, interference with feedback regulation and neuroendocrine cells, changes in DNA methylation or histone modifications, and genomic instability by interference with the spindle figure can play a role. Also it was found that effects of receptor activation can differ in function of the ligand.

  12. Disruptive sexual selection for plumage coloration in a passerine bird.

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    Greene, E; Lyon, B E; Muehter, V R; Ratcliffe, L; Oliver, S J; Boag, P T

    2000-10-26

    The theory of sexual selection was developed to explain the evolution of highly exaggerated sexual ornaments. Now supported by vast empirical evidence, sexual selection is generally considered to favour individuals with the most extreme trait expression. Here we describe disruptive selection on a sexual ornament, plumage coloration, in yearling male lazuli buntings (Passerina amoena). In habitats with limited good-quality nesting cover, the dullest and the brightest yearlings were more successful in obtaining high-quality territories, pairing with females and siring offspring, than yearlings with intermediate plumage. This pattern reflects the way that territorial adult males vary levels of aggression to influence the structure of their social neighbourhood. Adult males showed less aggression towards dull yearlings than intermediate and bright ones, permitting the dull yearlings to settle on good territories nearby. Fitness comparisons based on paternity analyses showed that both the adults and dull yearlings benefited genetically from this arrangement, revealing a rare example of sexually selected male-male cooperation.

  13. Disruption?

    DEFF Research Database (Denmark)

    2016-01-01

    This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray......This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray...

  14. Disruption?

    DEFF Research Database (Denmark)

    2016-01-01

    This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray......This is a short video on the theme disruption and entrepreneurship. It takes the form of an interview with John Murray...

  15. A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli.

    Science.gov (United States)

    Urfer, Matthias; Bogdanovic, Jasmina; Lo Monte, Fabio; Moehle, Kerstin; Zerbe, Katja; Omasits, Ulrich; Ahrens, Christian H; Pessi, Gabriella; Eberl, Leo; Robinson, John A

    2016-01-22

    Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM.

  16. Action spectrum for photochemical retinal pigment epithelium (RPE) disruption in an in vivo monkey model

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    Zhang, Jie; Sabarinathan, Ranjani; Bubel, Tracy; Williams, David R.; Hunter, Jennifer J.

    2016-03-01

    Observations of RPE disruption and autofluorescence (AF) photobleaching at light levels below the ANSI photochemical maximum permissible exposure (MPE) (Morgan et al., 2008) indicates a demand to modify future light safety standards to protect the retina from harm. To establish safe light exposures, we measured the visible light action spectrum for RPE disruption in an in vivo monkey model with fluorescence adaptive optics retinal imaging. Using this high resolution imaging modality can provide insight into the consequences of light on a cellular level and allow for longitudinal monitoring of retinal changes. The threshold retinal radiant exposures (RRE) for RPE disruption were determined for 4 wavelengths (460, 488, 544, and 594 nm). The anaesthetized macaque retina was exposed to a uniform 0.5° × 0.5° field of view (FOV). Imaging within a 2° × 2° FOV was performed before, immediately after and at 2 week intervals for 10 weeks. At each wavelength, multiple RREs were tested with 4 repetitions each to determine the threshold for RPE disruption. For qualitative analysis, RPE disruption is defined as any detectable change from the pre exposure condition in the cell mosaic in the exposed region relative to the corresponding mosaic in the immediately surrounding area. We have tested several metrics to evaluate the RPE images obtained before and after exposure. The measured action spectrum for photochemical RPE disruption has a shallower slope than the current ANSI photochemical MPE for the same conditions and suggests that longer wavelength light is more hazardous than other measurements would suggest.

  17. Selective algicidal action of peptides against harmful algal bloom species.

    Directory of Open Access Journals (Sweden)

    Seong-Cheol Park

    Full Text Available Recently, harmful algal bloom (HAB, also termed "red tide", has been recognized as a serious problem in marine environments according to climate changes worldwide. Many novel materials or methods to prevent HAB have not yet been employed except for clay dispersion, in which can the resulting sedimentation on the seafloor can also cause alteration in marine ecology or secondary environmental pollution. In the current study, we investigated that antimicrobial peptide have a potential in controlling HAB without cytotoxicity to harmless marine organisms. Here, antimicrobial peptides are proposed as new algicidal compounds in combating HAB cells. HPA3 and HPA3NT3 peptides which exert potent antimicrobial activity via pore forming action in plasma membrane showed that HPA3NT3 reduced the motility of algal cells, disrupted their plasma membrane, and induced the efflux of intracellular components. Against raphidoflagellate such as Heterosigma akashiwo, Chattonella sp., and C. marina, it displayed a rapid lysing action in cell membranes at 1~4 µM within 2 min. Comparatively, its lysing effects occurred at 8 µM within 1 h in dinoflagellate such as Cochlodium polykrikoides, Prorocentrum micans, and P. minimum. Moreover, its lysing action induced the lysis of chloroplasts and loss of chlorophyll a. In the contrary, this peptide was not effective against Skeletonema costatum, harmless algal cell, even at 256 µM, moreover, it killed only H. akashiwo or C. marina in co-cultivation with S. costatum, indicating to its selective algicidal activity between harmful and harmless algal cells. The peptide was non-hemolytic against red blood cells of Sebastes schlegeli, the black rockfish, at 120 µM. HAB cells were quickly and selectively lysed following treatment of antimicrobial peptides without cytotoxicity to harmless marine organisms. Thus, the antibiotic peptides examined in our study appear to have much potential in effectively controlling HAB with minimal

  18. Crime and Disruption in Schools. A Selected Bibliography.

    Science.gov (United States)

    Rubel, Robert, Comp.; And Others

    This annotated bibliography about crime and disruption in schools has been assembled from academic, professional, and government sources. The citations are organized into four major parts. "Overview: Nature and Extent of the Problem" contains studies that describe the cost of school crimes, primarily vandalism and arson, both in dollars and in…

  19. Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function.

    Science.gov (United States)

    Henley, Derek V; Korach, Kenneth S

    2006-06-01

    The term endocrine-disrupting chemicals is used to define a structurally diverse class of synthetic and natural compounds that possess the ability to alter various components of the endocrine system and potentially induce adverse health effects in exposed individuals and populations. Research on these compounds has revealed that they use a variety of both nuclear receptor-mediated and non-receptor-mediated mechanisms to modulate different components of the endocrine system. This review will describe in vitro and in vivo studies that highlight the spectrum of unique mechanisms of action and biological effects of four endocrine-disrupting chemicals--diethylstilbestrol, genistein, di(n-butyl)phthalate, and methoxyacetic acid--to illustrate the diverse and complex nature of this class of compounds.

  20. Mechanism of action of cytotoxic cyclotides: cycloviolacin O2 disrupts lipid membranes.

    Science.gov (United States)

    Svangård, Erika; Burman, Robert; Gunasekera, Sunithi; Lövborg, Henrik; Gullbo, Joachim; Göransson, Ulf

    2007-04-01

    In recent years, the cyclotides have emerged as the largest family of naturally cyclized proteins. Cyclotides display potent cytotoxic activity that varies with the structure of the proteins, and combined with their unique structure, they represent novel cytotoxic agents. However, their mechanism of action is yet unknown. In this work we show that disruption of cell membranes plays a crucial role in the cytotoxic effect of the cyclotide cycloviolacin O2 (1), which has been isolated from Viola odorata. Cell viability and morphology studies on the human lymphoma cell line U-937 GTB showed that cells exposed to 1 displayed disintegrated cell membranes within 5 min. Functional studies on calcein-loaded HeLa cells and on liposomes showed rapid concentration-dependent release of their respective internal contents. The present results show that cyclotides have specific membrane-disrupting activity.

  1. Isoeugenol has a non-Disruptive Detergent-like Mechanism of Action

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    Morten eHyldgaard

    2015-07-01

    Full Text Available Isoeugenol is an essential oil constituent of nutmeg, clove, and cinnamon. Despite isoeugenol’s promising antimicrobial activity, no studies have yet investigated its mode of antibacterial action at the molecular level. The aim of this study is to clarify isoeugenol’s antibacterial mode of action using the Gram-negative and Gram-positive model organisms Escherichia coli and Listeria innocua, respectively. We determined the antimicrobial activity of isoeugenol against the model organisms, and examined how isoeugenol affects cell morphology, cell membrane permeabilization, and how isoeugenol interacts with phospholipid membranes using vesicle and supported lipid bilayer models.Isoeugenol demonstrated a bactericidal activity against E. coli and L. innocua that did not affect cell morphology, although the cell membrane was permeabilized. We hypothesized that the cell membrane was the primary site of action, and studied this interaction in further detail using purified membrane model systems. Isoeugenol’s permeabilization of calcein-encapsulated vesicles was concentration dependent, and isoeugenol’s interaction with giant unilamellar vesicles indicated increased membrane fluidity and a non-disruptive permeabilization mechanism. This contradicted membrane fluidity measurements on supported lipid bilayers, which indicated decreased membrane fluidity. However, further investigations demonstrated that the interaction between isoeugenol and bilayers was reversible, and caused membranes to display heterogeneous topography, an increased mass, and a higher degree of hydration. In conclusion, we propose that isoeugenol interacts with membranes in a reversible non-disruptive detergent-like manner, which causes membrane destabilization. Furthermore, we argue that isoeugenol increases membrane fluidity.

  2. The long-term evolution of multilocus traits under frequency-dependent disruptive selection

    NARCIS (Netherlands)

    Van Doorn, G. Sander; Dieckmann, Ulf

    2006-01-01

    Frequency-dependent disruptive selection is widely recognized as an important source of genetic variation. Its evolutionary consequences have been extensively studied using phenotypic evolutionary models, based on quantitative genetics, game theory, or adaptive dynamics. However, the genetic

  3. Estrogenic endocrine-disrupting chemicals: molecular mechanisms of actions on putative human diseases.

    Science.gov (United States)

    Yoon, Kyungsil; Kwack, Seung Jun; Kim, Hyung Sik; Lee, Byung-Mu

    2014-01-01

    Endocrine-disrupting chemicals (EDC), including phthalates, bisphenol A (BPA), phytoestrogens such as genistein and daidzein, dichlorodiphenyltrichloroethane (DDT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), are associated with a variety of adverse health effects in organisms or progeny by altering the endocrine system. Environmental estrogens, including BPA, phthalates, and phytoestrogens, are the most extensively studied and are considered to mimic the actions of endogenous estrogen, 17β-estradiol (E2). Diverse modes of action of estrogen and estrogen receptors (ERα and ERβ) have been described, but the mode of action of estrogenic EDC is postulated to be more complex and needs to be more clearly elucidated. This review examines the adverse effects of estrogenic EDC on male or female reproductive systems and molecular mechanisms underlying EDC effects that modulate ER-mediated signaling. Mechanisms of action for estrogenic EDC may involve both ER-dependent and ER-independent pathways. Recent findings from systems toxicology of examining estrogenic EDC are also discussed.

  4. Selective disruption of the cerebral neocortex in Alzheimer's disease.

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    Rahul S Desikan

    Full Text Available BACKGROUND: Alzheimer's disease (AD and its transitional state mild cognitive impairment (MCI are characterized by amyloid plaque and tau neurofibrillary tangle (NFT deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF Aβ levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n = 724. Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals. CONCLUSIONS/SIGNIFICANCE: Cortical Aβ and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia.

  5. Selection-for-action in visual search

    NARCIS (Netherlands)

    Hannus, A; Cornelissen, FW; Lindemann, O; Bekkering, H

    2005-01-01

    Grasping an object rather than pointing to it enhances processing of its orientation but not its color. Apparently, visual discrimination is selectively enhanced for a behaviorally relevant feature. In two experiments we investigated the limitations and targets of this bias. Specifically, in Experim

  6. Selection and inhibition mechanisms for human voluntary action decisions.

    Science.gov (United States)

    Zhang, Jiaxiang; Hughes, Laura E; Rowe, James B

    2012-10-15

    One can choose between action alternatives that have no apparent difference in their outcomes. Such voluntary action decisions are associated with widespread frontal-parietal activation, and a tendency to inhibit the repetition of a previous action. However, the mechanism of initiating voluntary actions and the functions of different brain regions during this process remains largely unknown. Here, we combine computational modeling and functional magnetic resonance imaging to test the selection and inhibition mechanisms that mediate trial-to-trial voluntary action decisions. We fitted an optimized accumulator model to behavioral responses in a finger-tapping task in which participants were instructed to make chosen actions or specified actions. Model parameters derived from each individual were then applied to estimate the expected accumulated metabolic activity (EAA) engaged in every single trial. The EAA was associated with blood oxygenation level-dependent responses in a decision work that was maximal in the supplementary motor area and the caudal anterior cingulate cortex, consistent with a competitive accumulation-to-threshold mechanism for action decision by these regions. Furthermore, specific inhibition of the previous action's accumulator was related to the suppression of response repetition. This action-specific inhibition correlated with the activity of the right inferior frontal gyrus, when the option to repeat existed. Our findings suggest that human voluntary action decisions are mediated by complementary processes of intentional selection and inhibition.

  7. Computational Framework Explains How Animals Select Actions With Rewarding Outcomes

    OpenAIRE

    Gurney, K.N.; Humphries, M.D.; Redgrave, P.

    2015-01-01

    Operant learning requires that reinforcement signals interact with action representations at a suitable neural interface. Much evidence suggests that this occurs when phasic dopamine, acting as a reinforcement prediction error, gates plasticity at cortico-striatal synapses, and thereby changes the future likelihood of selecting the action(s) coded by striatal neurons. But this hypothesis faces serious challenges. First, cortico-striatal plasticity is inexplicably complex, depending on spike t...

  8. An Action Selection Architecture for an Emotional Agent

    NARCIS (Netherlands)

    Burghouts, G.J.; op den Akker, Hendrikus J.A.; Heylen, Dirk K.J.; Poel, Mannes; Nijholt, Antinus; Russell, I.; Haller, S.

    2003-01-01

    An architecture for action selection is presented linking emotion, cognition and behavior. It defines the information and emotion processes of an agent. The architecture has been implemented and used in a prototype environment.

  9. Neural and temporal dynamics underlying visual selection for action

    NARCIS (Netherlands)

    Elk, M. van; Schie, H.T. van; Neggers, S.F.W.; Bekkering, H.

    2010-01-01

    The present study investigated the selection for action hypothesis, according to which a subject's action intention to perform a movement influences the way in which visual information is being processed. Subjects were instructed in separate blocks either to grasp or to point to a three-dimensional

  10. Activity and action screening of selected disinfectants

    Directory of Open Access Journals (Sweden)

    Kateřina Balharová

    2006-01-01

    Full Text Available This research work is aimed to monitoring of selected disinfectants´activity in operational conditions. Hereby there have been monitored two acidic disinfectants Despon K and Mikasan D, which have had-by their producer-stated different recommended concentration. These solutions were monitored in viewpoint of their activity at different temperature, time of circulation, pH and water hardness. In this work there were measured pH of solutions in unloaded medium to be compared with pH of solutions in loaded medium and this measuring was carried out regularly each week within a one month period. During this period there was also monitored total plate count (TPC, which was stated in the dairy, where samples were taken two-times monthly. It has been found, that the disinfectants Mikasan D and Mikal 94D are effective even by high water hardness.

  11. Virtual screening as a strategy for the identification of xenobiotics disrupting corticosteroid action.

    Directory of Open Access Journals (Sweden)

    Lyubomir G Nashev

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

  12. Molecular imaging, an innovative methodology for whole-body profiling of endocrine disrupter action.

    Science.gov (United States)

    Di Lorenzo, Diego; Rando, Gianpaolo; Ciana, Paolo; Maggi, Adriana

    2008-12-01

    Endocrine disrupters (EDs) are environment and food contaminants known to alter metabolic functions of mammals by interfering with specific endocrine pathways. Many EDs act on steroid hormone target cells by interacting with intracellular receptors (IRs) like estrogen receptors, androgen receptors, and thyroid hormone receptors; other receptors may be engaged. IRs are ligand-operated transcription factors acting in concert with general or cell-specific coregulators. The newly acquired awareness on the panoply of IR functions has increased the concern on potential, unsought, harmful effects of EDs on human health and has questioned the capability of currently available methodologies to identify and study EDs in the environment and in the food chain. Indeed, current in vivo and in vitro methodologies restrict the analysis to very specific organs or cell systems, with obvious limitations in predicting the systemic metabolic consequences of ED exposure. The emphasis recently laid by Regulatory Authorities, including European Center for the Validation of Alternative Methods, on the generation of in vitro model systems for toxicological analyses discouraged the development of models suitable to envision the whole spectrum of ED body actions required when studying compounds acting through IRs. Molecular imaging now provides the opportunity to quantify ED effects in living organisms enabling, for the first time, to acquire a full comprehension of the systemic effects of acute and prolonged exposure to EDs, solving the issue of the potential harm due to repeated low-dose exposure. The systems here reviewed are of unquestionable toxicological relevance and need to be taken into consideration to improve the methodology currently available and in use.

  13. Mastication dyspraxia: a neurodevelopmental disorder reflecting disruption of the cerebellocerebral network involved in planned actions.

    Science.gov (United States)

    Mariën, Peter; Vidts, Annelies; Van Hecke, Wim; De Surgeloose, Didier; De Belder, Frank; Parizel, Paul M; Engelborghs, Sebastiaan; De Deyn, Peter P; Verhoeven, Jo

    2013-04-01

    cerebellocerebral network is crucially important in the planning and execution of skilled actions, but also seem to show for the first time that mastication deficits may be of true apraxic origin. As a result, it is hypothesized that "mastication dyspraxia" may have to be considered as a distinct nosological entity within the group of the developmental dyspraxias following a disruption of the cerebellocerebral network involved in planned actions.

  14. Endocrine disruption of sexual selection by an estrogenic herbicide in the mealworm beetle (Tenebrio molitor).

    Science.gov (United States)

    McCallum, Malcolm L; Matlock, Makensey; Treas, Justin; Safi, Barroq; Sanson, Wendy; McCallum, Jamie L

    2013-12-01

    The role that endocrine disruption could play in sexual selection remains relatively untested, and although estrogens occur in insects, little information exists about their biological role in insect reproduction. Atrazine is a commonly applied herbicide that mimics estrogen in vertebrates. Tenebrio molitor were raised from egg to adult under a gradation of environmentally relevant atrazine exposures and a non-treated control. Atrazine was delivered in the drinking water ad libitum. Female T. molitor were provided with a choice between unrelated males raised under three levels of atrazine exposures. Female preference for males demonstrated a non-monotonic inverted U-shaped response to atrazine exposure. There was no significant difference between the control and the high exposure to atrazine. Excluding the control, female preference increased as exposure concentration increased. These results have important repercussions for nonlethal effects of endocrine disruption on populations, their capacity to interfere with sexual selection, and the role of estrogen in pheromone communication among insects.

  15. Directional, stabilizing, and disruptive trait selection as alternative mechanisms for plant community assembly.

    Science.gov (United States)

    Rolhauser, Andrés G; Pucheta, Eduardo

    2017-03-01

    How plant functional traits (e.g., seed mass) drive species abundance within communities remains an unsolved question. Borrowing concepts from natural selection theory, we propose that trait-abundance relationships can generally correspond to one of three modes of trait selection: directional (a rectilinear relationship, where species at one end of a trait axis are most abundant), stabilizing (an n-shaped relationship), and disruptive (a u-shaped relationship). Stabilizing selection (i.e., the functional convergence of abundant species) would result from positive density-dependent interactions (e.g., facilitation) or due to generalized trade-offs in resource acquisition/use, while disruptive selection (i.e., the divergence of abundant species) would result from negative density-dependent interactions (e.g., competition) or due to environmental heterogeneity. These selection modes can be interpreted as proxies for community-level trait-fitness functions, which establish the degree to which traits are truly "functional". We searched for selection modes in a desert annual-plant community in Argentina (which was divided into winter and summer guilds) to test the hypothesis that the relative importance of disruptive mechanisms (competition, disturbances) decreases with the increase of abiotic stress, a stabilizing agent. Average density was analyzed as a function of eight traits generally linked to resource acquisition and competitive ability (maximum plant height, leaf size, specific leaf area, specific root length), resource retention and stress tolerance (leaf dissection, leaf dry matter content, specific root volume), and regeneration (seed mass) using multiple quadratic-regression models. Trait selection was stabilizing and/or directional when the environment was harshest (winter) and disruptive and/or directional when conditions were milder (summer). Selection patterns differed between guilds for two important traits: plant height and seed mass. These results

  16. Selective disruption of PPARγ2 impairs the development of adipose tissue and insulin sensitivity

    OpenAIRE

    Zhang, Jifeng; Fu, Mingui; Cui, Taixing; Xiong, Chen; Xu, Kefeng; Zhong,Wei; Xiao, Yan; Floyd, Donna; Liang, Jian; Li, En; Song, Qing; Chen, Yuqing E.

    2004-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that plays a pivotal role in obesity and diabetes. PPARγ has two isoforms, PPARγ1 and PPARγ2. We investigated the functional differences between PPARγ1 and PPARγ2 by selectively disrupting PPARγ2 in mice. In contrast to the embryonic lethality of PPARγ-deficient mice, PPARγ2-/- mice survived. Although normal development was identified in other tissues we examined, PPARγ2-/- mice exhibited an overall reduction in white ...

  17. Disruptive natural selection predicts divergence between the sexes during adaptive radiation.

    Science.gov (United States)

    De Lisle, Stephen P; Rowe, Locke

    2017-05-01

    Evolution of sexual dimorphism in ecologically relevant traits, for example, via resource competition between the sexes, is traditionally envisioned to stall the progress of adaptive radiation. An alternative view is that evolution of ecological sexual dimorphism could in fact play an important positive role by facilitating sex-specific adaptation. How competition-driven disruptive selection, ecological sexual dimorphism, and speciation interact during real adaptive radiations is thus a critical and open empirical question. Here, we examine the relationships between these three processes in a clade of salamanders that has recently radiated into divergent niches associated with an aquatic life cycle. We find that morphological divergence between the sexes has occurred in a combination of head shape traits that are under disruptive natural selection within breeding ponds, while divergence among species means has occurred independently of this disruptive selection. Further, we find that adaptation to aquatic life is associated with increased sexual dimorphism across taxa, consistent with the hypothesis of clade-wide character displacement between the sexes. Our results suggest the evolution of ecological sexual dimorphism may play a key role in niche divergence among nascent species and demonstrate that ecological sexual dimorphism and ecological speciation can and do evolve concurrently in the early stages of adaptive radiation.

  18. Disruptive selection as a driver of evolutionary branching and caste evolution in social insects.

    Science.gov (United States)

    Planqué, R; Powell, S; Franks, N R; van den Berg, J B

    2016-11-01

    Theory suggests that evolutionary branching via disruptive selection may be a relatively common and powerful force driving phenotypic divergence. Here, we extend this theory to social insects, which have novel social axes of phenotypic diversification. Our model, built around turtle ant (Cephalotes) biology, is used to explore whether disruptive selection can drive the evolutionary branching of divergent colony phenotypes that include a novel soldier caste. Soldier evolution is a recurrent theme in social insect diversification that is exemplified in the turtle ants. We show that phenotypic mutants can gain competitive advantages that induce disruptive selection and subsequent branching. A soldier caste does not generally appear before branching, but can evolve from subsequent competition. The soldier caste then evolves in association with specialized resource preferences that maximize defensive performance. Overall, our model indicates that resource specialization may occur in the absence of morphological specialization, but that when morphological specialization evolves, it is always in association with resource specialization. This evolutionary coupling of ecological and morphological specialization is consistent with recent empirical evidence, but contrary to predictions of classical caste theory. Our model provides a new theoretical understanding of the ecology of caste evolution that explicitly considers the process of adaptive phenotypic divergence and diversification. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

  19. Institutions as Incentives for Civic Action: Bureaucratic Structures, Civil Society, and Disruptive Protests

    DEFF Research Database (Denmark)

    Cornell, Agnes; Grimes, Marcia

    2015-01-01

    This paper examines the link between political control of government bureaucracies and citizens’ likelihood to stage disruptive protests. A public administration heavily controlled by politicians, and staffed to a large extent with political appointees, allows politicians to intervene in policy...

  20. Selection and Training for Small Independent Action Forces: Final Report.

    Science.gov (United States)

    Olmstead, Joseph A.; And Others

    The overall objective of this research was the development of procedures for selecting and training personnel to serve in Small Independent Action Forces (SIAF) units. This report of Phase III of the three-phase research and development project describes research that required two almost completely independent activities: (a) development of a…

  1. Robot soccer action selection based on Q learning

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    This paper researches robot soccer action selection based on Q learning . The robot learn to activate particular behavior given their current situation and reward signal. We adopt neural network to implementations of Q learning for their generalization properties and limited computer memory requirements

  2. Perception and Action Selection Dissociate Human Ventral and Dorsal Cortex

    Science.gov (United States)

    Ikkai, Akiko; Jerde, Trenton A.; Curtis, Clayton E.

    2011-01-01

    We test theories about the functional organization of the human cortex by correlating brain activity with demands on perception versus action selection. Subjects covertly searched for a target among an array of 4, 8, or 12 items (perceptual manipulation) and then, depending on the color of the array, made a saccade toward, away from, or at a right…

  3. A Novel Multiobjective Programming Model for Coping with Supplier Selection Disruption Risks under Mixed Uncertainties

    Directory of Open Access Journals (Sweden)

    Ying Li

    2016-01-01

    Full Text Available Supply chain has become more and more vulnerable to disruption since it is suffering widespread risk issues from inside or outside. Higher uncertainties in the supplier selection problem have gone beyond the traditional cost minimization concern. These uncertainties are related to an ever increasing product variety, more demanding customers, and a highly interconnected distribution network. This paper focuses on the supplier selection problem with disruption risks and mixed uncertainties. A novel multiobjective optimization model with mixed uncertain coefficients is developed, which maximizes the total profits and minimizes the percentage of items delivered late, percentage of items rejected, and total loss cost due to supplier dysfunction. Meanwhile, we also consider the customer demand to be a random fuzzy variable and the unit purchase cost to be a fuzzy variable. By examining a numerical example, we found that the confidence level and demand of customers have impact on the quantities purchased by customers from suppliers although the distribution of suppliers will not change. The cost, quality, and service also influence the selection of suppliers. The superevents have little influence on the distribution of supplier selection; however, when unique event occurs, the distribution of supplier selection will change.

  4. Selective disruption of the blood-brain barrier by photochemical internalization

    Science.gov (United States)

    Hirschberg, Henry; Zhang, Michelle J.; Gach, Michael H.; Uzal, Francisco A.; Chighvinadze, David; Madsen, Steen J.

    2009-02-01

    Introduction: Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that these migratory cells are protected by the blood-brain barrier (BBB) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of photochemical internalization (PCI) to selectively disrupt the BBB in rats. This will permit access of anti-cancer drugs to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: PCI treatment, coupling a macromolecule therapy of Clostridium perfringens (Cl p) epsilon prototoxin with AlPcS2a-PDT, was performed on non-tumor bearing inbred Fisher rats. T1-weighted post-contrast magnetic resonance imaging (MRI) scans were used to evaluate the extent of BBB disruption which can be inferred from the volume contrast enhancement. Results: The synergistic effect of PCI to disrupt the BBB was observed at a fluence level of 1 J with an intraperitoneal injection of Cl p prototoxin. At the fluence level of 2.5J, the extent of BBB opening induced by PCI was similar to the result of PDT suggesting no synergistic effect evoked under these conditions. Conclusion: PCI was found to be highly effective and efficient for inducing selective and localized disruption of the BBB. The extent of BBB opening peaked on day 3 and the BBB was completed restored by day 18 post treatment.

  5. Experimentally replicated disruptive selection on performance traits in a Caribbean lizard.

    Science.gov (United States)

    Calsbeek, Ryan; Smith, Thomas B

    2008-02-01

    A central theme underlying studies of adaptive radiation is that ecologically mediated selection drives diversification. However, demonstrating the ecological basis of natural selection and linking this process to patterns of morphological diversity represents a formidable challenge. This is because selection experiments that test correlations between an organism's phenotype and its ecology are difficult to perform in the wild. Previous studies of Anolis lizards have shown that divergent morphologies are correlated with habitat use and have evolved repeatedly on islands throughout the Greater Antilles. Here, we show that the forms of selection acting within a species support an ecological mechanism for diversification. In natural populations, performance-related traits such as limb length are subject to correlational and disruptive selection driven by differences in habitat use. Experimental manipulations in the wild verify the same pattern of selection and indicate that both the targets and forms of selection are consistent through time. Elsewhere, we have demonstrated that these traits are heritable and should therefore evolve in response to selection. Our results provide evidence for the short-term repeatability of selection and its potency in the diversification of anoles.

  6. Fish Reproduction Is Disrupted upon Lifelong Exposure to Environmental PAHs Fractions Revealing Different Modes of Action

    Directory of Open Access Journals (Sweden)

    Caroline Vignet

    2016-10-01

    Full Text Available Polycyclic aromatic hydrocarbons (PAHs constitute a large family of organic pollutants emitted in the environment as complex mixtures, the compositions of which depend on origin. Among a wide range of physiological defects, PAHs are suspected to be involved in disruption of reproduction. In an aquatic environment, the trophic route is an important source of chronic exposure to PAHs. Here, we performed trophic exposure of zebrafish to three fractions of different origin, one pyrolytic and two petrogenic. Produced diets contained PAHs at environmental concentrations. Reproductive traits were analyzed at individual, tissue and molecular levels. Reproductive success and cumulative eggs number were disrupted after exposure to all three fractions, albeit to various extents depending on the fraction and concentrations. Histological analyses revealed ovary maturation defects after exposure to all three fractions as well as degeneration after exposure to a pyrolytic fraction. In testis, hypoplasia was observed after exposure to petrogenic fractions. Genes expression analysis in gonads has allowed us to establish common pathways such as endocrine disruption or differentiation/maturation defects. Taken altogether, these results indicate that PAHs can indeed disrupt fish reproduction and that different fractions trigger different pathways resulting in different effects.

  7. Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

    Science.gov (United States)

    Skelly, M J; Ariwodola, O J; Weiner, J L

    2017-02-01

    Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline

  8. Disruption of Brewers' yeast by hydrodynamic cavitation: Process variables and their influence on selective release.

    Science.gov (United States)

    Balasundaram, B; Harrison, S T L

    2006-06-01

    Intracellular products, not secreted from the microbial cell, are released by breaking the cell envelope consisting of cytoplasmic membrane and an outer cell wall. Hydrodynamic cavitation has been reported to cause microbial cell disruption. By manipulating the operating variables involved, a wide range of intensity of cavitation can be achieved resulting in a varying extent of disruption. The effect of the process variables including cavitation number, initial cell concentration of the suspension and the number of passes across the cavitation zone on the release of enzymes from various locations of the Brewers' yeast was studied. The release profile of the enzymes studied include alpha-glucosidase (periplasmic), invertase (cell wall bound), alcohol dehydrogenase (ADH; cytoplasmic) and glucose-6-phosphate dehydrogenase (G6PDH; cytoplasmic). An optimum cavitation number Cv of 0.13 for maximum disruption was observed across the range Cv 0.09-0.99. The optimum cell concentration was found to be 0.5% (w/v, wet wt) when varying over the range 0.1%-5%. The sustained effect of cavitation on the yeast cell wall when re-circulating the suspension across the cavitation zone was found to release the cell wall bound enzyme invertase (86%) to a greater extent than the enzymes from other locations of the cell (e.g. periplasmic alpha-glucosidase at 17%). Localised damage to the cell wall could be observed using transmission electron microscopy (TEM) of cells subjected to less intense cavitation conditions. Absence of the release of cytoplasmic enzymes to a significant extent, absence of micronisation as observed by TEM and presence of a lower number of proteins bands in the culture supernatant on SDS-PAGE analysis following hydrodynamic cavitation compared to disruption by high-pressure homogenisation confirmed the selective release offered by hydrodynamic cavitation.

  9. Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium

    Science.gov (United States)

    Fan, Hanlu; Du, Xiaohong; Zhang, Jingyuan; Zheng, Han; Lu, Xiaohui; Wu, Qihui; Li, Haifeng; Wang, Han; Shi, Yi; Gao, George; Zhou, Zhuan; Tan, Dun-Xian; Li, Xiangdong

    2017-01-01

    The Ebola crisis occurred in West-Africa highlights the urgency for its clinical treatments. Currently, no Food and Drug Administration (FDA)-approved therapeutics are available. Several FDA-approved drugs, including selective estrogen receptor modulators (SERMs), possess selective anti-Ebola activities. However, the inhibitory mechanisms of these drugs remain elusive. By analyzing the structures of SERMs and their incidental biological activity (cholesterol accumulation), we hypothesized that this incidental biological activity induced by SERMs could be a plausible mechanism as to their inhibitory effects on Ebola infection. Herein, we demonstrated that the same dosages of SERMs which induced cholesterol accumulation also inhibited Ebola infection. SERMs reduced the cellular sphingosine and subsequently caused endolysosomal calcium accumulation, which in turn led to blocking the Ebola entry. Our study clarified the specific anti-Ebola mechanism of SERMs, even the cationic amphiphilic drugs (CADs), this mechanism led to the endolysosomal calcium as a critical target for development of anti-Ebola drugs. PMID:28117364

  10. Selecting the right bird model in experimental studies on endocrine disrupting chemicals

    Directory of Open Access Journals (Sweden)

    Veerle L.B. Jaspers

    2015-05-01

    Full Text Available Birds have been used as model species in ecotoxicological research for decades but have only recently been included in toxicity testing schemes. However, the avian fauna is very diverse. Given this diversity the ecology, behavior and reproduction should be considered when selecting the appropriate bird model in ecotoxicological studies. This article focusses on choosing the right bird model species for experimental studies with endocrine disrupting chemicals (EDCs. EDCs have been associated with adverse effects on the reproduction and development in birds and other wildlife. In addition, new EDCs continue to emerge and the concern for potential effects in humans and wildlife is calling for increased toxicity testing and hence appropriate model species. Common bird model species used in ecotoxicological studies investigating EDCs will be reviewed. In addition, considerations for selecting the right bird model, along with potential drawbacks and restrictions on the use of certain species will be discussed.

  11. Passive sampling of selected endocrine disrupting compounds using polar organic chemical integrative samplers

    Energy Technology Data Exchange (ETDEWEB)

    Arditsoglou, Anastasia [Environmental Pollution Control Laboratory, Chemistry Department, Aristotle University, 54 124 Thessaloniki (Greece); Voutsa, Dimitra [Environmental Pollution Control Laboratory, Chemistry Department, Aristotle University, 54 124 Thessaloniki (Greece)], E-mail: dvoutsa@chem.auth.gr

    2008-11-15

    Two types of polar organic chemical integrative samplers (pharmaceutical POCIS and pesticide POCIS) were examined for their sampling efficiency of selected endocrine disrupting compounds (EDCs). Laboratory-based calibration of POCISs was conducted by exposing them at high and low concentrations of 14 EDCs (4-alkyl-phenols, their ethoxylate oligomers, bisphenol A, selected estrogens and synthetic steroids) for different time periods. The kinetic studies showed an integrative uptake up to 28 days. The sampling rates for the individual compounds were obtained. The use of POCISs could result in an integrative approach to the quality status of the aquatic systems especially in the case of high variation of water concentrations of EDCs. The sampling efficiency of POCISs under various field conditions was assessed after their deployment in different aquatic environments. - Calibration and field performance of polar organic integrative samplers for monitoring EDCs in aquatic environments.

  12. Disruption of Saccharomyces cerevisiae by Plantaricin 149 and investigation of its mechanism of action with biomembrane model systems.

    Science.gov (United States)

    Lopes, José Luiz S; Nobre, Thatyane M; Siano, Alvaro; Humpola, Verónica; Bossolan, Nelma R S; Zaniquelli, Maria E D; Tonarelli, Georgina; Beltramini, Leila M

    2009-10-01

    The action of a synthetic antimicrobial peptide analog of Plantaricin 149 (Pln149a) against Saccharomyces cerevisiae and its interaction with biomembrane model systems were investigated. Pln149a was shown to inhibit S. cerevisiae growth by more than 80% in YPD medium, causing morphological changes in the yeast wall and remaining active and resistant to the yeast proteases even after 24 h of incubation. Different membrane model systems and carbohydrates were employed to better describe the Pln149a interaction with cellular components using circular dichroism and fluorescence spectroscopies, adsorption kinetics and surface elasticity in Langmuir monolayers. These assays showed that Pln149a does not interact with either mono/polysaccharides or zwitterionic LUVs, but is strongly adsorbed to and incorporated into negatively charged surfaces, causing a conformational change in its secondary structure from random-coil to helix upon adsorption. From the concurrent analysis of Pln149a adsorption kinetics and dilatational surface elasticity data, we determined that 2.5 muM is the critical concentration at which Pln149a will disrupt a negative DPPG monolayer. Furthermore, Pln149a exhibited a carpet-like mechanism of action, in which the peptide initially binds to the membrane, covering its surface and acquiring a helical structure that remains associated to the negatively charged phospholipids. After this electrostatic interaction, another peptide region causes a strain in the membrane, promoting its disruption.

  13. GAP1, a novel selection and counter-selection marker for multiple gene disruptions in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Regenberg, Birgitte; Hansen, J.

    2000-01-01

    We report on the use of a new homologous marker for use in multiple gene deletions in S, cerevisiae, the general amino acid permease gene (GAP1), A GAP1 strain can utilize L-citrulline as the sole nitrogen source but cannot grow in the presence of the toxic amino acid D-histidine, L-citrulline as......We report on the use of a new homologous marker for use in multiple gene deletions in S, cerevisiae, the general amino acid permease gene (GAP1), A GAP1 strain can utilize L-citrulline as the sole nitrogen source but cannot grow in the presence of the toxic amino acid D-histidine, L......-citrulline as well as D-histidine uptake is mediated solely by the general amino acid permease, and a gap1 strain is therefore able to grow in the presence of D-histidine but cannot utilize L-citrulline, Gene disruption is effected by transforming a gap1 strain with a gene cassette generated by PCR, containing GAP1...... the GAP1 gene. This is caused by recombination between two Salmonella typuimurium hisG direct repeats embracing GAP1, and will result in a sub-population of gap1 cells. Such cells are selected on a medium containing D-histidine, and may subsequently be used for a second gene disruption. Hence, multiple...

  14. Gender based disruptive selection maintains body size polymorphism in Drosophila melanogaster

    Indian Academy of Sciences (India)

    Jaya Handa; K T Chandrashekara; Khushboo Kashyap; Geetanjali Sageena; Mallikarjun N Shakarad

    2014-09-01

    Darwinian fitness in holometabolous insects like the fruit fly Drosophila melanogaster is reported to be positively correlated with body size. If large individuals in a population have higher fitness, then one would expect directional selection to operate leading to uniformly large individuals. However, size polymorphism persists in nature and needs further probing. We assessed the effect of body size on some of the fitness and fitness-related traits in replicate populations of genotypically large, genotypically small and phenotypically small D. melanogaster flies. In this study, the time taken to attain reproductive maturity and copulation duration were independent of fly size. Fecundity and longevity of large females were significantly higher when they partnered genotypically small males than when they were with genotypically larger or phenotypically small males. The increased female longevity when in association with genotypically small males was not due to selective early death of males that would release the female partner from presumed cost of persistent courtship. On the contrary, the genotypically as well as phenotypically small males had significantly higher longevity than large males. The virility of the genotypically small males was not significantly different from that of genotypically large males. Our results clearly show that selection on body size operates in the opposite direction (disruptive selection) for the two genders, thus explaining the persistence of size polymorphisms in the holometabolous insect, Drosophila melanogaster.

  15. Action of the mechanical disruption of the actin network on the gravisensitivity of the root statocyte

    Science.gov (United States)

    Lefranc, A.; Jeune, B.; Driss-Ecole, D.; Perbal, G.

    The effects of the mechanical disruption of the thin actin network of statocytes on gravisensitivity have been studied on lentil roots. Seedling roots were first inverted for 7 min (root tip upward) and then placed in the downward (normal) position for 7 min before gravitropic stimulation in the horizontal position. The period of inversion allowed the amyloplasts to move from the distal part to the proximal part of the statocyte, but did not fully sediment. When the roots were returned to the tip down position, the amyloplasts moved toward the distal part, but also did not completely sediment by the time the roots were placed horizontally. Thus, in these roots the amyloplasts could be still moving toward the distal wall after they had been replaced in the normal position and the actin network should not be fully restored. Gravisensitivity was estimated by the analysis of the dose-response curves of vertical and treated (inverted and returned to downward position) roots. The only effect, which has been observed on treated roots, was a delay of graviresponse for about 1 min. Our interpretation of this result is that in vertical roots the amyloplasts can exert tensions in the actin network that are directly transmitted to mechanoreceptors located in the plasma membrane. In roots with a partially disrupted actin network, a delay of 1 min is necessary for the amyloplasts to activate mechanoreceptors.

  16. Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal Disruption.

    Science.gov (United States)

    Master, Alyssa M; Williams, Philise N; Pothayee, Nikorn; Pothayee, Nipon; Zhang, Rui; Vishwasrao, Hemant M; Golovin, Yuri I; Riffle, Judy S; Sokolsky, Marina; Kabanov, Alexander V

    2016-09-20

    Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (>250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact.

  17. In vitro screening for endocrine disruptive activity in selected South African harbours and river mouths

    CSIR Research Space (South Africa)

    Truter, JC

    2015-12-01

    Full Text Available Various waterborne anthropogenic contaminants disrupt the endocrine systems of wildlife and humans, targeting reproductive pathways, among others. Very little is known, however, regarding the occurrence of endocrine disruptive activity in South...

  18. Weak disruptive selection and incomplete phenotypic divergence in two classic examples of sympatric speciation: cameroon crater lake cichlids.

    Science.gov (United States)

    Martin, Christopher H

    2012-10-01

    Recent documentation of a few compelling examples of sympatric speciation led to a proliferation of theoretical models. Unfortunately, plausible examples from nature have rarely been used to test model predictions, such as the initial presence of strong disruptive selection. Here I estimated the form and strength of selection in two classic examples of sympatric speciation: radiations of Cameroon cichlids restricted to Lakes Barombi Mbo and Ejagham. I measured five functional traits and relative growth rates in over 500 individuals within incipient species complexes from each lake. Disruptive selection was prevalent in both groups on single and multivariate trait axes but weak relative to stabilizing selection on other traits and most published estimates of disruptive selection. Furthermore, despite genetic structure, assortative mating, and bimodal species-diagnostic coloration, trait distributions were unimodal in both species complexes, indicating the earliest stages of speciation. Long waiting times or incomplete sympatric speciation may result when disruptive selection is initially weak. Alternatively, I present evidence of additional constraints in both species complexes, including weak linkage between coloration and morphology, reduced morphological variance aligned with nonlinear selection surfaces, and minimal ecological divergence. While other species within these radiations show complete phenotypic separation, morphological and ecological divergence in these species complexes may be slow or incomplete outside optimal parameter ranges, in contrast to rapid divergence of their sexual coloration.

  19. Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.

    Science.gov (United States)

    Planche, Vincent; Panatier, Aude; Hiba, Bassem; Ducourneau, Eva-Gunnel; Raffard, Gerard; Dubourdieu, Nadège; Maitre, Marlène; Lesté-Lasserre, Thierry; Brochet, Bruno; Dousset, Vincent; Desmedt, Aline; Oliet, Stéphane H; Tourdias, Thomas

    2017-02-01

    Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. From Disruptive Action to Political Lobbying: Causes and Consequences of the Institutionalization of Forms of Contention in a Protest Campaign

    Directory of Open Access Journals (Sweden)

    Zdeněk Janík

    2007-12-01

    Full Text Available The aim of the paper is to analyze the causes of the gradual institutionalization of tactics and strategies of the antimilitaristic protest campaign Arms, or Human Rights? [Zbraně, nebo lidská práva?] in the period 1997–2007. The campaign’s collective action evolved from an episodic contentious collective action to sustained interaction with opponents under the auspices of a newly formed social movement organization Nesehnutí and the campaign’s forms of contention progressed from radical, disruptive actions against opponents to political lobbying and negotiations with political actors and allies within the political establishment. The analysis of interaction between the campaign’s internal dynamics and its external conditions will clarify how the campaign’s active appropriation of the European Union Code of Conduct on Arms Exports and its politically binding criteria opened to the actors in the campaign an institutional access to negotiations of their claims with political actors and how the institutional access influenced interactive and communicative processes among the actors within the campaign and brought on the change in the campaign’s forms of contention. Apart from analysis of written documents, the research relies on data collected by means of participant-observation from April 2005 to May 2007.

  1. p53's mitochondrial translocation and MOMP action is independent of Puma and Bax and severely disrupts mitochondrial membrane integrity

    Institute of Scientific and Technical Information of China (English)

    Sonja Wolff; Susan Erster; Gustavo Palacios; Ute M Moll

    2008-01-01

    p53's apoptotic program consists of transcription-dependent and transcription-independent pathways. In the latter, physical interactions between mitochondrial p53 and anti-and pro-apoptotic members of the Bcl2 family of mitochondrial permeability regulators are central. Using isogenic cell systems with defined deficiencies, we characterize in detail how mitochondrial p53 contributes to mitochondrial permeabilization, to what extent its action depends on other key Bcl2 family members and define its release activity. We show that mitochondrial p53 is highly efficient in inducing the release of soluble and insoluble apoptogenic factors by severely disrupting outer and inner mitochondrial membrane integrity. This action is associated with wild-type p53-induced oligomerization of Bax, Bak and VDAC and the formation of a stress-induced endogenous complex between p53 and cyclophilin D, normally located at the inner membrane. Tumor-derived p53 mutants are deficient in activating the Bax/Bak lipid pore. These actions are independent of Puma and Bax. Importantly, the latter distinguishes the mitochondrial from the cytosolic p53 death pathway.

  2. Credibility-Based Biobjective Fuzzy Optimization for Supplier Selection Problem with Disruption

    Directory of Open Access Journals (Sweden)

    Xuejie Bai

    2015-01-01

    Full Text Available This paper addresses a supplier selection problem in which a buyer procures multiple products from multiple suppliers under disruption risk. The problem is formulated as a new credibility-based biobjective fuzzy optimization model. In the proposed model, cost, capacity, and demand are characterized by fuzzy variables with known possibility distributions. The objectives of our model are to maximize the total quality of purchased products and minimize the expected total cost. Two credibility constraints are used to guarantee that the chance about the supplier capacity and buyer demand can satisfy the predetermined levels. The main concern in solving the optimization model is to calculate the expected value of the objective function and the credibility in the constraints. When the key parameters are mutually independent triangular fuzzy variables, the expected cost objective and credibility constraints can be transformed into their equivalent forms. Taking advantage of the structural characteristics of the equivalent model, the goal programming method is employed to solve the supplier selection model, which can be solved by conventional optimization method. At last, some numerical experiments have been performed to illustrate the effectiveness of the proposed model and solution strategy.

  3. Feature selection for disruption prediction from scratch in JET by using genetic algorithms and probabilistic predictors

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, Augusto, E-mail: augusto.pereira@ciemat.es [Laboratorio Nacional de Fusión, CIEMAT, Madrid (Spain); Vega, Jesús; Moreno, Raúl [Laboratorio Nacional de Fusión, CIEMAT, Madrid (Spain); Dormido-Canto, Sebastián [Dpto. Informática y Automática – UNED, Madrid (Spain); Rattá, Giuseppe A. [Laboratorio Nacional de Fusión, CIEMAT, Madrid (Spain); Pavón, Fernando [Dpto. Informática y Automática – UNED, Madrid (Spain)

    2015-10-15

    Recently, a probabilistic classifier has been developed at JET to be used as predictor from scratch. It has been applied to a database of 1237 JET ITER-like wall (ILW) discharges (of which 201 disrupted) with good results: success rate of 94% and false alarm rate of 4.21%. A combinatorial analysis between 14 features to ensure the selection of the best ones to achieve good enough results in terms of success rate and false alarm rate was performed. All possible combinations with a number of features between 2 and 7 were tested and 9893 different predictors were analyzed. An important drawback in this analysis was the time required to compute the results that can be estimated in 1731 h (∼2.4 months). Genetic algorithms (GA) are searching algorithms that simulate the process of natural selection. In this article, the GA and the Venn predictors are combined with the objective not only of finding good enough features within the 14 available ones but also of reducing the computational time requirements. Five different performance metrics as measures of the GA fitness function have been evaluated. The best metric was the measurement called Informedness, with just 6 generations (168 predictors at 29.4 h).

  4. Action Selection and Operant Conditioning: A Neurorobotic Implementation

    Directory of Open Access Journals (Sweden)

    André Cyr

    2015-01-01

    Full Text Available Action selection (AS is thought to represent the mechanism involved by natural agents when deciding what should be the next move or action. Is there a functional elementary core sustaining this cognitive process? Could we reproduce the mechanism with an artificial agent and more specifically in a neurorobotic paradigm? Unsupervised autonomous robots may require a decision-making skill to evolve in the real world and the bioinspired approach is the avenue explored through this paper. We propose simulating an AS process by using a small spiking neural network (SNN as the lower neural organisms, in order to control virtual and physical robots. We base our AS process on a simple central pattern generator (CPG, decision neurons, sensory neurons, and motor neurons as the main circuit components. As novelty, this study targets a specific operant conditioning (OC context which is relevant in an AS process; choices do influence future sensory feedback. Using a simple adaptive scenario, we show the complementarity interaction of both phenomena. We also suggest that this AS kernel could be a fast track model to efficiently design complex SNN which include a growing number of input stimuli and motor outputs. Our results demonstrate that merging AS and OC brings flexibility to the behavior in generic dynamical situations.

  5. Disruption of growth hormone receptor prevents calorie restriction from improving insulin action and longevity.

    Directory of Open Access Journals (Sweden)

    Michael S Bonkowski

    Full Text Available Most mutations that delay aging and prolong lifespan in the mouse are related to somatotropic and/or insulin signaling. Calorie restriction (CR is the only intervention that reliably increases mouse longevity. There is considerable phenotypic overlap between long-lived mutant mice and normal mice on chronic CR. Therefore, we investigated the interactive effects of CR and targeted disruption or knock out of the growth hormone receptor (GHRKO in mice on longevity and the insulin signaling cascade. Every other day feeding corresponds to a mild (i.e. 15% CR which increased median lifespan in normal mice but not in GHRKO mice corroborating our previous findings on the effects of moderate (30% CR on the longevity of these animals. To determine why insulin sensitivity improves in normal but not GHRKO mice in response to 30% CR, we conducted insulin stimulation experiments after one year of CR. In normal mice, CR increased the insulin stimulated activation of the insulin signaling cascade (IR/IRS/PI3K/AKT in liver and muscle. Livers of GHRKO mice responded to insulin by increased activation of the early steps of insulin signaling, which was dissipated by altered PI3K subunit abundance which putatively inhibited AKT activation. In the muscle of GHRKO mice, there was elevated downstream activation of the insulin signaling cascade (IRS/PI3K/AKT in the absence of elevated IR activation. Further, we found a major reduction of inhibitory Ser phosphorylation of IRS-1 seen exclusively in GHRKO muscle which may underpin their elevated insulin sensitivity. Chronic CR failed to further modify the alterations in insulin signaling in GHRKO mice as compared to normal mice, likely explaining or contributing to the absence of CR effects on insulin sensitivity and longevity in these long-lived mice.

  6. The effects of disruptive and stabilizing selection on body size in Drosophila melanogaster. III. Genetic analysis of two lines with different reactions to disruptive selection with mating of opposite extremes

    NARCIS (Netherlands)

    Bos, M.; Scharloo, W.

    1974-01-01

    A genetic analysis was made of two lines which when subjected to disruptive selection with compulsary mating of opposite extremes (D−) showed a different response viz. one, D−-1, showing predominantly an increase of environmental variance and possibly interaction variance, the other, D−-2, showing a

  7. The effects of disruptive and stabilizing selection on body size in Drosophila melanogaster. III. Genetic analysis of two lines with different reactions to disruptive selection with mating of opposite extremes

    NARCIS (Netherlands)

    Bos, M.; Scharloo, W.

    1974-01-01

    A genetic analysis was made of two lines which when subjected to disruptive selection with compulsary mating of opposite extremes (D−) showed a different response viz. one, D−-1, showing predominantly an increase of environmental variance and possibly interaction variance, the other, D−-2, showing

  8. Endocrine-Disrupting Chemicals: Some Actions of POPs on Female Reproduction

    Directory of Open Access Journals (Sweden)

    Ewa L. Gregoraszczuk

    2013-01-01

    Full Text Available Persistent organic pollutants (POPs, such as polychlorinated dibenzo-p-dioxins (PCDDs and dibenzofurans (PCDFs, polychlorinated biphenyls (PCBs, and polybrominated ethers (PBDEs, chloronaftalens (PCNs, and bisphenol A (BPA, are stable, lipophilic pollutants that affect fertility and cause serious reproductive problems, including ovotoxic action, lack of ovulation, premature ovarian failure (POF, or polycystic ovarian syndrome (PCOS. Most of the representatives of POPs influence the activation of transcription factors, not only activation of aromatic hydrocarbon receptor (AhR, but also the steroid hormone receptors. This minireview will focus on a variety of PAH activities in oocyte, ovary, placenta, and mammary gland. The complexity and diversity of factors belonging to POPs and disorders of the reproductive function of women indicate that the impact of environmental pollution as an important determinant factor in fertility should not be minimize.

  9. Female Infertility and Disrupted Angiogenesis Are Actions of Specific Follistatin Isoforms

    Science.gov (United States)

    Lin, Shyr-Yeu; Craythorn, Rebecca G.; O’Connor, Anne E.; Matzuk, Martin M.; Girling, Jane E.; Morrison, John R.; de Kretser, David M.

    2008-01-01

    The circulating and tissue-bound forms of follistatin (FST315 and FST288, respectively) modulate the actions of activins. FST knockout (KO/null) mice, lacking both isoforms, die perinatally with defects in lung, skin, and the musculoskeletal system. Using constructs of the human FST gene engineered to enable expression of each isoform under the control of natural regulatory elements, transgenic mouse lines were created and crossed with FST null mice to attempt to rescue the neonatal lethality. FST288 expression alone did not rescue the neonatal lethality, but mice expressing FST315 on the KO background survived to adulthood with normal lung and skin morphology and partial reversal of the musculoskeletal defects noted in FST KO mice. The FST315 rescue mice displayed a short period of neonatal growth retardation, impaired tail growth, and female infertility. The latter may be due to failure of corpus luteum formation, a decline in the ovarian follicular population, and an augmented uterine inflammatory response to mating. Failure of corpus luteum formation and impaired tail growth indicate abnormal vascularization and suggest that FST288 is required for the promotion of angiogenesis. The augmented uterine inflammatory response may result from the failure of FST315 to modulate the proinflammatory actions of activin A in the uterus or may result from the altered steroid milieu associated with the ovarian abnormalities. Although we cannot definitively conclude that the remaining defects are due to the absence of a particular isoform or due to variable expression of each, these models have demonstrated novel physiological processes that are influenced by FST. PMID:17932109

  10. A high efficiency gene disruption strategy using a positive-negative split selection marker and electroporation for Fusarium oxysporum.

    Science.gov (United States)

    Liang, Liqin; Li, Jianqiang; Cheng, Lin; Ling, Jian; Luo, Zhongqin; Bai, Miao; Xie, Bingyan

    2014-11-01

    The Fusarium oxysporum species complex consists of fungal pathogens that cause serial vascular wilt disease on more than 100 cultivated species throughout the world. Gene function analysis is rapidly becoming more and more important as the whole-genome sequences of various F. oxysporum strains are being completed. Gene-disruption techniques are a common molecular tool for studying gene function, yet are often a limiting step in gene function identification. In this study we have developed a F. oxysporum high-efficiency gene-disruption strategy based on split-marker homologous recombination cassettes with dual selection and electroporation transformation. The method was efficiently used to delete three RNA-dependent RNA polymerase (RdRP) genes. The gene-disruption cassettes of three genes can be constructed simultaneously within a short time using this technique. The optimal condition for electroporation is 10μF capacitance, 300Ω resistance, 4kV/cm field strength, with 1μg of DNA (gene-disruption cassettes). Under these optimal conditions, we were able to obtain 95 transformants per μg DNA. And after positive-negative selection, the transformants were efficiently screened by PCR, screening efficiency averaged 85%: 90% (RdRP1), 85% (RdRP2) and 77% (RdRP3). This gene-disruption strategy should pave the way for high throughout genetic analysis in F. oxysporum. Copyright © 2014 Elsevier GmbH. All rights reserved.

  11. Embodied perspective-taking indicated by selective disruption from aberrant self motion.

    Science.gov (United States)

    Gardner, Mark R; Stent, Chloé; Mohr, Christine; Golding, John F

    2017-03-01

    Spatial perspective-taking that involves imagined changes in one's spatial orientation is facilitated by vestibular stimulation inducing a congruent sensation of self-motion. We examined further the role of vestibular resources in perspective-taking by evaluating whether aberrant and conflicting vestibular stimulation impaired perspective-taking performance. Participants (N = 39) undertook either an "own body transformation" (OBT) task, requiring speeded spatial judgments made from the perspective of a schematic figure, or a control task requiring reconfiguration of spatial mappings from one's own visuo-spatial perspective. These tasks were performed both without and with vestibular stimulation by whole-body Coriolis motion, according to a repeated measures design, balanced for order. Vestibular stimulation was found to impair performance during the first minute post stimulus relative to the stationary condition. This disruption was task-specific, affecting only the OBT task and not the control task, and dissipated by the second minute post-stimulus. Our experiment thus demonstrates selective temporary impairment of perspective-taking from aberrant vestibular stimulation, implying that uncompromised vestibular resources are necessary for efficient perspective-taking. This finding provides evidence for an embodied mechanism for perspective-taking whereby vestibular input contributes to multisensory processing underlying bodily and social cognition. Ultimately, this knowledge may contribute to the design of interventions that help patients suffering sudden vertigo adapt to the cognitive difficulties caused by aberrant vestibular stimulation.

  12. Disruption of action potential and calcium signaling properties in malformed myofibers from dystrophin-deficient mice.

    Science.gov (United States)

    Hernández-Ochoa, Erick O; Pratt, Stephen J P; Garcia-Pelagio, Karla P; Schneider, Martin F; Lovering, Richard M

    2015-04-01

    Duchenne muscular dystrophy (DMD), the most common and severe muscular dystrophy, is caused by the absence of dystrophin. Muscle weakness and fragility (i.e., increased susceptibility to damage) are presumably due to structural instability of the myofiber cytoskeleton, but recent studies suggest that the increased presence of malformed/branched myofibers in dystrophic muscle may also play a role. We have previously studied myofiber morphology in healthy wild-type (WT) and dystrophic (MDX) skeletal muscle. Here, we examined myofiber excitability using high-speed confocal microscopy and the voltage-sensitive indicator di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate (di-8-ANEPPS) to assess the action potential (AP) properties. We also examined AP-induced Ca(2+) transients using high-speed confocal microscopy with rhod-2, and assessed sarcolemma fragility using elastimetry. AP recordings showed an increased width and time to peak in malformed MDX myofibers compared to normal myofibers from both WT and MDX, but no significant change in AP amplitude. Malformed MDX myofibers also exhibited reduced AP-induced Ca(2+) transients, with a further Ca(2+) transient reduction in the branches of malformed MDX myofibers. Mechanical studies indicated an increased sarcolemma deformability and instability in malformed MDX myofibers. The data suggest that malformed myofibers are functionally different from myofibers with normal morphology. The differences seen in AP properties and Ca(2+) signals suggest changes in excitability and remodeling of the global Ca(2+) signal, both of which could underlie reported weakness in dystrophic muscle. The biomechanical changes in the sarcolemma support the notion that malformed myofibers are more susceptible to damage. The high prevalence of malformed myofibers in dystrophic muscle may contribute to the progressive strength loss and fragility seen in dystrophic muscles. © 2015 The Authors. Physiological Reports published by Wiley

  13. Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection.

    Science.gov (United States)

    Xia, Jiangyan; Wang, Hongjun; Guo, Jianfei; Zhang, Zhijie; Coder, Brandon; Su, Dong-Ming

    2012-06-01

    The hymic medulla plays an essential role in the generation of central tolerance by eliminating self-reactive T-cell clones through thymic negative selection and developing natural regulatory T cells. Age-related FoxN1 decline induces disruption of medullary thymic epithelial cells (mTECs). However, it is unknown whether this perturbs central tolerance to increase autoimmune predisposition in the elderly. Using a loxP-floxed-FoxN1 (FoxN1(flox)) mouse model, which exhibits a spontaneous ubiquitous deletion of FoxN1 with age to accelerate thymic aging, we investigated whether disruption of steady-state thymic medulla results in an increase of autoimmune-prone associated with age. We demonstrated age-associated ubiquitous loss of FoxN1(flox)-formed two-dimensional thymic epithelial cysts were primarily located in the medulla. This resulted in disruption of thymic medullary steady state, with evidence of perturbed negative selection, including reduced expression of the autoimmune regulator (Aire) gene and disrupted accumulation of thymic dendritic cells in the medulla, which are required for negative selection. These provoke autoimmune phenotypes, including increased inflammatory cell infiltration in multiple organs in these mice. This finding in an animal model provides a mechanistic explanation of increased susceptibility to autoimmunity in aged humans, although they may not show clinic manifestations without induction.

  14. Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action

    Science.gov (United States)

    Taylor, Matthew J.; Freemantle, Nick; Geddes, John R.; Bhagwagar, Zubin

    2008-01-01

    Context: Selective serotonin reuptake inhibitors (SSRIs) are often described as having a delayed onset of effect in the treatment of depression. However, some trials have reported clinical improvement as early as the first week of treatment. Objective: To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression. Data Sources: Trials identified by searching CENTRAL, The Cochrane Collaboration database of controlled trials (2005), and the reference lists of identified trials and other systematic reviews. Study Selection: Randomized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment (50 trials from >500 citations identified). Trials were excluded if limited to participants older than 65 years or specific comorbidities. Data Extraction: Data were extracted on trial design, participant characteristics, and outcomes by a single reviewer. Data Synthesis: Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment. In the primary analysis, the pattern of response seen was tested against alternative models of onset of response. The primary analysis incorporated data from 28 randomized controlled trials (n=5872). A model of early treatment response best fit the experimental data. Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use. A secondary analysis indicated an increased chance of achieving a 50% reduction in Hamilton Depression Rating Scale scores by 1 week (relative risk, 1.64; 95% confidence interval, 1.2-2.25) with SSRI treatment compared with placebo. Conclusions: Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6

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

    Science.gov (United States)

    Jiao, Baowei; Cheng, Christopher H K

    2010-06-01

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

  16. Removal of Selected Endocrine Disrupting Chemicals During On-Site Wastewater Treatment Using A Constructed Wetland

    Science.gov (United States)

    Significant research has shown that domestic and industrial wastewater can be a source of endocrine disrupting chemicals (EDCs) to the environment. Much of this research has focused on municipal and industrial centralized wastewater treatment plants. These plants have been show...

  17. Biotransformation of endocrine disrupting compounds by selected phase I and phase II enzymes--formation of estrogenic and chemically reactive metabolites by cytochromes P450 and sulfotransferases.

    Science.gov (United States)

    Reinen, J; Vermeulen, N P E

    2015-01-01

    The endocrine system is a major communication system in the body and is involved in maintenance of the reproductive system, fetal development, growth, maturation, energy production, and metabolism,. The endocrine system responds to the needs of an organism by secreting a wide variety of hormones that enable the body to maintain homeostasis, to respond to external stimuli, and to follow various developmental programs. This occurs through complex signalling cascades,with multiple sites at which the signals can be regulated. Endocrine disrupting compounds (EDCs) affect the endocrine system by simulating the action of the naturally produced hormones, by inhibiting the action of natural hormones, by changing the function and synthesis of hormone receptors, or by altering the synthesis, transport, metabolism, and elimination of hormones. It has been established that exposure to environmental EDCs is a risk factor for disruption of reproductive development and oncogenesis in both humans and wildlife. For accurate risk assessment of EDCs, the possibility of bioactivation through biotransformation processes needs to be included since neglecting these mechanisms may lead to undervaluation of adverse effects on human health caused by EDCs and/or their metabolites. This accurate risk assessment should include: (1) possibility of EDCs to be bioactivated into metabolites with enhanced endocrine disruption (ED) effects, and (2) possibility of EDCs to be biotransformed into reactive metabolites that may cause DNA damage. Here, we present an overview of different metabolic enzymes that are involved in the biotransformation of EDCs. In addition, we describe how biotransformation by Cytochromes P450 (CYPs), human estrogen sulfotransferase 1E1 (SULT1E1) and selected other phase II enzymes, can lead to the formation of bioactive metabolites. This review mainly focuses on CYP- and SULT-mediated bioactivation of estrogenic EDCs and summarizes our views on this topic while also showing

  18. The origin of gender dimorphism in animal-dispersed plants: disruptive selection in a model of social evolution.

    Science.gov (United States)

    Biernaskie, Jay M

    2010-06-01

    Dioecy (separate sexes) in plants is associated with animal fruit dispersal, but hypotheses for a role of dispersal in the origin of gender dimorphism have received little support. Here, I present a patch-structured model to explore the conditions that favor dimorphism when dispersal is coupled with sex allocation. The model shows that if the proportion of fruits dispersed from a cosexual plant increases with its allocation to fruits (causing accelerating fitness returns from dispersed fruits), disruptive selection can arise when the cost of dispersal is minimal and the correlation among patchmates (i.e., relatedness) is high. In reality, however, the proportion of fruits dispersed from a plant's patch may decline with further allocation to fruits. Even in this case, novel contexts that lead to disruptive selection on sex allocation are discovered, occurring when dispersal costs are high and relatedness is low, which causes accelerating returns from nondispersed fruits. Hence, surprisingly, gender dimorphism can evolve because female specialists are better able to escape local competition or to succeed in it. Building on the few existing models of disruptive selection on social traits, the mechanisms here show that selection for relaxed local competition (cooperation) can sometimes facilitate diversification and sometimes prevent it.

  19. Actions of estrogens and endocrine disrupting chemicals on human prostate stem/progenitor cells and prostate cancer risk.

    Science.gov (United States)

    Hu, Wen-Yang; Shi, Guang-Bin; Hu, Dan-Ping; Nelles, Jason L; Prins, Gail S

    2012-05-06

    Estrogen reprogramming of the prostate gland as a function of developmental exposures (aka developmental estrogenization) results in permanent alterations in structure and gene expression that lead to an increased incidence of prostatic lesions with aging. Endocrine disrupting chemicals (EDCs) with estrogenic activity have been similarly linked to an increased prostate cancer risk. Since it has been suggested that stem cells and cancer stem cells are potential targets of cancer initiation and disease management, it is highly possible that estrogens and EDCs influence the development and progression of prostate cancer through reprogramming and transforming the prostate stem and early stage progenitor cells. In this article, we review recent literature highlighting the effects of estrogens and EDCs on prostate cancer risk and discuss recent advances in prostate stem/progenitor cell research. Our laboratory has recently developed a novel prostasphere model using normal human prostate stem/progenitor cells and established that these cells express estrogen receptors (ERs) and are direct targets of estrogen action. Further, using a chimeric in vivo prostate model derived from these normal human prostate progenitor cells, we demonstrated for the first time that estrogens initiate and promote prostatic carcinogenesis in an androgen-supported environment. We herein discuss these findings and highlight new evidence using our in vitro human prostasphere assay for perturbations in human prostate stem cell self-renewal and differentiation by natural steroids as well as EDCs. These findings support the hypothesis that tissue stem cells may be direct EDC targets which may underlie life-long reprogramming as a consequence of developmental and/or transient adult exposures.

  20. Nuclear facility decommissioning and site remedial actions: a selected bibliography

    Energy Technology Data Exchange (ETDEWEB)

    Owen, P.T.; Knox, N.P.; Fielden, J.M.; Johnson, C.A.

    1982-09-01

    This bibliography contains 693 references with abstracts on the subject of nuclear facility decommissioning, uranium mill tailings management, and site remedial actions. Foreign, as well as domestic, literature of all types - technical reports, progress reports, journal articles, conference papers, symposium proceedings, theses, books, patents, legislation, and research project descriptions - has been included in this publication. The bibliography contains scientific (basic research as well as applied technology), economic, regulatory, and legal literature pertinent to the US Department of Energy's Remedial Action Program. Major chapters are Surplus Facilities Management Program, Nuclear Facilities Decommissioning, Formerly Utilized Sites Remedial Action Program, Uranium Mill Tailings Remedial Action Program, Grand Junction Remedial Action Program, and Uranium Mill Tailings Management. Chapter sections for chapters 1 and 2 include: Design, Planning, and Regulations; Site Surveys; Decontamination Studies; Dismantlement and Demolition; Land Decontamination and Reclamation; Waste Disposal; and General Studies. The references within each chapter are arranged alphabetically by leading author. References having no individual author are arranged by corporate author or by title. Indexes are provided for (1) author; (2) corporate affiliation; (3) title; (4) publication description; (5) geographic location; and (6) keywords. An appendix of 202 bibliographic references without abstracts or indexes has been included in this bibliography. This appendix represents literature identified but not abstracted due to time constraints.

  1. Selective Disruption of Respiratory Supercomplexes as a New Strategy to Suppress Her2high Breast Cancer

    Science.gov (United States)

    Sachaphibulkij, Karishma; Stursa, Jan; Bezawork-Geleta, Ayenachew; Blecha, Jan; Endaya, Berwini; Werner, Lukas; Cerny, Jiri; Zobalova, Renata; Goodwin, Jacob; Spacek, Tomas; Alizadeh Pesdar, Elham; Yan, Bing; Nguyen, Maria Nga; Vondrusova, Magdalena; Sobol, Margaryta; Jezek, Petr; Hozak, Pavel; Truksa, Jaroslav; Dong, Lan-Feng

    2017-01-01

    Abstract Aims: Expression of the HER2 oncogene in breast cancer is associated with resistance to treatment, and Her2 may regulate bioenergetics. Therefore, we investigated whether disruption of the electron transport chain (ETC) is a viable strategy to eliminate Her2high disease. Results: We demonstrate that Her2high cells and tumors have increased assembly of respiratory supercomplexes (SCs) and increased complex I-driven respiration in vitro and in vivo. They are also highly sensitive to MitoTam, a novel mitochondrial-targeted derivative of tamoxifen. Unlike tamoxifen, MitoTam efficiently suppresses experimental Her2high tumors without systemic toxicity. Mechanistically, MitoTam inhibits complex I-driven respiration and disrupts respiratory SCs in Her2high background in vitro and in vivo, leading to elevated reactive oxygen species production and cell death. Intriguingly, higher sensitivity of Her2high cells to MitoTam is dependent on the mitochondrial fraction of Her2. Innovation: Oncogenes such as HER2 can restructure ETC, creating a previously unrecognized therapeutic vulnerability exploitable by SC-disrupting agents such as MitoTam. Conclusion: We propose that the ETC is a suitable therapeutic target in Her2high disease. Antioxid. Redox Signal. 26, 84–103. PMID:27392540

  2. Response selection difficulty modulates the behavioral impact of rapidly learnt action effects.

    Directory of Open Access Journals (Sweden)

    Uta eWolfensteller

    2014-12-01

    Full Text Available It is well established that we can pick up action effect associations when acting in a free-choice intentional mode. However, it is less clear whether and when action effect associations are learnt and actually affect behavior if we are acting in a forced-choice mode, applying a specific stimulus-response (S-R rule. In the present study, we investigated whether response selection difficulty imposed by S-R rules influences the initial rapid learning and the behavioral expression of previously learnt but weakly practiced action effect associations when those are re-activated by effect exposure. Experiment 1 showed that the rapid acquisition of action effect associations is not directly influenced by response selection difficulty. By contrast, the behavioral expression of re-activated action effect associations is prevented when actions are directly activated by highly over-learnt response cues and thus response selection difficulty is low. However, all three experiments showed that if response selection difficulty is sufficiently high during re-activation, the same action effect associations do influence behavior. Experiment 2 and 3 revealed that the effect of response selection difficulty cannot be fully reduced to giving action effects more time to prime an action, but seems to reflect competition during response selection. Finally, the present data suggest that when multiple novel rules are rapidly learnt in succession, which requires a lot of flexibility, action effect associations continue to influence behavior only if response selection difficulty is sufficiently high. Thus, response selection difficulty might modulate the impact of experiencing multiple learning episodes on action effect expression and learning, possibly via inducing different strategies.

  3. The Use of Evolution in a Central Action Selection Model

    Directory of Open Access Journals (Sweden)

    F. Montes-Gonzalez

    2007-01-01

    Full Text Available The use of effective central selection provides flexibility in design by offering modularity and extensibility. In earlier papers we have focused on the development of a simple centralized selection mechanism. Our current goal is to integrate evolutionary methods in the design of non-sequential behaviours and the tuning of specific parameters of the selection model. The foraging behaviour of an animal robot (animat has been modelled in order to integrate the sensory information from the robot to perform selection that is nearly optimized by the use of genetic algorithms. In this paper we present how selection through optimization finally arranges the pattern of presented behaviours for the foraging task. Hence, the execution of specific parts in a behavioural pattern may be ruled out by the tuning of these parameters. Furthermore, the intensive use of colour segmentation from a colour camera for locating a cylinder sets a burden on the calculations carried out by the genetic algorithm.

  4. 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.

  5. Phosphoproteome and transcription factor activity profiling identify actions of the anti-inflammatory agent UTL-5g in LPS stimulated RAW 264.7 cells including disrupting actin remodeling and STAT-3 activation.

    Science.gov (United States)

    Carruthers, Nicholas J; Stemmer, Paul M; Chen, Ben; Valeriote, Frederick; Gao, Xiaohua; Guatam, Subhash C; Shaw, Jiajiu

    2017-09-15

    UTL-5g is a novel small-molecule TNF-alpha modulator. It reduces cisplatin-induced side effects by protecting kidney, liver, and platelets, thereby increasing tolerance for cisplatin. UTL-5g also reduces radiation-induced acute liver toxicity. The mechanism of action for UTL-5g is not clear at the present time. A phosphoproteomic analysis to a depth of 4943 phosphopeptides and a luminescence-based transcription factor activity assay were used to provide complementary analyses of signaling events that were disrupted by UTL-5g in RAW 264.7 cells. Transcriptional activity downstream of the interferon gamma, IL-6, type 1 Interferon, TGF-β, PKC/Ca(2+) and the glucocorticoid receptor pathways were disrupted by UTL-5g. Phosphoproteomic analysis indicated that hyperphosphorylation of proteins involved in actin remodeling was suppressed by UTL-5g (gene set analysis, FDR 5g. This global characterization of UTL-5g activity in a macrophage cell line discovered that it disrupts selected aspects of LPS signaling including Stat3 activation and actin remodeling providing new insight on how UTL-5g acts to reduce cisplatin-induced side effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Selecting a process paradigm for an emergent disruptive technology: Evidence from the emerging microsystems technology base

    Energy Technology Data Exchange (ETDEWEB)

    Smith, J.H. [Sandia National Labs., Albuquerque, NM (United States). Intelligent Micromachine Dept.; Walsh, S.T. [New Jersey Inst. of Tech., Newark, NJ (United States). School of Industrial Management

    1998-08-01

    Emergent technologies often suffer from a lack of an installed manufacturing base and an obvious dominant manufacturing technique. Firms which base their search for competitive advantage on emergent disruptive technologies must make hard production choices and endure major manufacturing discontinuities. The authors as well as many other firms, are now facing these challenges with the embrace of microsystems technologies. They add to the literature by providing a set of criteria for firms investing in emergent disruptive technologies. Sandia has long been associated as a pioneer in the development of new manufacturing techniques. Microsystems is just the current in a long line of manufacturing technologies that have been considered for mission critical system applications. The authors as well as others, have had to make the hard choice of investing in specific microsystems manufacturing techniques. Important considerations in the technique choice include: the existing internal manufacturing bases, commonality with existing commercial manufacturing infrastructure, current and projected critical performance characteristics, learning curves, the promise to add new but un-thought-of functionally to existing systems, and the anticipated ability to qualify devices built from the technique for mission critical applications.

  7. Selecting a process paradigm for an emergent disruptive technology: Evidence from the emerging microsystems technology base

    Energy Technology Data Exchange (ETDEWEB)

    Smith, J.H. [Sandia National Labs., Albuquerque, NM (United States). Intelligent Micromachine Dept.; Walsh, S.T. [New Jersey Inst. of Tech., Newark, NJ (United States). School of Industrial Management

    1998-08-01

    Emergent technologies often suffer from a lack of an installed manufacturing base and an obvious dominant manufacturing technique. Firms which base their search for competitive advantage on emergent disruptive technologies must make hard production choices and endure major manufacturing discontinuities. The authors as well as many other firms, are now facing these challenges with the embrace of microsystems technologies. They add to the literature by providing a set of criteria for firms investing in emergent disruptive technologies. Sandia has long been associated as a pioneer in the development of new manufacturing techniques. Microsystems is just the current in a long line of manufacturing technologies that have been considered for mission critical system applications. The authors as well as others, have had to make the hard choice of investing in specific microsystems manufacturing techniques. Important considerations in the technique choice include: the existing internal manufacturing bases, commonality with existing commercial manufacturing infrastructure, current and projected critical performance characteristics, learning curves, the promise to add new but un-thought-of functionally to existing systems, and the anticipated ability to qualify devices built from the technique for mission critical applications.

  8. Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation.

    Science.gov (United States)

    Soden, Marta E; Jones, Graham L; Sanford, Christina A; Chung, Amanda S; Güler, Ali D; Chavkin, Charles; Luján, Rafael; Zweifel, Larry S

    2013-11-20

    The calcium-activated small conductance potassium channel SK3 plays an essential role in the regulation of dopamine neuron activity patterns. Here we demonstrate that expression of a human disease-related SK3 mutation (hSK3Δ) in dopamine neurons of mice disrupts the balance between tonic and phasic dopamine neuron activity. Expression of hSK3Δ suppressed endogenous SK currents, reducing coupling between SK channels and NMDA receptors (NMDARs) and increasing permissiveness for burst firing. Consistent with enhanced excitability of dopamine neurons, hSK3Δ increased evoked calcium signals in dopamine neurons in vivo and potentiated evoked dopamine release. Specific expression of hSK3Δ led to deficits in attention and sensory gating and heightened sensitivity to a psychomimetic drug. Sensory-motor alterations and psychomimetic sensitivity were recapitulated in a mouse model of transient, reversible dopamine neuron activation. These results demonstrate the cell-autonomous effects of a human ion channel mutation on dopamine neuron physiology and the impact of activity pattern disruption on behavior.

  9. How action selection influences the sense of agency: An ERP study.

    Science.gov (United States)

    Sidarus, Nura; Vuorre, Matti; Haggard, Patrick

    2017-02-08

    Sense of agency (SoA) refers to the feeling that we are in control of our actions and, through them, of events in the outside world. One influential view claims that the SoA depends on retrospectively matching the expected and actual outcomes of action. However, recent studies have revealed an additional, prospective component to SoA, driven by action selection processes. We used event-related potentials (ERPs) to clarify the neural mechanisms underlying prospective agency. Subliminal priming was used to manipulate the fluency of selecting a left or right hand action in response to a supraliminal target. These actions were followed by one of several coloured circles, after a variable delay. Participants then rated their degree of control over this visual outcome. Incompatible priming impaired action selection, and reduced sense of agency over action outcomes, relative to compatible priming. More negative ERPs immediately after the action, linked to post-decisional action monitoring, were associated with reduced agency ratings over action outcomes. Additionally, feedback-related negativity evoked by the outcome was also associated with reduced agency ratings. These ERP components may reflect brain processes underlying prospective and retrospective components of sense of agency respectively.

  10. Rational action selection in 1½- to 3-year-olds following an extended training experience.

    Science.gov (United States)

    Klossek, Ulrike M H; Dickinson, Anthony

    2012-02-01

    Previous studies failed to find evidence for rational action selection in children under 2 years of age. The current study investigated whether younger children required more training to encode the relevant causal relationships. Children between 1½ and 3 years of age were trained over two sessions to perform actions on a touch-sensitive screen to obtain video clips as outcomes. Subsequently, a visual habituation procedure was employed to devalue one of the training outcomes. As in previous studies, 2- and 3-year-olds chose actions associated with an expected valued outcome significantly more often during a subsequent choice test. Moreover, analysis of children's first responses in the post-devaluation test revealed evidence of rational action selection even in the youngest age group (18-23 months). Consistent with dual-process accounts of action control, the findings support the view that the ability to make rational action choices develops gradually.

  11. A Hexapod Walker Using a Heterarchical Architecture for Action Selection

    Directory of Open Access Journals (Sweden)

    Malte eSchilling

    2013-09-01

    Full Text Available Moving in a cluttered environment with a six-legged walking machine that has additional body actuators, therefore controlling 22 DoFs, is not a trivial task. Already simple forward walking on a flat plane requires the system to select between different internal states. The orchestration of these states depends on walking velocity and on external disturbances. Such disturbances occur continuously, for example due to irregular up-and-down movements of the body or slipping of the legs, even on flat surfaces, in particular when negotiating tight curves. The number of possible states is further increased when the system is allowed to walk backward or when front legs are used as grippers and cannot contribute to walking. Further states are necessary for expansion that allow for navigation. Here we demonstrate a solution for the selection and sequencing of different (attractor states required to control different behaviors as are forward walking at different speeds, backward walking, as well as negotiation of tight curves. This selection is made by a recurrent neural network of motivation units, controlling a bank of decentralized memory elements in combination with the feedback through the environment. The underlying heterarchical architecture of the network allows to select various combinations of these elements. This modular approach representing an example of neural reuse of a limited number of procedures allows for adaptation to different internal and external conditions. A way is sketched as to how this approach may be expanded to form a cognitive system being able to plan ahead. This architecture is characterized by different types of modules being arranged in layers and columns, but the complete network can also be considered as a holistic system showing emergent properties which cannot be attributed to a specific module.

  12. Mechanisms of selective antitumor action of cold atmospheric plasma

    Science.gov (United States)

    Graves, David; Bauer, Georg

    2016-09-01

    Transformed (precancerous) cells are known to be subject to elimination through intercellular RONS-dependent apoptosis-inducing signaling. It is a remarkable fact that the chemical species utilized by apoptosis induction in transformed cells are essentially identical to chemical species created by cold atmospheric plasma (CAP) in aqueous solutions. The association between CAP-induced biochemistry and natural cell anti-tumor mechanisms offers the opportunity to establish a rationale for the observed successes of CAP in selectively eliminating tumor cells in vitro and in vivo. In particular, 1O2 appears to act to selectively induce apoptosis in tumor cells, and can also result in self-perpetuating, cell-to-cell apoptotic signaling. Various CAP-generated liquid phase species can react to form 1O2, thus providing a hypothetical mechanism to explain how CAP can trigger therapeutic apoptosis in tumors. The analysis of model experiments performed with defined RONS in vitro implies that CAP-derived 1O2 induces the mechanism through which CAP acts selectively against cancer cells in vitro and tumors in vivo. This hypothesis needs to be tested experimentally in order to establish its validity.

  13. A well-monitored, X-ray selected, tidal disruption event

    Directory of Open Access Journals (Sweden)

    Komossa S.

    2012-12-01

    Full Text Available We report on a candidate tidal disruption event detected in the XMM-Newton slew survey from the nucleus of SDSS J120136.02+300305.5 (z = 0.146; hereafter SDSS J1201+30. The source, monitored by Swift and XMM-Newton, was highly variable on timescales of a week, reaching a peak X-ray luminosity of 3 × 1044 ergs/s. The light curve is reminiscent of the variations seen in SWIFT J1644+57, although in this case the absence of radio flux rules out a jet mechanism for the emission. The X-ray spectrum is steep, (spectral index = 3–5 and softens with diminishing flux. It is inconsistent with a single or multi-temperature black-body model but may be fit with Bremsstrahlung or comptonised thermal emission.

  14. Potential exposure to endocrine disrupting chemicals and selected adverse pregnancy outcomes

    DEFF Research Database (Denmark)

    Bengtsson, Jessica; Thygesen, Pernille Søgaard; Kaerlev, Linda

    2017-01-01

    Background: Experimental evidence indicates that fetal exposure to xenobiotics with the potential to interfere with the endogenous steroid hormone regulation of fetal development may reduce birth weight. However, epidemiological studies are limited. The aim of the study was to investigate whether...... potential occupational exposure to endocrine disrupting chemicals (EDC) of the mother during pregnancy is associated with preterm birth and low birth weight. Methods: Pregnant women referred to an Occupational Health Clinic (OHC) in two Danish regions (Copenhagen or Aarhus) between 1984 and 2010, suspected...... of being exposed to occupational reproductive hazards were included in the study. A job exposure matrix enabled estimation of potential occupational exposure to EDC on the basis of job title. Births by women potentially exposed to EDC (n = 582) were compared to births by women referred to an OHC...

  15. The Innovation Paradox: A Selective Review of the Literature on Action Learning and Innovation

    Science.gov (United States)

    Pedler, Mike; Brook, Cheryl

    2017-01-01

    This paper explores selective literatures in the two fields of action learning and innovation, and seeks insights into the processes of, and connections between, innovation, engagement and implementation. We searched the action learning articles for references to innovation, beginning with the work of Revans, who highlights the innovation paradox,…

  16. The preference of probability over negative values in action selection.

    Science.gov (United States)

    Neyedli, Heather F; Welsh, Timothy N

    2015-01-01

    It has previously been found that when participants are presented with a pair of motor prospects, they can select the prospect with the largest maximum expected gain (MEG). Many of those decisions, however, were trivial because of large differences in MEG between the prospects. The purpose of the present study was to explore participants' preferences when making non-trivial decisions between two motor prospects. Participants were presented with pairs of prospects that: 1) differed in MEG with either only the values or only the probabilities differing between the prospects; and 2) had similar MEG with one prospect having a larger probability of hitting the target and a higher penalty value and the other prospect a smaller probability of hitting the target but a lower penalty value. In different experiments, participants either had 400 ms or 2000 ms to decide between the prospects. It was found that participants chose the configuration with the larger MEG more often when the probability varied between prospects than when the value varied. In pairs with similar MEGs, participants preferred a larger probability of hitting the target over a smaller penalty value. These results indicate that participants prefer probability information over negative value information in a motor selection task.

  17. How selective are selective word class deficits? Two case studies of action and object naming

    NARCIS (Netherlands)

    Jonkers, R.; Bastiaanse, Y.R.M.

    1998-01-01

    In this article two case studies of fluent aphasic speakers are presented. Both patients performed significantly worse on an action-naming task than on an object-naming task, whereas comprehension of verbs was spared. The items of the action-naming test were controlled not only for the well-known fa

  18. Remedial action selection report Maybell, Colorado, site. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-12-01

    The Maybell uranium mill tailings site is 25 miles (mi) (40 kilometers [km]) west of the town of Craig, Colorado, in Moffat County, in the northwestern part of the state. The unincorporated town of Maybell is 5 road mi (8 km) southwest of the site. The site is 2.5 mi (4 km) northeast of the Yampa River on relatively flat terrain broken by low, flat-topped mesas. U.S. Highway 40 runs east-west 2 mi (3.2 km) south of the site. The designated site covers approximately 110 acres (ac) (45 hectares [ha]) and consists of a concave-shaped tailings pile and rubble from the demolition of the mill buildings buried in the former mill area. The site is situated between Johnson Wash to the east and Rob Pit Mine to the west. Numerous reclaimed and unreclaimed mines are in the immediate vicinity. Aerial photographs (included at the end of this executive summary) show evidence of mining activity around the Maybell site. Contaminated materials at the Maybell processing site include the tailings pile, which has an average depth of 20 feet (ft) (6 meters [ml]) and contains 2.8 million cubic yards (yd{sup 3}) (2.1 million cubic meters [m{sup 3}]) of tailings. The former mill processing area is on the north side of the site and contains 20,000 yd 3 (15,000 m{sup 3}) of contaminated demolition debris. Off-pile contamination is present and includes areas adjacent to the tailings pile, as well as contamination dispersed by wind and surface water flow. The volume of off-pile contamination to be placed in the disposal cell is 550,000 yd{sup 3}(420,000 m{sup 3}). The total volume of contaminated materials to be disposed of as part of the remedial action is estimated to be 3.37 million yd{sup 3} (2.58 million m{sup 3}).

  19. Long Term Spectral Evolution of Tidal Disruption Candidates Selected by Strong Coronal Lines

    CERN Document Server

    Yang, Chenwei; Ferland, Gary; Yuan, Weimin; Zhou, Hongyan; Jiang, Peng

    2013-01-01

    We present results of follow-up optical spectroscopic observations of seven rare, extreme coronal line emitting galaxies reported by Wang et al. (2012) with Multi-Mirror Telescope (MMT). Large variations in coronal lines are found in four objects, making them strong candidates of tidal disruption events (TDE). For the four TDE candidates, all the coronal lines with ionization status higher than [Fe VII] disappear within 5-9 years. The [Fe VII] faded by a factor of about five in one object (J0952+2143) within 4 years, whereas emerged in other two without them previously. A strong increment in the [O III] flux is observed, shifting the line ratios towards the loci of active galactic nucleus on the BPT diagrams. Surprisingly, we detect a non-canonical [O III]5007/[O III]4959 2 in two objects, indicating a large column density of O$^{2+}$ and thus probably optical thick gas. This also requires a very large ionization parameter and relatively soft ionizing spectral energy distribution (e.g. blackbody with $T < ...

  20. Adsorption of selected pharmaceuticals and an endocrine disrupting compound by granular activated carbon. 2. Model prediction

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Z.; Peldszus, S.; Huck, P.M. [University of Waterloo, Waterloo, ON (Canada). NSERC Chair in Water Treatment

    2009-03-01

    The adsorption of two representative pharmaceutically active compounds (PhACs) naproxen and carbamazepine and one endocrine disrupting compound (EDC) nonylphenol was studied in pilot-scale granular activated carbon (GAC) adsorbers using post-sedimentation (PS) water from a full-scale drinking water treatment plant. The GAC adsorbents were coal-based Calgon Filtrasorb 400 and coconut shell-based PICA CTIF TE. Acidic naproxen broke through fastest while nonylphenol was removed best, which was consistent with the degree to which fouling affected compound removals. Model predictions and experimental data were generally in good agreement for all three compounds, which demonstrated the effectiveness and robustness of the pore and surface diffusion model (PSDM) used in combination with the time-variable parameter approach for predicting removals at environmentally relevant concentrations (i.e., ng/L range). Sensitivity analyses suggested that accurate determination of film diffusion coefficients was critical for predicting breakthrough for naproxen and carbamazepine, in particular when high removals are targeted. Model simulations demonstrated that GAC carbon usage rates (CURs) for naproxen were substantially influenced by the empty bed contact time (EBCT) at the investigated conditions. Model-based comparisons between GAC CURs and minimum CURs for powdered activated carbon (PAC) applications suggested that PAC would be most appropriate for achieving 90% removal of naproxen, whereas GAC would be more suitable for nonylphenol. 25 refs., 4 figs., 1 tab.

  1. A cytochrome P450 monooxygenase commonly used for negative selection in transgenic plants causes growth anomalies by disrupting brassinosteroid signaling

    Directory of Open Access Journals (Sweden)

    Manivasagam Sindhu

    2011-04-01

    Full Text Available Abstract Background Cytochrome P450 monooxygenases form a large superfamily of enzymes that catalyze diverse reactions. The P450SU1 gene from the soil bacteria Streptomyces griseolus encodes CYP105A1 which acts on various substrates including sulfonylurea herbicides, vitamin D, coumarins, and based on the work presented here, brassinosteroids. P450SU1 is used as a negative-selection marker in plants because CYP105A1 converts the relatively benign sulfonyl urea pro-herbicide R7402 into a highly phytotoxic product. Consistent with its use for negative selection, transgenic Arabidopsis plants were generated with P450SU1 situated between recognition sequences for FLP recombinase from yeast to select for recombinase-mediated excision. However, unexpected and prominent developmental aberrations resembling those described for mutants defective in brassinosteroid signaling were observed in many of the lines. Results The phenotypes of the most affected lines included severe stunting, leaf curling, darkened leaves characteristic of anthocyanin accumulation, delayed transition to flowering, low pollen and seed yields, and delayed senescence. Phenotype severity correlated with P450SU1 transcript abundance, but not with transcript abundance of other experimental genes, strongly implicating CYP105A1 as responsible for the defects. Germination and seedling growth of transgenic and control lines in the presence and absence of 24-epibrassinolide indicated that CYP105A1 disrupts brassinosteroid signaling, most likely by inactivating brassinosteroids. Conclusions Despite prior use of this gene as a genetic tool, deleterious growth in the absence of R7402 has not been elaborated. We show that this gene can cause aberrant growth by disrupting brassinosteroid signaling and affecting homeostasis.

  2. Selective Attention and Control of Action: Comparative Psychology of an Artificial, Evolved Agent and People

    Science.gov (United States)

    Ward, Robert; Ward, Ronnie

    2008-01-01

    This study examined the selective attention abilities of a simple, artificial, evolved agent and considered implications of the agent's performance for theories of selective attention and action. The agent processed two targets in continuous time, catching one and then the other. This task required many cognitive operations, including prioritizing…

  3. DsdA (D-serine deaminase): a new heterologous MX cassette for gene disruption and selection in Saccharomyces cerevisiae.

    Science.gov (United States)

    Vorachek-Warren, Mara K; McCusker, John H

    2004-01-30

    Dominant drug resistance markers offer experimental flexibility in the study of Saccharomyces cerevisiae by eliminating the dependence on auxotrophic mutations and, because they are phenotypically neutral, avoid the deleterious effects of auxotrophic mutations. We have developed a new dominant resistance marker, dsdAMX4, for use in the genetic manipulation of S. cerevisiae. The dsdA gene, which is derived from Escherichia coli and encodes a D-serine deaminase, confers to S. cerevisiae resistance to D-serine and the ability to use D-serine as a nitrogen source. Here we describe the construction of a dsdAMX4 cassette, capable of expression in S. cerevisiae, and the characterization of this new marker for use in chromosomal gene disruption. The unique selection properties of the dsdAMX4 cassette make it an important addition to the existing array of S. cerevisiae genetic tools. Copyright 2004 John Wiley & Sons, Ltd.

  4. Selective progesterone receptor modulators (SPRMs): progesterone receptor action, mode of action on the endometrium and treatment options in gynecological therapies

    Science.gov (United States)

    Wagenfeld, Andrea; Saunders, Philippa T.K.; Whitaker, Lucy; Critchley, Hilary O.D.

    2016-01-01

    ABSTRACT Introduction: The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women’s quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention. Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone receptor modulator Associated Endometrial Changes) have been discussed. The clinical potential of this compound class including its impact on quality of life has been covered. Expert Opinion: Clinical studies indicate SPRMs hold promise for treatment of benign gynecological complaints (fibroids, heavy menstrual bleeding; HMB). There however remains a knowledge gap concerning mechanism of action. PMID:27138351

  5. Adsorption of selected endocrine disrupting compounds and pharmaceuticals on activated biochars

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Chanil [Department of Civil and Environmental Engineering, University of South Carolina, Columbia, SC 29208 (United States); Park, Junyeong [Department of Forest Biomaterials, North Carolina State University, Raleigh, NC 27695 (United States); Lim, Kwang Hun [Department of Chemistry, East Carolina University, Greenville, NC 27858 (United States); Park, Sunkyu [Department of Forest Biomaterials, North Carolina State University, Raleigh, NC 27695 (United States); Heo, Jiyong [Department of Civil and Environmental Engineering, Korea Army Academy at Young-Cheon, PO Box 135-1, Changhari, Gogyeongmeon, Young-cheon 770-849, Gyeongbuk (Korea, Republic of); Her, Namguk [Department of Chemistry and Environmental Sciences, Korea Army Academy at Young-Cheon, PO Box 135-1, Changhari, Gogyeongmeon, Young-cheon 770-849, Gyeongbuk (Korea, Republic of); Oh, Jeill; Yun, Soyoung [Department of Civil and Environmental Engineering, Chung-Ang University, Dongjak-Ku, Seoul 156-756 (Korea, Republic of); Yoon, Yeomin, E-mail: yoony@cec.sc.edu [Department of Civil and Environmental Engineering, University of South Carolina, Columbia, SC 29208 (United States)

    2013-12-15

    Highlights: • Biochars were prepared at different gas environments. • The competitive adsorption among EDCs/PhACs were investigated. • Aromaticity of adsorbent plays a significant role for EDCs/PhACs adsorption. -- Abstract: Chemically activated biochar produced under oxygenated (O-biochar) and oxygen-free (N-biochar) conditions were characterized and the adsorption of endocrine disrupting compounds (EDCs): bisphenol A (BPA), atrazine (ATR), 17 α-ethinylestradiol (EE2), and pharmaceutical active compounds (PhACs); sulfamethoxazole (SMX), carbamazepine (CBM), diclofenac (DCF), ibuprofen (IBP) on both biochars and commercialized powdered activated carbon (PAC) were investigated. Characteristic analysis of adsorbents by solid-state nuclear magnetic resonance (NMR) was conducted to determine better understanding about the EDCs/PhACs adsorption. N-biochar consisted of higher polarity moieties with more alkyl (0–45 ppm), methoxyl (45–63 ppm), O-alkyl (63–108 ppm), and carboxyl carbon (165–187 ppm) content than other adsorbents, while aromaticity of O-biochar was higher than that of N-biochar. O-biochar was composed mostly of aromatic moieties, with low H/C and O/C ratios compared to the highly polarized N-biochar that contained diverse polar functional groups. The higher surface area and pore volume of N-biochar resulted in higher adsorption capacity toward EDCs/PhACs along with atomic-level molecular structural property than O-biochar and PAC. N-biochar had a highest adsorption capacity of all chemicals, suggesting that N-biochar derived from loblolly pine chip is a promising sorbent for agricultural and environmental applications. The adsorption of pH-sensitive dissociable SMX, DCF, IBP, and BPA varied and the order of adsorption capacity was correlated with the hydrophobicity (K{sub ow}) of adsorbates throughout the all adsorbents, whereas adsorption of non-ionizable CBM, ATR, and EE2 in varied pH allowed adsorbents to interact with hydrophobic property

  6. Transient inactivation of basolateral amygdala during selective satiation disrupts reinforcer devaluation in rats.

    Science.gov (United States)

    West, Elizabeth A; Forcelli, Patrick A; Murnen, Alice T; McCue, David L; Gale, Karen; Malkova, Ludise

    2012-08-01

    Basolateral amygdala (BLA) function is critical for flexible, goal-directed behavior, including performance on reinforcer devaluation tasks. Here we tested, in rats, the hypothesis that BLA is critical for conditioned reinforcer devaluation during the period when the primary reinforcer (food) is being devalued (by feeding it to satiety), but not thereafter for guiding behavioral choices. We used a spatially independent task that used two visual cues, each predicting one of two foods. An instrumental action (lever press) was required for reinforcer delivery. After training, rats received BLA or sham lesions, or cannulae implanted in BLA. Under control conditions (sham lesions, saline infusions), devaluation of one food significantly decreased responding to the cue associated with that food, when both cues were presented simultaneously during extinction. BLA lesions impaired this devaluation effect. Transient inactivation of BLA by microinfusion of the γ-aminobutyric acid receptor type A agonist muscimol resulted in an impairment only when BLA was inactivated during satiation. When muscimol was infused after satiation and therefore, BLA was inactivated only during the choice test, rats showed no impairment. Thus, BLA is necessary for registering or updating cues to reflect updated reinforcer values, but not for guiding choices once the value has been updated. Our results are the first to describe the contribution of rat BLA to specific components of reinforcer devaluation and are the first to show impairment in reinforcer devaluation following transient inactivation in the rat.

  7. Sleep deprivation selectively disrupts top-down adaptation to cognitive conflict in the Stroop test.

    Science.gov (United States)

    Gevers, Wim; Deliens, Gaetane; Hoffmann, Sophie; Notebaert, Wim; Peigneux, Philippe

    2015-12-01

    Sleep deprivation is known to exert detrimental effects on various cognitive domains, including attention, vigilance and working memory. Seemingly at odds with these findings, prior studies repeatedly failed to evidence an impact of prior sleep deprivation on cognitive interference in the Stroop test, a hallmark paradigm in the study of cognitive control abilities. The present study investigated further the effect of sleep deprivation on cognitive control using an adapted version of the Stroop test that allows to segregate top-down (attentional reconfiguration on incongruent items) and bottom-up (facilitated processing after repetitions in responses and/or features of stimuli) components of performance. Participants underwent a regular night of sleep or a night of total sleep deprivation before cognitive testing. Results disclosed that sleep deprivation selectively impairs top-down adaptation mechanisms: cognitive control no longer increased upon detection of response conflict at the preceding trial. In parallel, bottom-up abilities were found unaffected by sleep deprivation: beneficial effects of stimulus and response repetitions persisted. Changes in vigilance states due to sleep deprivation selectively impact on cognitive control in the Stroop test by affecting top-down, but not bottom-up, mechanisms that guide adaptive behaviours. © 2015 European Sleep Research Society.

  8. Learning the selection of actions for an autonomous social robot by reinforcement learning based on motivations

    OpenAIRE

    Castro González, Álvaro; Malfaz, María; Miguel A. Salichs

    2011-01-01

    Autonomy is a prime issue on robotics field and it is closely related to decision making. Last researches on decision making for social robots are focused on biologically inspired mechanisms for taking decisions. Following this approach, we propose a motivational system for decision making, using internal (drives) and external stimuli for learning to choose the right action. Actions are selected from a finite set of skills in order to keep robot's needs within an acceptable range. The robot u...

  9. Spatial and viewpoint selectivity for others' observed actions in monkey ventral premotor mirror neurons.

    Science.gov (United States)

    Maranesi, Monica; Livi, Alessandro; Bonini, Luca

    2017-08-15

    The spatial location and viewpoint of observed actions are closely linked in natural social settings. For example, actions observed from a subjective viewpoint necessarily occur within the observer's peripersonal space. Neurophysiological studies have shown that mirror neurons (MNs) of the monkey ventral premotor area F5 can code the spatial location of live observed actions. Furthermore, F5 MN discharge can also be modulated by the viewpoint from which filmed actions are seen. Nonetheless, whether and to what extent MNs can integrate viewpoint and spatial location of live observed actions remains unknown. We addressed this issue by comparing the activity of 148 F5 MNs while macaque monkeys observed an experimenter grasping in three different combinations of viewpoint and spatial location, namely, lateral view in the (1) extrapersonal and (2) peripersonal space and (3) subjective view in the peripersonal space. We found that the majority of MNs were space-selective (60.8%): those selective for the peripersonal space exhibited a preference for the subjective viewpoint both at the single-neuron and population level, whereas space-unselective neurons were view invariant. These findings reveal the existence of a previously neglected link between spatial and viewpoint selectivity in MN activity during live-action observation.

  10. A behavioral task for investigating action discovery, selection and switching: comparison between types of reinforcer

    Directory of Open Access Journals (Sweden)

    Simon D Fisher

    2014-11-01

    Full Text Available Action discovery and selection are critical cognitive processes that are understudied at the cellular and systems neuroscience levels. Presented here is a new rodent joystick task suitable to test these processes due to the range of action possibilities that can be learnt while performing the task. Rats learned to manipulate a joystick while progressing through task milestones that required increasing degrees of movement accuracy. In a switching phase designed to measure action discovery, rats were repeatedly required to discover new target positions to meet changing task demands. Behavior was compared using both food and electrical brain stimulation reward (BSR of the substantia nigra as reinforcement. Rats reinforced with food and those with BSR performed similarly overall, although BSR-treated rats exhibited greater vigor in responding. In the switching phase, rats learnt new actions to adapt to changing task demands, reflecting action discovery processes. Because subjects are required to learn different goal-directed actions, this task could be employed in further investigations of the cellular mechanisms of action discovery and selection. Additionally, this task could be used to assess the behavioral flexibility impairments seen in conditions such as Parkinson’s disease and obsessive-compulsive disorder. The versatility of the task will enable cross-species investigations of these impairments.

  11. Properties of Neurons in External Globus Pallidus Can Support Optimal Action Selection.

    Directory of Open Access Journals (Sweden)

    Rafal Bogacz

    2016-07-01

    Full Text Available The external globus pallidus (GPe is a key nucleus within basal ganglia circuits that are thought to be involved in action selection. A class of computational models assumes that, during action selection, the basal ganglia compute for all actions available in a given context the probabilities that they should be selected. These models suggest that a network of GPe and subthalamic nucleus (STN neurons computes the normalization term in Bayes' equation. In order to perform such computation, the GPe needs to send feedback to the STN equal to a particular function of the activity of STN neurons. However, the complex form of this function makes it unlikely that individual GPe neurons, or even a single GPe cell type, could compute it. Here, we demonstrate how this function could be computed within a network containing two types of GABAergic GPe projection neuron, so-called 'prototypic' and 'arkypallidal' neurons, that have different response properties in vivo and distinct connections. We compare our model predictions with the experimentally-reported connectivity and input-output functions (f-I curves of the two populations of GPe neurons. We show that, together, these dichotomous cell types fulfil the requirements necessary to compute the function needed for optimal action selection. We conclude that, by virtue of their distinct response properties and connectivities, a network of arkypallidal and prototypic GPe neurons comprises a neural substrate capable of supporting the computation of the posterior probabilities of actions.

  12. Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema.

    Science.gov (United States)

    Yu, Jinyan; Ma, Zhongsen; Shetty, Sreerama; Ma, Mengshi; Fu, Jian

    2016-07-01

    Lung endothelial damage contributes to the pathogenesis of acute lung injury. New strategies against lung endothelial barrier dysfunction may provide therapeutic benefits against lung vascular injury. Cell-cell junctions and microtubule cytoskeleton are basic components in maintaining endothelial barrier integrity. HDAC6, a deacetylase primarily localized in the cytoplasm, has been reported to modulate nonnuclear protein function through deacetylation. Both α-tubulin and β-catenin are substrates for HDAC6. Here, we examined the effects of tubastatin A, a highly selective HDAC6 inhibitor, on TNF-α induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema. Selective HDAC6 inhibition by tubastatin A blocked TNF-α-induced lung endothelial cell hyperpermeability, which was associated with increased α-tubulin acetylation and microtubule stability. Tubastatin A pretreatment inhibited TNF-α-induced endothelial cell contraction and actin stress fiber formation with reduced myosin light chain phosphorylation. Selective HDAC6 inhibition by tubastatin A also induced β-catenin acetylation in human lung endothelial cells, which was associated with increased membrane localization of β-catenin and stabilization of adherens junctions. HDAC6 knockdown by small interfering RNA also prevented TNF-α-induced barrier dysfunction and increased α-tubulin and β-catenin acetylation in endothelial cells. Furthermore, in a mouse model of endotoxemia, tubastatin A was able to prevent endotoxin-induced deacetylation of α-tubulin and β-catenin in lung tissues, which was associated with reduced pulmonary edema. Collectively, our data indicate that selective HDAC6 inhibition by tubastatin A is a potent approach against lung endothelial barrier dysfunction.

  13. 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,...

  14. Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism.

    Science.gov (United States)

    Dodson, Paul D; Dreyer, Jakob K; Jennings, Katie A; Syed, Emilie C J; Wade-Martins, Richard; Cragg, Stephanie J; Bolam, J Paul; Magill, Peter J

    2016-04-12

    Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson's disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson's disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.

  15. Membrane-disruptive properties of the bioinsecticide Jaburetox-2Ec: implications to the mechanism of the action of insecticidal peptides derived from ureases.

    Science.gov (United States)

    Barros, Pedro R; Stassen, Hubert; Freitas, Mônica S; Carlini, Célia R; Nascimento, Marco A C; Follmer, Cristian

    2009-12-01

    Jaburetox-2Ec, a recombinant peptide derived from an urease isoform (JBURE-II), displays high insecticidal activity against important pests such as Spodoptera frugiperda and Dysdercus peruvianus. Although the molecular mechanism of action of ureases-derived peptides remains unclear, previous ab initio data suggest the presence of structural motifs in Jaburetox-2Ec with characteristics similar to those found in a class of pore-forming peptides. Here, we investigated the molecular aspects of the interaction between Jaburetox-2Ec and large unilamellar vesicles. Jaburetox-2Ec displays membrane-disruptive ability on acidic lipid bilayers and this effect is greatly influenced by peptide aggregation. Corroborating with this finding, molecular modeling studies revealed that Jaburetox-2Ec might adopt a well-defined beta-hairpin conformation similar to those found in antimicrobial peptides with membrane disruption properties. In addition, molecular dynamics simulations suggest that the protein is able to anchor at a polar/non-polar interface. In the light of these findings, for the first time it was possible to point out some evidence that the peptide Jaburetox-2Ec interacting with lipid vesicles promotes membrane permeabilization.

  16. Enhanced impulsive action selection in middle-aged adults - insights from an oculomotor Simon task

    Directory of Open Access Journals (Sweden)

    Joan Duprez

    2016-10-01

    Full Text Available Several studies have investigated the age-related impact in cognitive action control. However, to our knowledge, none has focused on the effect of moderate age on the strength of automatic activation according to the activation suppression model. We therefore investigated the effect of moderate age on cognitive action control using an oculomotor version of the Simon task and distributional analyses.A group of middle-aged (n = 39; 57 ± 9 years healthy adults was compared to a group of young healthy participants (n = 43; 24 ± 3 years. We first analyzed the overall impact of age on the congruence effect and then used conditional accuracy functions and delta plots to assess the strength of automatic activation and selective inhibition respectively.Compared to young participants, middle-aged participants showed a greater congruence effect as well as higher rates of fast errors in conflict situations indicating an enhanced impulsive action selection. Furthermore, the overall downward slope of the congruence effect’s evolution was significantly steeper in older participants and the last slope tended to be significantly steeper. This may indicate that the middle-aged participants exerted a stronger selective inhibition.Our results suggest that middle-aged adults are more prone to impulsive action selection than young adults. Recent theories postulate that older adults might implement compensatory mechanisms to supply cognitive difficulties. This is in line with our results suggesting a potential greater selective inhibition. Overall, this study proposes that moderate aging impacts both processes of impulsive response selection and suppression underlying cognitive action control.

  17. The Hijacking of Cellular Signaling and the Diabetes Epidemic: Mechanisms of Environmental Disruption of Insulin Action and Glucose Homeostasis

    Directory of Open Access Journals (Sweden)

    Robert M. Sargis

    2014-02-01

    Full Text Available The burgeoning epidemic of metabolic disease causes significant societal and individual morbidity and threatens the stability of health care systems around the globe. Efforts to understand the factors that contribute to metabolic derangements are critical for reversing these troubling trends. While excess caloric consumption and physical inactivity superimposed on a susceptible genetic background are central drivers of this crisis, these factors alone fail to fully account for the magnitude and rapidity with which metabolic diseases have increased in prevalence worldwide. Recent epidemiological evidence implicates endocrine disrupting chemicals in the pathogenesis of metabolic diseases. These compounds represent a diverse array of chemicals to which humans are exposed via multiple routes in adulthood and during development. Furthermore, a growing ensemble of animal- and cell-based studies provides preclinical evidence supporting the hypothesis that environmental contaminants contribute to the development of metabolic diseases, including diabetes. Herein are reviewed studies linking specific endocrine disruptors to impairments in glucose homeostasis as well as tying these compounds to disturbances in insulin secretion and impairments in insulin signal transduction. While the data remains somewhat incomplete, the current body of evidence supports the hypothesis that our chemically polluted environment may play a contributing role in the current metabolic crisis.

  18. Action Goal Selection and Motor Planning Can Be Dissociated by Tool Use

    Science.gov (United States)

    Collins, Therese; Schicke, Tobias; Roder, Brigitte

    2008-01-01

    The preparation of eye or hand movements enhances visual perception at the upcoming movement end position. The spatial location of this influence of action on perception could be determined either by goal selection or by motor planning. We employed a tool use task to dissociate these two alternatives. The instructed goal location was a visual…

  19. Transcutaneous vagus nerve stimulation (tVNS) enhances response selection during action cascading processes.

    Science.gov (United States)

    Steenbergen, Laura; Sellaro, Roberta; Stock, Ann-Kathrin; Verkuil, Bart; Beste, Christian; Colzato, Lorenza S

    2015-06-01

    The ever-changing environment we are living in requires us to apply different action control strategies in order to fulfill a task goal. Indeed, when confronted with multiple response options it is fundamental to prioritize and cascade different actions. So far, very little is known about the neuromodulation of action cascading. In this study we assessed the causal role of the gamma-aminobutyric acid (GABA)-ergic and noradrenergic system in modulating the efficiency of action cascading by applying transcutaneous vagus nerve stimulation (tVNS), a new non-invasive and safe method to stimulate the vagus nerve and to increase GABA and norepinephrine concentrations in the brain. A single-blind, sham-controlled, between-group design was used to assess the effect of on-line (i.e., stimulation overlapping with the critical task) tVNS in healthy young volunteers (n=30)-on a stop-change paradigm. Results showed that active, as compared to sham stimulation, enhanced response selection functions during action cascading and led to faster responses when two actions were executed in succession. These findings provide evidence for the important role of the GABA-ergic and noradrenergic system in modulating performance in action cascading.

  20. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 12. Environmental Restoration Program

    Energy Technology Data Exchange (ETDEWEB)

    1991-09-01

    The 664 abstracted references on environmental restoration, nuclear facility decommissioning, uranium mill tailings management, and site remedial actions constitute the twelfth in a series of reports prepared annually for the US Department of Energy Remedial Action Programs. Citations to foreign and domestic literature of all types -- technical reports, progress reports, journal articles, symposia proceedings, theses, books, patents, legislation, and research project descriptions -- have been included. The bibliography contains scientific, technical, economic, regulatory, and legal information pertinent to the US Department of Energy Remedial Action Programs. Major sections are (1) Decontamination and Decommissioning Program, (2) Nuclear Facilities Decommissioning, (3) Formerly Utilized Sites Remedial Action Program, (4) Facilities Contaminated with Naturally Occurring Radionuclides, (5) Uranium Mill Tailings Remedial Action Program, (6) Uranium Mill Tailings Management, (7) Technical Measurements Center, and (8) Environmental Restoration Program. Within these categories, references are arranged alphabetically by first author. Those references having no individual author are listed by corporate affiliation or by publication title. Indexes are provided for author, corporate affiliation, title word, publication description, geographic location, subject category, and key word. This report is a product of the Remedial Action Program Information Center (RAPIC), which selects, analyzes, and disseminates information on environmental restoration and remedial actions. RAPIC staff and resources are available to meet a variety of information needs. Contact the center at FTS 624-7764 or (615) 574-7764.

  1. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 12

    Energy Technology Data Exchange (ETDEWEB)

    Owen, P. T.; Webb, J. R.; Knox, N. P.; Goins, L. F.; Harrell, R. E.; Mallory, P. K.; Cravens, C. D.

    1991-09-01

    The 664 abstracted references on environmental restoration, nuclear facility decommissioning, uranium mill tailings management, and site remedial actions constitute the twelfth in a series of reports prepared annually for the US Department of Energy Remedial Action Programs. Citations to foreign and domestic literature of all types -- technical reports, progress reports, journal articles, symposia proceedings, theses, books, patents, legislation, and research project descriptions -- have been included. The bibliography contains scientific, technical, economic, regulatory, and legal information pertinent to the US Department of Energy Remedial Action Programs. Major sections are (1) Decontamination and Decommissioning Program, (2) Nuclear Facilities Decommissioning, (3) Formerly Utilized Sites Remedial Action Program, (4) Facilities Contaminated with Naturally Occurring Radionuclides, (5) Uranium Mill Tailings Remedial Action Program, (6) Uranium Mill Tailings Management, (7) Technical Measurements Center, and (8) Environmental Restoration Program. Within these categories, references are arranged alphabetically by first author. Those references having no individual author are listed by corporate affiliation or by publication title. Indexes are provided for author, corporate affiliation, title word, publication description, geographic location, subject category, and key word. This report is a product of the Remedial Action Program Information Center (RAPIC), which selects, analyzes, and disseminates information on environmental restoration and remedial actions. RAPIC staff and resources are available to meet a variety of information needs. Contact the center at FTS 624-7764 or (615) 574-7764.

  2. Corticostriatal circuit mechanisms of value-based action selection: Implementation of reinforcement learning algorithms and beyond.

    Science.gov (United States)

    Morita, Kenji; Jitsev, Jenia; Morrison, Abigail

    2016-09-15

    Value-based action selection has been suggested to be realized in the corticostriatal local circuits through competition among neural populations. In this article, we review theoretical and experimental studies that have constructed and verified this notion, and provide new perspectives on how the local-circuit selection mechanisms implement reinforcement learning (RL) algorithms and computations beyond them. The striatal neurons are mostly inhibitory, and lateral inhibition among them has been classically proposed to realize "Winner-Take-All (WTA)" selection of the maximum-valued action (i.e., 'max' operation). Although this view has been challenged by the revealed weakness, sparseness, and asymmetry of lateral inhibition, which suggest more complex dynamics, WTA-like competition could still occur on short time scales. Unlike the striatal circuit, the cortical circuit contains recurrent excitation, which may enable retention or temporal integration of information and probabilistic "soft-max" selection. The striatal "max" circuit and the cortical "soft-max" circuit might co-implement an RL algorithm called Q-learning; the cortical circuit might also similarly serve for other algorithms such as SARSA. In these implementations, the cortical circuit presumably sustains activity representing the executed action, which negatively impacts dopamine neurons so that they can calculate reward-prediction-error. Regarding the suggested more complex dynamics of striatal, as well as cortical, circuits on long time scales, which could be viewed as a sequence of short WTA fragments, computational roles remain open: such a sequence might represent (1) sequential state-action-state transitions, constituting replay or simulation of the internal model, (2) a single state/action by the whole trajectory, or (3) probabilistic sampling of state/action.

  3. Prior Cocaine Self-Administration Increases Response-Outcome Encoding That Is Divorced from Actions Selected in Dorsal Lateral Striatum.

    Science.gov (United States)

    Burton, Amanda C; Bissonette, Gregory B; Zhao, Adam C; Patel, Pooja K; Roesch, Matthew R

    2017-08-09

    Dorsal lateral striatum (DLS) is a highly associative structure that encodes relationships among environmental stimuli, behavioral responses, and predicted outcomes. DLS is known to be disrupted after chronic drug abuse; however, it remains unclear what neural signals in DLS are altered. Current theory suggests that drug use enhances stimulus-response processing at the expense of response-outcome encoding, but this has mostly been tested in simple behavioral tasks. Here, we investigated what neural correlates in DLS are affected by previous cocaine exposure as rats performed a complex reward-guided decision-making task in which predicted reward value was independently manipulated by changing the delay to or size of reward associated with a response direction across a series of trial blocks. After cocaine self-administration, rats exhibited stronger biases toward higher-value reward and firing in DLS more strongly represented action-outcome contingencies independent from actions subsequently taken rather than outcomes predicted by selected actions (chosen-outcome contingencies) and associations between stimuli and actions (stimulus-response contingencies). These results suggest that cocaine self-administration strengthens action-outcome encoding in rats (as opposed to chosen-outcome or stimulus-response encoding), which abnormally biases behavior toward valued reward when there is a choice between two options during reward-guided decision-making.SIGNIFICANCE STATEMENT Current theories suggest that the impaired decision-making observed in individuals who chronically abuse drugs reflects a decrease in goal-directed behaviors and an increase in habitual behaviors governed by neural representations of response-outcome (R-O) and stimulus-response associations, respectively. We examined the impact that prior cocaine self-administration had on firing in dorsal lateral striatum (DLS), a brain area known to be involved in habit formation and affected by drugs of abuse

  4. Natural genetic variation in social niche construction: social effects of aggression drive disruptive sexual selection in Drosophila melanogaster.

    Science.gov (United States)

    Saltz, Julia B; Foley, Brad R

    2011-05-01

    Social niche construction (SNC) occurs when animals actively shape their social environments. Currently the fitness consequences of SNC are poorly understood, and no study has examined whether variation in SNC has a genetic basis. Here we report the first instance of genetic variation in SNC by showing that Drosophila male aggression shapes the social environment. We allowed flies of different genotypes to interact in complex arenas; we measured the number and sex of individuals in the groups that formed and counted instances of mating. Arenas containing more aggressive male genotypes formed groups with fewer males, demonstrating that aggressive male genotypes experienced different social environments than nonaggressive genotypes. Further, genotypes with highest mating success were those whose SNC behavior generated the social environment in which they were most adept at mating: genotypes who mate most often after winning aggressive encounters benefit from aggressive SNC, while genotypes who mate most often after losing achieve high mating rates by forgoing aggression. The presence of these alternative strategies-which were robust across eight population densities-revealed that selection on aggression and context-dependent mating was disruptive, consistent with the hypothesis that SNC can maintain genetic variation in multiple behaviors.

  5. Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease.

    Science.gov (United States)

    Lecomte, Marie-José; Bertolus, Chloé; Santamaria, Julie; Bauchet, Anne-Laure; Herbin, Marc; Saurini, Françoise; Misawa, Hidemi; Maisonobe, Thierry; Pradat, Pierre-François; Nosten-Bertrand, Marika; Mallet, Jacques; Berrard, Sylvie

    2014-05-01

    Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology.

  6. Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations.

    Science.gov (United States)

    Cui, Yuanyuan; Yang, Fan; Cao, Xu; Yarov-Yarovoy, Vladimir; Wang, KeWei; Zheng, Jie

    2012-04-01

    The capsaicin receptor transient receptor potential vanilloid (TRPV)1 is a highly heat-sensitive ion channel. Although chemical activation and heat activation of TRPV1 elicit similar pungent, painful sensation, the molecular mechanism underlying synergistic activation remains mysterious. In particular, where the temperature sensor is located and whether heat and capsaicin share a common activation pathway are debated. To address these fundamental issues, we searched for channel mutations that selectively affected one form of activation. We found that deletion of the first 10 amino acids of the pore turret significantly reduced the heat response amplitude and shifted the heat activation threshold, whereas capsaicin activation remained unchanged. Removing larger portions of the turret disrupted channel function. Introducing an artificial sequence to replace the deleted region restored sensitive capsaicin activation in these nonfunctional channels. The heat activation, however, remained significantly impaired, with the current exhibiting diminishing heat sensitivity to a level indistinguishable from that of a voltage-gated potassium channel, Kv7.4. Our results demonstrate that heat and capsaicin activation of TRPV1 are structurally and mechanistically distinct processes, and the pore turret is an indispensible channel structure involved in the heat activation process but is not part of the capsaicin activation pathway. Synergistic effect of heat and capsaicin on TRPV1 activation may originate from convergence of the two pathways on a common activation gate.

  7. Nuclear facility decommissioning and site remedial actions: A selected bibliography, volume 9

    Energy Technology Data Exchange (ETDEWEB)

    Owen, P.T.; Knox, N.P.; Michelson, D.C.; Turmer, G.S.

    1988-09-01

    The 604 abstracted references on nuclear facility decommissioning, uranium mill tailings management, and site remedial actions constitute the ninth in a series of reports prepared annually for the US Department of Energy's Remedial Action Programs. Foreign and domestic literature of all types--technical reports, progress reports, journal articles, symposia proceedings, theses, books, patents, legislation, and research project descriptions--has been included. The bibliography contains scientific, technical, economic, regulatory, and legal information pertinent to the US Department of Energy's remedial action programs. Major sections are (1) Surplus Facilities Management Program, (2) Nuclear Facilities Decommissioning, (3) Formerly Utilized Sites Remedial Action Program, (4) Facilities Contaminated with Naturally Occurring Radionuclides, (5) Uranium Mill Tailings Remedial Action Program, (6) Uranium Mill Tailings Management, (7) Technical Measurements Center, and (8) General Remedial Action Program Studies. Subsections for sections 1, 2, 5, and 6 include: Design, Planning, and Regulations; Environmental Studies and Site Surveys; Health, Safety, and Biomedical Studies; Decontamination Studies; Dismantlement and Demolition; Site Stabilization and Reclamation; Waste Disposal; Remedial Action Experience; and General Studies. Within these categories, references are arranged alphabetically by first author. Those references having no individual author are listed by corporate affiliation or by publication description. Indexes are provided for author, corporate affiliation, title word, publication description, geographic location, and keywords. This report is a product of the Remedial Action Program Information Center (RAPIC), which selects and analyzes information on remedial actions and relevant radioactive waste management technologies. RAPIC staff and resources are available to meet a variety of information needs. Contact the center at (615) 576-0568 or FTS 626-0568.

  8. Development of goal-directed action selection guided by intrinsic motivations: an experiment with children.

    Science.gov (United States)

    Taffoni, Fabrizio; Tamilia, Eleonora; Focaroli, Valentina; Formica, Domenico; Ricci, Luca; Di Pino, Giovanni; Baldassarre, Gianluca; Mirolli, Marco; Guglielmelli, Eugenio; Keller, Flavio

    2014-07-01

    Action selection is extremely important, particularly when the accomplishment of competitive tasks may require access to limited motor resources. The spontaneous exploration of the world plays a fundamental role in the development of this capacity, providing subjects with an increasingly diverse set of opportunities to acquire, practice and refine the understanding of action-outcome connection. The computational modeling literature proposed a number of specific mechanisms for autonomous agents to discover and target interesting outcomes: intrinsic motivations hold a central importance among those mechanisms. Unfortunately, the study of the acquisition of action-outcome relation was mostly carried out with experiments involving extrinsic tasks, either based on rewards or on predefined task goals. This work presents a new experimental paradigm to study the effect of intrinsic motivation on action-outcome relation learning and action selection during free exploration of the world. Three- and four-year-old children were observed during the free exploration of a new toy: half of them were allowed to develop the knowledge concerning its functioning; the other half were not allowed to learn anything. The knowledge acquired during the free exploration of the toy was subsequently assessed and compared.

  9. Selective histamine H1 antagonism: novel hypnotic and pharmacologic actions challenge classical notions of antihistamines.

    Science.gov (United States)

    Stahl, Stephen M

    2008-12-01

    Numerous "antihistamines" as well as various psychotropic medications with antihistamine properties are widely utilized to treat insomnia. Over-the-counter sleep aids usually contain an antihistamine and various antidepressants and antipsychotics with antihistamine properties have sedative-hypnotic actions. Although widely used for the treatment of insomnia, many agents that block the histamine H1 receptor are also widely considered to have therapeutic limitations, including the development of next-day carryover sedation, as well as problems with chronic use, such as the development of tolerance to sedative-hypnotic actions and weight gain. Although these clinical actions are classically attributed to blockade of the H1 receptor, recent findings with H1 selective agents and H1 selective dosing of older agents are challenging these notions and suggest that some of the clinical limitations of current H1-blocking agents at their currently utilized doses could be attributable to other properties of these drugs, especially to their simultaneous actions on muscarinic, cholinergic, and adrenergic receptors. Selective H1 antagonism is emerging as a novel approach to the treatment of insomnia, without tolerance, weight gain, or the need for the restrictive prescription scheduling required of other hypnotics.

  10. Increased dependence of action selection on recent motor history in Parkinson's disease.

    Science.gov (United States)

    Helmich, Rick C; Aarts, Esther; de Lange, Floris P; Bloem, Bastiaan R; Toni, Ivan

    2009-05-13

    It is well known that the basal ganglia are involved in switching between movement sequences. Here we test the hypothesis that this contribution is an instance of a more general role of the basal ganglia in selecting actions that deviate from the context defined by the recent motor history, even when there is no sequential structure to learn or implement. We investigated the effect of striatal dopamine depletion [in Parkinson's disease (PD)] on the ability to switch between independent action plans. PD patients with markedly lateralized signs performed a hand laterality judgment task that involved action selection of their most and least affected hand. Trials where patients selected the same (repeat) or the alternative (switch) hand as in a previous trial were compared, and this was done separately for the most and least affected hand. Behaviorally, PD patients showed switch-costs that were specific to the most affected hand and that increased with disease severity. Functional magnetic resonance imaging (fMRI) showed that this behavioral effect was related to the state of the frontostriatal system: as disease severity increased, contributions of the basal ganglia to the selection process and their effective connectivity with the medial frontal cortex (MFC) decreased, whereas involvement of the MFC increased. We conclude that the basal ganglia are important for rapidly switching toward novel motor plans even when there is no sequential structure to learn or implement. The enhanced MFC activity may result either from reduced focusing abilities of the basal ganglia or from compensatory processes.

  11. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Vol. 18. Part 2. Indexes

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-09-01

    This bibliography contains 3638 citations with abstracts of documents relevant to environmental restoration, nuclear facility decontamination and decommissioning (D&D), uranium mill tailings management, and site remedial actions. This report is the eighteenth in a series of bibliographies prepared annually for the U.S. Department of Energy (DOE) Office of Environmental Restoration. Citations to foreign and domestic literature of all types - technical reports, progress reports, journal articles, symposia proceedings, theses, books, patents, legislation, and research project descriptions - have been included in Part 1 of the report. The bibliography contains scientific, technical, financial, and regulatory information that pertains to DOE environmental restoration programs. The citations are separated by topic into 16 sections, including (1) DOE Environmental Restoration Program; (2) DOE D&D Program; (3) Nuclear Facilities Decommissioning; (4) DOE Formerly Utilized Sites Remedial Action Programs; (5) NORM-Contaminated Site Restoration; (6) DOE Uranium Mill Tailings Remedial Action Project; (7) Uranium Mill Tailings Management; (8) DOE Site-Wide Remedial Actions; (9) DOE Onsite Remedial Action Projects; (10) Contaminated Site Remedial Actions; (11) DOE Underground Storage Tank Remediation; (12) DOE Technology Development, Demonstration, and Evaluations; (13) Soil Remediation; (14) Groundwater Remediation; (15) Environmental Measurements, Analysis, and Decision-Making; and (16) Environmental Management Issues. Within the 16 sections, the citations are sorted by geographic location. If a geographic location is not specified, the citations are sorted according to the document title. In Part 2 of the report, indexes are provided for author, author affiliation, selected title phrase, selected title word, publication description, geographic location, and keyword.

  12. Adsorption and biodegradation of three selected endocrine disrupting chemicals in river-based artificial groundwater recharge with reclaimed municipal wastewater.

    Science.gov (United States)

    Ma, Weifang; Nie, Chao; Chen, Bin; Cheng, Xiang; Lun, Xiaoxiu; Zeng, Fangang

    2015-05-01

    Endocrine disrupting chemical (EDC) pollution in river-based artificial groundwater recharge using reclaimed municipal wastewater poses a potential threat to groundwater-based drinking water supplies in Beijing, China. Lab-scale leaching column experiments simulating recharge were conducted to study the adsorption, biodegradation, and transport characteristics of three selected EDCs: 17β-estradiol (E2), 17α-ethinylestradiol (EE2) and bisphenol A (BPA). The three recharge columns were operated under the conditions of continual sterilization recharge (CSR), continual recharge (CR), and wetting and drying alternative recharge (WDAR). The results showed that the attenuation effect of the EDCs was in the order of WDAR>CR>CSR system and E2>EE2>BPA, which followed first-order kinetics. The EDC attenuation rate constants were 0.0783, 0.0505, and 0.0479 m(-1) for E2, EE2 and BPA in the CR system, respectively. The removal rates of E2, EE2, and BPA in the CR system were 98%, 96% and 92%, which mainly depended on biodegradation and were affected by water temperature. In the CR system, the concentrations of BPA, EE2, and E2 in soil were 4, 6 and 10 times higher than in the WDAR system, respectively. According to the DGGE fingerprints, the bacterial community in the bottom layer was more diverse than in the upper layer, which was related to the EDC concentrations in the water-soil system. The dominant group was found to be proteobacteria, including Betaproteobacteria and Alphaproteobacteria, suggesting that these microbes might play an important role in EDC degradation. Copyright © 2015. Published by Elsevier B.V.

  13. Patterns of recombination in HIV-1M are influenced by selection disfavouring the survival of recombinants with disrupted genomic RNA and protein structures.

    Directory of Open Access Journals (Sweden)

    Michael Golden

    Full Text Available Genetic recombination is a major contributor to the ongoing diversification of HIV. It is clearly apparent that across the HIV-genome there are defined recombination hot and cold spots which tend to co-localise both with genomic secondary structures and with either inter-gene boundaries or intra-gene domain boundaries. There is also good evidence that most recombination breakpoints that are detectable within the genes of natural HIV recombinants are likely to be minimally disruptive of intra-protein amino acid contacts and that these breakpoints should therefore have little impact on protein folding. Here we further investigate the impact on patterns of genetic recombination in HIV of selection favouring the maintenance of functional RNA and protein structures. We confirm that chimaeric Gag p24, reverse transcriptase, integrase, gp120 and Nef proteins that are expressed by natural HIV-1 recombinants have significantly lower degrees of predicted folding disruption than randomly generated recombinants. Similarly, we use a novel single-stranded RNA folding disruption test to show that there is significant, albeit weak, evidence that natural HIV recombinants tend to have genomic secondary structures that more closely resemble parental structures than do randomly generated recombinants. These results are consistent with the hypothesis that natural selection has acted both in the short term to purge recombinants with disrupted RNA and protein folds, and in the longer term to modify the genome architecture of HIV to ensure that recombination prone sites correspond with those where recombination will be minimally deleterious.

  14. Action planning intervention to identify how to improve selection processes for internships

    Directory of Open Access Journals (Sweden)

    Juan A. Marin-Garcia

    2016-12-01

    Full Text Available In this research into participatory action research, by a team formed by researchers and people in charge in various areas of several multinational companies, we reflected on the advantages and disadvantages of internships and we proposed a procedure for companies to improve the recruitment and selection of industrial engineers, while strengthening relationships between the university and companies, attracting students’ interest, improving their professional competences and providing evidence for their students’ real learning to degree managers at the same time.

  15. Unspeakable motion: Selective action-verb impairments in Parkinson's disease patients without mild cognitive impairment.

    Science.gov (United States)

    Bocanegra, Yamile; García, Adolfo M; Lopera, Francisco; Pineda, David; Baena, Ana; Ospina, Paula; Alzate, Diana; Buriticá, Omar; Moreno, Leonardo; Ibáñez, Agustín; Cuetos, Fernando

    2017-05-01

    Parkinson's disease (PD) patients show marked impairments in processing action verbs, and to a lesser extent, concrete (specially, manipulable) nouns. However, it is still unclear to what extent deficits in each of these categories are influenced by more general cognitive dysfunctions, and whether they are modulated by the words' implied motility. To examine these issues, we evaluated 49 non-demented PD patients and 49 healthy volunteers in an oral production task. The patients were divided into two groups depending on the presence or absence of mild cognitive impairment (PD-MCI and PD-nMCI, respectively). Participants named pictures of actions varying in motion content (low and high) and of objects varying in manipulability (low and high). The PD-MCI group showed deficits across all four categories. However, PD-nMCI patients exhibited a selective difficulty for high-motion action verbs. This finding corroborates and refines previous results suggesting that disturbances of action-related lexico-semantic information in PD constitute a sui generis alteration manifested early in the course of the disease's physiopathology. Moreover, it suggests that the grounding of action verbs on motor circuits could depend on fine-grained intracategorical semantic distinctions.

  16. Action video games and improved attentional control: Disentangling selection- and response-based processes.

    Science.gov (United States)

    Chisholm, Joseph D; Kingstone, Alan

    2015-10-01

    Research has demonstrated that experience with action video games is associated with improvements in a host of cognitive tasks. Evidence from paradigms that assess aspects of attention has suggested that action video game players (AVGPs) possess greater control over the allocation of attentional resources than do non-video-game players (NVGPs). Using a compound search task that teased apart selection- and response-based processes (Duncan, 1985), we required participants to perform an oculomotor capture task in which they made saccades to a uniquely colored target (selection-based process) and then produced a manual directional response based on information within the target (response-based process). We replicated the finding that AVGPs are less susceptible to attentional distraction and, critically, revealed that AVGPs outperform NVGPs on both selection-based and response-based processes. These results not only are consistent with the improved-attentional-control account of AVGP benefits, but they suggest that the benefit of action video game playing extends across the full breadth of attention-mediated stimulus-response processes that impact human performance.

  17. [Initial selectivity of the antiplatelet covalent action of biogenic chloramines on platelet-rich plasma].

    Science.gov (United States)

    Roshchupkin, D I; Murina, M A; Kravchenko, N N; Sergienko, V I

    2007-01-01

    To describe in full the peculiarities of the antiplatelet action of covalent inhibitors on platelet-rich plasma, we have proposed to take into account the initial selectivity that determines the elevated efficacy of inactivation of platelet molecular target (receptor). The quantitative index of initial selectivity is the ratio of rate constant of inactivation of the platelet molecular target to the rate constant of the chemical reaction of an inhibitor with reactive atomic groups in plasma proteins. For the important case of the domination of the inhibitor expenditure in the reaction with plasma proteins, a formula was derived which depicts the dependence of the share of inactivated targets on the concentration of the inhibitor introduced and reactive atomic groups contained in plasma. In the case of chloramine derivatives of amino acids, evidence was obtained indicating that the degree of inhibition of platelet aggregation measured by the turbidimetric method is equal to the square of the share of inactivated receptors. The index of initial selectivity can be evaluated by measuring the degree of inhibition of platelet aggregation and the operating concentration of the inhibitor. According to experimental evidence, the effects of a number of chloramine derivatives of amino acids (biochloramines) on aggregation of platelets stimulated by ADP show selectivity at the molecular target level, so that the index of initial selectivity is greater than 1. The mechanism of the selective action of the biochloramines having significant molecular masses (150-200 Da) probably consists in the inactivation of the molecular target via chemical modification of several reactive atomic groups in its different sites. One may suppose that the biochloramines with lower molecular masses (150-100 Da) exhibit a high anti-aggregatory capacity owing to another mechanism of initial selectivity, which involves the modification of highly sensitive sulfur-containing atomic groups.

  18. Searching and selecting online information: analysis of the strategic actions of the university students

    Directory of Open Access Journals (Sweden)

    María José Hernández Serrano

    2013-08-01

    Full Text Available 0 0 1 113 622 USAL 5 1 734 14.0 Normal 0 21 false false false ES JA X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Tabla normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-ansi-language:ES; mso-fareast-language:EN-US;} As complex and dynamic activity, the searching and selection of online information needs a strategic performance in order to achieve effective and meaningful results and processes. The aim of this paper is to analyze whether university students perceive a need to be strategic, for what actions, what times, and what are their predispositions towards the strategic actions in the Internet information searching and selection process. Results showed differences between students by course, those in their final courses, who have also received training, showed better predisposition to strategic actions. Two factors that explain the university students’ predispositions were found, in terms of basic actions and complementary actions.

  19. Attentional selection in visual perception, memory and action: a quest for cross-domain integration.

    Science.gov (United States)

    Schneider, Werner X; Einhäuser, Wolfgang; Horstmann, Gernot

    2013-10-19

    For decades, the cognitive and neural sciences have benefitted greatly from a separation of mind and brain into distinct functional domains. The tremendous success of this approach notwithstanding, it is self-evident that such a view is incomplete. Goal-directed behaviour of an organism requires the joint functioning of perception, memory and sensorimotor control. A prime candidate for achieving integration across these functional domains are attentional processes. Consequently, this Theme Issue brings together studies of attentional selection from many fields, both experimental and theoretical, that are united in their quest to find overreaching integrative principles of attention between perception, memory and action. In all domains, attention is understood as combination of competition and priority control ('bias'), with the task as a decisive driving factor to ensure coherent goal-directed behaviour and cognition. Using vision as the predominant model system for attentional selection, many studies of this Theme Issue focus special emphasis on eye movements as a selection process that is both a fundamental action and serves a key function in perception. The Theme Issue spans a wide range of methods, from measuring human behaviour in the real word to recordings of single neurons in the non-human primate brain. We firmly believe that combining such a breadth in approaches is necessary not only for attentional selection, but also to take the next decisive step in all of the cognitive and neural sciences: to understand cognition and behaviour beyond isolated domains.

  20. Selective readout and back-action reduction for wideband acoustic gravitational wave detectors

    CERN Document Server

    Bonaldi, M; Conti, L; Pinard, M; Prodi, G A; Zendri, J P

    2003-01-01

    We present the concept of selective readout for broadband resonant mass gravitational wave detectors. This detection scheme is capable of specifically selecting the signal from the contributions of the vibrational modes sensitive to the gravitational waves, and efficiently rejecting the contribution from non gravitationally sensitive modes. Moreover this readout, applied to a dual detector, is capable to give an effective reduction of the back-action noise within the frequency band of interest. The overall effect is a significant enhancement in the predicted sensitivity, evaluated at the standard quantum limit for a dual torus detector. A molybdenum detector, 1 m in diameter and equipped with a wide area selective readout, would reach spectral strain sensitivities 2x10^{-23}/sqrt{Hz} between 2-6 kHz.

  1. Nuclear facility decommissioning and site remedial actions. Volume 1. A selected bibliography

    Energy Technology Data Exchange (ETDEWEB)

    Faust, R.A.; Fore, C.S.; Knox, N.P.

    1980-09-01

    This bibliography of 633 references represents the first in a series to be produced by the Remedial Actions Program Information Center (RAPIC) containing scientific, technical, economic, and regulatory information concerning the decommissioning of nuclear facilities. Major chapters selected for this bibliography are Facility Decommissioning, Uranium Mill Tailings Cleanup, Contaminated Site Restoration, and Criteria and Standards. The references within each chapter are arranged alphabetically by leading author, corporate affiliation, or title of the document. When the author is not given, the corporate affiliation appears first. If these two levels of authorship are not given, the title of the document is used as the identifying level. Indexes are provided for (1) author(s), (2) keywords, (3) title, (4) technology development, and (5) publication description. An appendix of 123 entries lists recently acquired references relevant to decommissioning of nuclear facilities. These references are also arranged according to one of the four subject categories and followed by author, title, and publication description indexes. The bibliography was compiled from a specialized data base established and maintained by RAPIC to provide information support for the Department of Energy's Remedial Actions Program, under the cosponsorship of its three major components: Surplus Facilities Management Program, Uranium Mill Tailings Remedial Actions Program, and Formerly Utilized Sites Remedial Actions Program. RAPIC is part of the Ecological Sciences Information Center within the Information Center Complex at Oak Ridge National Laboratory.

  2. Inherited, selective hyporesponsiveness to the analgesic action of nicotine in mice.

    Science.gov (United States)

    Seale, T W; Nael, R; Basmadjian, G

    1996-12-20

    The acute dose-dependent analgesic activity of nicotine, as measured by the tail-flick assay, differed significantly between CD-1 and CF-1 outbred strains of mice. Differing responsiveness to the tail-flick stimulus did not explain this pharmacological effect. The inherent analgesic hyporesponsiveness of CF-1 mice was pharmacologically selective. Xilocaine and morphine produced an analgesic response of large magnitude in CF-1 mice. Reduced efficacy of nicotine in the CF-1 analgesia assay was not observed in its action on locomotor activity or in the induction of seizures and lethality. These findings have practical significance in identifying the importance of genotype in choice of strain for preclinical pharmacological studies of nicotine-induced analgesia and indicate that genetic analysis may provide a valuable tool for investigating the mechanism underlying the analgesic action of nicotine.

  3. In vitro assessment of antiproliferative action selectivity of dietary isothiocyanates for tumor versus normal human cells

    Directory of Open Access Journals (Sweden)

    Konić-Ristić Aleksandra

    2016-01-01

    Full Text Available Background/Aim. Numerous epidemiological studies have shown beneficial effects of cruciferous vegetables consumption in cancer chemoprevention. Biologically active compounds of different Brassicaceae species with antitumor potential are isothiocyanates, present in the form of their precursors - glucosinolates. The aim of this study was to determine the selectivity of antiproliferative action of dietary isothiocyanates for malignant versus normal cells. Methods. Antiproliferative activity of three isothiocyanates abundant in human diet: sulforaphane, benzyl isothiocyanate (BITC and phenylethyl isothiocyanate, on human cervix carcinoma cell line - HeLa, melanoma cell line - Fem-x, and colon cancer cell line - LS 174, and on peripheral blood mononuclear cells (PBMC, with or without mitogen, were determined by MTT colorimetric assay 72 h after their continuous action. Results. All investigated isothiocyanates inhibited the proliferation of HeLa, Fem-x and LS 174 cells. On all cell lines treated, BITC was the most potent inhibitor of cell proliferation with half-maximum inhibitory concentration (IC50 values of 5.04 mmoL m-3 on HeLa cells, 2.76 mmol m-3 on Fem-x, and 14.30 mmol m-3 on LS 174 cells. Antiproliferative effects on human PBMC were with higher IC50 than on malignant cells. Indexes of selectivity, calculated as a ratio between IC50 values obtained on PBMC and malignant cells, were between 1.12 and 16.57, with the highest values obtained for the action of BITC on melanoma Fem-x cells. Conclusion. Based on its antiproliferative effects on malignant cells, as well as the selectivity of the action to malignant vs normal cells, benzyl isothiocyanate can be considered as a promising candidate in cancer chemoprevention. In general, the safety of investigated compounds, in addition to their antitumor potential, should be considered as an important criterion in cancer chemoprevention. Screening of selectivity is a plausible approach to the evaluation

  4. The action of stabilizing selection, mutation, and drift on epistatic quantitative traits.

    Science.gov (United States)

    Avila, Victoria; Pérez-Figueroa, Andrés; Caballero, Armando; Hill, William G; García-Dorado, Aurora; López-Fanjul, Carlos

    2014-07-01

    For a quantitative trait under stabilizing selection, the effect of epistasis on its genetic architecture and on the changes of genetic variance caused by bottlenecking were investigated using theory and simulation. Assuming empirical estimates of the rate and effects of mutations and the intensity of selection, we assessed the impact of two-locus epistasis (synergistic/antagonistic) among linked or unlinked loci on the distribution of effects and frequencies of segregating loci in populations at the mutation-selection-drift balance. Strong pervasive epistasis did not modify substantially the genetic properties of the trait and, therefore, the most likely explanation for the low amount of variation usually accounted by the loci detected in genome-wide association analyses is that many causal loci will pass undetected. We investigated the impact of epistasis on the changes in genetic variance components when large populations were subjected to successive bottlenecks of different sizes, considering the action of genetic drift, operating singly (D), or jointly with mutation (MD) and selection (MSD). An initial increase of the different components of the genetic variance, as well as a dramatic acceleration of the between-line divergence, were always associated with synergistic epistasis but were strongly constrained by selection.

  5. Selective attention and control of action: comparative psychology of an artificial, evolved agent and people.

    Science.gov (United States)

    Ward, Robert; Ward, Ronnie

    2008-10-01

    This study examined the selective attention abilities of a simple, artificial, evolved agent and considered implications of the agent's performance for theories of selective attention and action. The agent processed two targets in continuous time, catching one and then the other. This task required many cognitive operations, including prioritizing the first target (T1) over the second (T2); selectively focusing responses on T1, while preventing T2 from interfering with responses; creating a memory for the unselected T2 item, so that it could be efficiently processed later; and reallocating processing towards T2 after catching T1. The evolved agent demonstrated all these abilities. Analysis shows that the agent used reactive inhibition to selectively focus behavior. That is, the more salient T2, the more strongly responses towards T2 were inhibited and the slower the agent was to subsequently reallocate processing towards T2. Reactive inhibition was also suggested in two experiments with people, performing a virtually identical catch task. The presence of reactive inhibition in the simple agent and in people suggests that it is an important mechanism for selective processing.

  6. Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials

    Science.gov (United States)

    Radivojevic, Milos; Jäckel, David; Altermatt, Michael; Müller, Jan; Viswam, Vijay; Hierlemann, Andreas; Bakkum, Douglas J.

    2016-08-01

    A detailed, high-spatiotemporal-resolution characterization of neuronal responses to local electrical fields and the capability of precise extracellular microstimulation of selected neurons are pivotal for studying and manipulating neuronal activity and circuits in networks and for developing neural prosthetics. Here, we studied cultured neocortical neurons by using high-density microelectrode arrays and optical imaging, complemented by the patch-clamp technique, and with the aim to correlate morphological and electrical features of neuronal compartments with their responsiveness to extracellular stimulation. We developed strategies to electrically identify any neuron in the network, while subcellular spatial resolution recording of extracellular action potential (AP) traces enabled their assignment to the axon initial segment (AIS), axonal arbor and proximal somatodendritic compartments. Stimulation at the AIS required low voltages and provided immediate, selective and reliable neuronal activation, whereas stimulation at the soma required high voltages and produced delayed and unreliable responses. Subthreshold stimulation at the soma depolarized the somatic membrane potential without eliciting APs.

  7. Differential actions of insecticides on target sites: basis for selective toxicity.

    Science.gov (United States)

    Narahashi, T; Zhao, X; Ikeda, T; Nagata, K; Yeh, J Z

    2007-04-01

    Whereas the selective toxicity of insecticides between insects and mammals has a long history of studies, it is now becoming abundantly clear that, in many cases, the differential action of insecticides on insects and mammalian target receptor sites is an important factor. In this paper, we first introduce the mechanism of action and the selective toxicity of pyrethroids as a prototype of study. Then, a more detailed account is given for fipronil, based primarily on our recent studies. Pyrethroids keep the sodium channels open for a prolonged period of time, causing elevation of the depolarizing after-potential. Once the after-potential reaches the threshold for excitation, repetitive after-discharges are produced, resulting in hyperexcitation of intoxicated animals. Only about 1% of sodium channels needs to be modified to produce hyperexcitation, indicating a high degree of toxicity amplification from sodium channels to animals. Pyrethroids were >1000-fold more potent on cockroach sodium channels than rat sodium channels, and this forms the most significant factor to explain the selective toxicity of pyrethroids in insects over mammals. Fipronil, a phenylpyrazole, is known to act on the gamma-aminobutyric acid receptor to block the chloride channel. It is effective against certain species of insects that have become resistant to most insecticides, including those acting on the gamma-aminobutyric acid receptor, and is much more toxic to insects than to mammals. Recently, fipronil has been found to block glutamate-activated chloride channels in cockroach neurons in a potent manner. Since mammals are devoid of this type of chloride channel, fipronil block of the glutamate-activated chloride channel is deemed responsible, at least partially, for the higher selective toxicity to insects over mammals and for the lack of cross-resistance.

  8. Computational perspectives on forebrain microcircuits implicated in reinforcement learning, action selection, and cognitive control.

    Science.gov (United States)

    Bullock, Daniel; Tan, Can Ozan; John, Yohan J

    2009-01-01

    Abundant new information about signaling pathways in forebrain microcircuits presents many challenges, and opportunities for discovery, to computational neuroscientists who strive to bridge from microcircuits to flexible cognition and action. Accurate treatment of microcircuit pathways is especially critical for creating models that correctly predict the outcomes of candidate neurological therapies. Recent models are trying to specify how cortical circuits that enable planning and voluntary actions interact with adaptive subcortical microcircuits in the basal ganglia. The basal ganglia are strongly implicated in reinforcement learning, and in all behavior and cognition over which the frontal lobes exert flexible control. The persisting role of the basal ganglia shows that ancient vertebrate designs for motivated action selection proved adaptable enough to support many "modern" behavioral innovations, including fluent generation of language and speech. This paper summarizes how recent models have incorporated realistic representations of microcircuit features, and have begun to trace their computational implications. Also summarized are recent empirical discoveries that provide guidance regarding how to formulate the rules for synaptic modification that govern learning in cortico-striatal pathways. Such efforts are contributing to an emerging synthesis based on an interlocking set of computational hypotheses regarding cortical interactions with basal ganglia and thalamic nuclei. These hypotheses specify how specialized microcircuits solve learning and control problems inherent to the brain's parallel design.

  9. Still at the choice-point: action selection and initiation in instrumental conditioning.

    Science.gov (United States)

    Balleine, Bernard W; Ostlund, Sean B

    2007-05-01

    Contrary to classic stimulus-response (S-R) theory, recent evidence suggests that, in instrumental conditioning, rats encode the relationship between their actions and the specific consequences that these actions produce. It has remained unclear, however, how encoding this relationship acts to control instrumental performance. Although S-R theories were able to give a clear account of how learning translates into performance, the argument that instrumental learning constitutes the acquisition of information of the form "response R leads to outcome O" does not directly imply a particular performance rule or policy; this information can be used both to perform R and to avoid performing R. Recognition of this problem has forced the development of accounts that allow the O and stimuli that predict the O (i.e., S-O) to play a role in the initiation of specific Rs. In recent experiments, we have used a variety of behavioral procedures in an attempt to isolate the processes that contribute to instrumental performance, including outcome devaluation, reinstatement, and Pavlovian-instrumental transfer. Our results, particularly from experiments assessing outcome-selective reinstatement, suggest that both "feed-forward" (O-R) and "feed-back" (R-O) associations are critical and that although the former appear to be important to response selection, the latter-together with processes that determine outcome value-mediate response initiation. We discuss a conceptual model that integrates these processes and its neural implementation.

  10. The intralaminar thalamus – an expressway linking visual stimuli to circuits determining agency and action selection

    Directory of Open Access Journals (Sweden)

    Simon eFisher

    2014-04-01

    Full Text Available Anatomical investigations have revealed connections between the intralaminar thalamic nuclei and areas such as the superior colliculus that receive short latency input from visual and auditory primary sensory areas. The intralaminar nuclei in turn project to the major input nucleus of the basal ganglia, the striatum, providing this nucleus with a source of subcortical excitatory input. Together with a converging input from the cerebral cortex, and a neuromodulatory dopaminergic input from the midbrain, the components previously found necessary for reinforcement learning in the basal ganglia are present. With this intralaminar sensory input, the basal ganglia are thought to play a primary role in determining what aspect of an organism’s own behavior has caused salient environmental changes. Additionally, subcortical loops through thalamic and basal ganglia nuclei are proposed to play a critical role in action selection. In this mini review we will consider the anatomical and physiological evidence underlying the existence of these circuits. We will propose how the circuits interact to modulate basal ganglia output and solve common behavioral learning problems of agency determination and action selection.

  11. Rational Action Selection in 1 1/2- to 3-Year-Olds Following an Extended Training Experience

    Science.gov (United States)

    Klossek, Ulrike M. H.; Dickinson, Anthony

    2012-01-01

    Previous studies failed to find evidence for rational action selection in children under 2 years of age. The current study investigated whether younger children required more training to encode the relevant causal relationships. Children between 1 1/2 and 3 years of age were trained over two sessions to perform actions on a touch-sensitive screen…

  12. An integrated methodology for assessment and selection of the project risk response actions.

    Science.gov (United States)

    Seyedhoseini, Seyed Mohammad; Noori, Siamak; Hatefi, Mohammad Ali

    2009-05-01

    In a systematic process of project risk management, after risk assessment is implemented, the risk analysts encounter the phase of assessment and selection of the project risk response actions (RA). As indicated by many researchers, there are less systematic and well-developed solutions in the area of risk response assessment and selection. The present article introduces a methodology including a modeling approach with the objective of selecting a set of RA that minimizes the undesirable deviation from achieving the project scope. The developed objective function comprises the three key success criteria of a project, namely, time, quality, and cost. Our model integrates overall project management into the project risk response planning (P2RP). Furthermore, the proposed model stresses on an equivalent importance for both "risk" and "response." We believe that applying the proposed model helps the project risk analyst in most effective and efficient manner dealing with his or her complicated RA selection problems. The application of the proposed model was implemented in projects in the construction industry in which it showed tremendous time, cost, and quality improvements.

  13. Direction-selective circuitry in rat retina develops independently of GABAergic, cholinergic and action potential activity.

    Directory of Open Access Journals (Sweden)

    Le Sun

    Full Text Available The ON-OFF direction selective ganglion cells (DSGCs in the mammalian retina code image motion by responding much more strongly to movement in one direction. They do so by receiving inhibitory inputs selectively from a particular sector of processes of the overlapping starburst amacrine cells, a type of retinal interneuron. The mechanisms of establishment and regulation of this selective connection are unknown. Here, we report that in the rat retina, the morphology, physiology of the ON-OFF DSGCs and the circuitry for coding motion directions develop normally with pharmacological blockade of GABAergic, cholinergic activity and/or action potentials for over two weeks from birth. With recent results demonstrating light independent formation of the retinal DS circuitry, our results strongly suggest the formation of the circuitry, i.e., the connections between the second and third order neurons in the visual system, can be genetically programmed, although emergence of direction selectivity in the visual cortex appears to require visual experience.

  14. Striatal indirect pathway contributes to selection accuracy of learned motor actions.

    Science.gov (United States)

    Nishizawa, Kayo; Fukabori, Ryoji; Okada, Kana; Kai, Nobuyuki; Uchigashima, Motokazu; Watanabe, Masahiko; Shiota, Akira; Ueda, Masatsugu; Tsutsui, Yuji; Kobayashi, Kazuto

    2012-09-26

    The dorsal striatum, which contains the dorsolateral striatum (DLS) and dorsomedial striatum (DMS), integrates the acquisition and implementation of instrumental learning in cooperation with the nucleus accumbens (NAc). The dorsal striatum regulates the basal ganglia circuitry through direct and indirect pathways. The mechanism by which these pathways mediate the learning processes of instrumental actions remains unclear. We investigated how the striatal indirect (striatopallidal) pathway arising from the DLS contributes to the performance of conditional discrimination. Immunotoxin targeting of the striatal neuronal type containing dopamine D(2) receptor in the DLS of transgenic rats resulted in selective, efficient elimination of the striatopallidal pathway. This elimination impaired the accuracy of response selection in a two-choice reaction time task dependent on different auditory stimuli. The impaired response selection was elicited early in the test sessions and was gradually restored as the sessions continued. The restoration from the deficits in auditory discrimination was prevented by excitotoxic lesion of the NAc but not by that of the DMS. In addition, lesion of the DLS mimicked the behavioral consequence of the striatopallidal removal at the early stage of test sessions of discriminative performance. Our results demonstrate that the DLS-derived striatopallidal pathway plays an essential role in the execution of conditional discrimination, showing its contribution to the control of selection accuracy of learned motor responses. The results also suggest the presence of a mechanism that compensates for the learning deficits during the repetitive sessions, at least partly, demanding accumbal function.

  15. Where neuroscience and dynamic system theory meet autonomous robotics: A contracting basal ganglia model for action selection.

    OpenAIRE

    Girard, B.; Tabareau, N.; Pham, Q. C.; Berthoz, A.; Slotine, J.-J.

    2008-01-01

    Action selection, the problem of choosing what to do next, is central to any autonomous agent architecture. We use here a multi-disciplinary approach at the convergence of neuroscience, dynamical system theory and autonomous robotics, in order to propose an efficient action selection mechanism based on a new model of the basal ganglia. We first describe new developments of contraction theory regarding locally projected dynamical systems. We exploit these results to design a stable computation...

  16. Alcohol disrupts sleep homeostasis.

    Science.gov (United States)

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  17. Microtubule drugs: action, selectivity, and resistance across the kingdoms of life.

    Science.gov (United States)

    Dostál, V; Libusová, L

    2014-09-01

    Microtubule drugs such as paclitaxel, colchicine, vinblastine, trifluralin, or oryzalin form a chemically diverse group that has been reinforced by a large number of novel compounds over time. They all share the ability to change microtubule properties. The profound effects of disrupted microtubule systems on cell physiology can be used in research as well as anticancer treatment and agricultural weed control. The activity of microtubule drugs generally depends on their binding to α- and β-tubulin subunits. The microtubule drugs are often effective only in certain taxonomic groups, while other organisms remain resistant. Available information on the molecular basis of this selectivity is summarized. In addition to reviewing published data, we performed sequence data mining, searching for kingdom-specific signatures in plant, animal, fungal, and protozoan tubulin sequences. Our findings clearly correlate with known microtubule drug resistance determinants and add more amino acid positions with a putative effect on drug-tubulin interaction. The issue of microtubule network properties in plant cells producing microtubule drugs is also addressed.

  18. 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.

  19. 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. 

  20. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism

    Science.gov (United States)

    Hasbi, Ahmed; Perreault, Melissa L.; Shen, Maurice Y. F.; Zhang, Lucia; To, Ryan; Fan, Theresa; Nguyen, Tuan; Ji, Xiaodong; O'Dowd, Brian F.; George, Susan R.

    2014-01-01

    Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues 404Glu and 405Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment.—Hasbi, A., Perreault, M. L., Shen, M. Y. F., Zhang, L., To, R., Fan, T., Nguyen, T., Ji, X., O'Dowd, B. F., George, S. R. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism. PMID:25063849

  1. Stable expression of green fluorescent protein and targeted disruption of thioredoxin peroxidase-1 gene in Babesia bovis with the WR99210/dhfr selection system.

    Science.gov (United States)

    Asada, Masahito; Tanaka, Miho; Goto, Yasuyuki; Yokoyama, Naoaki; Inoue, Noboru; Kawazu, Shin-ichiro

    2012-02-01

    We have achieved stable expression of green fluorescent protein (GFP) in Babesia bovis by using the WR99210/human dihydrofolate reductase (DHFR) gene selection system. A GFP-expression plasmid with a dhfr expression cassette (DHFR-gfp) was constructed and transfected into B. bovis by nucleofection. Following WR99210 selection, a GFP-fluorescent parasite population was obtained and the fluorescent parasite was maintained for more than 7 months under WR99210 drug pressure. The DHFR-gfp was used to construct a small circular chromosome and to target gene disruption in the parasite. For construction of the small circular chromosome (DHFR-gfp-Bbcent2), the putative centromere region of B. bovis chromosome 2 (Bbcent2) was cloned and inserted into the DHFR-gfp plasmid. Addition of Bbcent2 to the DHFR-gfp plasmid improved its segregation efficiency during parasite multiplication and GFP-expressing parasites were maintained for more than 2 months without drug pressure. For targeted disruption of a B. bovis gene we attempted to knockout the thioredoxin peroxidase-1 (TPx-1) gene (a single-copy 2-Cys peroxiredoxin gene, Tbtpx-1) by homologous recombination. To generate the targeting construct (DHFR-gfp-Bbtpx1KO), 5' and 3' portions of Bbtpx-1 were cloned into the DHFR-gfp plasmid. Following nucleofection, WR99210 selection and cloning, a GFP-fluorescent parasite population was obtained. Integration of the construct into the Bbtpx-1 locus was confirmed by PCR. The absence of Bbtpx-1 mRNA and protein were verified by reverse transcription PCR and western blot analysis/indirect immunofluorescence assay, respectively. This is the first report of targeted gene disruption of a Babesia gene. These advances in the methodology of genetic manipulation in B. bovis will facilitate functional analysis of Babesia genomes and will improve our understanding of the basic biology of apicomplexan parasites.

  2. Neural strategies for selective attention distinguish fast-action video game players.

    Science.gov (United States)

    Krishnan, Lavanya; Kang, Albert; Sperling, George; Srinivasan, Ramesh

    2013-01-01

    We investigated the psychophysical and neurophysiological differences between fast-action video game players (specifically first person shooter players, FPS) and non-action players (role-playing game players, RPG) in a visual search task. We measured both successful detections (hit rates) and steady-state visually evoked EEG potentials (SSVEPs). Search difficulty was varied along two dimensions: number of adjacent attended and ignored regions (1, 2 and 4), and presentation rate of novel search arrays (3, 8.6 and 20 Hz). Hit rates decreased with increasing presentation rates and number of regions, with the FPS players performing on average better than the RPG players. The largest differences in hit rate, between groups, occurred when four regions were simultaneously attended. We computed signal-to-noise ratio (SNR) of SSVEPs and used partial least squares regression to model hit rates, SNRs and their relationship at 3 Hz and 8.6 Hz. The following are the most significant results: RPG players' parietal responses to the attended 8.6 Hz flicker were predictive of hit rate and were positively correlated with it, indicating attentional signal enhancement. FPS players' parietal responses to the ignored 3 Hz flicker were predictive of hit rate and were positively correlated with it, indicating distractor suppression. Consistent with these parietal responses, RPG players' frontal responses to the attended 8.6 Hz flicker, increased as task difficulty increased with number of regions; FPS players' frontal responses to the ignored 3 Hz flicker increased with number of regions. Thus the FPS players appear to employ an active suppression mechanism to deploy selective attention simultaneously to multiple interleaved regions, while RPG primarily use signal enhancement. These results suggest that fast-action gaming can affect neural strategies and the corresponding networks underlying attention, presumably by training mechanisms of distractor suppression.

  3. ACTION OF UNIFORM SEARCH ALGORITHM WHEN SELECTING LANGUAGE UNITS IN THE PROCESS OF SPEECH

    Directory of Open Access Journals (Sweden)

    Nekipelova Irina Mikhaylovna

    2013-04-01

    Full Text Available The article is devoted to research of action of uniform search algorithm when selecting by human of language units for speech produce. The process is connected with a speech optimization phenomenon. This makes it possible to shorten the time of cogitation something that human want to say, and to achieve the maximum precision in thoughts expression. The algorithm of uniform search works at consciousness and subconsciousness levels. It favours the forming of automatism produce and perception of speech. Realization of human's cognitive potential in the process of communication starts up complicated mechanism of self-organization and self-regulation of language. In turn, it results in optimization of language system, servicing needs not only human's self-actualization but realization of communication in society. The method of problem-oriented search is used for researching of optimization mechanisms, which are distinctive to speech producing and stabilization of language.

  4. Where neuroscience and dynamic system theory meet autonomous robotics: a contracting basal ganglia model for action selection.

    Science.gov (United States)

    Girard, B; Tabareau, N; Pham, Q C; Berthoz, A; Slotine, J-J

    2008-05-01

    Action selection, the problem of choosing what to do next, is central to any autonomous agent architecture. We use here a multi-disciplinary approach at the convergence of neuroscience, dynamical system theory and autonomous robotics, in order to propose an efficient action selection mechanism based on a new model of the basal ganglia. We first describe new developments of contraction theory regarding locally projected dynamical systems. We exploit these results to design a stable computational model of the cortico-baso-thalamo-cortical loops. Based on recent anatomical data, we include usually neglected neural projections, which participate in performing accurate selection. Finally, the efficiency of this model as an autonomous robot action selection mechanism is assessed in a standard survival task. The model exhibits valuable dithering avoidance and energy-saving properties, when compared with a simple if-then-else decision rule.

  5. Endocrine disrupting chemicals and disease susceptibility.

    Science.gov (United States)

    Schug, Thaddeus T; Janesick, Amanda; Blumberg, Bruce; Heindel, Jerrold J

    2011-11-01

    Environmental chemicals have significant impacts on biological systems. Chemical exposures during early stages of development can disrupt normal patterns of development and thus dramatically alter disease susceptibility later in life. Endocrine disrupting chemicals (EDCs) interfere with the body's endocrine system and produce adverse developmental, reproductive, neurological, cardiovascular, metabolic and immune effects in humans. A wide range of substances, both natural and man-made, are thought to cause endocrine disruption, including pharmaceuticals, dioxin and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and components of plastics such as bisphenol A (BPA) and phthalates. EDCs are found in many everyday products--including plastic bottles, metal food cans, detergents, flame retardants, food additives, toys, cosmetics, and pesticides. EDCs interfere with the synthesis, secretion, transport, activity, or elimination of natural hormones. This interference can block or mimic hormone action, causing a wide range of effects. This review focuses on the mechanisms and modes of action by which EDCs alter hormone signaling. It also includes brief overviews of select disease endpoints associated with endocrine disruption.

  6. Syntax in Action Has Priority over Movement Selection in Piano Playing: An ERP Study.

    Science.gov (United States)

    Bianco, Roberta; Novembre, Giacomo; Keller, Peter E; Scharf, Florian; Friederici, Angela D; Villringer, Arno; Sammler, Daniela

    2016-01-01

    Complex human behavior is hierarchically organized. Whether or not syntax plays a role in this organization is currently under debate. The present ERP study uses piano performance to isolate syntactic operations in action planning and to demonstrate their priority over nonsyntactic levels of movement selection. Expert pianists were asked to execute chord progressions on a mute keyboard by copying the posture of a performing model hand shown in sequences of photos. We manipulated the final chord of each sequence in terms of Syntax (congruent/incongruent keys) and Manner (conventional/unconventional fingering), as well as the strength of its predictability by varying the length of the Context (five-chord/two-chord progressions). The production of syntactically incongruent compared to congruent chords showed a response delay that was larger in the long compared to the short context. This behavioral effect was accompanied by a centroparietal negativity in the long but not in the short context, suggesting that a syntax-based motor plan was prepared ahead. Conversely, the execution of the unconventional manner was not delayed as a function of Context and elicited an opposite electrophysiological pattern (a posterior positivity). The current data support the hypothesis that motor plans operate at the level of musical syntax and are incrementally translated to lower levels of movement selection.

  7. Antiviral activity and mode of action of propolis extracts and selected compounds.

    Science.gov (United States)

    Schnitzler, Paul; Neuner, Annett; Nolkemper, Silke; Zundel, Christine; Nowack, Hans; Sensch, Karl Heinz; Reichling, Jürgen

    2010-01-01

    Aqueous and ethanol extracts of propolis were analysed phytochemically and examined for their antiviral activity in vitro. Different polyphenols, flavonoids and phenylcarboxylic acids were identified as major constituents. The antiviral effect of propolis extracts and selected constituents, e.g. caffeic acid (1), p-coumaric acid (2), benzoic acid (3), galangin (4), pinocembrin (5) and chrysin (6) against herpes simplex virus type 1 (HSV-1) was analysed in cell culture. The 50% inhibitory concentration (IC(50)) of aqueous and ethanol propolis extracts for HSV-1 plaque formation was determined at 0.0004% and 0.000035%, respectively. Both propolis extracts exhibited high levels of antiviral activity against HSV-1 in viral suspension tests, plaque formation was significantly reduced by >98%. In order to determine the mode of antiviral action of propolis, the extracts were added at different times during the viral infection cycle. Both propolis extracts exhibited high anti-HSV-1 activity when the viruses were pretreated with these drugs prior to infection. Among the analysed compounds, only galangin and chrysin displayed some antiviral activity. However, the extracts containing many different components exhibited significantly higher antiherpetic effects as well as higher selectivity indices than single isolated constituents. Propolis extracts might be suitable for topical application against herpes infection.

  8. L-ALLIANCE: a mechanism for adaptive action selection in heterogeneous multi-robot teams

    Energy Technology Data Exchange (ETDEWEB)

    Parker, L.E.

    1995-11-01

    In practical applications of robotics, it is usually quite difficult, if not impossible, for the system designer to fully predict the environmental states in which the robots will operate. The complexity of the problem is further increased when dealing with teams of robots which themselves may be incompletely known and characterized in advance. It is thus highly desirable for robot teams to be able to adapt their performance during the mission due to changes in the environment, or to changes in other robot team members. In previous work, we introduced a behavior-based mechanism called the ALLIANCE architecture -- that facilitates the fault tolerant cooperative control of multi-robot teams. However, this previous work did not address the issue of how to dynamically update the control parameters during a mission to adapt to ongoing changes in the environment or in the robot team, and to ensure the efficiency of the collective team actions. In this paper, we address this issue by proposing the L-ALLIANCE mechanism, which defines an automated method whereby robots can use knowledge learned from previous experience to continually improve their collective action selection when working on missions composed of loosely coupled, discrete subtasks. This ability to dynamically update robotic control parameters provides a number of distinct advantages: it alleviates the need for human tuning of control parameters, it facilitates the use of custom-designed multi-robot teams for any given application, it improves the efficiency of the mission performance, and It allows robots to continually adapt their performance over time due to changes in the robot team and/or the environment. We describe the L-ALLIANCE mechanism, present the results of various alternative update strategies we investigated, present the formal model of the L-ALLIANCE mechanism, and present the results of a simple proof of concept implementation on a small team of heterogeneous mobile robots.

  9. Determination of acidic pharmaceuticals and potential endocrine disrupting compounds in wastewaters and spring waters by selective elution and analysis by gas chromatography-mass spectrometry.

    Science.gov (United States)

    Gibson, Richard; Becerril-Bravo, Elías; Silva-Castro, Vanessa; Jiménez, Blanca

    2007-10-26

    Although the trend in development of analytical methods for emerging contaminants is towards reduced sample preparation and increased detector selectivity, there are still benefits from removal of matrix material during sample preparation. This paper describes a simple method for acidic pharmaceuticals and a range of potential endocrine disrupting compounds in untreated wastewaters and spring waters. It is based on separation of the two classes during elution from the extraction cartridge with final analysis by gas chromatography-mass spectrometry. 3,4-D was used as the recovery standard for the acids while 4-n-nonylphenol and [2H4]estrone were used for the endocrine disrupters; mean recoveries varied between 89% and 111%. The method was also extensively validated by fortification with the target compounds. Recoveries of acids were from 68% to 97% with relative standard deviations generally less than 10% and recoveries of endocrine disrupters were 68-109% with relative standard deviations less than 20%. Detection limits varied from 0.005 to 1 ng/L in spring water, and from 0.5 to 100 ng/L in untreated wastewater. Concentrations of the analytes in the wastewater ranged from 0.018 to 22.4 microg/L. Values were comparable to reported data, although concentrations were generally relatively high, probably because of a lack of treatment. Triclosan, phthalates, estrone, 17beta-estradiol, ibuprofen, and naproxen were present in the spring water from aquifers recharged indirectly with this wastewater after its use for irrigation; concentrations ranged from 0.01 to 25.0 ng/L. The much lower concentrations compared to wastewater indicate effective removal processes on passage through the soil and subsoil.

  10. In and out of control: brain mechanisms linking fluency of action selection to self-agency in patients with schizophrenia.

    Science.gov (United States)

    Voss, Martin; Chambon, Valérian; Wenke, Dorit; Kühn, Simone; Haggard, Patrick

    2017-08-01

    Sense of agency refers to the feeling of control over one's actions, and their consequences. It involves both predictive processes linked to action control, and retrospective 'sense-making' causal inferences. Schizophrenia has been associated with impaired predictive processing, but the underlying mechanisms that impair patients' sense of agency remain unclear. We introduce a new 'prospective' aspect of agency and show that subliminally priming an action not only influences response times, but also influences reported sense of agency over subsequent action outcomes. This effect of priming was associated with altered connectivity between frontal areas and the angular gyrus. The effects on response times and on frontal action selection mechanisms were similar in patients with schizophrenia and in healthy volunteers. However, patients showed no effects of priming on sense of agency, no priming-related activation of angular gyrus, and no priming-related changes in fronto-parietal connectivity. We suggest angular gyrus activation reflects the experiences of agency, or non-agency, in part by processing action selection signals generated in the frontal lobes. The altered action awareness that characterizes schizophrenia may be due to impaired communication between these areas. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Regulation and regulatory role of WNT signaling in potentiating FSH action during bovine dominant follicle selection.

    Directory of Open Access Journals (Sweden)

    P S P Gupta

    Full Text Available Follicular development occurs in wave like patterns in monotocous species such as cattle and humans and is regulated by a complex interaction of gonadotropins with local intrafollicular regulatory molecules. To further elucidate potential mechanisms controlling dominant follicle selection, granulosa cell RNA harvested from F1 (largest and F2 (second largest follicles isolated at predeviation (PD and onset of diameter deviation (OD stages of the first follicular wave was subjected to preliminary RNA transcriptome analysis. Expression of numerous WNT system components was observed. Hence experiments were performed to test the hypothesis that WNT signaling modulates FSH action on granulosa cells during follicular waves. Abundance of mRNA for WNT pathway members was evaluated in granulosa cells harvested from follicles at emergence (EM, PD, OD and early dominance (ED stages of the first follicular wave. In F1 follicles, abundance of CTNNB1 and DVL1 mRNAs was higher and AXIN2 mRNA was lower at ED versus EM stages and DVL1 and FZD6 mRNAs were higher and AXIN2 mRNA was lower in F1 versus F2 follicle at the ED stage. Bovine granulosa cells were treated in vitro with increasing doses of the WNT inhibitor IWR-1+/- maximal stimulatory dose of FSH. IWR-1 treatment blocked the FSH-induced increase in granulosa cell numbers and reduced the FSH-induced increase in estradiol. Granulosa cells were also cultured in the presence or absence of FSH +/- IWR-1 and hormonal regulation of mRNA for WNT pathway members and known FSH targets determined. FSH treatment increased CYP19A1, CCND2, CTNNB1, AXIN2 and FZD6 mRNAs and the stimulatory effect on CYP19A1 mRNA was reduced by IWR-1. In contrast, FSH reduced CARTPT mRNA and IWR-1 partially reversed the inhibitory effect of FSH. Results support temporal and hormonal regulation and a potential role for WNT signaling in potentiating FSH action during dominant follicle selection.

  12. The exposure of fetuses and children to endocrine disrupting chemicals: a European Society for Paediatric Endocrinology (ESPE) and Pediatric Endocrine Society (PES) call to action statement

    DEFF Research Database (Denmark)

    Skakkebæk, Niels E; Toppari, Jorma; Söder, Olle

    2011-01-01

    During recent years, evidence has accumulated that both wildlife species and humans are exposed to ubiquitous endocrine-disrupting chemicals. Some are persistent in our bodies; others are nonpersistent but are produced in large quantities. Hitherto, the bulk of research in this area has been carr...

  13. The exposure of fetuses and children to endocrine disrupting chemicals: a European Society for Paediatric Endocrinology (ESPE) and Pediatric Endocrine Society (PES) call to action statement

    DEFF Research Database (Denmark)

    Skakkebæk, Niels E; Toppari, Jorma; Söder, Olle

    2011-01-01

    carried out by basic and experimental scientists and wildlife researchers. Relatively few clinical scientists have been engaged in research on this topic to date. The aim of this statement is to have pediatric endocrinologists consider the issue of endocrine disrupters in their clinical work and research....

  14. Family Disruptions

    Science.gov (United States)

    ... stay angry, or avoid fights altogether? Your children model themselves on you. Departures and Returns Do you or your spouse frequently travel on business? These can be disruptive times for your child and for the family ...

  15. Adsorption characteristics of selected pharmaceuticals and an endocrine disrupting compound-Naproxen, carbamazepine and nonylphenol-on activated carbon.

    Science.gov (United States)

    Yu, Zirui; Peldszus, Sigrid; Huck, Peter M

    2008-06-01

    The adsorption of two representative pharmaceutically active compounds (PhACs) (naproxen and carbamazepine) and one endocrine disrupting compound (nonylphenol) were evaluated on two types of activated carbon. When determining their isotherms at environmentally relevant concentration levels, it was found that at this low concentration range (10-800 ng/L), removals of the target compounds were contrary to expectations based on their hydrophobicity. Nonylphenol (log K(ow) 5.8) was most poorly adsorbed, whereas carbamazepine (log K(ow) 2.45) was most adsorbable. Nonylphenol Freundlich isotherms at this very low concentration range had a much higher 1/n compared to isotherms at much higher concentrations. This indicates that extrapolation from an isotherm obtained at a high concentration range to predict the adsorption of nonylphenol at a concentration well below the range of the original isotherm, leads to a substantial overestimation of its removals. Comparison of isotherms for the target compounds to those for other conventional micropollutants suggested that naproxen and carbamazepine could be effectively removed by applying the same dosage utilized to remove odorous compounds (geosmin and MIB) at very low concentrations. The impact of competitive adsorption by background natural organic matter (NOM) on the adsorption of the target compounds was quantified by using the ideal adsorbed solution theory (IAST) in combination with the equivalent background compound (EBC) approach. The fulfilment of the requirements for applying the simplified IAST-EBC model, which leads to the conclusion that the percentage removal of the target compounds at a given carbon dosage is independent of the initial contaminant concentration, was confirmed for the situation examined in the paper. On this basis it is suggested that the estimated minimum carbon usage rates (CURs) to achieve 90% removal of these emerging contaminants would be valid at concentrations of less than 500 ng/L in

  16. Skeletal unloading induces selective resistance to the anabolic actions of growth hormone on bone

    Science.gov (United States)

    Halloran, B. P.; Bikle, D. D.; Harris, J.; Autry, C. P.; Currier, P. A.; Tanner, S.; Patterson-Buckendahl, P.; Morey-Holton, E.

    1995-01-01

    Loss of skeletal weight bearing or physical unloading of bone in the growing animal inhibits bone formation and induces a bone mineral deficit. To determine whether the inhibition of bone formation induced by skeletal unloading in the growing animal is a consequence of diminished sensitivity to growth hormone (GH) we studied the effects of skeletal unloading in young hypophysectomized rats treated with GH (0, 50, 500 micrograms/100 g body weight/day). Skeletal unloading reduced serum osteocalcin, impaired uptake of 3H-proline into bone, decreased proximal tibial mass, and diminished periosteal bone formation at the tibiofibular junction. When compared with animals receiving excipient alone, GH administration increased bone mass in all animals. The responses in serum osteocalcin, uptake of 3H-proline and 45Ca into the proximal tibia, and proximal tibial mass in non-weight bearing animals were equal to those in weight bearing animals. The responses in trabecular bone volume in the proximal tibia and bone formation at the tibiofibular junction to GH, however, were reduced significantly by skeletal unloading. Bone unloading prevented completely the increase in metaphyseal trabecular bone normally induced by GH and severely dampened the stimulatory effect (158% vs. 313%, p bone formation. These results suggest that while GH can stimulate the overall accumulation of bone mineral in both weight bearing and non-weight bearing animals, skeletal unloading selectively impairs the response of trabecular bone and periosteal bone formation to the anabolic actions of GH.

  17. Skeletal unloading induces selective resistance to the anabolic actions of growth hormone on bone

    Science.gov (United States)

    Halloran, B. P.; Bikle, D. D.; Harris, J.; Autry, C. P.; Currier, P. A.; Tanner, S.; Patterson-Buckendahl, P.; Morey-Holton, E.

    1995-01-01

    Loss of skeletal weight bearing or physical unloading of bone in the growing animal inhibits bone formation and induces a bone mineral deficit. To determine whether the inhibition of bone formation induced by skeletal unloading in the growing animal is a consequence of diminished sensitivity to growth hormone (GH) we studied the effects of skeletal unloading in young hypophysectomized rats treated with GH (0, 50, 500 micrograms/100 g body weight/day). Skeletal unloading reduced serum osteocalcin, impaired uptake of 3H-proline into bone, decreased proximal tibial mass, and diminished periosteal bone formation at the tibiofibular junction. When compared with animals receiving excipient alone, GH administration increased bone mass in all animals. The responses in serum osteocalcin, uptake of 3H-proline and 45Ca into the proximal tibia, and proximal tibial mass in non-weight bearing animals were equal to those in weight bearing animals. The responses in trabecular bone volume in the proximal tibia and bone formation at the tibiofibular junction to GH, however, were reduced significantly by skeletal unloading. Bone unloading prevented completely the increase in metaphyseal trabecular bone normally induced by GH and severely dampened the stimulatory effect (158% vs. 313%, p < 0.002) of GH on periosteal bone formation. These results suggest that while GH can stimulate the overall accumulation of bone mineral in both weight bearing and non-weight bearing animals, skeletal unloading selectively impairs the response of trabecular bone and periosteal bone formation to the anabolic actions of GH.

  18. ACTION OF UNIFORM SEARCH ALGORITHM WHEN SELECTING LANGUAGE UNITS IN THE PROCESS OF SPEECH

    Directory of Open Access Journals (Sweden)

    Ирина Михайловна Некипелова

    2013-05-01

    Full Text Available The article is devoted to research of action of uniform search algorithm when selecting by human of language units for speech produce. The process is connected with a speech optimization phenomenon. This makes it possible to shorten the time of cogitation something that human want to say, and to achieve the maximum precision in thoughts expression. The algorithm of uniform search works at consciousness  and subconsciousness levels. It favours the forming of automatism produce and perception of speech. Realization of human's cognitive potential in the process of communication starts up complicated mechanism of self-organization and self-regulation of language. In turn, it results in optimization of language system, servicing needs not only human's self-actualization but realization of communication in society. The method of problem-oriented search is used for researching of optimization mechanisms, which are distinctive to speech producing and stabilization of language.DOI: http://dx.doi.org/10.12731/2218-7405-2013-4-50

  19. Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1 in breast cancer.

    Directory of Open Access Journals (Sweden)

    Lynda Mezil

    Full Text Available BACKGROUND: Targeted therapies, associated with standard chemotherapies, have improved breast cancer care. However, primary and acquired resistances are frequently observed and the development of new concepts is needed. High-throughput approaches to identify new active and safe molecules with or without an "a priori" are currently developed. Also, repositioning already-approved drugs in cancer therapy is of growing interest. The thiomorpholine hydroxamate compound TMI-1 has been previously designed to inhibit metalloproteinase activity for the treatment of rheumatoid arthritis. We present here the repositioning of TMI-1 drug in breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: We tested the effect of TMI-1 on luminal, basal and ERBB2-overexpressing breast tumor cell lines and on MMTV-ERBB2/neu tumor evolution. We measured the effects on i cell survival, ii cell cycle, iii extrinsic and intrinsic apoptotic pathways, iv association with doxorubicin, docetaxel and lapatinib, v cancer stem cells compartment. In contrast with conventional cytotoxic drugs, TMI-1 was highly selective for tumor cells and cancer stem cells at submicromolar range. All non-malignant cells tested were resistant even at high concentration. TMI-1 was active on triple negative (TN and ERBB2-overexpressing breast tumor cell lines, and was also highly efficient on human and murine "primary" ERBB2-overexpressing cells. Treatment of transgenic MMTV-ERBB2/neu mice with 100 mg/kg/day TMI-1 alone induced tumor apoptosis, inhibiting mammary gland tumor occurrence and development. No adverse effects were noticed during the treatment. This compound had a strong synergistic effect in association with docetaxel, doxorubicin and lapatinib. We showed that TMI-1 mediates its selective effects by caspase-dependent apoptosis. TMI-1 was efficient in 34/40 tumor cell lines of various origins (ED50: 0.6 µM to 12.5 µM. CONCLUSIONS/SIGNIFICANCE: This is the first demonstration of the tumor selective

  20. Bound simian virus 40 translocates to caveolin-enriched membrane domains, and its entry is inhibited by drugs that selectively disrupt caveolae.

    Science.gov (United States)

    Anderson, H A; Chen, Y; Norkin, L C

    1996-11-01

    Simian virus 40 (SV40) entry leading to infection occurred only after the virus was at the cell surface for 1.5 to 2 h. SV40 infectious entry was not sensitive to cytosol acidification, a treatment that blocks endocytosis via clathrin-coated vesicles. Instead, SV40 infectious entry was blocked by treating cells with the phorbol ester PMA or nystatin, which selectively disrupts caveolae. In control experiments, transferrin internalization was sensitive to cytosol acidification but was not sensitive to PMA or nystatin. Also, absorbed transferrin entered cells within minutes. Finally, bound SV40 translocated to caveolin-enriched membrane complexes isolated by a Triton X-100 insolubility protocol. Treatment with nystatin did not impair SV40 binding but did block the partitioning of virus into the caveolin-enriched complexes.

  1. A peptide targeting an interaction interface disrupts the dopamine D1-D2 receptor heteromer to block signaling and function in vitro and in vivo: effective selective antagonism.

    Science.gov (United States)

    Hasbi, Ahmed; Perreault, Melissa L; Shen, Maurice Y F; Zhang, Lucia; To, Ryan; Fan, Theresa; Nguyen, Tuan; Ji, Xiaodong; O'Dowd, Brian F; George, Susan R

    2014-11-01

    Although the dopamine D1-D2 receptor heteromer has emerging physiological relevance and a postulated role in different neuropsychiatric disorders, such as drug addiction, depression, and schizophrenia, there is a need for pharmacological tools that selectively target such receptor complexes in order to analyze their biological and pathophysiological functions. Since no selective antagonists for the D1-D2 heteromer are available, serial deletions and point mutations were used to precisely identify the amino acids involved in an interaction interface between the receptors, residing within the carboxyl tail of the D1 receptor that interacted with the D2 receptor to form the D1-D2 receptor heteromer. It was determined that D1 receptor carboxyl tail residues (404)Glu and (405)Glu were critical in mediating the interaction with the D2 receptor. Isolated mutation of these residues in the D1 receptor resulted in the loss of agonist activation of the calcium signaling pathway mediated through the D1-D2 receptor heteromer. The physical interaction between the D1 and D2 receptor could be disrupted, as shown by coimmunoprecipitation and BRET analysis, by a small peptide generated from the D1 receptor sequence that contained these amino acids, leading to a switch in G-protein affinities and loss of calcium signaling, resulting in the inhibition of D1-D2 heteromer function. The use of the D1-D2 heteromer-disrupting peptide in vivo revealed a pathophysiological role for the D1-D2 heteromer in the modulation of behavioral despair. This peptide may represent a novel pharmacological tool with potential therapeutic benefits in depression treatment. © FASEB.

  2. The SPIRIT Action Framework: A structured approach to selecting and testing strategies to increase the use of research in policy.

    Science.gov (United States)

    Redman, Sally; Turner, Tari; Davies, Huw; Williamson, Anna; Haynes, Abby; Brennan, Sue; Milat, Andrew; O'Connor, Denise; Blyth, Fiona; Jorm, Louisa; Green, Sally

    2015-07-01

    The recent proliferation of strategies designed to increase the use of research in health policy (knowledge exchange) demands better application of contemporary conceptual understandings of how research shapes policy. Predictive models, or action frameworks, are needed to organise existing knowledge and enable a more systematic approach to the selection and testing of intervention strategies. Useful action frameworks need to meet four criteria: have a clearly articulated purpose; be informed by existing knowledge; provide an organising structure to build new knowledge; and be capable of guiding the development and testing of interventions. This paper describes the development of the SPIRIT Action Framework. A literature search and interviews with policy makers identified modifiable factors likely to influence the use of research in policy. An iterative process was used to combine these factors into a pragmatic tool which meets the four criteria. The SPIRIT Action Framework can guide conceptually-informed practical decisions in the selection and testing of interventions to increase the use of research in policy. The SPIRIT Action Framework hypothesises that a catalyst is required for the use of research, the response to which is determined by the capacity of the organisation to engage with research. Where there is sufficient capacity, a series of research engagement actions might occur that facilitate research use. These hypotheses are being tested in ongoing empirical work.

  3. Modeling the Maturation of Grip Selection Planning and Action Representation: Insights from Typical and Atypical Motor Development.

    Directory of Open Access Journals (Sweden)

    Ian eFuelscher

    2016-02-01

    Full Text Available We investigated the purported association between developmental changes in grip selection planning and improvements in an individual’s capacity to represent action at an internal level (i.e., motor imagery. Participants were groups of healthy children aged 6-7 years and 8-12 years respectively, while a group of adolescents (13-17 years and adults (18-34 years allowed for consideration of childhood development in the broader context of motor maturation. A group of children aged 8-12 years with probable DCD (pDCD was included as a reference group for atypical motor development. Participants’ proficiency to generate and/or engage internal action representations was inferred from performance on the hand rotation task, a well-validated measure of motor imagery. A grip selection task designed to elicit the end-state comfort (ESC effect provided a window into the integrity of grip selection planning. Consistent with earlier accounts, the efficiency of grip selection planning followed a non-linear developmental progression in neurotypical individuals. As expected, analysis confirmed that these developmental improvements were predicted by an increased capacity to generate and/or engage internal action representations. The profile of this association remained stable throughout the (typical developmental spectrum. These findings are consistent with computational accounts of action planning that argue that internal action representations are associated with the expression and development of grip selection planning across typical development. However, no such association was found for our sample of children with pDCD, suggesting that individuals with atypical motor skill may adopt an alternative, sub-optimal strategy to plan their grip selection compared to their same-age control peers.

  4. Modeling the Maturation of Grip Selection Planning and Action Representation: Insights from Typical and Atypical Motor Development

    Science.gov (United States)

    Fuelscher, Ian; Williams, Jacqueline; Wilmut, Kate; Enticott, Peter G.; Hyde, Christian

    2016-01-01

    We investigated the purported association between developmental changes in grip selection planning and improvements in an individual’s capacity to represent action at an internal level [i.e., motor imagery (MI)]. Participants were groups of healthy children aged 6–7 years and 8–12 years respectively, while a group of adolescents (13–17 years) and adults (18–34 years) allowed for consideration of childhood development in the broader context of motor maturation. A group of children aged 8–12 years with probable DCD (pDCD) was included as a reference group for atypical motor development. Participants’ proficiency to generate and/or engage internal action representations was inferred from performance on the hand rotation task, a well-validated measure of MI. A grip selection task designed to elicit the end-state comfort (ESC) effect provided a window into the integrity of grip selection planning. Consistent with earlier accounts, the efficiency of grip selection planning followed a non-linear developmental progression in neurotypical individuals. As expected, analysis confirmed that these developmental improvements were predicted by an increased capacity to generate and/or engage internal action representations. The profile of this association remained stable throughout the (typical) developmental spectrum. These findings are consistent with computational accounts of action planning that argue that internal action representations are associated with the expression and development of grip selection planning across typical development. However, no such association was found for our sample of children with pDCD, suggesting that individuals with atypical motor skill may adopt an alternative, sub-optimal strategy to plan their grip selection compared to their same-age control peers. PMID:26903915

  5. Removal of selected endocrine disrupting chemicals and personal care products in surface waters and secondary wastewater by ozonation.

    Science.gov (United States)

    Tay, Kheng Soo; Rahman, Noorsaadah Abd; Abas, Mhd Radzi Bin

    2011-08-01

    This study investigated the removal of parabens, N,N-diethyl-m-toluamide (DEET), and phthalates by ozonation. The second-order rate constants for the reaction between selected compounds with ozone at pH 7 were of (2.2 +/-0.2) X 10(6) to (2.9 +/-0.3) X 10(6) M 1/s for parabens, (2.1+/- 0.3) to (3.9 +/-0.5) M-1/s for phthalates, and (5.2 +/-0.3) M-1/s for DEET. The rate constants for the reaction between selected compounds with hydroxyl radical ranged from (2.49 +/-0.06) x 10(9) to (8.5 +/-0.2) x 10(9) M-1/s. Ozonation of selected compounds in secondary wastewater and surface waters revealed that ozone dose of 1 and 3 mg/L yielded greater than 99% depletion of parabens and greater than 92% DEET and phthalates, respectively. In addition, parabens were found to transform almost exclusively through the reaction with ozone, while DEET and phthalates were transformed almost entirely by hydroxyl radicals (.OH).

  6. The serotonergic hallucinogen 5-methoxy-N,N-dimethyltryptamine disrupts cortical activity in a regionally-selective manner via 5-HT(1A) and 5-HT(2A) receptors.

    Science.gov (United States)

    Riga, Maurizio S; Bortolozzi, Analia; Campa, Letizia; Artigas, Francesc; Celada, Pau

    2016-02-01

    5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT(1A)/5-HT(2A)-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT(1A)-R and 5-HT(2A)-R, using wild type (WT) and 5-HT(2A)-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT(1A)-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT(1A)-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT(1A)-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT(1A)-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT(2A)-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Design of an Action Selection Mechanism for Cooperative Soccer Robots Based on Fuzzy Decision Making Algorithm

    Directory of Open Access Journals (Sweden)

    S. Alireza Mohades Kasaei

    2010-04-01

    Full Text Available Robocup is an international competition for multi agent research and related subject like: Artificial intelligence, Image processing, machine learning, robot path planning, control, and
    obstacle avoidance. In a soccer robot game, the environment is highly competitive and dynamic. In order to work in the dynamically changing environment, the decision-making system of a soccer robot system should have the features of flexibility and real-time adaptation. In this paper we will
    focus on the Middle Size Soccer Robot league (MSL and new hierarchical hybrid fuzzy methods for decision making and action selection of a robot in Middle Size Soccer Robot league (MSL are presented. First, the behaviors of an agent are introduced, implemented and classified in two layers,
    the Low_Level_Behaviors and the High_Level_Behaviors. In the second layer, a two phase mechanism for decision making is introduced. In phase one, some useful methods are implemented which check the robot’s situation for performing required behaviors. In the next phase, the team strategy, team formation, robot’s role and the robot’s positioning system are introduced. A fuzzy logical approach is employed to recognize the team strategy and further more to tell the player the
    best position to move. We believe that a Dynamic role engine is necessary for a successful team. Dynamic role engine and formation control during offensive or defensive play, help us to prevent collision avoidance among own players when attacking the ball and obstacle avoidance of the opponents. At last, we comprised our implemented algorithm in the Robocup 2007 and 2008 and results showed the efficiency of the introduced methodology. The results are satisfactory which has already been successfully implemented in ADRO RoboCup team. This project is still in progress and some new interesting methods are described in the current report.

  8. Nuclear facility decommissioning and site remedial actions. Volume 6. A selected bibliography

    Energy Technology Data Exchange (ETDEWEB)

    Owen, P.T.; Michelson, D.C.; Knox, N.P.

    1985-09-01

    This bibliography of 683 references with abstracts on the subject of nuclear facility decommissioning, uranium mill tailings management, and site remedial actions is the sixth in a series of annual reports prepared for the US Department of Energy's Remedial Action Programs. Foreign as well as domestic literature of all types - technical reports, progress reports, journal articles, conference papers, symposium proceedings, theses, books, patents, legislation, and research project descriptions - has been included. The bibliography contains scientific (basic research as well as applied technology), economic, regulatory, and legal literature pertinent to the US Department of Energy's remedial action program. Major chapters are: (1) Surplus Facilities Management Program; (2) Nuclear Facilities Decommissioning; (3) Formerly Utilized Sites Remedial Action Program; (4) Facilities Contaminated with Natural Radioactivity; (5) Uranium Mill Tailings Remedial Action Program; (6) Grand Junction Remedial Action Program; (7) Uranium Mill Tailings Management; (8) Technical Measurements Center; and (9) General Remedial Action Program Studies. Chapter sections for chapters 1, 2, 5, and 7 include Design, Planning, and Regulations; Environmental Studies and Site Surveys; Health, Safety, and Biomedical Studies; Decontamination Studies; Dismantlement and Demolition; Site Stabilization and Reclamation; Waste Disposal; Remedial Action Experience; and General Studies. The references within each chapter or section are arranged alphabetically by leading author. References having no individual author are arranged by corporate affiliation or by publication description.

  9. Civil Society Action and Governance in Vietnam: Selected Findings from an Empirical Survey

    Directory of Open Access Journals (Sweden)

    Jörg Wischermann

    2010-01-01

    Full Text Available In this article, findings from 300 standardized interviews with representatives of Civic Organizations in Ho Chi Minh-City and Ha Noi are presented. Following a view of civil society as a specific mode of social action and interaction, data analysis unveils the existence of core dimensions of such action (respect, empathy/ sympathy, and the willingness to compromise and stick to agreed-upon rules, though the respective values of those dimensions vary strongly. Inseparably linked with such civil society action of whatever kind is consensus-seeking, an aversion to conflicts, and an affinity to synthesis. These attitudes and practices, dominating various Civic Organizations’ internal decision-making processes, represent elements of authoritarian political thinking in Civic Organizations’ leaders’ mindsets and courses of action. Combined, those characteristics make up civil society action “in Vietnamese colours”.

  10. Novel Design of Heptad Amphiphiles To Enhance Cell Selectivity, Salt Resistance, Antibiofilm Properties and Their Membrane-Disruptive Mechanism.

    Science.gov (United States)

    Dou, Xiujing; Zhu, Xin; Wang, Jiajun; Dong, Na; Shan, Anshan

    2017-03-23

    Coiled-coil, a basic folding pattern of native proteins, was previously demonstrated to be associated with the specific spatial recognition, association, and dissociation of proteins and can be used to perfect engineering peptide model. Thus, in this study, a series of amphiphiles composed of heptads repeats with coiled-coil structures was constructed, and the designed peptides exhibited a broad spectrum of antimicrobial activities. Circular dichroism and biological assays showed that the heptad repeats and length of the linker between the heptads largely influenced the amphiphile's helical propensity and cell selectivity. The engineered amphiphiles were also found to efficiently reduce sessile P. aeruginosa biofilm biomass, neutralize endotoxins, inhibit the inflammatory response, and remain active under physiological salt concentrations. In summary, these findings are helpful for short AMP design with a highly therapeutic index to treat bacteria-induced infection.

  11. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  12. Disrupting Business

    DEFF Research Database (Denmark)

    Cox, Geoff; Bazzichelli, Tatiana

    Disruptive Business explores some of the interconnections between art, activism and the business concept of disruptive innovation. With a backdrop of the crisis of financial capitalism, austerity cuts in the cultural sphere, the idea is to focus on potential art strategies in relation to a broken...... economy. In a perverse way, we ask whether this presents new opportunities for cultural producers to achieve more autonomy over their production process. If it is indeed possible, or desirable, what alternative business models emerge? The book is concerned broadly with business as material for reinvention...

  13. Politisk disruption

    DEFF Research Database (Denmark)

    Tække, Jesper

    2017-01-01

    Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på.......Dette blogindlæg giver en kort analyse af hvordan de sociale medier ved at give en ny tid har åbnet for den disruption af de politiske processer som især Trump stå som et eksempel på....

  14. Maintenance of Mouse Gustatory Terminal Field Organization Is Disrupted following Selective Removal of Peripheral Sodium Salt Taste Activity at Adulthood.

    Science.gov (United States)

    Skyberg, Rolf; Sun, Chengsan; Hill, David L

    2017-08-09

    Neural activity plays a critical role in the development of central circuits in sensory systems. However, the maintenance of these circuits at adulthood is usually not dependent on sensory-elicited neural activity. Recent work in the mouse gustatory system showed that selectively deleting the primary transduction channel for sodium taste, the epithelial sodium channel (ENaC), throughout development dramatically impacted the organization of the central terminal fields of three nerves that carry taste information to the nucleus of the solitary tract. More specifically, deleting ENaCs during development prevented the normal maturation of the fields. The present study was designed to extend these findings by testing the hypothesis that the loss of sodium taste activity impacts the maintenance of the normal adult terminal field organization in male and female mice. To do this, we used an inducible Cre-dependent genetic recombination strategy to delete ENaC function after terminal field maturation occurred. We found that removal of sodium taste neural activity at adulthood resulted in significant reorganization of mature gustatory afferent terminal fields in the nucleus of the solitary tract. Specifically, the chorda tympani and greater superficial petrosal nerve terminal fields were 1.4× and 1.6× larger than age-matched controls, respectively. By contrast, the glossopharyngeal nerve, which is not highly sensitive to sodium taste stimulation, did not undergo terminal field reorganization. These surprising results suggest that gustatory nerve terminal fields remain plastic well into adulthood, which likely impacts central coding of taste information and taste-related behaviors with altered taste experience.SIGNIFICANCE STATEMENT Neural activity plays a major role in the development of sensory circuits in the mammalian brain. However, the importance of sensory-driven activity in maintaining these circuits at adulthood, especially in subcortical structures, appears to be

  15. Development and characterization of a nanodendritic silver-based solid-phase extraction sorbent for selective enrichment of endocrine-disrupting chemicals in water and milk samples.

    Science.gov (United States)

    Gao, Yuanji; Xia, Bing; Liu, Jie; Ji, Baocheng; Ma, Fengwei; Ding, Lisheng; Li, Bangjing; Zhou, Yan

    2015-11-01

    In this study, 4-[4-phenylazo-phenoxy] butyl-1-thiol (AzSH) functionalized nanodendritic silver (AzS@AgNDs) materials were prepared as a solid-phase extraction (SPE) sorbent for the selective extraction of estrogens. AzS@AgNDs possess an extremely large surface-to-volume ratio and a small average particle size. The performance of the material was evaluated by selective enrichment of hexestrol, diethylstilbestrol, dienestrol and bisphenol A in water and milk samples followed by rapid ultra-performance liquid chromatography-electrospray ionization mass spectrometry (UPLC-ESI-MS) analyses. The results exhibited that AzS@AgNDs had excellent adsorption capability for the targeted estrogens. The limits of detection of the four estrogens ranged from 0.1 to 5.0 pg/mL. The recoveries of the estrogens spiked into tap water were over the range of 83.6-105.3% with relative standard deviations of 2.8-6.0%. The results indicated the capability of this method for the rapid determination of estrogens in milk and other environmental water samples. In addition, this method would be useful for the determination of human exposure and health risk assessments trace level of endocrine-disrupting compounds (EDCs) in drinking water.

  16. Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors.

    Science.gov (United States)

    Tripathy, Debu; Bardia, Aditya; Sellers, William R

    2017-07-01

    The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here, we describe the mechanism of action of ribociclib and review preclinical and clinical data from phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. On the basis of the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies, and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology. Clin Cancer Res; 23(13); 3251-62. ©2017 AACR. ©2017 American Association for Cancer Research.

  17. Nuclear facility decommissioning and site remedial actions: a selected bibliography. Volume 5

    Energy Technology Data Exchange (ETDEWEB)

    Owen, P.T.; Knox, N.P.; Chilton, B.D.; Baldauf, M.F.

    1984-09-01

    This bibliography of 756 references with abstracts on the subject of nuclear facility decommissioning, uranium mill tailings management, and site remedial actions is the fifth in a series of annual reports prepared for the US Department of Energy, Division of Remedial Action Projects. Foreign as well as domestic literature of all types - technical reports, progress reports, journal articles, conference papers, symposium proceedings, theses, books, patents, legislation, and research project descriptions - has been included in this publication. The bibliography contains scientific (basic research as well as applied technology), economic, regulatory, and legal literature pertinent to the US Department of Energy's Remedial Action Program. Major chapters are: (1) Surplus Facilities Management Program; (2) Nuclear Facilities Decommissioning; (3) Formerly Utilized Sites Remedial Action Program; (4) Uranium Mill Tailings Remedial Action Program; (5) Grand Junction Remedial Action Program; (6) Uranium Mill Tailings Management; and (7) Technical Measurements Center. Chapter sections for chapters 1, 2, 4, and 6 include Design, Planning, and Regulations; Environmental Studies and Site Surveys; Decontamination Studies; Dismantlement and Demolition; Site Stabilization and Reclamation; Waste Disposal; Remedial Action Experience; and General Studies. The references within each chapter or section are arranged alphabetically by leading author. References having no individual author are arranged by corporate author or by title. Indexes are provided for the categories of author, corporate affiliation, title, publication description, geographic location, and keywords. The Appendix contains a list of frequently used acronyms.

  18. Reduced dosage of the chromosome axis factor Red1 selectively disrupts the meiotic recombination checkpoint in Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Tovah E Markowitz

    2017-07-01

    Full Text Available Meiotic chromosomes assemble characteristic "axial element" structures that are essential for fertility and provide the chromosomal context for meiotic recombination, synapsis and checkpoint signaling. Whether these meiotic processes are equally dependent on axial element integrity has remained unclear. Here, we investigated this question in S. cerevisiae using the putative condensin allele ycs4S. We show that the severe axial element assembly defects of this allele are explained by a linked mutation in the promoter of the major axial element gene RED1 that reduces Red1 protein levels to 20-25% of wild type. Intriguingly, the Red1 levels of ycs4S mutants support meiotic processes linked to axis integrity, including DNA double-strand break formation and deposition of the synapsis protein Zip1, at levels that permit 70% gamete survival. By contrast, the ability to elicit a meiotic checkpoint arrest is completely eliminated. This selective loss of checkpoint function is supported by a RED1 dosage series and is associated with the loss of most of the cytologically detectable Red1 from the axial element. Our results indicate separable roles for Red1 in building the structural axis of meiotic chromosomes and mounting a sustained recombination checkpoint response.

  19. Adsorption of selected pharmaceuticals and an endocrine disrupting compound by granular activated carbon. 1. Adsorption capacity and kinetics

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Z.; Peldszus, S.; Huck, P.M. [University of Waterloo, Waterloo, ON (Canada). NSERC Chair in Water Treatment

    2009-03-01

    The adsorption of two representative PhACs (naproxen and carbamazepine) and one EDC (nonylphenol) were evaluated on two granular activated carbons (GAC) namely coal-based Calgon Filtrasorb 400 and coconut shell-based PICA CTIF TE. The primary objective was to investigate preloading effects by natural organic matter (NOM) on adsorption capacity and kinetics under conditions and concentrations (i.e., ng/L) relevant for drinking water treatment. Isotherms demonstrated that all compounds were significantly negatively impacted by NOM fouling. Adsorption capacity reduction was most severe for the acidic naproxen, followed by the neutral carbamazepine and then the more hydrophobic nonylphenol. The GAC with the wider pore size distribution had considerably greater NOM loading, resulting in lower adsorption capacity. Different patterns for the change in Freundlich KF and 1/n with time revealed different competitive mechanisms for the different compounds. Mass transport coefficients determined by short fixed-bed (SFB) tests with virgin and preloaded GAC demonstrated that film diffusion primarily controls mass transfer on virgin and preloaded carbon. Naproxen suffered the greatest deteriorative effect on kinetic parameters due to preloading, followed by carbamazepine, and then nonylphenol. A type of surface NOM/biofilm, which appeared to add an additional mass transfer resistance layer and thus reduce film diffusion, was observed. In addition, electrostatic interactions between NOM/biofilm and the investigated compounds are proposed to contribute to the reduction of film diffusion. A companion paper building on this work describes treatability studies in pilot-scale GAC adsorbers and the effectiveness of a selected fixed-bed model. 32 refs., 3 figs., 2 tabs.

  20. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 13: Part 2, Indexes

    Energy Technology Data Exchange (ETDEWEB)

    Goins, L.F.; Webb, J.R.; Cravens, C.D.; Mallory, P.K.

    1992-09-01

    This is part 2 of a bibliography on nuclear facility decommissioning and site remedial action. This report contains indexes on the following: authors, corporate affiliation, title words, publication description, geographic location, subject category, and key word.

  1. Nuclear facility decommissioning and site remedial actions: A selected bibliography: Volume 8

    Energy Technology Data Exchange (ETDEWEB)

    Owen, P.T.; Michelson, D.C.; Knox, N.P.

    1987-09-01

    The 553 abstracted references on nuclear facility decommissioning, uranium mill tailings management, and site remedial actions constitute the eighth in a series of reports. Foreign and domestic literature of all types - technical reports, progress reports, journal articles, symposia proceedings, theses, books, patents, legislation, and research project descriptions - has been included. The bibliography contains scientific, technical, economic, regulatory, and legal information pertinent to the US Department of energy's remedial action program. Major chapters are Surplus Facilities Management Program, Nuclear Facilities Decommissioning, Formerly Utilized Sites Remedial Action Program, Facilities Contaminated with Naturally Occurring Radionuclides, Uranium Mill Tailings Remedial Action Program, Uranium Mill Tailings Management, Technical Measurements Center, and General Remedial Action Program Studies. Chapter sections for chapters 1, 2, 5, and 6 include Design, Planning, and Regulations; Environmental Studies and Site Surveys; Health, Safety, and Biomedical Studies; Decontamination Studies; Dismantlement and Demolition; Site Stabilization and Reclamation; Waste Disposal; Remedial Action Experience; and General Studies. Within these categories, references are arranged alphabetically by first author. Those references having no individual author are listed by corporate affiliation or by publication description. Indexes are provided for author, corporate affiliation, title word, publication description, geographic location, and keywords. The appendix contains a list of frequently used acronyms and abbreviations.

  2. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 13: Part 1, Main text

    Energy Technology Data Exchange (ETDEWEB)

    Goins, L.F.; Webb, J.R.; Cravens, C.D.; Mallory, P.K.

    1992-09-01

    This publication contains 1035 abstracted references on environmental restoration, nuclear facility decommissioning, uranium mill tailings management, and site remedial actions. These citations constitute the thirteenth in a series of reports prepared annually for the US Department of Energy (DOE) Environmental Restoration programs. Citations to foreign and domestic literature of all types. There are 13 major sections of the publication, including: (1) DOE Decontamination and Decommissioning Program; (2) Nuclear Facilities Decommissioning; (3) DOE Formerly Utilized Sites Remedial Action Program; (4) DOE Uranium Mill Tailings Remedial Action Project; (5) Uranium Mill Tailings Management; (6) DOE Environmental Restoration Program; (7) DOE Site-Specific Remedial Actions; (8) Contaminated Site Restoration; (9) Remediation of Contaminated Soil and Groundwater; (10) Environmental Data Measurements, Management, and Evaluation; (11) Remedial Action Assessment and Decision-Making; (12) Technology Development and Evaluation; and (13) Environmental and Waste Management Issues. Bibliographic references are arranged in nine subject categories by geographic location and then alphabetically by first author, corporate affiliation, or publication title. Indexes are provided for author, corporate affiliation, title word, publication description, geographic location, subject category, and key word.

  3. Selective weighting of action-related feature dimensions in visual working memory.

    Science.gov (United States)

    Heuer, Anna; Schubö, Anna

    2016-11-28

    Planning an action primes feature dimensions that are relevant for that particular action, increasing the impact of these dimensions on perceptual processing. Here, we investigated whether action planning also affects the short-term maintenance of visual information. In a combined memory and movement task, participants were to memorize items defined by size or color while preparing either a grasping or a pointing movement. Whereas size is a relevant feature dimension for grasping, color can be used to localize the goal object and guide a pointing movement. The results showed that memory for items defined by size was better during the preparation of a grasping movement than during the preparation of a pointing movement. Conversely, memory for color tended to be better when a pointing movement rather than a grasping movement was being planned. This pattern was not only observed when the memory task was embedded within the preparation period of the movement, but also when the movement to be performed was only indicated during the retention interval of the memory task. These findings reveal that a weighting of information in visual working memory according to action relevance can even be implemented at the representational level during maintenance, demonstrating that our actions continue to influence visual processing beyond the perceptual stage.

  4. DISRUPTION OF CIRCADIAN RHYTHMICITY AND SUPRACHIASMATIC ACTION POTENTIAL FREQUENCY IN A MOUSE MODEL WITH CONSTITUTIVE ACTIVATION OF GLYCOGEN SYNTHASE KINASE-3

    Science.gov (United States)

    Paul, Jodi R.; Johnson, Russell L.; Jope, Richard S.; Gamble, Karen L.

    2012-01-01

    Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in psychiatric diseases, neurodevelopment, and circadian regulation. Both GSK3 isoforms, α and β, exhibit a 24-hour variation of inhibitory phosphorylation within the suprachiasmatic nucleus (SCN), the primary circadian pacemaker. We examined the hypothesis that rhythmic GSK3 activity is critical for robust circadian rhythmicity using GSK3α21A/21A/β9A/9A knock-in mice with serine-alanine substitutions at the inhibitory phosphorylation sites, making both forms constitutively active. We monitored wheel-running locomotor activity of GSK3 knock-in mice and used loose-patch electrophysiology to examine the effect of chronic GSK3 activity on circadian behavior and SCN neuronal activity. Double transgenic GSK3α/β knock-in mice exhibit disrupted behavioral rhythmicity, including significantly decreased rhythmic amplitude, lengthened active period, and increased activity bouts per day. This behavioral disruption was dependent on chronic activation of both GSK3 isoforms and was not seen in single transgenic GSK3α or GSK3β knock-in mice. Underlying the behavioral changes, SCN neurons from double transgenic GSK3α/β knock-in mice exhibited significantly higher spike rates during the subjective night compared to those from WT controls, with no differences detected during the subjective day. These results suggest that constitutive activation of GSK3 results in loss of the typical day/night variation of SCN neuronal activity. Together, these results implicate GSK3 activity as a critical regulator of circadian behavior and neurophysiological rhythms. Because GSK3 has been implicated in numerous pathologies, understanding how GSK3 modulates circadian rhythms and neurophysiological activity may lead to novel therapeutics for pathological disorders and circadian rhythm dysfunction. PMID:22986169

  5. Disruption of circadian rhythmicity and suprachiasmatic action potential frequency in a mouse model with constitutive activation of glycogen synthase kinase 3.

    Science.gov (United States)

    Paul, J R; Johnson, R L; Jope, R S; Gamble, K L

    2012-12-13

    Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in psychiatric diseases, neurodevelopment, and circadian regulation. Both GSK3 isoforms, α and β, exhibit a 24-h variation of inhibitory phosphorylation within the suprachiasmatic nucleus (SCN), the primary circadian pacemaker. We examined the hypothesis that rhythmic GSK3 activity is critical for robust circadian rhythmicity using GSK3α(21A/21A)/β(9A/9A) knock-in mice with serine-alanine substitutions at the inhibitory phosphorylation sites, making both forms constitutively active. We monitored wheel-running locomotor activity of GSK3 knock-in mice and used loose-patch electrophysiology to examine the effect of chronic GSK3 activity on circadian behavior and SCN neuronal activity. Double transgenic GSK3α/β knock-in mice exhibit disrupted behavioral rhythmicity, including significantly decreased rhythmic amplitude, lengthened active period, and increased activity bouts per day. This behavioral disruption was dependent on chronic activation of both GSK3 isoforms and was not seen in single transgenic GSK3α or GSK3β knock-in mice. Underlying the behavioral changes, SCN neurons from double transgenic GSK3α/β knock-in mice exhibited significantly higher spike rates during the subjective night compared to those from wild-type controls, with no differences detected during the subjective day. These results suggest that constitutive activation of GSK3 results in the loss of the typical day/night variation of SCN neuronal activity. Together, these results implicate GSK3 activity as a critical regulator of circadian behavior and neurophysiological rhythms. Because GSK3 has been implicated in numerous pathologies, understanding how GSK3 modulates circadian rhythms and neurophysiological activity may lead to novel therapeutics for pathological disorders and circadian rhythm dysfunction. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Differential mechanisms associated with vascular disrupting action of electrochemotherapy: intravital microscopy on the level of single normal and tumor blood vessels.

    Directory of Open Access Journals (Sweden)

    Bostjan Markelc

    Full Text Available Electropermeabilization/electroporation (EP provides a tool for the introduction of molecules into cells and tissues. In electrochemotherapy (ECT, cytotoxic drugs are introduced into cells in tumors, and nucleic acids are introduced into cells in gene electrotransfer. The normal and tumor tissue blood flow modifying effects of EP and the vascular disrupting effect of ECT in tumors have already been determined. However, differential effects between normal vs. tumor vessels, to ensure safety in the clinical application of ECT, have not been determined yet. Therefore, the aim of our study was to determine the effects of EP and ECT with bleomycin on the HT-29 human colon carcinoma tumor model and its surrounding blood vessels. The response of blood vessels to EP and ECT was monitored in real time, directly at the single blood vessel level, by in vivo optical imaging in a dorsal window chamber in SCID mice with 70 kDa fluorescently labeled dextrans. The response of tumor blood vessels to EP and ECT started to differ within the first hour. Both therapies induced a vascular lock, decreased functional vascular density (FVD and increased the diameter of functional blood vessels within the tumor. The effects were more pronounced for ECT, which destroyed the tumor blood vessels within 24 h. Although the vasculature surrounding the tumor was affected by EP and ECT, it remained functional. The study confirms the current model of tumor blood flow modifying effects of EP and provides conclusive evidence that ECT is a vascular disrupting therapy with a specific effect on the tumor blood vessels.

  7. Differential mechanisms associated with vascular disrupting action of electrochemotherapy: intravital microscopy on the level of single normal and tumor blood vessels.

    Science.gov (United States)

    Markelc, Bostjan; Sersa, Gregor; Cemazar, Maja

    2013-01-01

    Electropermeabilization/electroporation (EP) provides a tool for the introduction of molecules into cells and tissues. In electrochemotherapy (ECT), cytotoxic drugs are introduced into cells in tumors, and nucleic acids are introduced into cells in gene electrotransfer. The normal and tumor tissue blood flow modifying effects of EP and the vascular disrupting effect of ECT in tumors have already been determined. However, differential effects between normal vs. tumor vessels, to ensure safety in the clinical application of ECT, have not been determined yet. Therefore, the aim of our study was to determine the effects of EP and ECT with bleomycin on the HT-29 human colon carcinoma tumor model and its surrounding blood vessels. The response of blood vessels to EP and ECT was monitored in real time, directly at the single blood vessel level, by in vivo optical imaging in a dorsal window chamber in SCID mice with 70 kDa fluorescently labeled dextrans. The response of tumor blood vessels to EP and ECT started to differ within the first hour. Both therapies induced a vascular lock, decreased functional vascular density (FVD) and increased the diameter of functional blood vessels within the tumor. The effects were more pronounced for ECT, which destroyed the tumor blood vessels within 24 h. Although the vasculature surrounding the tumor was affected by EP and ECT, it remained functional. The study confirms the current model of tumor blood flow modifying effects of EP and provides conclusive evidence that ECT is a vascular disrupting therapy with a specific effect on the tumor blood vessels.

  8. Action semantics: A unifying conceptual framework for the selective use of multimodal and modality-specific object knowledge.

    Science.gov (United States)

    van Elk, Michiel; van Schie, Hein; Bekkering, Harold

    2014-06-01

    Our capacity to use tools and objects is often considered one of the hallmarks of the human species. Many objects greatly extend our bodily capabilities to act in the physical world, such as when using a hammer or a saw. In addition, humans have the remarkable capability to use objects in a flexible fashion and to combine multiple objects in complex actions. We prepare coffee, cook dinner and drive our car. In this review we propose that humans have developed declarative and procedural knowledge, i.e. action semantics that enables us to use objects in a meaningful way. A state-of-the-art review of research on object use is provided, involving behavioral, developmental, neuropsychological and neuroimaging studies. We show that research in each of these domains is characterized by similar discussions regarding (1) the role of object affordances, (2) the relation between goals and means in object use and (3) the functional and neural organization of action semantics. We propose a novel conceptual framework of action semantics to address these issues and to integrate the previous findings. We argue that action semantics entails both multimodal object representations and modality-specific sub-systems, involving manipulation knowledge, functional knowledge and representations of the sensory and proprioceptive consequences of object use. Furthermore, we argue that action semantics are hierarchically organized and selectively activated and used depending on the action intention of the actor and the current task context. Our framework presents an integrative account of multiple findings and perspectives on object use that may guide future studies in this interdisciplinary domain.

  9. Action semantics: A unifying conceptual framework for the selective use of multimodal and modality-specific object knowledge

    Science.gov (United States)

    van Elk, Michiel; van Schie, Hein; Bekkering, Harold

    2014-06-01

    Our capacity to use tools and objects is often considered one of the hallmarks of the human species. Many objects greatly extend our bodily capabilities to act in the physical world, such as when using a hammer or a saw. In addition, humans have the remarkable capability to use objects in a flexible fashion and to combine multiple objects in complex actions. We prepare coffee, cook dinner and drive our car. In this review we propose that humans have developed declarative and procedural knowledge, i.e. action semantics that enables us to use objects in a meaningful way. A state-of-the-art review of research on object use is provided, involving behavioral, developmental, neuropsychological and neuroimaging studies. We show that research in each of these domains is characterized by similar discussions regarding (1) the role of object affordances, (2) the relation between goals and means in object use and (3) the functional and neural organization of action semantics. We propose a novel conceptual framework of action semantics to address these issues and to integrate the previous findings. We argue that action semantics entails both multimodal object representations and modality-specific sub-systems, involving manipulation knowledge, functional knowledge and representations of the sensory and proprioceptive consequences of object use. Furthermore, we argue that action semantics are hierarchically organized and selectively activated and used depending on the action intention of the actor and the current task context. Our framework presents an integrative account of multiple findings and perspectives on object use that may guide future studies in this interdisciplinary domain.

  10. Disruptive innovations

    OpenAIRE

    Viglia, Giampaolo; Werthner, H.; Buhalis, Dimitrios

    2016-01-01

    The diffusion of disrupting innovations has generated significant market changes, modifying the dominant logic and affecting the strategic positioning of companies. This structural change is affecting market structure, the networks and the services that tourism players are supposed to use (Gretzel et al. 2015). One can also refer to the notion of digital infrastructure, which provides a nice framework that connects the different stakeholders, their relations as well as internal dynamics. At t...

  11. Disruptive innovations

    OpenAIRE

    Viglia, Giampaolo; H. Werthner; Buhalis, Dimitrios

    2016-01-01

    The diffusion of disrupting innovations has generated significant market changes, modifying the dominant logic and affecting the strategic positioning of companies. This structural change is affecting market structure, the networks and the services that tourism players are supposed to use (Gretzel et al. 2015). One can also refer to the notion of digital infrastructure, which provides a nice framework that connects the different stakeholders, their relations as well as internal dynamics. At t...

  12. Multi-Features Encoding and Selecting Based on Genetic Algorithm for Human Action Recognition from Video

    Directory of Open Access Journals (Sweden)

    Chenglong Yu

    2013-05-01

    Full Text Available In this study, we proposed multiple local features encoded for recognizing the human actions. The multiple local features were obtained from the simple feature description of human actions in video. The simple features are two kinds of important features, optical flow and edge, to represent the human perception for the video behavior. As the video information descriptors, optical flow and edge, which their computing speeds are very fast and their requirement of memory consumption is very low, can represent respectively the motion information and shape information. Furthermore, key local multi-features are extracted and encoded by GA in order to reduce the computational complexity of the algorithm. After then, the Multi-SVM classifier is applied to discriminate the human actions.

  13. Nuclear facility decommissioning and site remedial actions: a selected bibliography. Volume 4

    Energy Technology Data Exchange (ETDEWEB)

    Owen, P.T.; Knox, N.P.; Fielden, J.M.; Faust, R.A.

    1983-09-01

    This bibliography of 657 references with abstracts on the subject of nuclear facility decommissioning, uranium mill tailings management, and site remedial actions is the fourth in a series of annual reports prepared for the US Department of Energy, Division of Remedial Action Projects. Foreign as well as domestic documents of all types - technical reports, progress reports, journal articles, conference papers, symposium proceedings, theses, books, patents, legislation, and research project descriptions - have been references in this publication. The bibliography contains scientific (basic research as well as applied technology), economic, regulatory, and legal literature pertinent to the US Department of Energy's Remedial Action Program. Major chapters are: (1) Surplus Facilities Management Program; (2) Nuclear Facilities Decommissioning; (3) Formerly Utilized Sites Remedial Action Program; (4) Uranium Mill Tailings Remedial Action Program; (5) Grand Junction Remedial Action Program; and (6) Uranium Mill Tailings Management. Chapter sections for chapters 1 and 2 include: Design, Planning, and Regulations; Site Surveys; Decontamination Studies; Dismantlement and Demolition; Land Decontamination and Reclamation; Waste Disposal; and General studies. The references within each chapter or section are arranged alphabetically by leading author. References having no individual author are arranged by corporate author, or by title. Indexes are provided for the categories of author, corporate affiliation, title, publication description, geographic location, and keywords. Appendix A lists 264 bibliographic references to literature identified during this reporting period but not abstracted due to time constraints. Title and publication description indexes are given for this appendix. Appendix B defines frequently used acronyms, and Appendix C lists the recipients of this report according to their corporate affiliation.

  14. A Randomized Trial of the Self-Management Training and Regulation Strategy (STARS): A Selective Intervention for Students with Disruptive Behaviors

    Science.gov (United States)

    Thompson, Aaron M.

    2012-01-01

    To attain academic goals, school personnel must effectively manage 20% of students who engage in the disruptive behaviors that interrupt instruction, create teacher stress, and contribute to poor student outcomes. Without effective strategies, school personnel often respond to disruptive students with ineffective authoritarian tactics,…

  15. A Randomized Trial of the Self-Management Training and Regulation Strategy (STARS): A Selective Intervention for Students with Disruptive Behaviors

    Science.gov (United States)

    Thompson, Aaron M.

    2012-01-01

    To attain academic goals, school personnel must effectively manage 20% of students who engage in the disruptive behaviors that interrupt instruction, create teacher stress, and contribute to poor student outcomes. Without effective strategies, school personnel often respond to disruptive students with ineffective authoritarian tactics,…

  16. Influence of the bilayer composition on the binding and membrane disrupting effect of Polybia-MP1, an antimicrobial mastoparan peptide with leukemic T-lymphocyte cell selectivity.

    Science.gov (United States)

    dos Santos Cabrera, Marcia Perez; Arcisio-Miranda, Manoel; Gorjão, Renata; Leite, Natália Bueno; de Souza, Bibiana Monson; Curi, Rui; Procopio, Joaquim; Ruggiero Neto, João; Palma, Mario Sérgio

    2012-06-19

    This study shows that MP-1, a peptide from the venom of the Polybia paulista wasp, is more toxic to human leukemic T-lymphocytes than to human primary lymphocytes. By using model membranes and electrophysiology measurements to investigate the molecular mechanisms underlying this selective action, the porelike activity of MP-1 was identified with several bilayer compositions. The highest average conductance was found in bilayers formed by phosphatidylcholine or a mixture of phosphatidylcholine and phosphatidylserine (70:30). The presence of cholesterol or cardiolipin substantially decreases the MP-1 pore activity, suggesting that the membrane fluidity influences the mechanism of selective toxicity. The determination of partition coefficients from the anisotropy of Trp indicated higher coefficients for the anionic bilayers. The partition coefficients were found to be 1 order of magnitude smaller when the bilayers contain cholesterol or a mixture of cholesterol and sphingomyelin. The blue shift fluorescence, anisotropy values, and Stern-Volmer constants are indications of a deeper penetration of MP-1 into anionic bilayers than into zwitterionic bilayers. Our results indicate that MP-1 prefers to target leukemic cell membranes, and its toxicity is probably related to the induction of necrosis and not to DNA fragmentation. This mode of action can be interpreted considering a number of bilayer properties like fluidity, lipid charge, and domain formation. Cholesterol-containing bilayers are less fluid and less charged and have a tendency to form domains. In comparison to healthy cells, leukemic T-lymphocyte membranes are deprived of this lipid, resulting in decreased peptide binding and lower conductance. We showed that the higher content of anionic lipids increases the level of binding of the peptide to bilayers. Additionally, the absence of cholesterol resulted in enhanced pore activity. These findings may drive the selective toxicity of MP-1 to Jurkat cells.

  17. Inspection of Disruptive Behaviours at Jet Using Generative Topographic Mapping

    Science.gov (United States)

    Ratta, G. A.; Vega, J. A.; Murari, A.; Vagliasindi, G.

    Tokamaks are the most promising configuration of magnetic confinement fusion devices. However, a physical phenomenon that leads the plasma out to its operational bounds, called disruption, remains unavoidable. Disruptions cause the abrupt termination of the discharge and in addition to affecting the execution of the research program, they can constitute a risk for the structural integrity of the machine. In this article two important aspects that can facilitate the better understanding of the phenomenon are presented. First, the selection of the physical parameters and their main characteristics related to disruptions are reviewed. Second, the application of Generative Topographic Mapping (GTM) to visualize and compare disruptive and non disruptive experiments at different times is shown. The resulting maps are aimed to evidence the evolution of the phenomenon, since it is unrecognizable till it can be distinguished. The identification of the instant when precursors of disruptions can be noticed is highly relevant in nuclear fusion since it determines the time margin the control systems have to apply mitigation or avoidance actions.

  18. Hydroxyproline-induced Helical Disruption in Conantokin Rl-B Affects Subunit-selective Antagonistic Activities toward Ion Channels of N-Methyl-d-aspartate Receptors.

    Science.gov (United States)

    Kunda, Shailaja; Yuan, Yue; Balsara, Rashna D; Zajicek, Jaroslav; Castellino, Francis J

    2015-07-17

    Conantokins are ~20-amino acid peptides present in predatory marine snail venoms that function as allosteric antagonists of ion channels of the N-methyl-d-aspartate receptor (NMDAR). These peptides possess a high percentage of post-/co-translationally modified amino acids, particularly γ-carboxyglutamate (Gla). Appropriately spaced Gla residues allow binding of functional divalent cations, which induces end-to-end α-helices in many conantokins. A smaller number of these peptides additionally contain 4-hydroxyproline (Hyp). Hyp should prevent adoption of the metal ion-induced full α-helix, with unknown functional consequences. To address this disparity, as well as the role of Hyp in conantokins, we have solved the high resolution three-dimensional solution structure of a Gla/Hyp-containing 18-residue conantokin, conRl-B, by high field NMR spectroscopy. We show that Hyp(10) disrupts only a small region of the α-helix of the Mn(2+)·peptide complex, which displays cation-induced α-helices on each terminus of the peptide. The function of conRl-B was examined by measuring its inhibition of NMDA/Gly-mediated current through NMDAR ion channels in mouse cortical neurons. The conRl-B displays high inhibitory selectivity for subclasses of NMDARs that contain the functionally important GluN2B subunit. Replacement of Hyp(10) with N(8)Q results in a Mg(2+)-complexed end-to-end α-helix, accompanied by attenuation of NMDAR inhibitory activity. However, replacement of Hyp(10) with Pro(10) allowed the resulting peptide to retain its inhibitory property but diminished its GluN2B specificity. Thus, these modified amino acids, in specific peptide backbones, play critical roles in their subunit-selective inhibition of NMDAR ion channels, a finding that can be employed to design NMDAR antagonists that function at ion channels of distinct NMDAR subclasses.

  19. Changing Preschool Children's Attitudes into Behavior towards Selected Environmental Issues: An Action Research Study

    Science.gov (United States)

    Ertürk Kara, Gözde; Aydos, E. Hande; Aydin, Özge

    2015-01-01

    The purpose of this study is to provide the transform of attitudes into behavior of 60-72 month of age children continued early childhood education toward environmental issues. Collaborative action research method of qualitative design was used. The whole participants of the study were 60-72 months of age children who were attending in an early…

  20. Seeing the World through Another Person's Eyes: Simulating Selective Attention via Action Observation

    Science.gov (United States)

    Frischen, Alexandra; Loach, Daniel; Tipper, Steven P.

    2009-01-01

    Selective attention is usually considered an egocentric mechanism, biasing sensory information based on its behavioural relevance to oneself. This study provides evidence for an equivalent allocentric mechanism that allows passive observers to selectively attend to information from the perspective of another person. In a negative priming task,…

  1. Putting the "affirm" into affirmative action: preferential selection and academic performance.

    Science.gov (United States)

    Brown, R P; Charnsangavej, T; Keough, K A; Newman, M L; Rentfrow, P J

    2000-11-01

    Two studies explored the relation between academic performance and preferential selection. In Study 1, female participants were led to believe that they had been selected to be leaders in a team problem-solving task because of their gender, because of their gender and ability, or at random. Results showed that women who believed they had been selected because of their gender performed significantly worse on a subsequent problem-solving test than women who believed they had been selected at random and women who believed they were selected because of both their gender and their ability. In Study 2, students' suspicion of having benefited from race-based preferences in college admissions was negatively related to their grade point average (GPA). Furthermore, this suspicion partially mediated the GPA gap between academically stigmatized (Black and Latino) and nonstigmatized (Caucasian and Asian) students.

  2. Disrupted Disclosure

    DEFF Research Database (Denmark)

    Krause Hansen, Hans; Uldam, Julie

    While projects of governance by transparency have become widespread over the past decades, theyare usually investigated and theorized in isolation from the wider field of visibility and surveillancein which they are embedded. Building on theories of governance, visibility and surveillance...... appearances become challenged through disruptive disclosures in mediaenvironments characterized by multiple levels of visibility, with companies both observing andbeing observed by civil society groups that criticize them; (c) why and how the mobilization aroundtransparency and ensuing practices...... of surveillance produce new forms of governing, potentiallywidening the space of manoeuvring for corporations....

  3. Facial Action and Emotional Language: ERP Evidence that Blocking Facial Feedback Selectively Impairs Sentence Comprehension.

    Science.gov (United States)

    Davis, Joshua D; Winkielman, Piotr; Coulson, Seana

    2015-11-01

    There is a lively and theoretically important debate about whether, how, and when embodiment contributes to language comprehension. This study addressed these questions by testing how interference with facial action impacts the brain's real-time response to emotional language. Participants read sentences about positive and negative events (e.g., "She reached inside the pocket of her coat from last winter and found some (cash/bugs) inside it.") while ERPs were recorded. Facial action was manipulated within participants by asking participants to hold chopsticks in their mouths using a position that allowed or blocked smiling, as confirmed by EMG. Blocking smiling did not influence ERPs to the valenced words (e.g., cash, bugs) but did influence ERPs to final words of sentences describing positive events. Results show that affectively positive sentences can evoke smiles and that such facial action can facilitate the semantic processing indexed by the N400 component. Overall, this study offers causal evidence that embodiment impacts some aspects of high-level comprehension, presumably involving the construction of the situation model.

  4. Service Reliability of Batelec–1 in Selected Barangays of Calatagan, Batangas, Philippines: Basis for an Action Plan

    Directory of Open Access Journals (Sweden)

    JOANEL U. BUENAVENTURA

    2014-04-01

    Full Text Available This study aimed to help Batelec-1 in Calatagan to expand and improve their service to provide a more reliable service to end – users. Descriptive type of research method was utilized in the study. The results reveal that the overall assessment of the respondents on the level of service reliability in terms of construction services was reliable. However, clearing of line schedule and available maintenance equipment and machine was assessed less reliable. On the level of consumers’ satisfaction in construction and maintenance services, the overall assessment of the respondents was satisfied but interruption duration and action on complaints and request got the lowest mean score and interpreted as less satisfied. The results also show that the common problems and complaints encountered by the consumers were lack of information drive, unavailability of consumer hotline, inadequate facilities and equipment, and delayed action on service request/complaints. A proposed action plan is designed to provide continuous reliability on Batelec-1 services. Based on the results of the study, construction and maintenance services of Batelec-1 in the selected Barangays in Calatagan are considered reliable, yet, can still be improved. Electric consumers are generally satisfied on personnel, construction and maintenance services yet less satisfied on information dissemination. The common problems and complaints from the consumers include lack of information drive and inavailability of consumer hotline. An action plan is proposed to provide continuous reliability on Batelec-1 services.

  5. Screening of Various Herbicide Modes of Action for Selective Control of Algae Responsible for Harmful Blooms

    Science.gov (United States)

    2009-01-01

    that have selective activity against harmful algal blooms (HAB). The U.S. Army Corps of Engineers is responsible for managing numerous large reservoirs ...selective herbicides against numerous aquatic macrophyte species. Because algae, including cyanobacteria, and higher plants have many of the same enzyme...to be multifaceted and poorly understood (Dokulil and Teubner 2000). The proliferation of freshwater HAB in lakes and reservoirs around the world

  6. Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells

    Directory of Open Access Journals (Sweden)

    Ryuta Saito

    2016-01-01

    Full Text Available Adrenal toxicity is one of the major concerns in drug development. To quantitatively understand the effect of endocrine-active compounds on adrenal steroidogenesis and to assess the human adrenal toxicity of novel pharmaceutical drugs, we developed a mathematical model of steroidogenesis in human adrenocortical carcinoma NCI-H295R cells. The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1. It was reconstructed in an experimental dynamics of cholesterol and 14 steroids from an in vitro steroidogenesis assay using NCI-H295R cells. Results of dynamic sensitivity analysis suggested that HSD3B2 plays the most important role in the metabolic balance of adrenal steroidogenesis. Based on differential metabolic profiling of 12 steroid hormones and 11 adrenal toxic compounds, we could estimate which steroidogenic enzymes were affected in this mathematical model. In terms of adrenal steroidogenic inhibitors, the predicted action sites were approximately matched to reported target enzymes. Thus, our computer-aided system based on systems biological approach may be useful to understand the mechanism of action of endocrine-active compounds and to assess the human adrenal toxicity of novel pharmaceutical drugs.

  7. Estimation of the Mechanism of Adrenal Action of Endocrine-Disrupting Compounds Using a Computational Model of Adrenal Steroidogenesis in NCI-H295R Cells.

    Science.gov (United States)

    Saito, Ryuta; Terasaki, Natsuko; Yamazaki, Makoto; Masutomi, Naoya; Tsutsui, Naohisa; Okamoto, Masahiro

    2016-01-01

    Adrenal toxicity is one of the major concerns in drug development. To quantitatively understand the effect of endocrine-active compounds on adrenal steroidogenesis and to assess the human adrenal toxicity of novel pharmaceutical drugs, we developed a mathematical model of steroidogenesis in human adrenocortical carcinoma NCI-H295R cells. The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1. It was reconstructed in an experimental dynamics of cholesterol and 14 steroids from an in vitro steroidogenesis assay using NCI-H295R cells. Results of dynamic sensitivity analysis suggested that HSD3B2 plays the most important role in the metabolic balance of adrenal steroidogenesis. Based on differential metabolic profiling of 12 steroid hormones and 11 adrenal toxic compounds, we could estimate which steroidogenic enzymes were affected in this mathematical model. In terms of adrenal steroidogenic inhibitors, the predicted action sites were approximately matched to reported target enzymes. Thus, our computer-aided system based on systems biological approach may be useful to understand the mechanism of action of endocrine-active compounds and to assess the human adrenal toxicity of novel pharmaceutical drugs.

  8. Selective Antimicrobial Activities and Action Mechanism of Micelles Self-Assembled by Cationic Oligomeric Surfactants.

    Science.gov (United States)

    Zhou, Chengcheng; Wang, Fengyan; Chen, Hui; Li, Meng; Qiao, Fulin; Liu, Zhang; Hou, Yanbo; Wu, Chunxian; Fan, Yaxun; Liu, Libing; Wang, Shu; Wang, Yilin

    2016-02-17

    This work reports that cationic micelles formed by cationic trimeric, tetrameric, and hexameric surfactants bearing amide moieties in spacers can efficiently kill Gram-negative E. coli with a very low minimum inhibitory concentration (1.70-0.93 μM), and do not cause obvious toxicity to mammalian cells at the concentrations used. With the increase of the oligomerization degree, the antibacterial activity of the oligomeric surfactants increases, i.e., hexameric surfactant > tetrameric surfactant > trimeric surfactant. Isothermal titration microcalorimetry, scanning electron microscopy, and zeta potential results reveal that the cationic micelles interact with the cell membrane of E. coli through two processes. First, the integrity of outer membrane of E. coli is disrupted by the electrostatic interaction of the cationic ammonium groups of the surfactants with anionic groups of E. coli, resulting in loss of the barrier function of the outer membrane. The inner membrane then is disintegrated by the hydrophobic interaction of the surfactant hydrocarbon chains with the hydrophobic domains of the inner membrane, leading to the cytoplast leakage. The formation of micelles of these cationic oligomeric surfactants at very low concentration enables more efficient interaction with bacterial cell membrane, which endows the oligomeric surfactants with high antibacterial activity.

  9. Modeling the Maturation of Grip Selection Planning and Action Representation: Insights from Typical and Atypical Motor Development.

    OpenAIRE

    Ian eFuelscher; Jacqueline eWilliams; Kate eWilmut; Enticott, Peter G.; Christian eHyde

    2016-01-01

    We investigated the purported association between developmental changes in grip selection planning and improvements in an individual’s capacity to represent action at an internal level (i.e., motor imagery). Participants were groups of healthy children aged 6-7 years and 8-12 years respectively, while a group of adolescents (13-17 years) and adults (18-34 years) allowed for consideration of childhood development in the broader context of motor maturation. A group of children aged 8-12 years w...

  10. Modeling the Maturation of Grip Selection Planning and Action Representation: Insights from Typical and Atypical Motor Development

    OpenAIRE

    Fuelscher, Ian; Williams, Jacqueline; Wilmut, Kate; Enticott, Peter G.; Hyde, Christian

    2016-01-01

    We investigated the purported association between developmental changes in grip selection planning and improvements in an individual’s capacity to represent action at an internal level [i.e., motor imagery (MI)]. Participants were groups of healthy children aged 6–7 years and 8–12 years respectively, while a group of adolescents (13–17 years) and adults (18–34 years) allowed for consideration of childhood development in the broader context of motor maturation. A group of children aged 8–12 ye...

  11. Sustainable Disruptions

    DEFF Research Database (Denmark)

    Friis, Silje Alberthe Kamille; Kjær, Lykke Bloch

    2016-01-01

    Since 2012 the Sustainable Disruptions (SD) project at the Laboratory for Sustainability at Design School Kolding (DK) has developed and tested a set of design thinking tools, specifically targeting the barriers to economically, socially, and environmentally sustainable business development...... invested in the issue of sustainable business development, in particular the leaders and employees of SMEs, but also to design education seeking new ways to consciously handle and teach the complexity inherent in sustainable transformation. Findings indicate that the SD design thinking approach contributes....... The tools have been applied in practice in collaboration with 11 small and medium sized companies (SMEs). The study investigates these approaches to further understand how design thinking can contribute to sustainable transition in a business context. The study and the findings are relevant to organizations...

  12. SELECTIVE ACTIONS OF OPIOID PEPTIDES ON GnRH RELEASE FROM THE MEDIAN EMINENCE OF RATS

    Institute of Scientific and Technical Information of China (English)

    ZHAOBai-Ge; LUOLu--Guang; BICKNELLR.J.; CHAPMANC.; HEAVENSR.P.

    1989-01-01

    It has been known that morphine inhibits the secretion of pituitary gonadotrophins[1l and the inhibition may be mediated by preventing GnRH release from hypothalamus[2]. In the present study, We examined the direct and selective effects of a series of opioid

  13. Mate Choice in Soldier Beetles: Field & Laboratory Experiments that Demonstrate Sexual Selection in Action

    Science.gov (United States)

    Eason, Perri K.; Sherman, Peter T.

    2003-01-01

    Although the theory of evolution is the foundation of modern biology, students too rarely have an opportunity to watch selection operate in natural populations of animals. This lack may be partially responsible for the unfortunate ignorance of many people regarding the significance of evolution in biology. Laboratory exercises that directly study…

  14. The effect of Parkinson's disease on interference control during action selection

    NARCIS (Netherlands)

    Wylie, S.A.; van den Wildenberg, W.P.M.; Ridderinkhof, K.R.; Bashore, T.R.; Powell, V.D.; Manning, C.A.; Wooten, G.F.

    2009-01-01

    Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinson's disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to s

  15. Effect of selected anti-inflammatory drugs on the lethal actions of Leiurus quinquestriatus venom

    Directory of Open Access Journals (Sweden)

    N. A. Abdoon

    2006-01-01

    Full Text Available The cumulative actions of scorpion neurotoxins are complex and may be traced to activation of different ion channels with subsequent release of various transmitters and modulators including inflammatory mediators. This could lead to various pathological manifestations such as acute respiratory distress syndrome (ARDS, systemic inflammatory response syndrome (SIRS, and multiple organ failure (MOF. Several approaches have been advocated to treat the multitude of scorpion-venom-elicited pathological changes. However, few have tried to combat the venom-induced effects on the inflammatory process, which manifest as ARDS, SIDS and MOF. Thus, the aim of this study was to determine the capability of inhibitors of different steps of the inflammatory sequence of events in scorpion envenomation to ameliorate the detrimental action of the venom and prolong survival of mice injected with Leiurus quinquestriatus quinquestriatus (LQQ venom. Animals were divided into groups (n = 10 and given montelukast (10 or 20 mg.kg-1, orally, hydrocortisone (5 or 10 mg.kg-1, intravenously or indomethacin (10 or 20 mg kg-1, intravenously. Then, all animals were subcutaneously injected with either 0.25 or 0.3 mg.kg-1 LQQ venom. Signs and symptoms of envenomation were recorded and survival percentages after 24 hours as well as survival time were determined in each group. To analyze data, we utilized Covariance Wilcoxon survival statistics and survival distribution curves. In general, when compared to venom alone, administration of montelukast (p<0.001, hydrocortisone (p<0.05 and indomethacin (p<0.05 prolonged survival time and increased the percentage of surviving animals per group, with montelukast exhibiting the greatest protecting power. Thus, anti-inflammatory drugs may play an important role in protection against the lethal effects of scorpion venoms.

  16. Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels.

    Science.gov (United States)

    Falcón, Beverly L; Hashizume, Hiroya; Koumoutsakos, Petros; Chou, Jeyling; Bready, James V; Coxon, Angela; Oliner, Jonathan D; McDonald, Donald M

    2009-11-01

    Angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) have complex actions in angiogenesis and vascular remodeling due to their effects on Tie2 receptor signaling. Ang2 blocks Ang1-mediated activation of Tie2 in endothelial cells under certain conditions but is a Tie2 receptor agonist in others. We examined the effects of selective inhibitors of Ang1 (mL4-3) or Ang2 (L1-7[N]), alone or in combination, on the vasculature of human Colo205 tumors in mice. The Ang2 inhibitor decreased the overall abundance of tumor blood vessels by reducing tumor growth and keeping vascular density constant. After inhibition of Ang2, tumor vessels had many features of normal blood vessels (normalization), as evidenced by junctional accumulation of vascular endothelial-cadherin, junctional adhesion molecule-A, and platelet/endothelial cell adhesion molecule-1 in endothelial cells, increased pericyte coverage, reduced endothelial sprouting, and remodeling into smaller, more uniform vessels. The Ang1 inhibitor by itself had little noticeable effect on the tumor vasculature. However, when administered with the Ang2 inhibitor, the Ang1 inhibitor prevented tumor vessel normalization, but not the reduction in tumor vascularity produced by the Ang2 inhibitor. These findings are consistent with a model whereby inhibition of Ang2 leads to normalization of tumor blood vessels by permitting the unopposed action of Ang1, but decreases tumor vascularity primarily by blocking Ang2 actions.

  17. The effect of Parkinson’s disease on interference control during action selection

    OpenAIRE

    Wylie, S.A.; van den Wildenberg, W.P.M.; Ridderinkhof, K.R.; Bashore, T.R.; Powell, V.D.; Manning, C.A.; Wooten, G.F.

    2008-01-01

    Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinson’s disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to suppress interference arising from the automatic activation of salient or overlearned responses. Empirical observations thus far have confirmed this assumption in some studies, but not in others, du...

  18. 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

  19. 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.

  20. Tissue selective action of tamoxifen methiodide, raloxifene and tamoxifen on creatine kinase B activity in vitro and in vivo.

    Science.gov (United States)

    Sömjen, D; Waisman, A; Kaye, A M

    1996-12-01

    We have compared the cell and tissue selective estrogenic and antiestrogenic activities of tamoxifen, raloxifene, ICI 164,384 and a permanently ionized derivative of tamoxifen--tamoxifen methiodide (TMI). This non-steroidal antiestrogen has limited ability to cross the blood brain barrier and is therefore less likely to cause the central nervous system disturbances caused by tamoxifen. We have used the stimulation of the specific activity of the "estrogen induced protein", creatine kinase BB, as a response marker in bone, cartilage, uterine and adipose cells and in rat skeletal tissues, uterus and mesometrial adipose tissue. In vitro, TMI, tamoxifen and raloxifene mimicked the agonistic action of 17beta-estradiol in ROS 17/2.8 rat osteogenic osteosarcoma, female calvaria, and SaOS2 human osteoblast cells. In Ishikawa endometrial cancer cells, tamoxifen showed reduced agonistic effects and raloxifene showed no stimulation. However, as antagonists, tamoxifen and raloxifene were equally effective in Ishikawa or SaOS2 cells. In immature rats, all four of the antiestrogens inhibited estrogen action in diaphysis, epiphysis, uterus and mesometrial adipose tissue; when administered alone, tamoxifen stimulated creatine kinase (CK) specific activity in all these tissues. Raloxifene and TMI, however, stimulated only the skeletal tissues and had no stimulatory effect in the uterus or mesometrial fat, and the pure antiestrogen ICI 164,384 showed no stimulatory effect in any of the tissues. The simultaneous injection of estrogen, plus an antiestrogen which acted as an agonist, resulted in lower CK activity than after injection of either agent alone. These differential effects, in vivo and in vitro, may point the way to a wider therapeutic choice of an appropriate antiestrogen which, although antagonizing E2 action in mammary cancer, can still protect against osteoporosis and cardiovascular disease and not stimulate the uterus with its attendant undesirable changes, or interfere

  1. Selective actions of Lynx proteins on different nicotinic acetylcholine receptors in the locust, Locusta migratoria manilensis.

    Science.gov (United States)

    Wang, Xin; Bao, Haibo; Sun, Huahua; Zhang, Yixi; Fang, Jichao; Liu, Qinghong; Liu, Zewen

    2015-08-01

    Nicotinic acetylcholine receptors (nAChRs) are major neurotransmitter receptors and targets of neonicotinoid insecticides in the insect nervous system. The full function of nAChRs is often dependent on associated proteins, such as chaperones, regulators and modulators. Here, three Lynx (Ly-6/neurotoxin) proteins, Loc-lynx1, Loc-lynx2 and Loc-lynx3, were identified in the locust, Locusta migratoria manilensis. Co-expression with Lynx resulted in a dramatic increase in agonist-evoked macroscopic currents on nAChRs Locα1/β2 and Locα2/β2 in Xenopus oocytes, but no changes in agonist sensitivity. Loc-lynx1 and Loc-lynx3 only modulated nAChRs Locα1/β2 while Loc-lynx2 modulated Locα2/β2 specifically. Meanwhile, Loc-lynx1 induced a more significant increase in currents evoked by imidacloprid and epibatidine than Loc-lynx3, and the effects of Loc-lynx1 on imidacloprid and epibatidine were significantly higher than those on acetylcholine. Among three lynx proteins, only Loc-lynx1 significantly increased [(3) H]epibatidine binding on Locα1/β2. The results indicated that Loc-lynx1 had different modulation patterns in nAChRs compared to Loc-lynx2 and Loc-lynx3. Taken together, these findings indicated that three Lynx proteins were nAChR modulators and had selective activities in different nAChRs. Lynx proteins might display their selectivities from three aspects: nAChR subtypes, various agonists and different modulation patterns. Insect Lynx (Ly-6/neurotoxin) proteins act as the allosteric modulators on insect nicotinic acetylcholine receptors (nAChRs), the important targets of insecticides. We found that insect lynx proteins showed their selectivities from at least three aspects: nAChR subtypes, various agonists and different modulation patterns.

  2. Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479.

    Science.gov (United States)

    Furuya, Kazuyuki; Yamamoto, Noriko; Ohyabu, Yuki; Morikyu, Teruyuki; Ishige, Hirohide; Albers, Michael; Endo, Yasuhisa

    2013-01-01

    Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue-selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known. In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S-101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation. Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, β-catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1. The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues.

  3. Determination of ecologically vital groundwaters at selected sites in the Formerly Utilized Sites Remedial Action Program

    Energy Technology Data Exchange (ETDEWEB)

    Vinikour, W.S.; Yin, S.C.L.

    1989-08-01

    The US Department of Energy is classifying groundwaters at sites in its Formerly Utilized Sites Remedial Action Program (FUSRAP). Of particular concern is the potential presence of groundwaters that are highly vulnerable to contamination and that are either (1) irreplaceable sources of drinking water or (2) ecologically vital. Conditions at nine FUSRAP sites were evaluated to determine if ecologically vital groundwaters are present. The sites evaluated were Wayne Interim Storage Site, Maywood Interim Storage Site, and Middlesex Sampling Plant in New Jersey; Ashland 2 Site, Seaway Industrial Park, Colonie Interim storage Site, and Niagara Falls Storage Site in New York; and the St. Louis Airport Site and Hazelwood Interim Storage Site in Missouri. The analyses indicated that groundwaters are vulnerable to contamination at all but two of the sites -- the Ashland 2 and Seaway Industrial Park sites in New York. Groundwater discharge points were identified within a 2-mile radius (i.e., the classification review area) of all of the sites. No ecologically vital groundwater areas exist in the vicinities of any of the nine FUSRAP sites evaluated. 35 refs., 17 figs.

  4. [Myoanabolic steroids and selective androgen receptor modulators: mechanism of action and perspectives].

    Science.gov (United States)

    Tóth, Miklós

    2009-11-01

    Interest in anabolic steroids has been renewed in the last decade with the discovery of tissue-selective androgen receptor modulators exhibiting high myotropic and small androgenic activity. An explanation put forward by us in 1982 for the mechanism of the preferential myotropic effect of nandrolone (19-nortestosterone) exploits the fundamental difference between the 5alpha-reductase concentrations in skeletal muscle and androgenic target tissue. In androgenic tissue, testosterone is converted to the more potent 5alpha-dihydrotestosterone whereas nandrolone is converted to a less potent derivative. As 5alpha-reduction is negligible in skeletal muscle, this explains why nandrolone shows a greater myotropic to androgenic ratio when compared with testosterone. Anabolic steroids that do not undergo 5alpha-reduction exert myotropic-androgenic dissociation because their effect in androgenic tissues is not amplified by 5alpha-reduction. Tissue selectivity by receptor modulators may be achieved by inducing specific conformational changes of the androgen receptor that affect its interaction with transcriptional coregulators. Anabolic activity is mediated by the stimulation of ribosomal RNA synthesis therefore regulation of this synthesis by anabolic steroids would deserve detailed studies.

  5. Action of selected agents on the accumulation of /sup 18/F by Streptococcus mutans

    Energy Technology Data Exchange (ETDEWEB)

    Yotis, W.W.; Zeb, M.; Brennan, P.C.; Kirchner, F.R.; Glendenin, L.E.; Wu-Yuan, C.D.

    1983-01-01

    The action of certain substances known to induce cellular alterations, or encountered in the oral cavity, on the accumulation of /sup 18/F by Streptococcus mutans GS-5 has been investigated. A 62-67% inhibition in the number of /sup 18/F atoms bound per mg dry weight of cells could be induced by a 15 min pretreatment with 2.7 x 10/sup -4/ M cetyltrimethylammoniumbromide, 1 x 10/sup -1/ M acetic anhydride, or 7 x 10/sup -2/ M HCl. Plate counts indicated that alteration of the cellular composition rather than viability was responsible for this diminution in /sup 18/F accumulation. Prior exposure for 15 min of this organism to 1 M HCHO or 0.1 M NaOH did not alter /sup 18/F accumulation. Of the common salts encountered in the oral cavity, CaCl/sub 2/ enhanced /sup 18/F binding. Pretreatment of the assay cells for 15-160 min with 0.1 mg/ml of trypsin, pronase, protease, ..cap alpha..-glucosidase, dextranase, or lactoferrin had no significant effect on the accumulation of /sup 18/. However, pre-exposure of cells for 60 min to 1-10 mg/ml of either amylase or lipase induced a 40-67% inhibition in the binding of /sup 18/F, while lysozyme enhanced the binding of /sup 18/F by the cells. It would appear then that the binding of /sup 18/F by S. mutans may be altered by certain substances encountered in the oral cavity. 17 references, 1 figure, 5 tables.

  6. 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.

  7. Secondary Bifurcations in a Lotka-Volterra Model for N Competitors with Applications to Action Selection and Compulsive Behaviors

    Science.gov (United States)

    Frank, T. D.

    A Lotka-Volterra model for an arbitrary number of competitors is studied for different ratios of self-inhibition versus cross-inhibition. It is shown that winner-takes-all fixed points (states of single surviving species) are the only stable fixed points of the model when cross-inhibition exceeds self-inhibition. Secondary bifurcations in terms of bifurcations between winner-takes-all fixed points induced by changes in the exponential growth rates of competitors are studied and the critical control parameters are identified. A selection principle is derived that states that evolution proceeds in such a way that exponential growth rates of surviving competitors are magnified in evolutionary bifurcation steps. The interacting competitor model is applied as an amplitude equation model for interacting patterns of self-organizing pattern formation systems with an eye on action selection and compulsive behaviors in humans. The possibility is discussed that human behavior is subjected to the selection principle of "faster growth rates".

  8. A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

    Science.gov (United States)

    Campaner, Elena; Rustighi, Alessandra; Zannini, Alessandro; Cristiani, Alberto; Piazza, Silvano; Ciani, Yari; Kalid, Ori; Golan, Gali; Baloglu, Erkan; Shacham, Sharon; Valsasina, Barbara; Cucchi, Ulisse; Pippione, Agnese Chiara; Lolli, Marco Lucio; Giabbai, Barbara; Storici, Paola; Carloni, Paolo; Rossetti, Giulia; Benvenuti, Federica; Bello, Ezia; D'Incalci, Maurizio; Cappuzzello, Elisa; Rosato, Antonio; Del Sal, Giannino

    2017-06-01

    The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

  9. Acoustic Aposematism and Evasive Action in Select Chemically Defended Arctiine (Lepidoptera: Erebidae) Species: Nonchalant or Not?

    Science.gov (United States)

    Dowdy, Nicolas J; Conner, William E

    2016-01-01

    Tiger moths (Erebidae: Arctiinae) have experienced intense selective pressure from echolocating, insectivorous bats for over 65 million years. One outcome has been the evolution of acoustic signals that advertise the presence of toxins sequestered from the moths' larval host plants, i.e. acoustic aposematism. Little is known about the effectiveness of tiger moth anti-bat sounds in their natural environments. We used multiple infrared cameras to reconstruct bat-moth interactions in three-dimensional (3-D) space to examine how functional sound-producing organs called tymbals affect predation of two chemically defended tiger moth species: Pygarctia roseicapitis (Arctiini) and Cisthene martini (Lithosiini). P. roseicapitis and C. martini with intact tymbals were 1.8 and 1.6 times less likely to be captured by bats relative to those rendered silent. 3-D flight path and acoustic analyses indicated that bats actively avoided capturing sound-producing moths. Clicking behavior differed between the two tiger moth species, with P. roseicapitis responding in an earlier phase of bat attack. Evasive flight behavior in response to bat attacks was markedly different between the two tiger moth species. P. roseicapitis frequently paired evasive dives with aposematic sound production. C. martini were considerably more nonchalant and employed evasion in fewer interactions. Our results show that acoustic aposematism is effective at deterring bat predation in a natural context and that this strategy is likely to be the ancestral function of tymbal organs within the Arctiinae.

  10. Antibacterial Action of Jineol Isolated from Scolopendra subspinipes mutilans against Selected Foodborne Pathogens

    Science.gov (United States)

    Bajpai, Vivek K.; Shukla, Shruti; Paek, Woon K.; Lim, Jeongheui; Kumar, Pradeep; Na, MinKyun

    2017-01-01

    This study was undertaken to assess the antibacterial potential of 3,8-dihydroxyquinoline (jineol) isolated from Scolopendra subspinipes mutilans against selected foodborne pathogens Escherichia coli O157:H7 and Staphylococcus aureus KCTC-1621. Jineol at the tested concentration (50 μL; corresponding to 250 μg/disk) exhibited significant antibacterial effects as a diameter of inhibition zones (11.6–13.6 mm), along with minimum inhibitory concentration (MIC) and minimum bactericidal concentration values found in the range of (62.5–125 μg/mL) and (125–250 μg/mL), respectively. Jineol also exhibited significant antibacterial effects as confirmed by the reduction in bacterial cell viabilities, increasing release of potassium (K+) ions (650 and 700 mmole/L) and 260 nm materials (optical density: 2.98–3.12) against both the tested pathogens, E. coli O157:H7 and S. aureus KCTC-1621, respectively. Moreover, changes in the cell wall morphology of E. coli O157:H7 and S. aureus KCTC-1621 cells treated with jineol at MIC further confirmed its inhibitory potential against the tested pathogens, suggesting its role as an effective antimicrobial to control foodborne pathogens.

  11. STIMA: a short screening test for ideo-motor apraxia, selective for action meaning and bodily district.

    Science.gov (United States)

    Tessari, Alessia; Toraldo, Alessio; Lunardelli, Alberta; Zadini, Antonietta; Rumiati, Raffaella Ida

    2015-06-01

    We propose STIMA, a short test for ideo-motor apraxia, allowing us to quantify the apraxic deficit according to action meaning and affected body segment. STIMA is based on a neurocognitive model holding that there are two processes involved in action imitation (i.e., a semantic route for recognizing and imitating known gestures, and a direct route for reproducing new gestures). The test allows to identify which imitative process has been selectively impaired by brain damage (direct vs. semantic route) and possible deficits depending on the body segment involved (hand/limb vs. hand/fingers). N = 111 healthy participants were administered with an imitation task in two separated blocks of known and new gestures. In each block, half of the gestures were performed mainly with the proximal part of the upper limb and the remaining half with the distal one. It resulted in 18 known gestures (nine proximal and nine distal) and 18 new gestures (nine proximal and nine distal) for a total of 36. Each gesture was presented up to a maximum of two times. Detailed criteria are used to assign the final imitation score. Cut offs, equivalent scores and main percentile scores were computed for each subscale. Participants imitated better known than new gestures, and proximal better than distal gestures. Age influenced performance on all subscales, while education only affected one subscale. STIMA is easy and quick to administer, and compared to previous tests, it offers important information for planning adequate rehabilitation programs based on the functional locus of the deficit.

  12. 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.

  13. Human urocortin II, a new CRF-related peptide, displays selective CRF(2)-mediated action on gastric transit in rats.

    Science.gov (United States)

    Million, Mulugeta; Maillot, Céline; Saunders, Paul; Rivier, Jean; Vale, Wylie; Taché, Yvette

    2002-01-01

    Human urocortin (hUcn) II is a new member of the corticotropin-releasing factor (CRF) family that selectively binds to the CRF(2) receptor. We investigated the CRF receptors involved in mediating the effects of hUcn II and human/rat CRF (h/rCRF) on gut transit. Gastric emptying, 4 h after a solid meal, and distal colonic transit (bead expulsion time) were monitored simultaneously in conscious rats. CRF antagonists were given subcutaneously 30 min before intravenous injection of peptides or partial restraint (for 90 min). hUcn II (3 or 10 microg/kg i.v.) inhibited gastric emptying (by 45% and 55%, respectively) and did not influence distal colonic transit. The CRF(2) peptide antagonist astressin(2)-B blocked hUcn II action. h/rCRF, rat Ucn, and restraint delayed gastric emptying while accelerating distal colonic transit. The gastric response to intravenous h/rCRF and restraint was blocked by the CRF(2) antagonist but not by the CRF(1) antagonist CP-154,526, whereas the colonic response was blocked only by CP-154,526. None of the CRF antagonists influenced postprandial gut transit. These data show that intravenous h/rCRF and restraint stress-induced delayed gastric emptying involve CRF(2) whereas stimulation of distal colonic transit involves CRF(1). The distinct profile of hUcn II, only on gastric transit, is linked to its CRF(2) selectivity.

  14. Endocrine disrupters as obesogens.

    Science.gov (United States)

    Grün, Felix; Blumberg, Bruce

    2009-05-25

    The recent dramatic rise in obesity rates is an alarming global health trend that consumes an ever increasing portion of health care budgets in Western countries. The root cause of obesity is thought to be a prolonged positive energy balance. Hence, the major focus of preventative programs for obesity has been to target overeating and inadequate physical exercise. Recent research implicates environmental risk factors, including nutrient quality, stress, fetal environment and pharmaceutical or chemical exposure as relevant contributing influences. Evidence points to endocrine disrupting chemicals that interfere with the body's adipose tissue biology, endocrine hormone systems or central hypothalamic-pituitary-adrenal axis as suspects in derailing the homeostatic mechanisms important to weight control. This review highlights recent advances in our understanding of the molecular targets and mechanisms of action for these compounds and areas of future research needed to evaluate the significance of their contribution to obesity.

  15. Conversion of homothallic yeast to heterothallism trough HO gene disruption

    CSIR Research Space (South Africa)

    Van Zyl, WH

    1993-04-01

    Full Text Available A simple method was developed for the conversion of homothallic Saccharomyces cerevisiae yeaststrains to heterothallism through HO gene disruption. An integrative ho:: neo disrupted allele was constructed by cloning a dominant selectable marker...

  16. An enhancer peptide for membrane-disrupting antimicrobial peptides

    Directory of Open Access Journals (Sweden)

    Zhang Hong

    2010-02-01

    Full Text Available Abstract Background NP4P is a synthetic peptide derived from a natural, non-antimicrobial peptide fragment (pro-region of nematode cecropin P4 by substitution of all acidic amino acid residues with amides (i.e., Glu → Gln, and Asp → Asn. Results In the presence of NP4P, some membrane-disrupting antimicrobial peptides (ASABF-α, polymyxin B, and nisin killed microbes at lower concentration (e.g., 10 times lower minimum bactericidal concentration for ASABF-α against Staphylococcus aureus, whereas NP4P itself was not bactericidal and did not interfere with bacterial growth at ≤ 300 μg/mL. In contrast, the activities of antimicrobial agents with a distinct mode of action (indolicidin, ampicillin, kanamycin, and enrofloxacin were unaffected. Although the membrane-disrupting activity of NP4P was slight or undetectable, ASABF-α permeabilized S. aureus membranes with enhanced efficacy in the presence of NP4P. Conclusions NP4P selectively enhanced the bactericidal activities of membrane-disrupting antimicrobial peptides by increasing the efficacy of membrane disruption against the cytoplasmic membrane.

  17. Selection of negative samples and two-stage combination of multiple features for action detection in thousands of videos

    NARCIS (Netherlands)

    Burghouts, G.J.; Schutte, K.; Bouma, H.; Hollander, R.J.M. den

    2013-01-01

    In this paper, a system is presented that can detect 48 human actions in realistic videos, ranging from simple actions such as ‘walk’ to complex actions such as ‘exchange’. We propose a method that gives a major contribution in performance. The reason for this major improvement is related to a diffe

  18. Network Formation under the Threat of Disruption

    NARCIS (Netherlands)

    Hoyer, B.

    2013-01-01

    The studies in this thesis are focused on the impact the presence of a network disruptor has on network formation models. In particular, we build two theoretical models to study the effect of network disruption on network formation and test the effect network disruption has on equilibrium selection

  19. Network Formation under the Threat of Disruption

    NARCIS (Netherlands)

    Hoyer, B.

    2013-01-01

    The studies in this thesis are focused on the impact the presence of a network disruptor has on network formation models. In particular, we build two theoretical models to study the effect of network disruption on network formation and test the effect network disruption has on equilibrium selection

  20. DSP4, a selective neurotoxin for the locus coeruleus noradrenergic system. A review of its mode of action.

    Science.gov (United States)

    Ross, Svante B; Stenfors, Carina

    2015-01-01

    DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) is a selective neurotoxin for the locus coeruleus noradrenergic system in the rodent and bird brain. It readily passes the blood-brain barrier and cyclizes to a reactive aziridinium derivative that is accumulated into the noradrenergic nerve terminals via the noradrenaline transporter. DSP4 is also an irreversible inhibitor of this transporter. Within the nerve terminals the aziridinium derivative reacts with unknown vital cellular components, destroying the terminals. At the dose 50 mg/kg i.p. this is characterized by a rapid and long-lasting loss of noradrenaline and a slower decrease in the dopamine-β-hydroxylase enzyme activity and immunoreactivity in the regions innervated from locus coeruleus. The tissue level of noradrenaline is reduced to 10-30% of the normal value. The extraneuronal concentration is, on the other hand, increased due to inflow from non-lesioned regions. Like the peripheral sympathetic nerves the non-locus coeruleus noradrenergic systems in the rodent brain is resistant to the neurotoxic action of DSP4. Serotoninergic and dopaminergic nerves are only slightly or not at all affected by DSP4. The neurotoxic effect is counteracted by pretreatment with noradrenaline uptake inhibitors (e.g., desipramine). MAO-B inhibitors of the N-propargylamine type (e.g., selegiline) also counteract the DSP4-induced neurotoxicity with another, yet unknown mechanism. Because of its selectivity for the locus coeruleus system DSP4 is a useful tool in studies of the functional role of this noradrenergic system in the brain.

  1. Dopamine receptor blockade attenuates the general incentive motivational effects of noncontingently delivered rewards and reward-paired cues without affecting their ability to bias action selection.

    Science.gov (United States)

    Ostlund, Sean B; Maidment, Nigel T

    2012-01-01

    Environmental cues affect our behavior in a variety of ways. Despite playing an invaluable role in guiding our daily activities, such cues also appear to trigger the harmful, compulsive behaviors that characterize addiction and other disorders of behavioral control. In instrumental conditioning, rewards and reward-paired cues bias action selection and invigorate reward-seeking behaviors, and appear to do so through distinct neurobehavioral processes. Although reward-paired cues are known to invigorate performance through a dopamine-dependent incentive motivational process, it is not known if dopamine also mediates the influence of rewards and reward-paired cues over action selection. The current study contrasted the effects of systemic administration of the nonspecific dopamine receptor antagonist flupentixol on response invigoration and action bias in Pavlovian-instrumental transfer, a test of cue-elicited responding, and in instrumental reinstatement, a test of noncontingent reward-elicited responding. Hungry rats were trained on two different stimulus-outcome relationships (eg, tone-grain pellets and noise-sucrose solution) and two different action-outcome relationships (eg, left press-grain and right press-sucrose). At test, we found that flupentixol pretreatment blocked the response invigoration generated by the cues but spared their ability to bias action selection to favor the action whose outcome was signaled by the cue being presented. The response-biasing influence of noncontingent reward deliveries was also unaffected by flupentixol. Interestingly, although flupentixol had a modest effect on the immediate response invigoration produced by those rewards, it was particularly potent in countering the lingering enhancement of responding produced by multiple reward deliveries. These findings indicate that dopamine mediates the general incentive motivational effects of noncontingent rewards and reward-paired cues but does not support their ability to bias

  2. The role of motor memory in action selection and procedural learning: insights from children with typical and atypical development

    Directory of Open Access Journals (Sweden)

    Jessica Tallet

    2015-07-01

    Full Text Available Motor memory is the process by which humans can adopt both persistent and flexible motor behaviours. Persistence and flexibility can be assessed through the examination of the cooperation/competition between new and old motor routines in the motor memory repertoire. Two paradigms seem to be particularly relevant to examine this competition/cooperation. First, a manual search task for hidden objects, namely the C-not-B task, which allows examining how a motor routine may influence the selection of action in toddlers. The second paradigm is procedural learning, and more precisely the consolidation stage, which allows assessing how a previously learnt motor routine becomes resistant to subsequent programming or learning of a new – competitive – motor routine. The present article defends the idea that results of both paradigms give precious information to understand the evolution of motor routines in healthy children. Moreover, these findings echo some clinical observations in developmental neuropsychology, particularly in children with Developmental Coordination Disorder. Such studies suggest that the level of equilibrium between persistence and flexibility of motor routines is an index of the maturity of the motor system.

  3. Remedial action plan and site design for stabilization of the inactive uranium mill tailings sites at Slick Rock, Colorado: Remedial Action Selection Report. Preliminary final

    Energy Technology Data Exchange (ETDEWEB)

    1994-03-01

    This proposed remedial action plan incorporates the results of detailed investigation of geologic, geomorphic, and seismic conditions at the proposed disposal site. The proposed remedial action will consist of relocating the uranium mill tailings, contaminated vicinity property materials, demolition debris, and windblown/waterborne materials to a permanent repository at the proposed Burro Canyon disposal cell. The proposed disposal site will be geomorphically stable. Seismic design parameters were developed for the geotechnical analyses of the proposed cell. Cell stability was analyzed to ensure long-term performance of the disposal cell in meeting design standards, including slope stability, settlement, and liquefaction potential. The proposed cell cover and erosion protection features were also analyzed and designed to protect the RRM (residual radioactive materials) against surface water and wind erosion. The location of the proposed cell precludes the need for permanent drainage or interceptor ditches. Rock to be used on the cell top-, side-, and toeslopes was sized to withstand probable maximum precipitation events.

  4. Effects of selected food phytochemicals in reducing the toxic actions of TCDD and p,p'-DDT in U937 macrophages.

    Science.gov (United States)

    Sciullo, Eric M; Vogel, Christoph F; Wu, Dalei; Murakami, Akira; Ohigashi, Hajime; Matsumura, Fumio

    2010-12-01

    To assess the effectiveness of selected food phytochemicals in reducing the toxic effects of the environmental toxicants, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and p,p'-DDT (DDT), we tested the potencies of auraptene, nobiletin, zerumbone, and (±)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA) in reversing the inflammatory action of these toxicants in U937 human macrophages. Using quantitative RT-PCR as the initial screening assay, we identified antagonistic actions of zerumbone and auraptene against the action of TCDD and DDT in up-regulating the mRNA expressions of COX-2 and VEGF. The functional significance of the inhibitory action of zerumbone on COX-2 expression was confirmed by demonstrating its suppression of TCDD-induced activation of COX-2 gene expression in mouse MMDD1 cells. We tested auraptene on DDT-induced reactive oxygen species (ROS) formation in U937 macrophages and found that auraptene is a powerful agent antagonizing this action of DDT. To confirm the significance of these actions of zerumbone and auraptene at the cellular level, we assessed their influence on TCDD-induced apoptosis resistance in intact U937 macrophages and found that they are capable of reversing this action of TCDD. In conclusion, zerumbone and auraptene were identified to be the most effective agents in protecting U937 macrophages from developing these cell toxic effects of TCDD and DDT.

  5. [Comparison of the action of Cordemcura on selected cardiovascular parameters following intraduodenal and intravenous application in beagles].

    Science.gov (United States)

    Hübler, D; Mudhaffar, A A; Schilling, G; Elze, M; Chemnitius, K H

    1986-03-01

    The novel cardiotonic Cordemcura was tested for its cardiovascular effects after intraduodenal application to anaesthetized dogs. For this purpose, beagles received Cordemcura intraduodenally as a Tylose suspension, with 4 bolus injections (10(-5), 3 X 10(-5), 6 X 10(-5), and 10(-4) mol/kg) given at 30-min intervals. The test parameters used to analyze the onset of action and its course include: heart frequency (HFR), maximum rate of pressure rise (dp/dtmax) and decline (dp/dtmin) in the left ventricle, cardiac output (CO), stroke volume (SV), total peripheral resistance (TPR) and peripheral arterial blood pressure, systolic (Ps) and diastolic (Pd), and dose-effect curves determined for the individual test parameters. There was a dose-dependent increase of dp/dtmax up to a maximum of 130%, which 3 h afterwards was still about 60% above the initial value. The heart frequency, too, rose dose-dependently by a maximum of 80%, though not being significantly different from the initial value any longer 3 h after the last bolus injection. The Ps was slightly, but significantly decreased with the higher dose levels used. The influence on dp/dtmin and Pd was insignificant. A significant rise was found in the cardiac output, whereas the peripheral resistance showed a slight decline. After 3 h, a significant rise was still seen in the contractility (dp/dtmax), whereas the other parameters were no longer significantly different from the initial values. Moreover, selected dose levels of Cordemcura were tested after i. v. application, and a comparison was made of their effect on heart frequency, peripheral blood pressure, and inotropism. The importance of the findings was discussed.

  6. The prefrontal cortex shows context-specific changes in effective connectivity to motor or visual cortex during the selection of action or colour

    DEFF Research Database (Denmark)

    Rowe, James B.; Stephan, Klaas E.; Friston, Karl

    2005-01-01

    The role of the prefrontal cortex remains controversial. Neuroimaging studies support modality-specific and process-specific functions related to working memory and attention. Its role may also be defined by changes in its influence over other brain regions including sensory and motor cortex. We...... included high-order interactions between modality, selection and regional activity. There was greater coupling between prefrontal cortex and motor cortex during free selection and action tasks, and between prefrontal cortex and visual cortex during free selection of colours. The results suggest...

  7. Selective inhibition of mutant isocitrate dehydrogenase 1 (IDH1) via disruption of a metal binding network by an allosteric small molecule.

    Science.gov (United States)

    Deng, Gejing; Shen, Junqing; Yin, Ming; McManus, Jessica; Mathieu, Magali; Gee, Patricia; He, Timothy; Shi, Chaomei; Bedel, Olivier; McLean, Larry R; Le-Strat, Frank; Zhang, Ying; Marquette, Jean-Pierre; Gao, Qiang; Zhang, Bailin; Rak, Alexey; Hoffmann, Dietmar; Rooney, Eamonn; Vassort, Aurelie; Englaro, Walter; Li, Yi; Patel, Vinod; Adrian, Francisco; Gross, Stefan; Wiederschain, Dmitri; Cheng, Hong; Licht, Stuart

    2015-01-09

    Cancer-associated point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) confer a neomorphic enzymatic activity: the reduction of α-ketoglutarate to d-2-hydroxyglutaric acid, which is proposed to act as an oncogenic metabolite by inducing hypermethylation of histones and DNA. Although selective inhibitors of mutant IDH1 and IDH2 have been identified and are currently under investigation as potential cancer therapeutics, the mechanistic basis for their selectivity is not yet well understood. A high throughput screen for selective inhibitors of IDH1 bearing the oncogenic mutation R132H identified compound 1, a bis-imidazole phenol that inhibits d-2-hydroxyglutaric acid production in cells. We investigated the mode of inhibition of compound 1 and a previously published IDH1 mutant inhibitor with a different chemical scaffold. Steady-state kinetics and biophysical studies show that both of these compounds selectively inhibit mutant IDH1 by binding to an allosteric site and that inhibition is competitive with respect to Mg(2+). A crystal structure of compound 1 complexed with R132H IDH1 indicates that the inhibitor binds at the dimer interface and makes direct contact with a residue involved in binding of the catalytically essential divalent cation. These results show that targeting a divalent cation binding residue can enable selective inhibition of mutant IDH1 and suggest that differences in magnesium binding between wild-type and mutant enzymes may contribute to the inhibitors' selectivity for the mutant enzyme.

  8. Remedial action plan and site design for stabilization of the inactive uranium processing site at Naturita, Colorado. Remedial Action Selection Report, Appendix B of Attachment 2: Geology report, Final

    Energy Technology Data Exchange (ETDEWEB)

    1994-03-01

    The uranium processing site near Naturita, Colorado, is one of 24 inactive uranium mill sites designated to be cleaned up by the US Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA), 42 USC {section} 7901 et seq. Part of the UMTRCA requires that the US Nuclear Regulatory Commission (NRC) concur with the DOE`s remedial action plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the US Environmental Protection Agency (EPA). Included in the RAP is this Remedial Action Selection Report (RAS), which describes the proposed remedial action for the Naturita site. An extensive amount of data and supporting information has been generated and evaluated for this remedial action. These data and supporting information are not incorporated into this single document but are included or referenced in the supporting documents. The RAP consists of this RAS and four supporting documents or attachments. This Attachment 2, Geology Report describes the details of geologic, geomorphic, and seismic conditions at the Dry Flats disposal site.

  9. Removal of selected pharmaceuticals and personal care products (PPCPs) and endocrine-disrupting chemicals (EDCs) during sand filtration and ozonation at a municipal sewage treatment plant.

    Science.gov (United States)

    Nakada, Norihide; Shinohara, Hiroyuki; Murata, Ayako; Kiri, Kentaro; Managaki, Satoshi; Sato, Nobuyuki; Takada, Hideshige

    2007-11-01

    We investigated the efficiencies of removal of 24 pharmaceutically active compounds (PhACs) during sand filtration and ozonation in an operating municipal sewage treatment plant (STP). The target compounds were 2 phenolic antiseptics (thymol, triclosan), 5 acidic analgesics or anti-inflammatories (ibuprofen, naproxen, ketoprofen, fenoprofen, mefenamic acid), 4 amide pharmaceuticals (propyphenazone, crotamiton, carbamazepine, diethyltoluamide), 7 antibiotics (sulfapyridine, sulfamethoxazole, trimethoprim, azithromycin, erythromycin anhydride, clarithromycin, roxithromycin), 3 phenolic endocrine-disrupting chemicals (EDCs) (nonylphenol:NP, octylphenol:OP, bisphenol A:BPA) and 3 natural estrogens (17 beta-estradiol:E2, estrone:E1, estriol:E3). Ozonation removed approximately 80% or more of the phenolic antiseptics, crotamiton, sulfonamide and macrolide antibiotics, and 17 beta-estradiol. Their removal is discussed in terms of chemical structure. The study ascertained the validity of ozonation mechanisms proposed by previous studies in an actually running STP. Compounds with a CC double bond or an aromatic structure with electron donors (e.g., phenol, alkyl, methoxy, or non-protonated amine) were susceptible to ozonation. Compounds with amide structures were resistant. Removal of the PhACs during sand filtration was generally inefficient, probably because of their low hydrophobicities. The combination of ozonation and sand filtration with activated sludge treatment gave efficient removal (>80%) of all the target compounds except carbamazepine and diethyltoluamide. Among all the steps in the plant, ozonation contributed substantially to overall removal of naproxen, ketoprofen, triclosan, crotamiton, sulfapyridine, macrolide antibiotics, and estrone.

  10. Remedial Action Plan and Site Design for Stabilization of the Inactive Uranium Mill Tailings Site, Maybell, Colorado. Remedial action selection report: Attachment 2, Geology report, Final

    Energy Technology Data Exchange (ETDEWEB)

    1994-06-01

    The Maybell uranium mill tailings site is 25 miles (mi) (40 kilometers [km]) west of the town of Craig, Colorado, in Moffat County, in the northwestern part of the state. The unincorporated town of Maybell is 5 road mi (8 km) southwest of the site. The designated site covers approximately 110 acres (ac) (45 hectares [ha]) and consists of a concave-shaped tailings pile and rubble from the demolition of the mill buildings buried in the former mill area. Contaminated materials at the Maybell processing site include the tailings pile, which has an average depth of 20 feet (ft) (6 meters [m]) and contains 2.8 million cubic yards (yd{sup 3}) (2.1 million cubic meters [m{sup 3}]) of tailings. The former mill processing area is on the north side of the site and contains 20,000 yd{sup 3} (15,000 m{sup 3}) of contaminated demolition debris. Off-pile contamination is present and includes areas adjacent to the tailings pile, as well as contamination dispersed by wind and surface water flow. The volume of off-pile contamination to be placed in the disposal cell is 550,000 yd{sup 3} (420,000 m{sup 3}). The total volume of contaminated materials to be disposed of as part of the remedial action is estimated to be 3.37 million yd{sup 3} (2.58 million m{sup 3}). Information presented in this Final Remedial Action Plan (RAP) and referenced in supporting documents represents the current disposal cell design features and ground water compliance strategy proposed by the US Department of Energy (DOE) for the Maybell, Colorado, tailings site. Both the disposal cell design and the ground water compliance strategy have changed from those proposed prior to the preliminary final RAP document as a result of prudent site-specific technical evaluations.

  11. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 13: Part 2, Indexes. Environmental Restoration Program

    Energy Technology Data Exchange (ETDEWEB)

    Goins, L.F.; Webb, J.R.; Cravens, C.D.; Mallory, P.K.

    1992-09-01

    This is part 2 of a bibliography on nuclear facility decommissioning and site remedial action. This report contains indexes on the following: authors, corporate affiliation, title words, publication description, geographic location, subject category, and key word.

  12. The RNA-binding Protein TDP-43 Selectively Disrupts MicroRNA-1/206 Incorporation into the RNA-induced Silencing Complex*♦

    Science.gov (United States)

    King, Isabelle N.; Yartseva, Valeria; Salas, Donaldo; Kumar, Abhishek; Heidersbach, Amy; Ando, D. Michael; Stallings, Nancy R.; Elliott, Jeffrey L.; Srivastava, Deepak; Ivey, Kathryn N.

    2014-01-01

    MicroRNA (miRNA) maturation is regulated by interaction of particular miRNA precursors with specific RNA-binding proteins. Following their biogenesis, mature miRNAs are incorporated into the RNA-induced silencing complex (RISC) where they interact with mRNAs to negatively regulate protein production. However, little is known about how mature miRNAs are regulated at the level of their activity. To address this, we screened for proteins differentially bound to the mature form of the miR-1 or miR-133 miRNA families. These muscle-enriched, co-transcribed miRNA pairs cooperate to suppress smooth muscle gene expression in the heart. However, they also have opposing roles, with the miR-1 family, composed of miR-1 and miR-206, promoting myogenic differentiation, whereas miR-133 maintains the progenitor state. Here, we describe a physical interaction between TDP-43, an RNA-binding protein that forms aggregates in the neuromuscular disease, amyotrophic lateral sclerosis, and the miR-1, but not miR-133, family. Deficiency of the TDP-43 Drosophila ortholog enhanced dmiR-1 activity in vivo. In mammalian cells, TDP-43 limited the activity of both miR-1 and miR-206, but not the miR-133 family, by disrupting their RISC association. Consistent with TDP-43 dampening miR-1/206 activity, protein levels of the miR-1/206 targets, IGF-1 and HDAC4, were elevated in TDP-43 transgenic mouse muscle. This occurred without corresponding Igf-1 or Hdac4 mRNA increases and despite higher miR-1 and miR-206 expression. Our findings reveal that TDP-43 negatively regulates the activity of the miR-1 family of miRNAs by limiting their bioavailability for RISC loading and suggest a processing-independent mechanism for differential regulation of miRNA activity. PMID:24719334

  13. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 13: Part 1, Main text. Environmental Restoration Program

    Energy Technology Data Exchange (ETDEWEB)

    Goins, L.F.; Webb, J.R.; Cravens, C.D.; Mallory, P.K.

    1992-09-01

    This publication contains 1035 abstracted references on environmental restoration, nuclear facility decommissioning, uranium mill tailings management, and site remedial actions. These citations constitute the thirteenth in a series of reports prepared annually for the US Department of Energy (DOE) Environmental Restoration programs. Citations to foreign and domestic literature of all types. There are 13 major sections of the publication, including: (1) DOE Decontamination and Decommissioning Program; (2) Nuclear Facilities Decommissioning; (3) DOE Formerly Utilized Sites Remedial Action Program; (4) DOE Uranium Mill Tailings Remedial Action Project; (5) Uranium Mill Tailings Management; (6) DOE Environmental Restoration Program; (7) DOE Site-Specific Remedial Actions; (8) Contaminated Site Restoration; (9) Remediation of Contaminated Soil and Groundwater; (10) Environmental Data Measurements, Management, and Evaluation; (11) Remedial Action Assessment and Decision-Making; (12) Technology Development and Evaluation; and (13) Environmental and Waste Management Issues. Bibliographic references are arranged in nine subject categories by geographic location and then alphabetically by first author, corporate affiliation, or publication title. Indexes are provided for author, corporate affiliation, title word, publication description, geographic location, subject category, and key word.

  14. Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study

    OpenAIRE

    Marinho, Eduardo Ary Villela; Oliveira-Lima, Alexandre Justo de [UNIFESP; Wuo-Silva, Raphael; Santos, Renan [UNIFESP; Baldaia, Marilia Araujo [UNIFESP; Hollais, André Willian [UNIFESP; Longo, Beatriz Monteiro; Berro, Laís Fernanda; Frussa-Filho, Roberto

    2014-01-01

    An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared...

  15. Cognitive effects of endocrine-disrupting chemicals in animals.

    Science.gov (United States)

    Schantz, S L; Widholm, J J

    2001-12-01

    A large number of chemical pollutants including phthalates, alkylphenolic compounds, polychlorinated biphenyls and polychlorinated dibenzodioxins, organochlorine pesticides, bisphenol A, and metals including lead, mercury, and cadmium have the ability to disrupt endocrine function in animals. Some of these same chemicals have been shown to alter cognitive function in animals and humans. Because hormonally mediated events play a central role in central nervous system development and function, a number of researchers have speculated that the changes in cognitive function are mediated by the endocrine-like actions of these chemicals. In this paper we review the evidence that cognitive effects of chemicals classified as environmental endocrine disruptors are mediated by changes in hormonal function. We begin by briefly reviewing the role of gonadal steroids, thyroid hormones, and glucocorticoids in brain development and brain function. We then review the endocrine changes and cognitive effects that have been reported for selected endocrine-disrupting chemicals, discuss the evidence for causal relationships between endocrine disruption and cognitive effects, and suggest directions for future research.

  16. Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium.

    Science.gov (United States)

    Matsuda, Tomoyuki; Takeda, Kentaro; Ito, Mie; Yamagishi, Reiko; Tamura, Miku; Nakamura, Hideki; Tsuruoka, Noriko; Saito, Tomoaki; Masumiya, Haruko; Suzuki, Takeshi; Iida-Tanaka, Naoko; Itokawa-Matsuda, Maho; Yamashita, Toru; Tsuruzoe, Nobutomo; Tanaka, Hikaru; Shigenobu, Koki

    2005-05-01

    NIP-142 is a novel benzopyran compound that was shown to prolong the atrial effective refractory period and terminate experimental atrial fibrillation in the dog. In the present study, we examined the effects of NIP-142 on isolated guinea pig myocardium and on the G-protein-coupled inwardly rectifying potassium channel current (acetylcholine-activated potassium current; I(KACh)) expressed in Xenopus oocytes. NIP-142 (10 and 100 microM) concentration-dependently prolonged the refractory period and action potential duration in the atrium but not in the ventricle. E-4031 and 4-aminopyridine prolonged action potential duration in both left atrium and right ventricle. Prolongation by NIP-142 of the atrial action potential duration was observed at stimulation frequencies between 0.5 and 5 Hz. In contrast, the prolongation by E-4031 was not observed at higher frequencies. Tertiapin, a blocker of I(KACh), prolonged action potential duration in the atrium but not in the ventricle. NIP-142 completely reversed the carbachol-induced shortening of atrial action potential duration. NIP-142 (1 to 100 microM), as well as tertiapin (0.1 to 100 nM), concentration-dependently blocked I(KACh) expressed in Xenopus oocytes; the blockade by NIP-142 was not affected by membrane voltage. In conclusion, NIP-142 was shown to prolong atrial refractory period and action potential duration through blockade of I(KACh) which may possibly explain its previously described antiarrhythmic activity. NIP-142 has pharmacological properties that are different from classical class III antiarrhythmic agents such as atria specificity and lack of reverse frequency dependence, and thus appears promising for the treatment of supraventricular arrhythmia.

  17. Development and evaluation of a tool for retrospective exposure assessment of selected endocrine disrupting chemicals and EMF in the car manufacturing industry.

    Science.gov (United States)

    Mester, Birte; Schmeisser, Nils; Lünzmann, Hauke; Pohlabeln, Hermann; Langner, Ingo; Behrens, Thomas; Ahrens, Wolfgang

    2011-08-01

    A system for retrospective occupational exposure assessment combining the efficiency of a job exposure matrix (JEM) and the precision of a subsequent individual expert exposure assessment (IEEA) was developed. All steps of the exposure assessment were performed by an interdisciplinary expert panel in the context of a case-control study on male germ cell cancer nested in the car manufacturing industries. An industry-specific JEM was developed and automatic exposure estimation was performed based on this JEM. A subsample of exposure ratings was done by IEEA to identify determinants of disagreement between the JEM and the individual review. Possible determinants were analyzed by calculating odds ratios (ORs) of disagreement between ratings with regard to different dimensions (e.g. high versus low intensity of exposure). Disagreement in ≥20% of the sampled exposure ratings with a statistically significant OR was chosen as a threshold for inclusion of the exposure ratings into a final IEEA. The most important determinants of disagreement between JEM and individual review were working outside of the production line (disagreement 80%), low probability of exposure (disagreement 25%), and exposure depending on specific activities like usage of specific lacquers (disagreement 32%) for jobs within the production line. These determinants were the selection criteria of exposure ratings for the subsequent final IEEA. Combining a JEM and a subsequent final IEEA for a selected subset of exposure ratings is a feasible and labor-saving approach for exposure assessment in large occupational epidemiological studies.

  18. Synthesis of core-shell magnetic molecular imprinted polymer by the surface RAFT polymerization for the fast and selective removal of endocrine disrupting chemicals from aqueous solutions

    Energy Technology Data Exchange (ETDEWEB)

    Li Ying [Department of Chemistry, Harbin Institute of Technology, Harbin 150090 (China); Li Xin, E-mail: lixin@hit.edu.c [Department of Chemistry, Harbin Institute of Technology, Harbin 150090 (China); Chu Jia; Dong Cunku [Department of Chemistry, Harbin Institute of Technology, Harbin 150090 (China); Qi Jingyao; Yuan Yixing [School of Municipal and Environmental Engineering, Harbin Institute of Technology, Harbin 150090 (China)

    2010-06-15

    In this study, we present a general protocol for the making of surface-imprinted core-shell magnetic beads via reversible addition-fragmentation chain transfer (RAFT) polymerization using RAFT agent functionalized iron oxide nanoparticles as the chain transfer agent. The resulting composites were characterized by X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) analysis, thermogravimetric analysis (TGA), vibrating sample magnetometer (VSM), and scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The surface-imprinted magnetic beads were demonstrated with a homogeneous polymer films (thickness of about 22 nm), spherical shape, and exhibited magnetic property (Ms = 0.41 mA m{sup 2} g{sup -1}) and thermal stability. Rebinding experiments were carried out to determine the specific binding capacity and selective recognition. The as-synthesized surface-imprinted core-shell magnetic beads showed outstanding affinity and selectivity towards bisphenol A over structurally related compounds, and easily reach the magnetic separation under an external magnetic field. In addition, the resulting composites reusability without obviously deterioration in performance was demonstrated at least five repeated cycles. - Magnetic molecular imprinted polymers have potential as adsorptive materials in water treatment.

  19. Disrupting Educational Inequalities through Youth Digital Activism

    Science.gov (United States)

    Stornaiuolo, Amy; Thomas, Ebony Elizabeth

    2017-01-01

    This article reviews scholarship on youth and young adult activism in digital spaces, as young users of participatory media sites are engaging in political, civic, social, or cultural action and advocacy online to create social change. The authors argue that youth's digital activism serves as a central mechanism to disrupt inequality, and that…

  20. Mutating the Conserved Q-loop Glutamine 1291 Selectively Disrupts Adenylate Kinase-dependent Channel Gating of the ATP-binding Cassette (ABC) Adenylate Kinase Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Reduces Channel Function in Primary Human Airway Epithelia.

    Science.gov (United States)

    Dong, Qian; Ernst, Sarah E; Ostedgaard, Lynda S; Shah, Viral S; Ver Heul, Amanda R; Welsh, Michael J; Randak, Christoph O

    2015-05-29

    The ATP-binding cassette (ABC) transporter cystic fibrosis transmembrane conductance regulator (CFTR) and two other non-membrane-bound ABC proteins, Rad50 and a structural maintenance of chromosome (SMC) protein, exhibit adenylate kinase activity in the presence of physiologic concentrations of ATP and AMP or ADP (ATP + AMP ⇆ 2 ADP). The crystal structure of the nucleotide-binding domain of an SMC protein in complex with the adenylate kinase bisubstrate inhibitor P(1),P(5)-di(adenosine-5') pentaphosphate (Ap5A) suggests that AMP binds to the conserved Q-loop glutamine during the adenylate kinase reaction. Therefore, we hypothesized that mutating the corresponding residue in CFTR, Gln-1291, selectively disrupts adenylate kinase-dependent channel gating at physiologic nucleotide concentrations. We found that substituting Gln-1291 with bulky side-chain amino acids abolished the effects of Ap5A, AMP, and adenosine 5'-monophosphoramidate on CFTR channel function. 8-Azidoadenosine 5'-monophosphate photolabeling of the AMP-binding site and adenylate kinase activity were disrupted in Q1291F CFTR. The Gln-1291 mutations did not alter the potency of ATP at stimulating current or ATP-dependent gating when ATP was the only nucleotide present. However, when physiologic concentrations of ADP and AMP were added, adenylate kinase-deficient Q1291F channels opened significantly less than wild type. Consistent with this result, we found that Q1291F CFTR displayed significantly reduced Cl(-) channel function in well differentiated primary human airway epithelia. These results indicate that a highly conserved residue of an ABC transporter plays an important role in adenylate kinase-dependent CFTR gating. Furthermore, the results suggest that adenylate kinase activity is important for normal CFTR channel function in airway epithelia.

  1. Selective Preference of Parallel DNA Triplexes Is Due to the Disruption of Hoogsteen Hydrogen Bonds Caused by the Severe Nonisostericity between the G*GC and T*AT Triplets.

    Directory of Open Access Journals (Sweden)

    Gunaseelan Goldsmith

    Full Text Available Implications of DNA, RNA and RNA.DNA hybrid triplexes in diverse biological functions, diseases and therapeutic applications call for a thorough understanding of their structure-function relationships. Despite exhaustive studies mechanistic rationale for the discriminatory preference of parallel DNA triplexes with G*GC & T*AT triplets still remains elusive. Here, we show that the highest nonisostericity between the G*GC & T*AT triplets imposes extensive stereochemical rearrangements contributing to context dependent triplex destabilisation through selective disruption of Hoogsteen scheme of hydrogen bonds. MD simulations of nineteen DNA triplexes with an assortment of sequence milieu reveal for the first time fresh insights into the nature and extent of destabilization from a single (non-overlapping, double (overlapping and multiple pairs of nonisosteric base triplets (NIBTs. It is found that a solitary pair of NIBTs, feasible either at a G*GC/T*AT or T*AT/G*GC triplex junction, does not impinge significantly on triplex stability. But two overlapping pairs of NIBTs resulting from either a T*AT or a G*GC interruption disrupt Hoogsteen pair to a noncanonical mismatch destabilizing the triplex by ~10 to 14 kcal/mol, implying that their frequent incidence in multiples, especially, in short sequences could even hinder triplex formation. The results provide (i an unambiguous and generalised mechanistic rationale for the discriminatory trait of parallel triplexes, including those studied experimentally (ii clarity for the prevalence of antiparallel triplexes and (iii comprehensive perspectives on the sequence dependent influence of nonisosteric base triplets useful in the rational design of TFO's against potential triplex target sites.

  2. Disrupting Ethnography through Rhizoanalysis

    Directory of Open Access Journals (Sweden)

    Diana Masny

    2014-10-01

    Full Text Available This article interrogates principles of ethnography in education proposed by Mills and Morton: raw tellings, analytic pattern, vignette and empathy. This article adopts a position that is uncomfortable, unconventional and interesting. It involves a deterritorialization/ rupture of ethnography in education in order to reterritorialize a different concept: rhizoanalysis, a way to position theory and data that is multilayered, complex and messy. Rhizoanalysis, the main focus of this article is not a method. It is an approach to research conditioned by a reality in which Deleuze and Guattari disrupt representation, interpretation and subjectivity. In this article, Multiple Literacies Theory, a theoretical and practical framework, becomes a lens to examine a rhizomatic study of a Korean family recently arrived to Australia and attending English as a second language classes. Observations and interviews recorded the daily lives of the family. The vignettes were selected by reading data intensively and immanently through a process of palpation, an innovative approach to educational research. Rhizoanalysis proposes to abandon the given and invent different ways of thinking about and doing research and what might happen when reading data differently, intensively and immanently, through Multiple Literacies Theory. Rhizoanalysis, a game-changer in the way research can be conducted, affords a different lens to tackle issues in education through research.

  3. Remedial Action Assessment System (RAAS): Evaluation of selected feasibility studies of CERCLA (Comprehensive Environmental Response, Compensation, and Liability Act) hazardous waste sites

    Energy Technology Data Exchange (ETDEWEB)

    Whelan, G. (Pacific Northwest Lab., Richland, WA (USA)); Hartz, K.E.; Hilliard, N.D. (Beck (R.W.) and Associates, Seattle, WA (USA))

    1990-04-01

    Congress and the public have mandated much closer scrutiny of the management of chemically hazardous and radioactive mixed wastes. Legislative language, regulatory intent, and prudent technical judgment, call for using scientifically based studies to assess current conditions and to evaluate and select costeffective strategies for mitigating unacceptable situations. The NCP requires that a Remedial Investigation (RI) and a Feasibility Study (FS) be conducted at each site targeted for remedial response action. The goal of the RI is to obtain the site data needed so that the potential impacts on public health or welfare or on the environment can be evaluated and so that the remedial alternatives can be identified and selected. The goal of the FS is to identify and evaluate alternative remedial actions (including a no-action alternative) in terms of their cost, effectiveness, and engineering feasibility. The NCP also requires the analysis of impacts on public health and welfare and on the environment; this analysis is the endangerment assessment (EA). In summary, the RI, EA, and FS processes require assessment of the contamination at a site, of the potential impacts in public health or the environment from that contamination, and of alternative RAs that could address potential impacts to the environment. 35 refs., 7 figs., 1 tab.

  4. Review of decision methodologies for evaluating regulatory actions affecting public health and safety. [Nuclear industry site selection

    Energy Technology Data Exchange (ETDEWEB)

    Hendrickson, P.L.; McDonald, C.L.; Schilling, A.H.

    1976-12-01

    This report examines several aspects of the problems and choices facing the governmental decision maker who must take regulatory actions with multiple decision objectives and attributes. Particular attention is given to the problems facing the U.S. Nuclear Regulatory Commission (NRC) and to the decision attribute of chief concern to NRC, the protection of human health and safety, with emphasis on nuclear power plants. The study was undertaken to provide background information for NRC to use in refining its process of value/impact assessment of proposed regulatory actions. The principal conclusion is that approaches to rationally consider the value and impact of proposed regulatory actions are available. These approaches can potentially improve the decision-making process and enable the agency to better explain and defend its decisions. They also permit consistent examination of the impacts, effects of uncertainty and sensitivity to various assumptions of the alternatives being considered. Finally, these approaches can help to assure that affected parties are heard and that technical information is used appropriately and to the extent possible. The principal aspects of the regulatory decision problem covered in the report are: the legal setting for regulatory decisions which affect human health and safety, elements of the decision-making process, conceptual approaches to decision making, current approaches to decision making in several Federal agencies, and the determination of acceptable risk levels.

  5. Biological fitness and action opportunity of natural selection in an urban population of Cuba: Plaza de la Revolución, Havana.

    Science.gov (United States)

    Vazquez, Vanessa; Alonso, Verónica; Luna, Francisco

    2012-03-01

    This paper describes the biological fitness of an urban population of Havana city, Plaza de la Revolución, which has the lowest fertility and the highest demographic ageing in Cuba. The aim is to assess the biological fitness of this community through the indexes of action opportunity of natural selection, to determine its evolutionary pattern and the influence of its socio-cultural peculiarity. Demographic data were obtained from the reproductive histories of 1200 women between the ages of 55 and 64. Data concerning mortality and surviving offspring from the first embryonic stages until age of reproduction were also collected. In order to measure the level of biological fitness two indexes were used: the Crow index of action opportunity of natural selection and the corrected index proposed by Johnston and Kensinger, which takes into account prenatal mortality. This corrected index was calculated including and excluding induced abortions in order to evaluate the contribution of these to biological fitness. When only postnatal mortality was considered, the results showed an evolutionary pattern similar to that of developed countries, based on low mortality and fertility. However, when prenatal mortality was taken into account, biological fitness decreased and the corrected index of natural selection was 4.5 times higher than when miscarriages and fetal deaths were not considered. Moreover, this corrected index was 2.65 times higher when induced miscarriages were considered, indicating the large decrease in biological fitness as a result of the current reproductive behaviour of frequent induced abortion.

  6. Confronting the disruptive physician.

    Science.gov (United States)

    Linney, B J

    1997-01-01

    Ignoring disruptive behavior is no longer an option in today's changing health care environment. Competition and managed care have caused more organizations to deal with the disruptive physician, rather than look the other way as many did in years past. But it's not an easy task, possibly the toughest of your management career. How should you confront a disruptive physician? By having clearly stated expectations for physician behavior and policies in place for dealing with problem physicians, organizations have a context from which to address the situation.

  7. Identification of an unconventional process of instrumental learning characteristically initiated with outcome devaluation-insensitivity and generalized action selection

    Science.gov (United States)

    Iguchi, Yoshio; Lin, Ziqiao; Nishikawa, Hiromi; Minabe, Yoshio; Toda, Shigenobu

    2017-01-01

    The distinction between goal-directed action and habitual response, particularly with respect to moderate or extended appetitive instrumental training, is well documented; however, the propensity toward instrumental behavior in the early training stage has not been elucidated. In this study, we trained Sprague Dawley rats to press a lever to obtain food as an outcome for various time periods and monitored the changes in their sensitivity to outcome devaluation and choice between the levers they had been trained with and unfamiliar levers. After the extensive training with a random interval schedule, the rats were insensitive to outcome devaluation, and exhibited a typical habit-like phenotype, as previously reported, and the untrained leverpresses were relatively rare and sporadic. During the initial stage of training (≤1 week), the rats exhibited a similar insensitivity to the devaluation; however, in contrast to the overtrained condition, they performed distinctive unbiased leverpresses on both the trained and untrained levers. Thus, we propose a possibility that, contrary to the authentic concept that instrumental learning is initiated with an outcome devaluation-sensitive goal-directed stage, under some conditions, this learning can unconventionally begin with the initial stage that is distinct from both goal-directed action and habitual response. PMID:28240299

  8. Identification of an unconventional process of instrumental learning characteristically initiated with outcome devaluation-insensitivity and generalized action selection.

    Science.gov (United States)

    Iguchi, Yoshio; Lin, Ziqiao; Nishikawa, Hiromi; Minabe, Yoshio; Toda, Shigenobu

    2017-02-27

    The distinction between goal-directed action and habitual response, particularly with respect to moderate or extended appetitive instrumental training, is well documented; however, the propensity toward instrumental behavior in the early training stage has not been elucidated. In this study, we trained Sprague Dawley rats to press a lever to obtain food as an outcome for various time periods and monitored the changes in their sensitivity to outcome devaluation and choice between the levers they had been trained with and unfamiliar levers. After the extensive training with a random interval schedule, the rats were insensitive to outcome devaluation, and exhibited a typical habit-like phenotype, as previously reported, and the untrained leverpresses were relatively rare and sporadic. During the initial stage of training (≤1 week), the rats exhibited a similar insensitivity to the devaluation; however, in contrast to the overtrained condition, they performed distinctive unbiased leverpresses on both the trained and untrained levers. Thus, we propose a possibility that, contrary to the authentic concept that instrumental learning is initiated with an outcome devaluation-sensitive goal-directed stage, under some conditions, this learning can unconventionally begin with the initial stage that is distinct from both goal-directed action and habitual response.

  9. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts....... The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improves search in complementary technologies, while demoting it when strategic interests are misaligned in disruptive technologies....... However, incumbent sources engaged in capability reconfiguration to accommodate disruption improve search efforts in disruptive technologies. The paper concludes that the value of external sources is contingent on more than their knowledge. Specifically, interdependence of sources in search gives rise...

  10. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts....... The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improves search in complementary technologies, while demoting it when strategic interests are misaligned in disruptive technologies....... However, incumbent sources engaged in capability reconfiguration to accommodate disruption improve search efforts in disruptive technologies. The paper concludes that the value of external sources is contingent on more than their knowledge. Specifically, interdependence of sources in search gives rise...

  11. Disruptive technologies in higher education

    Directory of Open Access Journals (Sweden)

    Michael Flavin

    2012-08-01

    Full Text Available This paper analyses the role of “disruptive” innovative technologies in higher education. In this country and elsewhere, Higher Education Institutions (HEIs have invested significant sums in learning technologies, with Virtual Learning Environments (VLEs being more or less universal, but these technologies have not been universally adopted and used by students and staff. Instead, other technologies not owned or controlled by HEIs are widely used to support learning and teaching. According to Christensen's theory of Disruptive Innovation, these disruptive technologies are not designed explicitly to support learning and teaching in higher education, but have educational potential. This study uses Activity Theory and Expansive Learning to analyse data regarding the impact of disruptive technologies. The data were obtained through a questionnaire survey about awareness and use of technologies, and through observation and interviews, exploring participants’ actual practice. The survey answers tended to endorse Disruptive Innovation theory, with participants establishing meanings for technologies through their use of them, rather than in keeping with a designer's intentions. Observation revealed that learners use a narrow range of technologies to support learning, but with a tendency to use resources other than those supplied by their HEIs. Interviews showed that participants use simple and convenient technologies to support their learning and teaching. This study identifies a contradiction between learning technologies made available by HEIs, and technologies used in practice. There is no evidence to suggest that a wide range of technologies is being used to support learning and teaching. Instead, a small range of technologies is being used for a wide range of tasks. Students and lecturers are not dependent on their HEIs to support learning and teaching. Instead, they self-select technologies, with use weighted towards established brands. The

  12. Tidal disruption events from supermassive black hole binaries

    CERN Document Server

    Coughlin, Eric R; Nixon, Chris; Begelman, Mitchell C

    2016-01-01

    We investigate the pre-disruption gravitational dynamics and post-disruption hydrodynamics of the tidal disruption of stars by supermassive black hole (SMBH) binaries. We focus on binaries with relatively low mass primaries ($10^6M_{\\odot}$), moderate mass ratios, and separations with reasonably long gravitational wave inspiral times (tens of Myr). First, we generate a large ensemble (between 1 and 10 million) of restricted three-body integrations to quantify the statistical properties of tidal disruptions by circular SMBH binaries of initially-unbound stars. Compared to the reference case of a disruption by a single SMBH, the binary potential induces significant variance into the specific energy and angular momentum of the star at the point of disruption. Second, we use Newtonian numerical hydrodynamics to study the detailed evolution of the fallback debris from 120 disruptions randomly selected from the three-body ensemble (excluding only the most deeply penetrating encounters). We find that the overall mor...

  13. Synergistic action of octopamine receptor agonists on the activity of selected novel insecticides for control of dengue vector Aedes aegypti (Diptera: Culicidae) mosquito.

    Science.gov (United States)

    Ahmed, Mohamed Ahmed Ibrahim; Vogel, Christoph Franz Adam

    2015-05-01

    Studying insecticide resistance in mosquitoes has attracted the attention of many scientists to elucidate the pathways of resistance development and to design novel strategies in order to prevent or minimize the spread and evolution of resistance. Here, we tested the synergistic action of piperonyl butoxide (PBO) and two octopamine receptor (OR) agonists, amitraz (AMZ) and chlordimeform (CDM) on selected novel insecticides to increase their lethal action on the fourth instar larvae of Aedes aegypti L. However, chlorfenapyr was the most toxic insecticide (LC50 = 193, 102, and 48 ng/ml, after 24, 48, and 72 h exposure, respectively) tested. Further, PBO synergized all insecticides and the most toxic combinatorial insecticide was nitenpyram even after 48 and 72 h exposure. In addition, OR agonists significantly synergized most of the selected insecticides especially after 48 and 72 h exposure. The results imply that the synergistic effects of amitraz are a promising approach in increasing the potency of certain insecticides in controlling the dengue vector Ae. aegypti mosquito.

  14. Selective action of an atypical neuroleptic on the mechanisms related to the development of cocaine addiction: a pre-clinical behavioural study.

    Science.gov (United States)

    Marinho, Eduardo A V; Oliveira-Lima, Alexandre J; Wuo-Silva, Raphael; Santos, Renan; Baldaia, Marilia A; Hollais, André W; Longo, Beatriz M; Berro, Laís F; Frussa-Filho, Roberto

    2014-04-01

    An increased function in the mesolimbic dopaminergic system has been extensively associated with the rewarding effects of both natural stimuli and drugs of abuse. Thus, dopamine receptor blockers, such as neuroleptic drugs, can be proposed as candidates for potential therapeutic approaches to treat drug dependence. Notwithstanding, this therapeutic potential of neuroleptics critically depends on a selective action on the specific mechanisms related to the development of addiction. We compared the effects of different doses of haloperidol, ziprasidone and aripiprazole (first-, second- and third-generation neuroleptics, respectively) on spontaneous locomotor activity of mice in a novel environment, hyperlocomotion induced by acute cocaine administration and cocaine-induced locomotor sensitization by a two-injection protocol. Whereas high doses of haloperidol abolished the three behavioural paradigms without selectivity, low doses of ziprasidone selectively abolished the development of the behavioural sensitization phenomenon. Finally, low doses of aripiprazole inhibited acute cocaine-induced hyperlocomotion and behavioural sensitization without modifying spontaneous locomotor activity. Thus, aripiprazole at lower doses was the most selective antipsychotic drug concerning the inhibition of the development of behavioural sensitization to cocaine. Because locomotor sensitization in rodents has been proposed to share plastic mechanisms with drug addiction in humans, our data provide relevant suggestions to the clinical practice.

  15. Structural basis for matrix metalloproteinase-2 (MMP-2)-selective inhibitory action of β-amyloid precursor protein-derived inhibitor.

    Science.gov (United States)

    Hashimoto, Hiroshi; Takeuchi, Tomoka; Komatsu, Kyoko; Miyazaki, Kaoru; Sato, Mamoru; Higashi, Shouichi

    2011-09-23

    Unlike other synthetic or physiological inhibitors for matrix metalloproteinases (MMPs), the β-amyloid precursor protein-derived inhibitory peptide (APP-IP) having an ISYGNDALMP sequence has a high selectivity toward MMP-2. Our previous study identified amino acid residues of MMP-2 essential for its selective inhibition by APP-IP and demonstrated that the N to C direction of the decapeptide inhibitor relative to the substrate-binding cleft of MMP-2 is opposite that of substrate. However, detailed interactions between the two molecules remained to be clarified. Here, we determined the crystal structure of the catalytic domain of MMP-2 in complex with APP-IP. We found that APP-IP in the complex is indeed embedded into the substrate-binding cleft of the catalytic domain in the N to C direction opposite that of substrate. With the crystal structure, it was first clarified that the aromatic side chain of Tyr(3) of the inhibitor is accommodated into the S1' pocket of the protease, and the carboxylate group of Asp(6) of APP-IP coordinates bidentately to the catalytic zinc of the enzyme. The Ala(7) to Pro(10) and Tyr(3) to Ile(1) strands of the inhibitor extend into the nonprime and the prime sides of the cleft, respectively. Therefore, the decapeptide inhibitor has long range contact with the substrate-binding cleft of the protease. This mode of interaction is probably essential for the high MMP-2 selectivity of the inhibitor because MMPs share a common architecture in the vicinity of the catalytic center, but whole structures of their substrate-binding clefts have sufficient variety for the inhibitor to distinguish MMP-2 from other MMPs.

  16. Influence of sildenafil on the anticonvulsant action of selected antiepileptic drugs against pentylenetetrazole-induced clonic seizures in mice.

    Science.gov (United States)

    Nieoczym, Dorota; Socała, Katarzyna; Łuszczki, Jarogniew J; Czuczwar, Stanisław J; Wlaz, Piotr

    2012-08-01

    The aim of the present study was to investigate the effect of sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, on threshold for clonic seizures in mice. In addition, the effects of sildenafil on the anticonvulsant activity of selected antiepileptic drugs (AEDs), i.e., clonazepam (CZP), valproate (VPA), phenobarbital (PB), ethosuximide (ETS) and tiagabine (TGB), were also evaluated. The subcutaneous pentylenetetrazole (PTZ) test was used to determine the effects of sildenafil on convulsive susceptibility and the anticonvulsant activity of the studied AEDs in mice, while the acute side effects of sildenafil and its combinations with the studied AEDs were evaluated in the chimney test, step-through passive-avoidance task and grip-strength test in mice. Total brain concentrations of AEDs were also determined. Sildenafil (5–40 mg/kg) did not influence the threshold for PTZ-induced clonic seizures in mice, but increased the anticonvulsant activity of ETS in this test without any significant changes in the total brain concentration. The activity of the remaining AEDs was not significantly changed by sildenafil. Neither sildenafil alone nor its combinations with the studied AEDs produced any changes in the motor coordination, long-term memory and muscular strength in mice. Co-administration of sildenafil with ETS in male epileptic patients with co-existing erectile dysfunctions might lead to the pharmacodynamic interactions that may be beneficial for the patients. Combinations of sildenafil with CZP, VPA, PB and TGB appear to be neutral in terms of their influence on seizures.

  17. Endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Mandrup, Karen

    BACKGROUND: Endocrine disrupting chemicals (EDCs) may contribute to reproductive changes in boys in the Western world, however, less is known about influence of EDCs in women. The incidence of precocious breast development is increasing in USA and Europe and mammary gland development has been...... suggested as particularly sensitive to endocrine disruption. Mammary gland examination in toxicological studies may be useful for improving knowledge on possible influences of EDCs on human mammary glands and also be useful for detection of endocrine disrupting effects of chemicals as part of safety testing...... and genistein, a mixture of phytoestrogens, and a mixture of environmentally relevant estrogenic EDCs of various origins. Moreover, mixtures of antiandrogenic chemicals were investigated. These include a mixture of pesticides and a mixture of environmentally relevant anti-androgenic EDCs of various origins...

  18. The disruption management model.

    Science.gov (United States)

    McAlister, James

    2011-10-01

    Within all organisations, business continuity disruptions present a set of dilemmas that managers may not have dealt with before in their normal daily duties. The disruption management model provides a simple but effective management tool to enable crisis management teams to stay focused on recovery in the midst of a business continuity incident. The model has four chronological primary headlines, which steer the team through a quick-time crisis decision-making process. The procedure facilitates timely, systematic, rationalised and justified decisions, which can withstand post-event scrutiny. The disruption management model has been thoroughly tested within an emergency services environment and is proven to significantly support clear and concise decision making in a business continuity context.

  19. Search and Disrupt

    DEFF Research Database (Denmark)

    Ørding Olsen, Anders

    Extant research on external knowledge search and open innovation assumes that collaborators are aligned in their strategic interests towards solving innovation problems. However, disruptive innovation is known to threaten the competitive advantage of incumbent firms, thereby creating a potential...... conflict of interest between these firms and their collaborators. This paper explores the extent to which strategic interests influence joint problem solving in both complementary and disruptive technologies by analyzing the effects of incumbent collaboration. The analysis disentangles inability...... and strategic intent to find that non-incumbents experience suppression of problem solving likelihood within disruptive technologies when incumbent collaborators are not strategically committed. The paper contributes to extant theory by showing the influence of firms’ underlying strategic interests...

  20. Emerging and Disruptive Technologies

    Science.gov (United States)

    2016-01-01

    Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home testing formats), new types of specimens (e.g., cell free DNA), big biology/data (e.g., million genome projects), and new regulations (e.g., for laboratory developed tests). In addition, there are many emerging technologies (e.g., planar arrays, mass spectrometry) that might find even broader application in the future and therefore also disrupt current practice. One interesting source of disruptive technology may prove to be the Qualcomm Tricorder XPrize, currently in its final stages. PMID:27683538

  1. Changing circumstances, disrupting habits.

    Science.gov (United States)

    Wood, Wendy; Witt, Melissa Guerrero; Tam, Leona

    2005-06-01

    The present research investigated the mechanisms guiding habitual behavior, specifically, the stimulus cues that trigger habit performance. When usual contexts for performance change, habits cannot be cued by recurring stimuli, and performance should be disrupted. Thus, the exercising, newspaper reading, and TV watching habits of students transferring to a new university were found to survive the transfer only when aspects of the performance context did not change (e.g., participants continued to read the paper with others). In some cases, the disruption in habits also placed behavior under intentional control so that participants acted on their current intentions. Changes in circumstances also affected the favorability of intentions, but changes in intentions alone could not explain the disruption of habits. Furthermore, regardless of whether contexts changed, nonhabitual behavior was guided by intentions.

  2. Emerging and Disruptive Technologies.

    Science.gov (United States)

    Kricka, Larry J

    2016-08-01

    Several emerging or disruptive technologies can be identified that might, at some point in the future, displace established laboratory medicine technologies and practices. These include increased automation in the form of robots, 3-D printing, technology convergence (e.g., plug-in glucose meters for smart phones), new point-of-care technologies (e.g., contact lenses with sensors, digital and wireless enabled pregnancy tests) and testing locations (e.g., Retail Health Clinics, new at-home testing formats), new types of specimens (e.g., cell free DNA), big biology/data (e.g., million genome projects), and new regulations (e.g., for laboratory developed tests). In addition, there are many emerging technologies (e.g., planar arrays, mass spectrometry) that might find even broader application in the future and therefore also disrupt current practice. One interesting source of disruptive technology may prove to be the Qualcomm Tricorder XPrize, currently in its final stages.

  3. Interruptions disrupt reading comprehension.

    Science.gov (United States)

    Foroughi, Cyrus K; Werner, Nicole E; Barragán, Daniela; Boehm-Davis, Deborah A

    2015-06-01

    Previous research suggests that being interrupted while reading a text does not disrupt the later recognition or recall of information from that text. This research is used as support for Ericsson and Kintsch's (1995) long-term working memory (LT-WM) theory, which posits that disruptions while reading (e.g., interruptions) do not impair subsequent text comprehension. However, to fully comprehend a text, individuals may need to do more than recognize or recall information that has been presented in the text at a later time. Reading comprehension often requires individuals to connect and synthesize information across a text (e.g., successfully identifying complex topics such as themes and tones) and not just make a familiarity-based decision (i.e., recognition). The goal for this study was to determine whether interruptions while reading disrupt reading comprehension when the questions assessing comprehension require participants to connect and synthesize information across the passage. In Experiment 1, interruptions disrupted reading comprehension. In Experiment 2, interruptions disrupted reading comprehension but not recognition of information from the text. In Experiment 3, the addition of a 15-s time-out prior to the interruption successfully removed these negative effects. These data suggest that the time it takes to process the information needed to successfully comprehend text when reading is greater than that required for recognition. Any interference (e.g., an interruption) that occurs during the comprehension process may disrupt reading comprehension. This evidence supports the need for transient activation of information in working memory for successful text comprehension and does not support LT-WM theory. (c) 2015 APA, all rights reserved).

  4. The depolarizing action of 5-hydroxytryptamine on rabbit vagal primary afferent and sympathetic neurones and its selective blockade by MDL 72222.

    Science.gov (United States)

    Azami, J; Fozard, J R; Round, A A; Wallis, D I

    1985-02-01

    MDL 72222 (1 alpha H,3 alpha,5 alpha H-tropan-3-yl-3,5-dichlorobenzoate) is a novel compound with potent and selective blocking actions at certain excitatory 5-hydroxytryptamine (5-HT) receptors on mammalian peripheral neurones. In the present study, the sucrose-gap technique has been used to record depolarizing responses to 5-HT from the cells of the rabbit nodose and superior cervical ganglia and to investigate the potency and selectivity of MDL 72222 as an antagonist of these responses. On nodose ganglia, responses to 5-HT were inhibited surmountably by MDL 72222 at concentrations up to 100 nmol/l. The threshold for antagonism was 2-10 nmol/l and the apparent pA2 value (Schild 1947) was 7.7 +/- 0.2, n = 10. Blockade was selective since responses to GABA and noradrenaline were unaffected by MDL 72222, 100 nmol/l. With concentrations of MDL 72222 higher than 100 nmol/l, antagonism was concentration-related but not in a manner consistent with simple competitive antagonism and even a concentration of 1 mumol/l failed to abolish the response to 5-HT. The results from the superior cervical ganglion were essentially similar to those obtained from the nodose ganglion. The threshold concentration of MDL 72222 for inhibition of 5-HT was 1-10 nmol/l and blockade was selective in that depolarizing responses to dimethylphenyl-piperazinium (DMPP) was unaffected by a concentration of MDL 72222 of 1 mumol/l. The data provide direct evidence that MDL 72222 is a potent and selective antagonist of the receptors for 5-HT which mediate depolarizing responses in vagal primary afferent cell bodies and in sympathetic ganglion cells.

  5. Diversity in the glucose transporter-4 gene (SLC2A4 in humans reflects the action of natural selection along the old-world primates evolution.

    Directory of Open Access Journals (Sweden)

    Eduardo Tarazona-Santos

    Full Text Available BACKGROUND: Glucose is an important source of energy for living organisms. In vertebrates it is ingested with the diet and transported into the cells by conserved mechanisms and molecules, such as the trans-membrane Glucose Transporters (GLUTs. Members of this family have tissue specific expression, biochemical properties and physiologic functions that together regulate glucose levels and distribution. GLUT4 -coded by SLC2A4 (17p13 is an insulin-sensitive transporter with a critical role in glucose homeostasis and diabetes pathogenesis, preferentially expressed in the adipose tissue, heart muscle and skeletal muscle. We tested the hypothesis that natural selection acted on SLC2A4. METHODOLOGY/PRINCIPAL FINDINGS: We re-sequenced SLC2A4 and genotyped 104 SNPs along a approximately 1 Mb region flanking this gene in 102 ethnically diverse individuals. Across the studied populations (African, European, Asian and Latin-American, all the eight common SNPs are concentrated in the N-terminal region upstream of exon 7 ( approximately 3700 bp, while the C-terminal region downstream of intron 6 ( approximately 2600 bp harbors only 6 singletons, a pattern that is not compatible with neutrality for this part of the gene. Tests of neutrality based on comparative genomics suggest that: (1 episodes of natural selection (likely a selective sweep predating the coalescent of human lineages, within the last 25 million years, account for the observed reduced diversity downstream of intron 6 and, (2 the target of natural selection may not be in the SLC2A4 coding sequence. CONCLUSIONS: We propose that the contrast in the pattern of genetic variation between the N-terminal and C-terminal regions are signatures of the action of natural selection and thus follow-up studies should investigate the functional importance of different regions of the SLC2A4 gene.

  6. Joint action of ultrasonic and Fe³⁺ to improve selectivity of acid hydrolysis for microcrystalline cellulose.

    Science.gov (United States)

    Li, Jinbao; Qiang, Dandan; Zhang, Meiyun; Xiu, Huijuan; Zhang, Xiangrong

    2015-09-20

    In this study, the combination of Fe(3+)/HCl and ultrasonic treatment was applied to selectively hydrolyze cellulose for the preparation of microcrystalline cellulose (MCC). It was found that the crystallinity and specific surface area of hydrocellulose samples were higher (78.92% and 2.23581 m(2)g(-1), respectively), compared with the method that only used Fe(3+)/HCl catalyst without ultrasonic treatment. Meanwhile, the hydrolysate can be extracted and reused for cellulose hydrolysis for three runs, which was effective in saving the dosage of chemicals and reducing the pollution of the environment without affecting the properties of hydrocellulose. Moreover, the increased concentration of total reducing sugar (TRS) after three runs may be used as a valuable source in biofuels production. The technology of cellulose hydrolysis, by retaining the crystalline region for MCC products while promoting hydrolysis of amorphous region for further utilization is of great novelty, which may prove valuable in converting biomass into chemicals and biofuels, environmentally and economically. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. The antimicrobial polymer PHMB enters cells and selectively condenses bacterial chromosomes

    DEFF Research Database (Denmark)

    Chindera, Kantaraja; Mahato, Manohar; Sharma, Ashwani Kumar;

    2016-01-01

    To combat infection and antimicrobial resistance, it is helpful to elucidate drug mechanism(s) of action. Here we examined how the widely used antimicrobial polyhexamethylene biguanide (PHMB) kills bacteria selectively over host cells. Contrary to the accepted model of microbial membrane disruption...

  8. Selective inhibition of MAO-A activity results in an antidepressant-like action of 2-benzoyl 4-iodoselenophene in mice.

    Science.gov (United States)

    Velasquez, Daniela; Quines, Caroline; Pistóia, Renan; Zeni, Gilson; Nogueira, Cristina W

    2017-03-01

    Depression is a leading cause of disability worldwide. For this reason, the aim of this study was to investigate the possible antidepressant-like activity of 2-benzoyl-4-iodoselenophene (C17H11IOSe), a selenophene compound, in two well-consolidated behavioral assays for screening antidepressant activity (forced swimming test and tail suspension test) in mice. In order to investigate the mechanism of action of C17H11IOSe, it was investigated the activities of cerebral enzymes: monoamine oxidase MAO A and B and Na(+), K(+) ATPase, and if an inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA) (100mg/kg) blocks the antidepressant-like effect of C17H11IOSe. Swiss mice received (C17H11IOSe) (5-50mg/kg) or canola oil by the intragastric (i.g.) route before behavioral tests. The results showed that C17H11IOSe at dose range of 5-50mg/kg decreased immobility time in the tail suspension test. In the forced swimming test, C17H11IOSe reduced the immobility time at the doses of 10 and 50mg/kg. C17H11IOSe differently affected the cerebral cortical Na(+), K(+) ATPase; the effects on this enzyme were dependent of the dose tested. At a dose of 10mg/kg, the compound increased Na(+), K(+) ATPase activity, while the activity was inhibited at a dose of 50mg/kg. pCPA blocked the antidepressant-like action of C17H11IOSe in mice. Therefore, C17H11IOSe (5-50mg/kg) selectively inhibited MAO-A activity in cerebral cortices of mice. The modulation of serotonergic system contributed to the antidepressant-like action of C17H11IOSe in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. In Vitro Antibacterial Mechanism of Action of Crude Garlic (Allium sativum) Clove Extract on Selected Probiotic Bifidobacterium Species as Revealed by SEM, TEM, and SDS-PAGE Analysis.

    Science.gov (United States)

    Booyens, J; Labuschagne, M C; Thantsha, M S

    2014-06-01

    There has been much research on the effects of garlic (Allium sativum) on numerous pathogens, but very few, if any, studies on its effect on beneficial, probiotic bifidobacteria. We have recently shown that garlic exhibits antibacterial activity against bifidobacteria. The mechanism by which garlic kills bifidobacteria is yet to be elucidated. This study sought to determine the mechanism of action of garlic clove extract on selected Bifidobacterium species using scanning and transmission electron microscopy and SDS-PAGE analysis. SEM micrographs revealed unusual morphological changes such as cell elongation, cocci-shaped cells with cross-walls, and distorted cells with bulbous ends. With TEM, observed changes included among others, condensation of cytoplasmic material, disintegration of membranes, and loss of structural integrity. SDS-PAGE analysis did not reveal any differences in whole-cell protein profiles of untreated and garlic clove extract-treated cells. The current study is the first to reveal the mechanism of action of garlic clove extract on probiotic Bifidobacterium species. The results indicate that garlic affects these beneficial bacteria in a manner similar to that exhibited in pathogens. These results therefore further highlight that caution should be taken especially when using raw garlic and probiotic bifidobacteria simultaneously as viability of these bacteria could be reduced by allicin released upon crushing of garlic cloves, thereby limiting the health benefits that the consumer anticipate to gain from probiotics.

  10. The depolarizing action of 5-hydroxytryptamine on rabbit vagal afferent and sympathetic neurones in vitro and its selective blockade by ICS 205-930.

    Science.gov (United States)

    Round, A; Wallis, D I

    1986-06-01

    Depolarizing responses to 5-hydroxytryptamine (5-HT) were recorded from rabbit nodose (NG) and superior cervical (SCG) ganglia using the sucrose-gap technique. The antagonist potency and selectivity of ICS 205-930 ([3 alpha-tropanyl]-1H-indole-3-carboxylic acid ester) were investigated. In NG, 5-HT (5 to 80 nmol) evoked depolarizations of graded amplitude. The ED50 was 18.2 (10.9-30.5) nmol (geometric mean, 95% confidence limits). Responses were blocked surmountably by ICS 205-930, 10(-11) and 10(-10) M, the threshold for blockade being below 10(-11) M. Parallel, rightward shifts in dose-response curves were seen with these concentrations of antagonist, but at higher concentrations (10(-9) and 10(-8) M) there was a further rightward shift with reduction in slope and maximum of the curves. In SCG, where 5-HT (20 to 320 nmol) evoked depolarizations of graded amplitude and the ED50 was 55.8 (22.3-139.6) nmol (geometric mean, 95% confidence limits), ICS 205-930 had a similar inhibitory effect to that observed in NG. The apparent pA2 values for the surmountable blockade produced by ICS 205-930 at concentrations of 10(-11) and 10(-10) M were 10.2 +/- 0.2 for NG and 10.4 +/- 0.1 for SCG (means +/- s.e. mean). ICS 205-930 was selective in its action since it had no effect on dimethylphenylpiperazinium (DMPP) responses in either ganglion or on GABA responses in NG. This study provides quantitative evidence on the blocking action of ICS 205-930 at neuronal 5-HT receptors using a technique that allows the depolarizing responses evoked by the amine to be directly recorded.

  11. An overview of nomegestrol acetate selective receptor binding and lack of estrogenic action on hormone-dependent cancer cells.

    Science.gov (United States)

    Shields-Botella, J; Duc, I; Duranti, E; Puccio, F; Bonnet, P; Delansorne, R; Paris, J

    2003-11-01

    receptor selectivity compared to MPA or some other synthetic progestins. It may provide a better pharmacological profile than those progestins currently in use in HRT and OC.

  12. Spatiotemporal variations in estrogenicity, hormones, and endocrine-disrupting compounds in influents and effluents of selected wastewater-treatment plants and receiving streams in New York, 2008-09

    Science.gov (United States)

    Baldigo, Barry P.; Phillips, Patrick J.; Ernst, Anne G.; Gray, James L.; Hemming, Jocelyn D.C.

    2014-01-01

    Endocrine-disrupting compounds (EDCs) in wastewater effluents have been linked to changes in sex ratios, intersex (in males), behavioral modifications, and developmental abnormalities in aquatic organisms. Yet efforts to identify and regulate specific EDCs in complex mixtures are problematic because little is known about the estrogen activity (estrogenicity) levels of many common and emerging contaminants. The potential effects of EDCs on the water quality and health of biota in streams of the New York City water supply is especially worrisome because more than 150 wastewater-treatment plants (WWTPs) are permitted to discharge effluents into surface waters and groundwaters of watersheds that provide potable water to more than 9 million people. In 2008, the U.S. Geological Survey (USGS), the New York State Department of Environmental Conservation (NYSDEC), New York State Department of Health (NYSDOH), and New York City Department of Environmental Protection (NYCDEP) began a pilot study to increase the understanding of estrogenicity and EDCs in effluents and receiving streams mainly in southeastern New York. The primary goals of this study were to document and assess the spatial and temporal variability of estrogenicity levels; the effectiveness of various treatment-plant types to remove estrogenicity; the concentrations of hormones, EDCs, and pharmaceuticals, personal care products (PPCPs); and the relations between estrogenicity and concentrations of hormones, EDCs, and PPCPs. The levels of estrogenicity and selected hormones, non-hormone EDCs, and PPCPs were characterized in samples collected seasonally in effluents from 7 WWTPs, once or twice in effluents from 34 WWTPs, and once in influents to 6 WWTPs. Estrogenicity was quantified, as estradiol equivalents, using both the biological e-screen assay and a chemical model. Results generally show that (1) estrogenicity levels in effluents varied spatially and seasonally, (2) a wide range of known and unknown EDCs

  13. Application of the Disruption Predictor Feature Developer to developing a machine-portable disruption predictor

    Science.gov (United States)

    Parsons, Matthew; Tang, William; Feibush, Eliot

    2016-10-01

    Plasma disruptions pose a major threat to the operation of tokamaks which confine a large amount of stored energy. In order to effectively mitigate this damage it is necessary to predict an oncoming disruption with sufficient warning time to take mitigative action. Machine learning approaches to this problem have shown promise but require further developments to address (1) the need for machine-portable predictors and (2) the availability of multi-dimensional signal inputs. Here we demonstrate progress in these two areas by applying the Disruption Predictor Feature Developer to data from JET and NSTX, and discuss topics of focus for ongoing work in support of ITER. The author is also supported under the Fulbright U.S. Student Program as a graduate student in the department of Nuclear, Plasma and Radiological Engineering at the University of Illinois at Urbana-Champaign.

  14. Search and Disrupt

    OpenAIRE

    Ørding Olsen, Anders

    2015-01-01

    This paper analyzes how external search is affected by strategic interest alignment among knowledge sources. I focus on misalignment arising from the heterogeneous effects of disruptive technologies by analyzing the influence of incumbents on 2,855 non-incumbents? external knowledge search efforts. The efforts most likely to solve innovation problems obtained funding from the European Commission?s 7th Framework Program (2007-2013). The results show that involving incumbents improv...

  15. Heavy Metals Acting as Endocrine Disrupters

    Directory of Open Access Journals (Sweden)

    Bogdan Georgescu

    2011-10-01

    Full Text Available Last years researches focused on several natural and synthetic compounds that may interfere with the major functionsof the endocrine system and were termed endocrine disrupters. Endocrine disrupters are defined as chemicalsubstances with either agonist or antagonist endocrine effects in human and animals. These effects may be achievedby interferences with the biosynthesis or activity of several endogenous hormones. Recently, it was demonstratedthat heavy metals such as cadmium (Cd, arsen (As, mercury (Hg, nickel (Ni, lead (Pb and zinc (Zn may exhibitendocrine-disrupting activity in animal experiments. Emerging evidence of the intimate mechanisms of action ofthese heavy metals is accumulating. It was revealed, for example, that the Zn atom from the Zn fingers of theestrogen receptor can be replaced by several heavy metal molecules such as copper, cobalt, Ni and Cd. By replacingthe Zn atom with Ni or copper, binding of the estrogen receptor to the DNA hormone responsive elements in the cellnucleus is prevented. In both males and females, low-level exposure to Cd interferes with the biological effects ofsteroid hormones in reproductive organs. Arsen has the property to bind to the glucocorticoid receptor thusdisturbing glucocorticoids biological effects. With regard to Hg, this may induce alterations in male and femalefertility, may affect the function of the hypothalamo-pituitary-thyroid axis or the hypothalamo-pituitary-adrenal axis,and disrupt biosynthesis of steroid hormones.

  16. Current concepts in neuroendocrine disruption.

    Science.gov (United States)

    León-Olea, Martha; Martyniuk, Christopher J; Orlando, Edward F; Ottinger, Mary Ann; Rosenfeld, Cheryl S; Wolstenholme, Jennifer T; Trudeau, Vance L

    2014-07-01

    In the last few years, it has become clear that a wide variety of environmental contaminants have specific effects on neuroendocrine systems in fish, amphibians, birds and mammals. While it is beyond the scope of this review to provide a comprehensive examination of all of these neuroendocrine disruptors, we will focus on select representative examples. Organochlorine pesticides bioaccumulate in neuroendocrine areas of the brain that directly regulate GnRH neurons, thereby altering the expression of genes downstream of GnRH signaling. Organochlorine pesticides can also agonize or antagonize hormone receptors, adversely affecting crosstalk between neurotransmitter systems. The impacts of polychlorinated biphenyls are varied and in many cases subtle. This is particularly true for neuroedocrine and behavioral effects of exposure. These effects impact sexual differentiation of the hypothalamic-pituitary-gonadal axis, and other neuroendocrine systems regulating the thyroid, metabolic, and stress axes and their physiological responses. Weakly estrogenic and anti-androgenic pollutants such as bisphenol A, phthalates, phytochemicals, and the fungicide vinclozolin can lead to severe and widespread neuroendocrine disruptions in discrete brain regions, including the hippocampus, amygdala, and hypothalamus, resulting in behavioral changes in a wide range of species. Behavioral features that have been shown to be affected by one or more these chemicals include cognitive deficits, heightened anxiety or anxiety-like, sociosexual, locomotor, and appetitive behaviors. Neuroactive pharmaceuticals are now widely detected in aquatic environments and water supplies through the release of wastewater treatment plant effluents. The antidepressant fluoxetine is one such pharmaceutical neuroendocrine disruptor. Fluoxetine is a selective serotonin reuptake inhibitor that can affect multiple neuroendocrine pathways and behavioral circuits, including disruptive effects on reproduction and

  17. Tracking federal land management: Report No. 3 on federal land management actions impacting geothermal commecialization at selected target prospects in the five Pacific Rim states

    Energy Technology Data Exchange (ETDEWEB)

    1980-05-20

    Generic land management actions affecting geothermal commerializtion in Pacific River states are reviewed. Specific federal land management actions affecting geothermal prospects in California and the Pacific Northwest are described. (MHR)

  18. Differential utilization of nuclear and extranuclear receptor signaling pathways in the actions of estrogens, SERMs, and a tissue-selective estrogen complex (TSEC).

    Science.gov (United States)

    Madak-Erdogan, Zeynep; Gong, Ping; Katzenellenbogen, Benita S

    2016-04-01

    Estrogens act through nuclear and extranuclear initiated pathways involving estrogen receptors (ERs) to regulate gene expression and activate protein kinases. We investigated the involvement of extracellular signal-regulated kinase2 (ERK2) and ERα in the activities of estradiol (E2), conjugated estrogens (CEs), selective estrogen receptor modulators (SERMs), and a Tissue-Selective Estrogen Complex (TSEC), a combination of a SERM and CE that has a blended activity. We found that CE and individual CE components were generally less effective than E2 in ERK2 recruitment to chromatin binding sites of E2-regulated genes. Likewise, CE was much less agonistic than E2 in stimulation of proliferation of ERα-positive breast cancer cells. The SERM bazedoxifene (BZA) fully suppressed proliferation stimulated by E2 or CE and reversed gene stimulation by CE or E2, as did the antiestrogen Faslodex. Thus, the balance of biological activities mediated through nuclear ERα vs. ERK2-mediated activities is different for CE vs. E2, with CE showing lower stimulation of kinase activity. Furthermore, at the BZA to CE concentrations in TSEC, BZA antagonized CE stimulation of gene expression and proliferation programs in ERα-positive breast cancer cells. The studies provide molecular underpinnings of the different ways in which SERMs and estrogens support or antagonize one another in regulating the chromatin binding of ERα and ERK2, and modulating gene and cell activities. They illuminate how the combined actions of two classes of ER ligands (SERM and CE, present in TSEC) can achieve unique modes of regulation and efficacy.

  19. Disruptive Space Technology

    OpenAIRE

    Benson, Jim

    2004-01-01

    In 1997 "The Innovator’s Dilemma" by Clayton M. Christensen became a popular book in the small satellite and launch vehicle communities. But like the weather, every one talks about “Disruptive Technology” but few do anything about it. In the ‘70s and ‘80s, people were looking for “Paradigm Shifts,” and since the resurrection of Donald Rumsfeld, a recent watchword has been “Transformational Technology.” But today’s buzzword is now “Responsive Space Systems.”

  20. Disruption - Access cards service

    CERN Multimedia

    2014-01-01

    We would like to inform you that between 10 November and 15 December 2014, the access cards service in Building 55 will be disrupted, as the GS Department has decided to improve the facilities for users of this building. During the work, you will find the registration, biometric registration and dosimeter exchange services on the second floor of Building 55 and the vehicle sticker service on the ground floor along with the access cards service. We thank you for your understanding and apologise for any inconvenience caused.

  1. Celibacy and Family Disruption

    Directory of Open Access Journals (Sweden)

    Emaletdinov B. M.

    2013-01-01

    Full Text Available Causes for celibacy, divorces and successful marriage are discussed in the article. Absence of true love and inability to build and keep it are the main reasons for family disruption. Amorousness, immature love and various forms of false or flawed love substitute the true feeling. It is caused by increased women’s independence, loss of mutual understanding and trust (due to infidelity or jealousy, incompatibility of characters or values. Celibacy is often conditioned by physical disability, revaluation of freedom and independence, huge requirements to partners, consumer attitude to life, infertility, alcohol and drug abuse, abnormalities in personality and sexuality.

  2. Manuel's asteroid disruption technique.

    Science.gov (United States)

    John, Manuel; Ipe, Abraham; Jacob, Ivan

    2015-06-01

    A seventy-year-old male presented with dense asteroid hyalosis in both eyes. He had undergone cataract extraction in one eye 3 years ago, and the other eye had immature cataract. Both the autorefractor and dilated streak retinoscopy did not give readings and subjective visual improvement could not be achieved. Immediately following YAG posterior capsulotomy and anterior vitreous asteroid disruption, the vision improved to 20/20 with recordable auto refractor and streak retinoscopy values. Our initial experience indicates that the treatment is simple, safe and effective but needs controlled and prospective studies to confirm its long-term safety.

  3. The Cu-CHA deNOx Catalyst in Action: Temperature-Dependent NH3-Assisted Selective Catalytic Reduction Monitored by Operando XAS and XES.

    Science.gov (United States)

    Lomachenko, Kirill A; Borfecchia, Elisa; Negri, Chiara; Berlier, Gloria; Lamberti, Carlo; Beato, Pablo; Falsig, Hanne; Bordiga, Silvia

    2016-09-21

    The small-pore Cu-CHA zeolite is today the object of intensive research efforts to rationalize its outstanding performance in the NH3-assisted selective catalytic reduction (SCR) of harmful nitrogen oxides and to unveil the SCR mechanism. Herein we exploit operando X-ray spectroscopies to monitor the Cu-CHA catalyst in action during NH3-SCR in the 150-400 °C range, targeting Cu oxidation state, mobility, and preferential N or O ligation as a function of reaction temperature. By combining operando XANES, EXAFS, and vtc-XES, we unambiguously identify two distinct regimes for the atomic-scale behavior of Cu active-sites. Low-temperature SCR, up to ∼200 °C, is characterized by balanced populations of Cu(I)/Cu(II) sites and dominated by mobile NH3-solvated Cu-species. From 250 °C upward, in correspondence to the steep increase in catalytic activity, the largely dominant Cu-species are framework-coordinated Cu(II) sites, likely representing the active sites for high-temperature SCR.

  4. Influence of MPEP (a selective mGluR5 antagonist) on the anticonvulsant action of novel antiepileptic drugs against maximal electroshock-induced seizures in mice.

    Science.gov (United States)

    Zolkowska, Dorota; Kondrat-Wrobel, Maria W; Florek-Luszczki, Magdalena; Luszczki, Jarogniew J

    2016-02-04

    The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)pyridine (MPEP - a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Amphibians as model to study endocrine disrupters.

    Science.gov (United States)

    Kloas, Werner; Lutz, Ilka

    2006-10-13

    Environmental compounds can interfere with endocrine systems of wildlife and humans. These so-called endocrine disrupters (ED) are known to affect reproductive biology and thyroid system. The classical model species for these endocrine systems are amphibians and therefore they can serve as sentinels for detection of the modes of action (MOAs) of ED. Recently, amphibians are being reviewed as suitable models to assess (anti)estrogenic and (anti)androgenic MOAs influencing reproductive biology as well as (anti)thyroidal MOAs interfering with the thyroid system. The development of targeted bioassays in combination with adequate chemical analyses is the prerequisite for a concise risk assessment of ED.

  6. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 18. Part 1B: Citations with abstracts, sections 10 through 16

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-09-01

    This bibliography contains 3,638 citations with abstracts of documents relevant to environmental restoration, nuclear facility decontamination and decommissioning (D and D), uranium mill tailings management, and site remedial actions. The bibliography contains scientific, technical, financial, and regulatory information that pertains to DOE environmental restoration programs. The citations are separated by topic into 16 sections, including (1) DOE Environmental Restoration Program; (2) DOE D and D Program; (3) Nuclear Facilities Decommissioning; (4) DOE Formerly Utilized sites Remedial Action Program; (5) NORM-Contaminated Site Restoration; (6) DOE Uranium Mill Tailings Remedial Action Project; (7) Uranium Mill Tailings Management; (8) DOE Site-Wide Remedial Actions; (9) DOE Onsite Remedial Action Projects; (10) Contaminated Site Remedial Actions; (11) DOE Underground Storage Tank Remediation; (12) DOE Technology Development, Demonstration, and Evaluation; (13) Soil Remediation; (14) Groundwater Remediation; (15) Environmental Measurements, Analysis, and Decision-Making; and (16) Environmental Management Issues.

  7. Nuclear facility decommissioning and site remedial actions: A selected bibliography, Volume 18. Part 1A: Citations with abstracts, sections 1 through 9

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-09-01

    This bibliography contains 3,638 citations with abstracts of documents relevant to environmental restoration, nuclear facility decontamination and decommissioning (D and D), uranium mill tailings management, and site remedial actions. The bibliography contains scientific, technical, financial, and regulatory information that pertains to DOE environmental restoration programs. The citations are separated by topic into 16 sections, including (1) DOE Environmental Restoration program; (2) DOE D and D Program; (3) Nuclear Facilities Decommissioning; (4) DOE Formerly Utilized Sites Remedial Action Program; (5) NORM-Contaminated Site Restoration; (6) DOE Uranium Mill Tailings Remedial Action Project; (7) Uranium Mill Tailings Management; (8) DOE Site-Wide Remedial Actions; (9) DOE Onsite Remedial Action Projects; (10) Contaminated Site Remedial Actions; (11) DOE Underground Storage Tank Remediation; (12) DOE Technology Development, Demonstration, and Evaluation; (13) Soil Remediation; (14) Groundwater Remediation; (15) Environmental Measurements, Analysis, and Decision-Making; and (16) Environmental Management Issues.

  8. Cell disruption for microalgae biorefineries.

    Science.gov (United States)

    Günerken, E; D'Hondt, E; Eppink, M H M; Garcia-Gonzalez, L; Elst, K; Wijffels, R H

    2015-01-01

    Microalgae are a potential source for various valuable chemicals for commercial applications ranging from nutraceuticals to fuels. Objective in a biorefinery is to utilize biomass ingredients efficiently similarly to petroleum refineries in which oil is fractionated in fuels and a variety of products with higher value. Downstream processes in microalgae biorefineries consist of different steps whereof cell disruption is the most crucial part. To maintain the functionality of algae biochemicals during cell disruption while obtaining high disruption yields is an important challenge. Despite this need, studies on mild disruption of microalgae cells are limited. This review article focuses on the evaluation of conventional and emerging cell disruption technologies, and a comparison thereof with respect to their potential for the future microalgae biorefineries. The discussed techniques are bead milling, high pressure homogenization, high speed homogenization, ultrasonication, microwave treatment, pulsed electric field treatment, non-mechanical cell disruption and some emerging technologies.

  9. 环境污染对几类水生无脊椎动物内分泌功能扰乱的研究现状%Current status of environmental endocrine disruption in selected aquatic invertebrates

    Institute of Scientific and Technical Information of China (English)

    Enmin ZOU

    2003-01-01

    近年来,在环境毒理学这门边缘学科中又诞生了一个新的领域,即环境污染对内分泌功能的扰乱.研究发现,许多人工合成的杀虫剂和工业化合物能够扰乱脊椎动物的内分泌功能,这些化合物也存在于水环境中.近年来,这些环境有机污染物是否对水生无脊椎动物的内分泌功能同样具有扰乱作用成了环境内分泌学这个新领域的热点之一.由于近年来的研究侧重于腔肠动物、轮虫、软体动物、甲壳动物及棘皮动物,因此,本文主要介绍有关环境污染物对这几类水生无脊椎动物内分泌功能扰乱的研究进展.另外,对环境污染对水生无脊椎动物内分泌扰乱这个研究热点的现状以及今后的发展方向进行了评述.在从事环境污染对无脊椎动物内分泌功能影响的研究时,研究者必须意识到无脊椎动物和脊椎动物在内分泌机制上的差异,不可随意地在这两大类动物类群之间互相引伸研究结果.%Endocrine disruption by environmental contaminants has recently emerged as a new subdiscipline of environmental toxicology. Aquatic environments are increasingly contaminated with various anthropogenic chemicals,many of which are capable of disrupting endocrine functions of vertebrates. Where aquatic invertebrates are concerned, most of the recent reports are concerned with the impact of organic xenobiotics on endocrine functions in cnidarians, rotifers, mollusks, crustaceans and echinoderms. This review provides an overview of the current status of this research on endocrine disruption in these invertebrates. Suggestions for future research directions in the field of invertebrate endocrine disruption are also presented. Because of the disparities between the endocrine systems of invertebrates and vertebrates, care must be exercised in extrapolating to invertebrates, particularly the non-deuterostome invertebrates, the results of endocrine disruption studies with vertebrates

  10. Sustainable Disruption Management

    DEFF Research Database (Denmark)

    Vaaben, Bo Valdemar

    an increasingly expensive resource, and it is being consumed in vast amounts by the transportation industry. The single largest expense for both airlines and shipping companies is fuel, which exceeds both labour costs and capital expenditure. This thesis addresses how fuel considerations can be taken into account...... management fits in to the larger scope of optimization related processes in an airline and provides a brief survey of these. The thesis goes into more detail with disruption management and does as its main contribution describe how this can be combined with flight planning. Flight planning is the calculation...... of the horizontal and vertical flight path, which an aircraft should follow in order to get from airport A to airport B. The objective of this calculation is typically to minimize fuel consumption, while satisfying airspace regulations. To the knowledge of the author the work in this thesis represents the first...

  11. Management Control System Support of Initiatives for Disruptive Students

    Science.gov (United States)

    Scott, Colin

    2011-01-01

    Purpose: The purpose of the paper is to investigate the management control system (MCS) support of school initiatives to develop the school climate and to re-engage disruptive students. Design/methodology/approach: The paper adopts an approach of critical action research interviews with management and document reviews informed by Habermasian…

  12. Management Control System Support of Initiatives for Disruptive Students

    Science.gov (United States)

    Scott, Colin

    2011-01-01

    Purpose: The purpose of the paper is to investigate the management control system (MCS) support of school initiatives to develop the school climate and to re-engage disruptive students. Design/methodology/approach: The paper adopts an approach of critical action research interviews with management and document reviews informed by Habermasian…

  13. The characteristics of railway service disruption: implications for disruption management.

    Science.gov (United States)

    Golightly, D; Dadashi, N

    2017-03-01

    Rail disruption management is central to operational continuity and customer satisfaction. Disruption is not a unitary phenomenon - it varies by time, cause, location and complexity of coordination. Effective, user-centred technology for rail disruption must reflect this variety. A repertory grid study was conducted to elicit disruption characteristics. Construct elicitation with a group of experts (n = 7) captured 26 characteristics relevant to rail disruption. A larger group of operational staff (n = 28) rated 10 types of rail incident against the 26 characteristics. The results revealed distinctions such as business impact and public perception, and the importance of management of the disruption over initial detection. There were clear differences between those events that stop the traffic, as opposed to those that only slow the traffic. The results also demonstrate the utility of repertory grid for capturing the characteristics of complex work domains. Practitioner Summary: The aim of the paper is to understand how variety in rail disruption influences socio-technical design. It uses repertory grid to identify and prioritise 26 constructs, and group 10 disruption types, identifying critical factors such as whether an incident stops or merely slows the service, and business reputation.

  14. Finding minimal action sequences with a simple evaluation of actions

    Directory of Open Access Journals (Sweden)

    Ashvin eShah

    2014-11-01

    Full Text Available Animals are able to discover the minimal number of actions that achieves an outcome (the minimal action sequence. In most accounts of this, actions are associated with a measure of behavior that is higher for actions that lead to the outcome with a shorter action sequence, and learning mechanisms find the actions associated with the highest measure. In this sense, previous accounts focus on more than the simple binary signal of ``was the outcome achieved?''; they focus on ``how well was the outcome achieved?'' However, such mechanisms may not govern all types of behavioral development. In particular, in the process of action discovery (Redgrave and Gurney, 2006, actions are reinforced if they simply lead to a salient outcome because biological reinforcement signals occur too quickly to evaluate the consequences of an action beyond an indication of the outcome's occurrence. Thus, action discovery mechanisms focus on the simple evaluation of ``was the outcome achieved?'' and not ``how well was the outcome achieved?'' Notwithstanding this impoverishment of information, can the process of action discovery find the minimal action sequence? We address this question by implementing computational mechanisms, referred to in this paper as no-cost learning rules, in which each action that leads to the outcome is associated with the same measure of behavior. No-cost rules focus on ``was the outcome achieved?'' and are consistent with action discovery. No-cost rules discover the minimal action sequence in simulated tasks and execute it for a substantial amount of time. Extensive training, however, results in extraneous actions, suggesting that a separate process (which has been proposed in action discovery must attenuate learning if no-cost rules participate in behavioral development. We describe how no-cost rules develop behavior, what happens when attenuation is disrupted, and relate the new mechanisms to wider computational and biological context.

  15. Direct action of endocrine disrupting chemicals on human sperm

    DEFF Research Database (Denmark)

    Schiffer, Christian; Müller, Astrid; Egeberg, Dorte L

    2014-01-01

    sperm. We show that structurally diverse EDCs activate the sperm-specific CatSper channel and, thereby, evoke an intracellular Ca(2+) increase, a motility response, and acrosomal exocytosis. Moreover, EDCs desensitize sperm for physiological CatSper ligands and cooperate in low-dose mixtures to elevate...

  16. Action semantics modulate action prediction.

    Science.gov (United States)

    Springer, Anne; Prinz, Wolfgang

    2010-11-01

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

  17. Action Between Plot and Discourse

    DEFF Research Database (Denmark)

    Grünbaum, Thor

    2007-01-01

    , these narrated actions disrupt the theoretical divisions, on the one hand, between the narrated story and the narrating discourse, and on the other hand, between plot-narratology and discourse-narratology. As narrated actions, they seem to belong to the domain of plot-narratology, but insofar as they serve...... an important visualizing function, these narrated actions have a communicative function and, as such, they can be said to belong to the domain of discourse-narratology. In the first part of the article, I argue that a certain type of plot-narratology, due to its retrospective epistemology and abstract...

  18. Action Between Plot and Discourse

    DEFF Research Database (Denmark)

    Grünbaum, Thor

    2007-01-01

    , these narrated actions disrupt the theoretical divisions, on the one hand, between the narrated story and the narrating discourse, and on the other hand, between plot-narratology and discourse-narratology. As narrated actions, they seem to belong to the domain of plot-narratology, but insofar as they serve...... an important visualizing function, these narrated actions have a communicative function and, as such, they can be said to belong to the domain of discourse-narratology. In the first part of the article, I argue that a certain type of plot-narratology, due to its retrospective epistemology and abstract...

  19. Tidal disruption event demographics

    Science.gov (United States)

    Kochanek, C. S.

    2016-09-01

    We survey the properties of stars destroyed in tidal disruption events (TDEs) as a function of black hole (BH) mass, stellar mass and evolutionary state, star formation history and redshift. For M_{BH} ≲ 10^7 M_{⊙}, the typical TDE is due to a M* ˜ 0.3 M⊙ M-dwarf, although the mass function is relatively flat for M_{ast } ≲ M_{⊙}. The contribution from older main-sequence stars and sub-giants is small but not negligible. From MBH ≃ 107.5-108.5 M⊙, the balance rapidly shifts to higher mass stars and a larger contribution from evolved stars, and is ultimately dominated by evolved stars at higher BH masses. The star formation history has little effect until the rates are dominated by evolved stars. TDE rates should decline very rapidly towards higher redshifts. The volumetric rate of TDEs is very high because the BH mass function diverges for low masses. However, any emission mechanism which is largely Eddington-limited for low BH masses suppresses this divergence in any observed sample and leads to TDE samples dominated by MBH ≃ 106.0-107.5 M⊙ BHs with roughly Eddington peak accretion rates. The typical fall-back time is relatively long, with 16 per cent having tfb plausible if tfb has any relation to the transient rise time. For almost any BH mass function, systematic searches for fainter, faster time-scale TDEs in smaller galaxies, and longer time-scale TDEs in more massive galaxies are likely to be rewarded.

  20. Interception and disruption

    Energy Technology Data Exchange (ETDEWEB)

    Solem, J.C.

    1995-07-01

    Given sufficient warning we might try to avert a collision with a comet or asteroid by using beamed energy or by using the kinetic energy of an interceptor rocket. If motivated by the opportunity to convert the object into a space asset, perhaps a microgravity mine for construction materials or spacecraft fuels, we might try a rendezvous to implant a propulsion system of some sort. But the most cost-effective means of disruption is a nuclear explosive. In this paper, I discuss optimal tactics for terminal intercept, which can be extended to remote-interdiction scenarios as well. I show that the optimal mass ratio of an interceptor rock carrying a nuclear explosive depends mainly on the ratio of the exhaust velocity to the assailant-object closing velocity. I compare the effectiveness of stand-off detonation, surface burst, and penetration, for both deflection and pulverization, concluding that a penetrator has no clear advantage over a surface-burst device for deflection, but is a distinctly more capable pulverizer. The advantage of a stand-off device is to distribute the impulse more evenly over the surface of the object and to prevent fracture, an event which would greatly complicate the intercept problem. Finally, I present some results of a model for gravitationally bound objects and obtain the maximum non-fracturing deflection speed for a variety of object sizes and structures. For a single engagement, I conclude that the non-fracturing deflection speed obtainable with a stand-off device is about four times the speed obtainable with a surface-burst device. Furthermore, the non-fracturing deflection speed is somewhat dependent on the number of competent components of the object, the speed for a 13 component object being about twice that for a 135 component object.

  1. Methods for the Determination of Endocrine-Disrupting Phthalate Esters.

    Science.gov (United States)

    Qureshi, Munawar Saeed; Yusoff, Abdull Rahim bin Mohd; Wirzal, Mohd Dzul Hakim; Sirajuddin; Barek, Jiri; Afridi, Hassan Imran; Üstündag, Zafer

    2016-01-01

    Phthalates are endocrine disruptors frequently occurring in the general and industrial environment and in many industrial products. Moreover, they are also suspected of being carcinogenic, teratogenic, and mutagenic, and they show diverse toxicity profiles depending on their structures. The European Union and the United States Environmental Protection Agency (US EPA) have included many phthalates in the list of priority substances with potential endocrine-disrupting action. They are: dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), butylbenzyl phthalate (BBP), diethylhexyl phthalate (DEHP), di-iso-nonyl phthalate (DINP), di-iso-decyl phthalate (DIDP), di-n-decyl phthalate (DnDP), and dioctyl phthalate (DOP). There is an ever-increasing demand for new analytical methods suitable for monitoring different phthalates in various environmental, biological, and other matrices. Separation and spectrometric methods are most frequently used. However, modern electroanalytical methods can also play a useful role in this field because of their high sensitivity, reasonable selectivity, easy automation, and miniaturization, and especially low investment and running costs, which makes them suitable for large-scale monitoring. Therefore, this review outlines possibilities and limitations of various analytical methods for determination of endocrine-disruptor phthalate esters in various matrices, including somewhat neglected electroanalytical methods.

  2. All in Action

    Directory of Open Access Journals (Sweden)

    Arto Annila

    2010-11-01

    Full Text Available The principle of least action provides a holistic worldview in which Nature in its entirety and every detail is described in terms of actions. Each and every action is ultimately composed of one or multiple of the most elementary actions which relates to Planck’s constant. Elements of space are closed actions, known as fermions, whereas elements of time are open actions, known as bosons. The actions span an energy landscape, the Universe, which evolves irreversibly according to the 2nd law of thermodynamics by diminishing energy density differences in least time. During evolution densely-curled actions unfold step-by-step when opening up and expelling one or multiple elementary actions to their surrounding sparser space. The energy landscape will process from one symmetry group to another until the equivalence to its dual, i.e., the surrounding density has been attained. The scale-free physical portrayal of nature in terms of actions does not recognize any fundamental difference between fundamental particles and fundamental forces. Instead a plethora of particles and a diaspora of forces are perceived merely as diverse manifestations of a natural selection for various mechanisms and ways to decrease free energy in the least time.

  3. Simulating Impacts of Disruptions to Liquid Fuels Infrastructure

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Michael [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Resilience and Regulatory Effects; Corbet, Thomas F. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Policy and Decision Analytics; Baker, Arnold B. [ABB Consulting, Albuquerque, NM (United States); O' Rourke, Julia M. [Univ. of Texas, Austin, TX (United States). Dept. of Mechanical Engineering

    2015-04-01

    This report presents a methodology for estimating the impacts of events that damage or disrupt liquid fuels infrastructure. The impact of a disruption depends on which components of the infrastructure are damaged, the time required for repairs, and the position of the disrupted components in the fuels supply network. Impacts are estimated for seven stressing events in regions of the United States, which were selected to represent a range of disruption types. For most of these events the analysis is carried out using the National Transportation Fuels Model (NTFM) to simulate the system-level liquid fuels sector response. Results are presented for each event, and a brief cross comparison of event simulation results is provided.

  4. Disrupted Stars in Unusual Galaxies

    Science.gov (United States)

    Kohler, Susanna

    2016-03-01

    Tidal disruption events (TDEs) occur when a star passes a little too close to a supermassive black hole at the center of a galaxy. Tidal forces from the black hole cause the passing star to be torn apart, resulting in a brief flare of radiation as the stars material accretes onto the black hole. A recent study asks the following question: do TDEs occur most frequently in an unusual type of galaxy?A Trend in DisruptionsSo far, we have data from eight candidate TDEs that peaked in optical and ultraviolet wavelengths. The spectra from these observations have shown an intriguing trend: many of these TDEs host galaxies exhibit weak line emission (indicating little or no current star-formation activity), and yet they show strong Balmer absorption lines (indicating star formation activity occurred within the last Gyr). These quiescent, Balmer-strong galaxies likely underwent a period of intense star formation that recently ended.To determine if TDEs are overrepresented in such galaxies, a team of scientists led by Decker French (Steward Observatory, University of Arizona) has quantified the fraction of galaxies in the Sloan Digital Sky Survey (SDSS) that exhibit similar properties to those of TDE hosts.Quantifying OverrepresentationSpectral characteristics of SDSS galaxies (gray) and TDE candidate host galaxies (colored points): line emission vs. Balmer absorption. The lower right-hand box identifies thequiescent, Balmer-strong galaxies which contain most TDE events, yet are uncommon among the galaxy sample as a whole. Click for a better look! [French et al. 2016]French and collaborators compare the optical spectra of the TDE host galaxies to those of nearly 600,000 SDSS galaxies, using two different cutoffs for the Balmer absorption the indicator of past star formation. Their strictest cut, filtering for very high Balmer absorption, selected only 0.2% of the SDSS galaxies, yet 38% of the TDEs are hosted in such galaxies. Using a more relaxed cutoff selects 2.3% of

  5. Tidal disruption of inviscid protoplanets

    Science.gov (United States)

    Boss, Alan P.; Cameron, A. G. W.; Benz, W.

    1991-01-01

    Roche showed that equilibrium is impossible for a small fluid body synchronously orbiting a primary within a critical radius now termed the Roche limit. Tidal disruption of orbitally unbound bodies is a potentially important process for planetary formation through collisional accumulation, because the area of the Roche limit is considerably larger then the physical cross section of a protoplanet. Several previous studies were made of dynamical tidal disruption and different models of disruption were proposed. Because of the limitation of these analytical models, we have used a smoothed particle hydrodynamics (SPH) code to model the tidal disruption process. The code is basically the same as the one used to model giant impacts; we simply choose impact parameters large enough to avoid collisions. The primary and secondary both have iron cores and silicate mantles, and are initially isothermal at a molten temperature. The conclusions based on the analytical and numerical models are summarized.

  6. Vortex disruption by magnetohydrodynamic feedback

    CERN Document Server

    Mak, Julian; Hughes, D W

    2016-01-01

    In an electrically conducting fluid, vortices stretch out a weak, large-scale magnetic field to form strong current sheets on their edges. Associated with these current sheets are magnetic stresses, which are subsequently released through reconnection, leading to vortex disruption, and possibly even destruction. This disruption phenomenon is investigated here in the context of two-dimensional, homogeneous, incompressible magnetohydrodynamics. We derive a simple order of magnitude estimate for the magnetic stresses --- and thus the degree of disruption --- that depends on the strength of the background magnetic field (measured by the parameter $M$, a ratio between the Alfv\\'en speed and a typical flow speed) and on the magnetic diffusivity (measured by the magnetic Reynolds number $\\mbox{Rm}$). The resulting estimate suggests that significant disruption occurs when $M^{2}\\mbox{Rm} = O(1)$. To test our prediction, we analyse direct numerical simulations of vortices generated by the breakup of unstable shear flo...

  7. Ultrasonic disruption of algae cells

    Science.gov (United States)

    King, P. M.; Nowotarski, K.; Joyce, E. M.; Mason, T. J.

    2012-05-01

    During last decade there has been increasing interest in the production of sustainable fuels from microalgae (R.H. Wijffels and M.J. Barbosa, 2010; Singh et al 2011; D.H. Lee 2011). The aim of this project was to determine if algal cells can be ultrasonically disrupted to release lipids for biofuel production. Ultrasonic disruption of two unicellular algal species: Dunnaliella salina and Nannochloropsis oculata was investigated using a 20 kHz probe. Haemocytometer, optical density, UV-Vis, fluoro-spectrophotometer and confocal microscopy results demonstrated complete cell destruction of Dunaliella salina within 16 minutes of sonication. Results obtained for Nannochloropsis oculata differed in that ultrasound dispersed clumped cells with little or no cell disruption, as observed by haemocytometer and confocal microscopy analysis. However, UV-Visible and fluoro-spectrophotometer analysis indicated chlorophyll release following sonication, suggesting some cell disruption had occurred.

  8. Neurotoxicity of Thyroid Disrupting Contaminants

    Science.gov (United States)

    Thyroid hormones playa critical role in the normal development ofthe mammalian brain. Thyroid disrupting chemicals (TDCs) are environmental contaminants that alter the structure or function ofthe thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeost...

  9. Persistent forecasting of disruptive technologies

    National Research Council Canada - National Science Library

    Committee on Forecasting Future Disruptive Technologies; National Research Council

    ...) and the Defense Intelligence Agency (DIA) tasked the Committee for Forecasting Future Disruptive Technologies with providing guidance and insight on how to build a persistent forecasting system to predict, analyze, and reduce the impact...

  10. Testing a participatory integrated assessment(PIA) approach to select climate change adaptation actions to enhance wetland sustainability: The case of Poyang Lake region in China

    Institute of Scientific and Technical Information of China (English)

    HUANG; Li; YIN; Yongyuan; DU; De-Bin

    2015-01-01

    The necessity of mainstreaming climate adaptation strategies or policies into natural resource management plans has been recognized by the UNFCCC.The IPCC AR5 report suggests a growing demand for research to provide information for a deeper and more useful understanding of climate adaptation options,and indicates a lack of effective methods to meet this increasing demand of policymakers.In this respect,a participatory integrated assessment(PIA) approach is presented in this paper to provide an effective means to mainstream wetland climate change adaptation in rural sustainable development strategies,and thus to reduce climate vulnerability and to enhance rural community livelihood.The PIA approach includes a series of research activities required to assess climate impacts on wetland ecosystems,and to prioritize adaptation responses.A range of adaptation options that address key aspects of the wetland ecosystem resilience and concerns are evaluated against community based on sustainable development indicators.The PIA approach is able to identify desirable adaptation options which can then be implemented to improve wetland ecosystem health and to enhance regional sustainable development in a changing climate.For illustration purpose,the PIA was applied in a case study in Poyang Lake(PYL) region,a critical wetland and water ecosystem in central China with important international biodiversity linkages,and a locale for key policy experiments with ecosystem rehabilitation.The PIA was used to facilitate the integration of wetland climate change adaptation in rural sustainable development actions with multi-stakeholders participation.In particular,the case shows how the PIA can be designed and implemented to select effective and practical climate change adaptation options to enhance ecosystem services management and to reduce resource use conflicts and rural poverty.Worked in partnership with multi-stakeholders and assisted with a multi-criteria decision making tool

  11. Disruptive innovation: the demand side.

    Science.gov (United States)

    Havighurst, Clark C

    2008-01-01

    The notion of disruptive innovation provides a welcome framework for considering the prospects for low-cost alternatives in American medicine. Such innovations as have been seen, however, are largely the result of demand by patients paying their own bills because they have high-deductible coverage or are uninsured. Many other cost-saving innovations are discouraged by financing systems that are themselves largely immune to competition from disruptive innovators.

  12. Remedial action plan for the inactive uranium processing site at Naturita, Colorado. Remedial action selection report: Attachment 2, geology report; Attachment 3, ground water hydrology report; Attachment 4, supplemental information

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-03-01

    The uranium processing site near Naturita, Colorado, is one of 24 inactive uranium mill sites designated to be cleaned up by the U.S. Department of Energy (DOE) under the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA), 42 USC {section} 7901 et seq. Part of the UMTRCA requires that the U.S. Nuclear Regulatory Commission (NRC) concur with the DOE`s remedial action plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the U.S. Environmental Protection Agency (EPA). This RAP serves two purposes. First, it describes the activities that are proposed by the DOE to accomplish remediation and long-term stabilization and control of the radioactive materials at the inactive uranium processing site near Naturita, Colorado. Second, this RAP, upon concurrence and execution by the DOE, the state of Colorado, and the NRC, becomes Appendix B of the cooperative agreement between the DOE and the state of Colorado.

  13. Transient disruption of non-homologous end-joining facilitates targeted genome manipulations in the filamentous fungus Aspergillus nidulans

    DEFF Research Database (Denmark)

    Nielsen, Jakob Blæsbjerg; Nielsen, Michael Lynge; Mortensen, Uffe Hasbro

    2008-01-01

    We have developed a transiently disrupted nkuA system in Aspergillus nidulans for efficient gene targeting. The nkuA disruption was made by inserting a counter-selectable marker flanked by a direct repeat (DR) composed of nkuA sequences. In the disrupted state, the non-homologous end-joining (NHE...

  14. Development of Object Control in the First Year: Emerging Category Discrimination and Generalization in Infants' Adaptive Selection of Action

    Science.gov (United States)

    Mash, Clay; Bornstein, Marc H.; Banerjee, Abhilasha

    2014-01-01

    This research examined the development of adaptive generalization in infants' object-directed actions. Infants ages 9 and 12 months participated in an object manipulation task with stimulus objects from 2 categories that differed in shape and weight and that bore a consistent shape or weight correspondence. Weight differences between…

  15. Action physics

    Science.gov (United States)

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

    2016-09-01

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

  16. Complementary Actions

    Directory of Open Access Journals (Sweden)

    Luisa eSartori

    2015-05-01

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

  17. Endocrine disrupting properties in vivo of widely used azole fungicides

    DEFF Research Database (Denmark)

    Taxvig, Camilla; Vinggaard, Anne; Hass, Ulla

    2008-01-01

    The endocrine-disrupting potential of four commonly used azole fungicides, propiconazole, tebuconazole, epoxiconazole and ketoconazole, were tested in two short-term in vivo studies. Initially, the antiandrogenic effects of propiconazole and tebuconazole (50, 100 and 150 mg/kg body weight/day eac...... as endocrine disruptors in vivo, although the profile of action in vivo varies. As ketoconazole is known to implicate numerous endocrine-disrupting effects in humans, the concern for the effects of the other tested azole fungicides in humans is growing.......The endocrine-disrupting potential of four commonly used azole fungicides, propiconazole, tebuconazole, epoxiconazole and ketoconazole, were tested in two short-term in vivo studies. Initially, the antiandrogenic effects of propiconazole and tebuconazole (50, 100 and 150 mg/kg body weight/day each...

  18. Reversibility of endocrine disruption in zebrafish (Danio rerio) - comparison of different effect levels

    DEFF Research Database (Denmark)

    Baumann, Lisa; Holbech, Henrik; Schiller, V.S.;

    -term effects on populations, it is essential to know whether such EDC-related effects are reversible. Three different substances selected for different modes of action were tested for their long-term impact on sex ratio, gonadal development, vitellogenin (VTG) induction and aromatase activity in zebrafish...... to estrogens. All compounds have previously been shown to cause striking effects in zebrafish, but recovery has never been studied in detail. In order to test whether EDC-related effects are reversible, an exposure scenario limited to 60 d was followed by (a) a recovery period of 40 d or (b) continued exposure...... of effects at all levels, but clear-cut differences between the two different exposure groups. We conclude that endocrine disruption in zebrafish following discontinuous exposure is only partially reversible and may thus have serious implications for fish....

  19. Endocrine disrupting effects in rats perinatally exposed to a dietary relevant mixture of phytoestrogens.

    Science.gov (United States)

    Boberg, Julie; Mandrup, Karen Riiber; Jacobsen, Pernille Rosenskjold; Isling, Louise Krag; Hadrup, Niels; Berthelsen, Line; Elleby, Anders; Kiersgaard, Maria; Vinggaard, Anne Marie; Hass, Ulla; Nellemann, Christine

    2013-09-01

    Dietary phytoestrogens may prevent certain human diseases, but endocrine activity has been reported in animal studies. Sprague-Dawley rats were exposed perinatally to a 1-, 10- or 100-fold "high human dietary intake" mixture of 12 phytoestrogens consisting of mainly the lignan secoisolarici resinol and the isoflavones genistein and daidzein. This mixture induced persistent adverse effects, as adult male mammary glands showed hypertrophic growth. A reduced anogenital distance in newborn males indicated an anti-androgenic mode of action. Testosterone levels, testis and prostate weights, and expression of selected genes in testis and prostate were unaffected. Decreased serum estradiol was seen in genistein-exposed dams. This study indicated adverse effects at high intake levels in rats, but does not provide evidence for risk of phytoestrogen-mediated endocrine disruption at normal human dietary consumption levels. Further studies are warranted to increase the knowledge upon which risk assessment on dietary phytoestrogen exposure during pregnancy and infancy is based.

  20. A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.

    Science.gov (United States)

    Vandenberg, Laura N; Ågerstrand, Marlene; Beronius, Anna; Beausoleil, Claire; Bergman, Åke; Bero, Lisa A; Bornehag, Carl-Gustaf; Boyer, C Scott; Cooper, Glinda S; Cotgreave, Ian; Gee, David; Grandjean, Philippe; Guyton, Kathryn Z; Hass, Ulla; Heindel, Jerrold J; Jobling, Susan; Kidd, Karen A; Kortenkamp, Andreas; Macleod, Malcolm R; Martin, Olwenn V; Norinder, Ulf; Scheringer, Martin; Thayer, Kristina A; Toppari, Jorma; Whaley, Paul; Woodruff, Tracey J; Rudén, Christina

    2016-07-14

    The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This

  1. Color Blind Affirmative Action

    OpenAIRE

    2003-01-01

    This paper presents a conceptual framework for understanding the consequences of the widespread adoption of race-neutral alternatives' to conventional racial affirmative action policies in college admissions. A simple model of applicant competition with endogenous effort is utilized to show that, in comparison to color-conscious affirmative action, these color-blind alternatives can significantly lower the efficiency of the student selection process in equilibrium. We examine data on matricul...

  2. Modeling Steroidogenesis Disruption Using High-Throughput ...

    Science.gov (United States)

    Environmental chemicals can elicit endocrine disruption by altering steroid hormone biosynthesis and metabolism (steroidogenesis) causing adverse reproductive and developmental effects. Historically, a lack of assays resulted in few chemicals having been evaluated for effects on steroidogenesis. The steroidogenic pathway is a series of hydroxylation and dehydrogenation steps carried out by CYP450 and hydroxysteroid dehydrogenase enzymes, yet the only enzyme in the pathway for which a high-throughput screening (HTS) assay has been developed is aromatase (CYP19A1), responsible for the aromatization of androgens to estrogens. Recently, the ToxCast HTS program adapted the OECD validated H295R steroidogenesis assay using human adrenocortical carcinoma cells into a high-throughput model to quantitatively assess the concentration-dependent (0.003-100 µM) effects of chemicals on 10 steroid hormones including progestagens, androgens, estrogens and glucocorticoids. These results, in combination with two CYP19A1 inhibition assays, comprise a large dataset amenable to clustering approaches supporting the identification and characterization of putative mechanisms of action (pMOA) for steroidogenesis disruption. In total, 514 chemicals were tested in all CYP19A1 and steroidogenesis assays. 216 chemicals were identified as CYP19A1 inhibitors in at least one CYP19A1 assay. 208 of these chemicals also altered hormone levels in the H295R assay, suggesting 96% sensitivity in the

  3. Disrupting neuronal transmission: Mechanism of DBS?

    Directory of Open Access Journals (Sweden)

    Satomi eChiken

    2014-03-01

    Full Text Available Applying high-frequency stimulation to deep brain rain structure, known as deep brain stimulation (DBS, has now been recognized an effective therapeutic option for a wide range of neurological and psychiatric disorders. DBS targeting the basal ganglia thalamo-cortical loop, especially the internal segment of the globus pallidus, subthalamic nucleus and thalamus, has been widely employed as a successful surgical therapy for movement disorders, such as Parkinson’s disease, dystonia and tremor. However, the neurophysiological mechanism underling the action of DBS remains unclear and is still under debate: does DBS inhibit or excite local neuronal elements? In this review, we will examine this question and propose the alternative interpretation: DBS dissociates inputs and outputs, resulting in disruption of abnormal signal transmission.

  4. Selective Maintenance Model Considering Cannibalization and Multiple Maintenance Actions%考虑拼修与多种维修活动的维修任务选择模型

    Institute of Scientific and Technical Information of China (English)

    吕学志; 于永利; 张柳; 曲长征

    2012-01-01

    选择维修策略与拼件维修策略是2种重要的装备群维修策略.将二者结合,给出了一种考虑拼件维修与多种维修活动的维修任务选择模型,此外在系统定义、任务定义、维修资源等方面都对维修任务选择模型进行了拓展.先给出模型的假设条件,针对考虑拼件维修策略与多种维修活动的维修任务选择问题,建立一种非线性的0-1规划模型,得出基于智能算法的分解算法框架,并通过具体实例证明了模型的有效性.该模型适用于管理人员在考虑拼件维修策略与多种维修活动情况下做出合理的维修任务选择决策.%Selective maintenance strategy and cannibalization maintenance strategy are two very important equipment maintenance strategies. The paper develops a selective maintenance model considering cannibalization and multiple maintenance actions, moreover it extends the selective maintenance model at system definition, mission definition and maintenance resource. Firstly, it expounds on the model assumption. Then, it establishes a non-linear, 0-1 programming model to resolve the selective maintenance problem considering cannibalization and multiple maintenance actions. Next, the paper presents a algorithm framework based on metaheuristics. Finally, it provides an example to verify the validity and feasibility of the model. The model suits manager to make reasonable decision considering cannibalization and multiple maintenance actions.

  5. Unique biochemical and molecular biological mechanism of synergistic actions of formamidine compounds on selected pyrethroid and neonicotinoid insecticides on the fourth instar larvae of Aedes aegypti (Diptera: Culicidae).

    Science.gov (United States)

    Ahmed, Mohamed Ahmed Ibrahim; Vogel, Christoph F A; Matsumura, Fumio

    2015-05-01

    We recently reported that formamidine pesticides such as amitraz and chlordimeform effectively synergize toxic actions of certain pyrethroid and neonicotinoid insecticides in some insect species on the 4th instar larvae of Aedes aegypti. Here we studied the biochemical basis of the synergistic actions of the formamidines in amplifying the toxicity of neonicotinoids and pyrethroids such as dinotefuran and thiamethoxam, as well as deltamethrin-fenvalerate type of pyrethroids. We tested the hypothesis that their synergistic actions are mediated by the octopamine receptor, and that the major consequence of octopamine receptor activation is induction of trehalase to increase glucose levels in the hemolymph. The results show that formamidines cause a significant up-regulation of the octopamine receptor and trehalase mRNA expressions. Furthermore, formamidines significantly elevate levels of free glucose when co-treated with dinotefuran, deltamethrin and fenvalerate, but not with permethrin or fenitrothion, which showed no synergistic toxic effects with formamidines. These results support the conclusion that the main mode of synergism is based on the ability to activate the octopamine receptor, which is particularly effective with insecticides causing hyperexcitation-induced glucose release and consequently leading to quick energy exhaustion.

  6. An Empirical Test of Crisis, Social Selection, and Role Explanations of the Relationship between Marital Disruption and Psychological Distress: A Pooled Time-Series Analysis of Four-Wave Panel Data.

    Science.gov (United States)

    Johnson, David R.; Wu, Jian

    2002-01-01

    Reviews three theoretical explanations (social role theory, crisis theory, social selection theory) for the reasons for psychological distress of divorced individuals. Evaluates the efficacy of these theories in a pooled analysis of married persons followed over 12 years. Results provide evidence that higher stress levels of the divorced primarily…

  7. Online Education Cast as "Disruptive Innovation"

    Science.gov (United States)

    Totter, Andrew

    2008-01-01

    Technology-based forces of "disruptive innovation" are gathering around public education and will overhaul the way K-12 students learn--with potentially dramatic consequences for established public schools, according to an upcoming book that draws parallels to disruptions in other industries. In his "Disrupting Class: How Disruptive Innovation…

  8. Wall force produced during disruptions

    Science.gov (United States)

    Strauss, H.; Paccagnella, R.; Breslau, J.

    2009-11-01

    The study of disruptions is of great importance for ITER. Previous work on disruptions [1] is extended to compute toroidally asymmetric wall force in ITER, using the M3D code. The disruptions are produced by n = 1 resistive wall modes or external kink modes. A thin wall resistive boundary model is used to calculate the wall forces. The symmetric wall force, produced by a VDE, and the asymmetric wall force, produced by n = 1 modes, are comparable in magnitude. It is found that the asymmetric and axisymmetric forces scale with the growth rate of the instability multiplied by the square of the current divided by magnetic field. A similar scaling was reported for VDEs in JET [2]. Numerically, the study of disruptions is very challenging. In the M3D extended MHD code, dealiasing was applied in the toroidal direction. Advection terms were treated with a numerical upwind method. These techniques provided sufficient numerical stability to simulate entire disruption events. [4pt] [1] R. Paccagnella, H. R. Strauss, and J. Breslau, Nucl. Fusion (2009) 49 035003. [2] V. Riccardo, T. C. Hender, P. J. Lomas, et al., Plasma Phys. Control. Fusion (2004)

  9. Endocrine-disrupting chemicals and the regulation of energy balance.

    Science.gov (United States)

    Nadal, Angel; Quesada, Ivan; Tudurí, Eva; Nogueiras, Rubén; Alonso-Magdalena, Paloma

    2017-09-01

    Energy balance involves the adjustment of food intake, energy expenditure and body fat reserves through homeostatic pathways. These pathways include a multitude of biochemical reactions, as well as hormonal cues. Dysfunction of this homeostatic control system results in common metabolism-related pathologies, which include obesity and type 2 diabetes mellitus. Metabolism-disrupting chemicals (MDCs) are a particular class of endocrine-disrupting chemicals that affect energy homeostasis. MDCs affect multiple endocrine mechanisms and thus different cell types that are implicated in metabolic control. MDCs affect gene expression and the biosynthesis of key enzymes, hormones and adipokines that are essential for controlling energy homeostasis. This multifaceted spectrum of actions precludes compensatory responses and favours metabolic disorders. Herein, we review the main mechanisms used by MDCs to alter energy balance. This work should help to identify new MDCs, as well as novel targets of their action.

  10. Tidal disruption of inviscid planetesimals

    Science.gov (United States)

    Boss, A. P.; Cameron, A. G. W.; Benz, W.

    1991-01-01

    In view of previous efforts' demonstration that strongly dissipative planetesimals are immune to tidal disruption, an examination is presently conducted of the complementary case of inviscid planetesimals arising from collisions that are sufficiently energetic to entirely melt the resulting planetesimal and debris. The tidal disruption is numerically simulated by means of the smoothed particle hydrodynamics (SPH) code of Cameron and Benz (1991), concentrating on the tidal disruption of 0.01 earth-mass planetesimals passing by the earth with variations in the impact parameter at perigee and velocity at infinity. The SPH models show that tidal forces during a close encounter can efficiently convert orbital angular momentum into spin angular momentum, thereby initiating equatorial mass-shedding to inviscid planetesimals that have been spun up beyond the limit of rotational stability.

  11. Application Transparent HTTP Over a Disruption Tolerant Smartnet

    Science.gov (United States)

    2014-09-01

    to action by a third party. For example, a microwave connection could be disconnected when a low flying aircraft passes through the two nodes. The...duration of a disconnection can be as short as a second, as in the microwave example, or could last hours or more, such as when a planetary satellite...mul- tiple tests. Each configuration was tested using a pseudo-random disruption pattern. The seeds to the pseudo-random number generator were saved

  12. DISRUPTIVE BEHAVIOUR AMONGST DOCTORS, MYTH OR REALITY?

    OpenAIRE

    Avtar Singh

    2014-01-01

    BACKGROUND : Disruptive behavior in a medical setting is defined as objectionable or offensive interpersonal behavior that leads to disruption of professional activities in the workplace. 1 It has been observed that majority of doctors do not show disruptive behavior in their day today conduct and only few doctors are identified for their disruptive behavior . Special commi ttee on professional conduct and ethics defines disruptive behavio...

  13. Market Susceptibility Toward Disruptive Business Model Innovation

    OpenAIRE

    Dover, Oliver; Nord, Erik

    2015-01-01

    This paper discusses the conditional factors indicating market susceptibility toward disruptive innovation. There is a need to separate the different forms of disruptive innovation into segments targeting; technology, product or business model disruption. The concepts are fundamentally different and the literature to date is very one sided toward disruptive technology/product innovation. A shortage of studies on disruptive business model innovation has been discovered. This study therefore pr...

  14. Antagonism of nucleus accumbens M(2) muscarinic receptors disrupts operant responding for sucrose under a progressive ratio reinforcement schedule.

    Science.gov (United States)

    Cousens, Graham A; Beckley, Jacob T

    2007-07-19

    Diverse cholinergic signaling mechanisms regulate the excitability of striatal principal neurons and modulate striatal-dependent behavior. These effects are mediated, in part, by action at muscarinic receptors (mAChR), subtypes of which exhibit distinct patterns of expression across striatal neuronal populations. Non-selective mAChR blockade within the nucleus accumbens (NAc) has been shown to disrupt operant responding for food and to inhibit food consumption. However, the specific receptor subtypes mediating these effects are not known. Thus, we evaluated effects of intra-NAc infusions of pirenzepine and methoctramine, mAChR antagonisits with distinct binding affinity profiles, on operant responding for sucrose reward under a progressive ratio (PR) reinforcement schedule. Moderate to high doses of methoctramine disrupted operant responding and reduced behavioral breakpoint. In contrast, pirenzepine failed to impact operant performance at any dose tested. Methoctramine failed to affect latencies to complete appetitive-consummatory response sequences or to impact measures of acoustic startle, suggesting that its' disruptive effects on operant behavior were not consequent to gross motor impairment. Since methoctramine has a greater affinity for M(2) receptors compared to pirenzepine, which has a greater relative affinity for M(1) and M(3) receptors, these findings suggest that M(2) mAChRs within the NAc regulate behavioral processes underling the acquisition of reward.

  15. Consequences of family disruption on children's educational outcomes in Norway.

    Science.gov (United States)

    Steele, Fiona; Sigle-Rushton, Wendy; Kravdal, Øystein

    2009-08-01

    Using high-quality data from Norwegian population registers, we examine the relationship between family disruption and children's educational outcomes. We distinguish between disruptions caused by parental divorce and paternal death and, using a simultaneous equation model, pay particular attention to selection bias in the effect of divorce. We also allow for the possibility that disruption may have different effects at different stages of a child's educational career. Our results suggest that selection on time-invariant maternal characteristics is important and works to overstate the effects of divorce on a child's chances of continuing in education. Nevertheless, the experience of marital breakdown during childhood is associated with lower levels of education, and the effect weakens with the child's age at disruption. The effects of divorce are most pronounced for the transitions during or just beyond the high school level. In models that do not allow for selection, children who experienced a father's death appear less disadvantaged than children whose parents divorced. After we control for selection, however differences in the educational qualifications of children from divorced and bereaved families narrow substantially and, at mean ages of divorce, are almost non-existent.

  16. Disc Golf Play: Using Recreation to Improve Disruptive Classroom Behaviors

    Science.gov (United States)

    Powell, Michael Lee; Newgent, Rebecca A.

    2008-01-01

    This study examined the use of disc golf as a creative, recreational play intervention for improving classroom behaviors in disruptive children. Twenty-two elementary students were randomly selected for either a treatment or control group and rated at pre- and post- by their teachers on the use of nine positive classroom behaviors (e.g., sharing,…

  17. Scopolamine induces disruption of latent inhibition which is prevented by antipsychotic drugs and an acetylcholinesterase inhibitor.

    Science.gov (United States)

    Barak, Segev; Weiner, Ina

    2007-05-01

    The fact that muscarinic antagonists may evoke a psychotic state ('antimuscarinic psychosis'), along with findings of cholinergic alterations in schizophrenia, have kindled an interest in the involvement of the cholinergic system in this disorder. Latent inhibition (LI) is a cross-species phenomenon manifested as a poorer conditioning of a stimulus seen when the stage of conditioning is preceded by a stage of repeated nonreinforced pre-exposure to that stimulus, and is considered to index the capacity to ignore irrelevant stimuli. Amphetamine-induced LI disruption and its reversal by antipsychotic drugs (APDs) is a well-established model of positive symptoms of schizophrenia. Here, we tested whether the muscarinic antagonist scopolamine would disrupt LI and whether such disruption would be reversed by APDs and by the acetylcholinesterase inhibitor physostigmine. The results showed that scopolamine at doses of 0.15 and 0.5 mg/kg disrupted LI, and that this effect was due to the action of the drug in the pre-exposure stage, suggesting a role of muscarinic transmission in attentional processes underlying LI. Both the typical and the atypical APDs, haloperidol and clozapine, reversed scopolamine-induced LI disruption when given in conditioning or in both stages, but not in pre-exposure, indicating that the mechanism of antipsychotic action in this model is independent of the mechanism of action of the propsychotic drug. Scopolamine-induced LI disruption was reversed by physostigmine (0.05 and 0.15 mg/kg), which was ineffective in reversing amphetamine-induced LI disruption, pointing to distinct mechanisms underlying LI disruption by these two propsychotic drugs. The latter was further supported by the finding that unlike amphetamine, the LI-disrupting doses of scopolamine did not affect activity levels. We propose scopolamine-induced LI disruption as a model of cholinergic-related positive symptoms in schizophrenia.

  18. Anion-selective channelrhodopsin expressed in neuronal cell culture and in vivo in murine brain: Light-induced inhibition of generation of action potentials.

    Science.gov (United States)

    Dolgikh, D A; Malyshev, A Yu; Salozhin, S V; Nekrasova, O V; Petrovskaya, L E; Roshchin, M V; Borodinova, A A; Feldman, T B; Balaban, P M; Kirpichnikov, M P; Ostrovsky, M A

    2015-01-01

    Anionic channelrhodopsin slow ChloC was expressed in the culture of nerve cells and in vivo in mouse brain. We demonstrated ability of slow ChloC to suppress effectively the activity of the neuron in response to the illumination with the visible light. It has been shown for a first time that slow ChloC works equally efficiently in both neuronal culture and in the whole brain being expressed in vivo. Thus, slow ChloC could be considered as an effective optogenetic tool capable in response to light stimulation to inhibit the generation of action potentials in the neuron.

  19. Sociology of Law Perspectivity in Action Selection of Administrative Law Enforcement Personnel%行政执法人员行动选择的法社会学透视

    Institute of Scientific and Technical Information of China (English)

    何富

    2015-01-01

    行政执法人员在进行行动选择时,不仅受到规范性因素的指引,也受到非规范性因素的制约,良好行政执法关系的形成必须是这两类因素合理互动的结果。由此,于现实主义法学理论中获得启示,从法社会学的视角分析行政执法人员的行动选择,总结出影响行政执法人员行动选择的四大规范性要素和四大非规范性要素,揭示出行政执法实际上是规范性因素和非规范性因素争夺控制权的过程。%In the process of action selection,administrative law enforcement personnel is not only guided by the“normative ele-ments”,also restricted by the“non-normative elements”. The good relationship between law enforcement agencies and the ad-ministrative relatives must be the result of the interaction of the two factors. Inspiration is got from the legal realism. Sociology of law perspectivity in action selection of administrative law enforcement personnel is used. The impact of administrative law en-forcement personnel action selection of the four“normative elements”and four“non-normative elements”are summed up. It reveals that the administrative law enforcement is actually process for control between“normative elements”and“non-norma-tive elements”.

  20. Cu(II)-vitamin D interaction leads to free radical-mediated cellular DNA damage: a novel putative mechanism for its selective cytotoxic action against malignant cells.

    Science.gov (United States)

    Rizvi, Asim; Chibber, Sandesh; Naseem, Imrana

    2015-03-01

    Vitamin D (vit D) is a known anticancer molecule, and cancer cells are reported to have elevated levels of Cu(II) ions. In this study, we show that interaction of vit D and Cu(II) leads to the formation of hydroxyl free radicals, superoxide anion and hydrogen peroxide, which causes severe oxidative stress, selectively in malignant cells. We show that the production of these reactive oxygen species causes cellular DNA fragmentation which may cause cell death. A novel putative chemical mechanism explaining how vit D causes cell death by DNA damage, selectively in malignant cells, is proposed.

  1. 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.

  2. Inhibition of New Delhi Metallo-β-Lactamase 1 (NDM-1 Producing Escherichia coli IR-6 by Selected Plant Extracts and Their Synergistic Actions with Antibiotics

    Directory of Open Access Journals (Sweden)

    Brinda Chandar

    2017-08-01

    Full Text Available Improper use of antibiotics has led to a great concern in the development of pathogenic microbial resistance. New Delhi metallo-β-lactamase 1 (NDM-1 producing bacteria are resistant to most of the β-lactam antibiotics, and so far, no new compounds have been clinically tested against these bacteria. In this study, ethanol extracts from the leaves of 240 medicinal plant species were screened for antibacterial activity against an NDM-1 Escherichia coli strain. The extracts that showed antibacterial activity were then tested for minimum inhibitory concentrations (MICs and zones of inhibition. The extract from Combretum albidum G. Don, Hibiscus acetosella Welw. ex Hiern, Hibiscus cannabinus L., Hibiscus furcatus Willd., Punica granatum L., and Tamarindus indica L. showed bactericidal activity between 5 and 15 mg/ml and the MIC was between 2.56 and 5.12 mg/ml. All six plant extracts inhibited activity of the NDM-1 enzyme in vitro, and the IC50 value ranged between 0.50 and 1.2 ng/μl. Disruption of bacterial cell wall integrity by the plant extracts was clearly visible with scanning electron microscopy. Increases in membrane permeability caused 79.4–89.7% bacterial cell deaths as investigated by fluorescence-activated cell sorting. All the plant extracts showed synergistic effects when combined with colistin [fractional inhibitory concentration (ΣFIC = 0.125–0.375], meropenem (ΣFIC = 0.09–0.313, and tetracycline (ΣFIC = 0.125–0.313. Thus, the plant extracts can be fractionated for the identification of active compounds, which could be used as new antibacterial compounds for the development of drugs against NDM-1 E. coli in addition to their use in combination therapy.

  3. Differential Effects of Seating Arrangements on Disruptive Behavior of Fifth Grade Students during Independent Seatwork

    Science.gov (United States)

    Bicard, David F.; Ervin, Angela; Bicard, Sara C.; Baylot-Casey, Laura

    2012-01-01

    We investigated teacher versus student seat selection in the context of group and individual seating arrangements. Disruptive behavior during group seating occurred at twice the rate when students chose their seats than when the teacher chose. During individual seating, disruptive behavior occurred more than three times as often when the students…

  4. Jogging Can Modify Disruptive Behaviors.

    Science.gov (United States)

    Allen, Jill I.

    1980-01-01

    Jogging was used to modify disruptive behavior as part of the classroom routine for 12 learning disabled elementary-grade boys. The number of incidents of each of five negative behaviors were reduced by half following the 10-minute jogging routine. (SBH)

  5. Strategic network disruption and defence

    NARCIS (Netherlands)

    Hoyer, Britta; De Jaegher, K.J.M.

    2016-01-01

    We study a game between a network designer, who uses costly links to connect nodes in a network, and a network disruptor who tries to disrupt the resulting network as much as possible by deleting either nodes or links. For low linking costs networks with all nodes in symmetric positions are a best r

  6. Disruptive Technologies in Higher Education

    Science.gov (United States)

    Flavin, Michael

    2012-01-01

    This paper analyses the role of "disruptive" innovative technologies in higher education. In this country and elsewhere, Higher Education Institutions (HEIs) have invested significant sums in learning technologies, with Virtual Learning Environments (VLEs) being more or less universal, but these technologies have not been universally…

  7. [Technological convergence will quickly generate disruptive innovations in oncology].

    Science.gov (United States)

    Coucke, Ph A

    2016-06-01

    Convergence between information and communication technology and recent developments in medical care will totally change the health care sector. The way we perform diagnosis, treatment and follow-up will undergo disruptive changes in a very near future. We intend to highlight this statement by a limited selection of examples of radical innovations, especially in the field of oncology. To be totally disruptive and to illustrate the concept of "lateral power" - especially cognitive distribution - the list of references is only made up of internet links. Anyone - patients included - can easily and instantly access to this information everywhere.

  8. CANEGROWERS Action Research Toolkit

    NARCIS (Netherlands)

    Mostert, R.H.; Brouwer, J.H.

    2015-01-01

    This toolkit contains a selection of tools to conduct action research, organized around four phases: Identify problems and possibilities; Analyze problems and possibilities; Search for solutions; and Reflection tools. The toolkit is customized for staff of Canegrowers in South Africa, who used the t

  9. CANEGROWERS Action Research Toolkit

    NARCIS (Netherlands)

    Mostert, R.H.; Brouwer, J.H.

    2015-01-01

    This toolkit contains a selection of tools to conduct action research, organized around four phases: Identify problems and possibilities; Analyze problems and possibilities; Search for solutions; and Reflection tools. The toolkit is customized for staff of Canegrowers in South Africa, who used the

  10. Schizophrenia risk gene CAV1 is both pro-psychotic and required for atypical antipsychotic drug actions in vivo.

    Science.gov (United States)

    Allen, J A; Yadav, P N; Setola, V; Farrell, M; Roth, B L

    2011-08-16

    Caveolin-1 (Cav-1) is a scaffolding protein important for regulating receptor signaling cascades by partitioning signaling molecules into membrane microdomains. Disruption of the CAV1 gene has recently been identified as a rare structural variant associated with schizophrenia. Although Cav-1 knockout (KO) mice displayed no baseline behavioral disruptions, Cav-1 KO mice, similar to schizophrenic individuals, exhibited increased sensitivity to the psychotomimetic N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). Thus, PCP disruption of prepulse inhibition (PPI) and PCP-induced mouse locomotor activity were both enhanced by genetic deletion of Cav-1. Interestingly, genetic deletion of Cav-1 rendered the atypical antipsychotics clozapine and olanzapine and the 5-HT(2A)-selective antagonist M100907 ineffective at normalizing PCP-induced disruption of PPI. We also discovered that genetic deletion of Cav-1 attenuated 5-HT(2A)-induced c-Fos and egr-1 expression in mouse frontal cortex and also reduced 5-HT(2A)-mediated Ca(2+) mobilization in primary cortical neuronal cultures. The behavioral effects of the 5-HT(2A) agonist (2,5-dimethoxy-4-iodoamphetamine) including head twitch responses and disruption of PPI were also attenuated by genetic deletion of Cav-1, indicating that Cav-1 is required for both inverse agonist (that is, atypical antipsychotic drug) and agonist actions at 5-HT(2A) receptors. This study demonstrates that disruption of the CAV1 gene--a rare structural variant associated with schizophrenia--is not only pro-psychotic but also attenuates atypical antipsychotic drug actions.

  11. 29 CFR 1607.13 - Affirmative action.

    Science.gov (United States)

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Affirmative action. 1607.13 Section 1607.13 Labor... EMPLOYEE SELECTION PROCEDURES (1978) General Principles § 1607.13 Affirmative action. A. Affirmative action... relieve users of any obligations they may have to undertake affirmative action to assure equal...

  12. Selection of a biocontrol agent based on a potential mechanism of action: degradation of nicotinic acid, a growth factor essential for Erwinia amylovora.

    Science.gov (United States)

    Paternoster, Thomas; Défago, Geneviève; Duffy, Brion; Gessler, Cesare; Pertot, Ilaria

    2010-12-01

    This work describes a medium-based screening method for selecting microbial biocontrol agents against Erwinia amylovora based on the degradation of a specific growth factor. Erwinia amylovora, the causal agent of the devastating fire blight disease, requires nicotinic acid or nicotinamide as an essential growth factor. Potential biocontrol agents are either selected for antimicrobial production in plate or directly on immature pears or apple blossoms. In this work, we have attempted to streamline the selection of a new potential biocontrol agent with a lower risk of non-target effects by isolation based on the ability to degrade nicotinic acid in vitro, using therefore few plant materials. A total of 735 bacteria and 1237 yeast were isolated from apple blossoms and pre-screened for nicotinic acid-degradation. Pseudomonas rhizosphaerae strain JAN was able to degrade both nicotinic acid and nicotinamide. Mutants deficient in this ability were constructed. JAN, but not the mutants, controlled E. amylovora on pear slices. On detached apple blossoms, JAN colonized apple hypanthia and strongly suppressed E. amylovora growth. Under greenhouse conditions, JAN was more effective in controlling blossom blight than P. fluorescens A506, a commercial biocontrol agent of fire blight unable to degrade nicotinic acid and nicotinamide.

  13. Vestibular loss disrupts daily rhythm in rats.

    Science.gov (United States)

    Martin, T; Mauvieux, B; Bulla, J; Quarck, G; Davenne, D; Denise, P; Philoxène, B; Besnard, S

    2015-02-01

    Hypergravity disrupts the circadian regulation of temperature (Temp) and locomotor activity (Act) mediated through the vestibular otolithic system in mice. In contrast, we do not know whether the anatomical structures associated with vestibular input are crucial for circadian rhythm regulation at 1 G on Earth. In the present study we observed the effects of bilateral vestibular loss (BVL) on the daily rhythms of Temp and Act in semipigmented rats. Our model of vestibular lesion allowed for selective peripheral hair cell degeneration without any other damage. Rats with BVL exhibited a disruption in their daily rhythms (Temp and Act), which were replaced by a main ultradian period (τ <20 h) for 115.8 ± 68.6 h after vestibular lesion compared with rats in the control group. Daily rhythms of Temp and Act in rats with BVL recovered within 1 wk, probably counterbalanced by photic and other nonphotic time cues. No correlation was found between Temp and Act daily rhythms after vestibular lesion in rats with BVL, suggesting a direct influence of vestibular input on the suprachiasmatic nucleus. Our findings support the hypothesis that the vestibular system has an influence on daily rhythm homeostasis in semipigmented rats on Earth, and raise the question of whether daily rhythms might be altered due to vestibular pathology in humans. Copyright © 2015 the American Physiological Society.

  14. Reproductive endocrine-disrupting effects of triclosan: Population exposure, present evidence and potential mechanisms.

    Science.gov (United States)

    Wang, Cai-Feng; Tian, Ying

    2015-11-01

    Triclosan has been used as a broad-spectrum antibacterial agent for over 40 years worldwide. Increasing reports indicate frequent detection and broad exposure to triclosan in the natural environment and the human body. Current laboratory studies in various species provide strong evidence for its disrupting effects on the endocrine system, especially reproductive hormones. Multiple modes of action have been suggested, including disrupting hormone metabolism, displacing hormones from hormone receptors and disrupting steroidogenic enzyme activity. Although epidemiological studies on its effects in humans are mostly negative but conflicting, which is typical of much of the early evidence on the toxicity of EDCs, overall, the evidence suggests that triclosan is an EDC. This article reviews human exposure to triclosan, describes the current evidence regarding its reproductive endocrine-disrupting effects, and discusses potential mechanisms to provide insights for further study on its endocrine-disrupting effects in humans.

  15. Tidal disruption events from supermassive black hole binaries

    Science.gov (United States)

    Coughlin, Eric R.; Armitage, Philip J.; Nixon, Chris; Begelman, Mitchell C.

    2017-03-01

    We investigate the pre-disruption gravitational dynamics and post-disruption hydrodynamics of the tidal disruption of stars by supermassive black hole (SMBH) binaries. We focus on binaries with relatively low mass primaries (106 M⊙), moderate mass ratios, and separations with reasonably long gravitational wave inspiral times (tens of Myr). First, we generate a large ensemble (between 1 and 10 million) of restricted three-body integrations to quantify the statistical properties of tidal disruptions by circular SMBH binaries of initially unbound stars. Compared to the reference case of a disruption by a single SMBH, the binary potential induces a significant variance into the specific energy and angular momentum of the star at the point of disruption. Second, we use Newtonian numerical hydrodynamics to study the detailed evolution of the fallback debris from 120 disruptions randomly selected from the three-body ensemble (excluding only the most deeply penetrating encounters). We find that the overall morphology of the debris is greatly altered by the presence of the second black hole, and the accretion rate histories display a wide range of behaviours, including order of magnitude dips and excesses relative to control simulations that include only one black hole. Complex evolution typically persists for many orbital periods of the binary. We find evidence for power in the accretion curves on time-scales related to the binary orbital period, though there is no exact periodicity. We discuss our results in the context of future wide-field surveys, and comment on the prospects of identifying and characterizing the subset of events occurring in nuclei with binary SMBHs.

  16. The depolarizing action of 5-hydroxytryptamine on rabbit vagal afferent and sympathetic neurones in vitro and its selective blockade by ICS 205-930.

    OpenAIRE

    1986-01-01

    Depolarizing responses to 5-hydroxytryptamine (5-HT) were recorded from rabbit nodose (NG) and superior cervical (SCG) ganglia using the sucrose-gap technique. The antagonist potency and selectivity of ICS 205-930 ([3 alpha-tropanyl]-1H-indole-3-carboxylic acid ester) were investigated. In NG, 5-HT (5 to 80 nmol) evoked depolarizations of graded amplitude. The ED50 was 18.2 (10.9-30.5) nmol (geometric mean, 95% confidence limits). Responses were blocked surmountably by ICS 205-930, 10(-11) an...

  17. Beta-CCT, a selective BZ-omega1 receptor antagonist, blocks the anti-anxiety but not the amnesic action of chlordiazepoxide in mice.

    Science.gov (United States)

    Belzung, C; Le Guisquet, A M; Griebel, G

    2000-04-01

    The aim of this study was to test further the hypothesis that different benzodiazepine (BZ-omega) receptor subtypes may mediate anxiolytic and amnesic effects of BZ agonists, using the selective BZ-omega1 receptor antagonist beta-CCT (beta-carboline-3-carboxylate t-butyl-ester). Experiments were performed in Swiss mice using the elevated plus-maze anxiety test and two learning tasks - passive avoidance and the radial arm maze. In the elevated plus-maze test, beta-CCT (30 mg/kg, i.p.) completely abolished the increase in open-arm entries induced by the BZ chlordiazepoxide (5mg/kg, i.p.). Chlordiazepoxide decreased retention latency in the passive avoidance step-through procedure, and increased the number of errors in the radial arm maze. These effects were not modified by beta-CCT. Except for a slight, albeit significant, amnesic effect in the passive avoidance test, beta-CCT was devoid of intrinsic activity when administered alone. These results are in agreement with previous studies using selective BZ-omega1 agonists, and thus provide further evidence that BZ-omega1 receptors may be involved in the anxiolytic but not in the amnesic effects of BZ agonists.

  18. Selective 5-hydroxytryptamine 2C receptor agonists derived from the lead compound tranylcypromine: identification of drugs with antidepressant-like action.

    Science.gov (United States)

    Cho, Sung Jin; Jensen, Niels H; Kurome, Toru; Kadari, Sudhakar; Manzano, Michael L; Malberg, Jessica E; Caldarone, Barbara; Roth, Bryan L; Kozikowski, Alan P

    2009-04-09

    We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test.

  19. Selective 5-Hydroxytrytamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine – Identification of Drugs with Antidepressant-Like Action

    Science.gov (United States)

    Cho, Sung Jin; Jensen, Niels H.; Kurome, Toru; Kadari, Sudhakar; Manzano, Michael L.; Malberg, Jessica E.; Caldarone, Barbara; Roth, Bryan L.; Kozikowski, Alan P.

    2009-01-01

    We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT2C agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT2C agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT2C receptor agonists with selectivity over both 5-HT2A and 5-HT2B receptors in functional assays. The most promising compound is 37 with 120- and 14-fold selectivity over 5-HT2A and 5-HT2B, respectively (EC50 = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10–60 mg/kg) decreased immobility time in the mouse forced swim test. PMID:19284718

  20. Evaluation of the ANSR for Salmonella assay for identification of Salmonella spp. from colony picks from selective/differential agar media: first action 2013.14.

    Science.gov (United States)

    Mozola, Mark; Botimer, Maximilian; Jagadics, Carolyn; Norton, Paul; Caballero, Oscar; Enslin, Nicole; Biswas, Preetha; Rice, Jennifer

    2014-01-01

    A collaborative study was conducted to evaluate performance of the ANSR for Salmonella assay for identification of Salmonella spp. from colony picks taken from selective/differential agar media. The ANSR Salmonella assay is an isothermal nucleic acid amplification test based on the nicking enzyme amplification reaction chemistry. The test can be completed in less than 40 min including sample preparation. A total of 18 laboratories representing industry, government, academic, and commercial testing laboratories participated in the study. Each collaborator tested up to 84 samples, comprised of colony picks of six Salmonella spp. and six non-salmonellae taken from six selective/differential agar media as well as tryptic soy agar. A total of 1441 analyses were performed, 1416 of which gave the correct identification, for overall accuracy of 98.3%. For identification of Salmonella spp., 755 of 756 tests (99.9%) produced the correct result. For identification of non-salmonellae as such, 661 of 685 assays (96.5%) produced the correct result. Of the 18 laboratories, 15 produced data sets with 99-100% accuracy. The majority of false-positive results were clustered in three laboratories; analysis of raw data suggests procedural difficulties in at least two cases, which may explain the atypical data from these collaborators. The ANSR Salmonella assay can be used as a rapid, accurate adjunct or alternative to biochemical testing for identification of presumptive Salmonella spp. isolates.

  1. Bodily illusions disrupt tactile sensations.

    Science.gov (United States)

    D'Amour, Sarah; Pritchett, Lisa M; Harris, Laurence R

    2015-02-01

    To accurately interpret tactile information, the brain needs to have an accurate representation of the body to which to refer the sensations. Despite this, body representation has only recently been incorporated into the study of tactile perception. Here, we investigate whether distortions of body representation affect tactile sensations. We perceptually altered the length of the arm and the width of the waist using a tendon vibration illusion and measured spatial acuity and sensitivity. Surprisingly, we found reduction in both tactile acuity and sensitivity thresholds when the arm or waist was perceptually altered, which indicates a general disruption of low-level tactile processing. We postulate that the disruptive changes correspond to the preliminary stage as the body representation starts to change and may give new insights into sensory processing in people with long-term or sudden abnormal body representation such as are found in eating disorders or following amputation.

  2. Optimal Disruption of Complex Networks

    CERN Document Server

    Zhao, Jin-Hua

    2016-01-01

    The collection of all the strongly connected components in a directed graph, among each cluster of which any node has a path to another node, is a typical example of the intertwining structure and dynamics in complex networks, as its relative size indicates network cohesion and it also composes of all the feedback cycles in the network. Here we consider finding an optimal strategy with minimal effort in removal arcs (for example, deactivation of directed interactions) to fragment all the strongly connected components into tree structure with no effect from feedback mechanism. We map the optimal network disruption problem to the minimal feedback arc set problem, a non-deterministically polynomial hard combinatorial optimization problem in graph theory. We solve the problem with statistical physical methods from spin glass theory, resulting in a simple numerical method to extract sub-optimal disruption arc sets with significantly better results than a local heuristic method and a simulated annealing method both...

  3. Disrupting the habit of interviewing

    Directory of Open Access Journals (Sweden)

    Eileen Honan

    2014-06-01

    Full Text Available This paper contributes to the growing domain of ‘post-qualitative’ research and experiments with a new (representational form to move away from traditional and clichéd descriptions of research methods. In this paper, I want to interrogate the category of interview, and the habit of interviewing, to disrupt the clichés, so as to allow thinking of different ways of writing/speaking/representing the interactions between researcher and researched that will breathe new life into qualitative inquiries. I will attempt to flatten and shred, destabilise and disrupt our common-sense ideas about interview, including those held most sacred to the qualitative community, that of anonymity and confidentiality, as well as the privilege of the ‘transcript’ in re-presenting interview data.

  4. Effects of estrogens and estrogenic disrupting compounds on fish mineralized tissues.

    Science.gov (United States)

    Pinto, Patricia I S; Estêvão, Maria D; Power, Deborah M

    2014-08-15

    Estrogens play well-recognized roles in reproduction across vertebrates, but also intervene in a wide range of other physiological processes, including mineral homeostasis. Classical actions are triggered when estrogens bind and activate intracellular estrogen receptors (ERs), regulating the transcription of responsive genes, but rapid non-genomic actions initiated by binding to plasma membrane receptors were recently described. A wide range of structurally diverse compounds from natural and anthropogenic sources have been shown to interact with and disrupt the normal functions of the estrogen system, and fish are particularly vulnerable to endocrine disruption, as these compounds are frequently discharged or run-off into waterways. The effect of estrogen disruptors in fish has mainly been assessed in relation to reproductive endpoints, and relatively little attention has been given to other disruptive actions. This review will overview the actions of estrogens in fish, including ER isoforms, their expression, structure and mechanisms of action. The estrogen functions will be considered in relation to mineral homeostasis and actions on mineralized tissues. The impact of estrogenic endocrine disrupting compounds on fish mineralized tissues will be reviewed, and the potential adverse outcomes of exposure to such compounds will be discussed. Current lacunae in knowledge are highlighted along with future research priorities.

  5. Effects of Estrogens and Estrogenic Disrupting Compounds on Fish Mineralized Tissues

    Directory of Open Access Journals (Sweden)

    Patricia I. S. Pinto

    2014-08-01

    Full Text Available Estrogens play well-recognized roles in reproduction across vertebrates, but also intervene in a wide range of other physiological processes, including mineral homeostasis. Classical actions are triggered when estrogens bind and activate intracellular estrogen receptors (ERs, regulating the transcription of responsive genes, but rapid non-genomic actions initiated by binding to plasma membrane receptors were recently described. A wide range of structurally diverse compounds from natural and anthropogenic sources have been shown to interact with and disrupt the normal functions of the estrogen system, and fish are particularly vulnerable to endocrine disruption, as these compounds are frequently discharged or run-off into waterways. The effect of estrogen disruptors in fish has mainly been assessed in relation to reproductive endpoints, and relatively little attention has been given to other disruptive actions. This review will overview the actions of estrogens in fish, including ER isoforms, their expression, structure and mechanisms of action. The estrogen functions will be considered in relation to mineral homeostasis and actions on mineralized tissues. The impact of estrogenic endocrine disrupting compounds on fish mineralized tissues will be reviewed, and the potential adverse outcomes of exposure to such compounds will be discussed. Current lacunae in knowledge are highlighted along with future research priorities.

  6. Remedial action plan and site design for stabilization of the inactive uranium mill tailings site at Falls City, Texas. Remedial action selection report, attachment 2, geology report; attachment 3, groundwater hydrology report; and attachment 4, water resources protection strategy. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1992-09-01

    The uranium processing site near Falls City, Texas, was one of 24 inactive uranium mill sites designated to be remediated by the U.S. Department of Energy (DOE) under Title I of the Uranium Mill Tailings Radiation Control Act of 1978 (UMTRCA). The UMTRCA requires that the U.S. Nuclear Regulatory Commission (NRC) concur with the DOE`s remedial action plan (RAP) and certify that the remedial action conducted at the site complies with the standards promulgated by the U.S. Environmental Protection Agency (EPA). The RAP, which includes this summary remedial action selection report (RAS), serves a two-fold purpose. First, it describes the activities proposed by the DOE to accomplish long-term stabilization and control of the residual radioactive materials at the inactive uranium processing site near Falls City, Texas. Second, this document and the remainder of the RAP, upon concurrence and execution by the DOE, the State of Texas, and the NRC, becomes Appendix B of the Cooperative Agreement between the DOE and the State of Texas.

  7. Disrupted Nighttime Sleep in Narcolepsy

    Science.gov (United States)

    Roth, Thomas; Dauvilliers, Yves; Mignot, Emmanuel; Montplaisir, Jacques; Paul, Josh; Swick, Todd; Zee, Phyllis

    2013-01-01

    Study Objectives: Characterize disrupted nighttime sleep (DNS) in narcolepsy, an important symptom of narcolepsy. Methods: A panel of international narcolepsy experts was convened in 2011 to build a consensus characterization of DNS in patients with narcolepsy. A literature search of the Medline (1965 to date), Medline In-Process (latest weeks), Embase (1974 to date), Embase Alert (latest 8 weeks), and Biosis (1965 to date) databases was conducted using the following search terms: narcolepsy and disrupted nighttime sleep, disturbed nighttime sleep, fragmented sleep, consolidated sleep, sleep disruption, and narcolepsy questionnaire. The purpose of the literature search was to identify publications characterizing the nighttime sleep of patients with narcolepsy. The panel reviewed the literature. Nocturnal sleep can also be disturbed by REM sleep abnormalities such as vivid dreaming and REM sleep behavior disorder; however, these were not reviewed in the current paper, as we were evaluating for idiopathic sleep disturbances. Results: The literature reviewed provide a consistent characterization of nighttime sleep in patients with narcolepsy as fragmented, with reports of frequent, brief nightly awakenings with difficulties returning to sleep and associated reports of poor sleep quality. Polysomnographic studies consistently report frequent awakenings/arousals after sleep onset, more stage 1 (S1) sleep, and more frequent shifts to S1 sleep or wake from deeper stages of sleep. The consensus of the International Experts' Panel on Narcolepsy was that DNS can be distressing for patients with narcolepsy and that treatment of DNS warrants consideration. Conclusions: Clinicians involved in the management of patients with narcolepsy should investigate patients' quality of nighttime sleep, give weight and consideration to patient reports of nighttime sleep experience, and consider DNS a target for treatment. Citation: Roth T; Dauvilliers Y; Mignot E; Montplaisir J; Paul J

  8. HOW TO IDENTIFY DISRUPTIVE NEW BUSINESSES

    OpenAIRE

    Elizabeth Robles

    2015-01-01

    In almost any industry, the most dramatic stories of growth and success were launched from a platform of disruptive innovation (Christensen et al., 2002). The probability of creating a successful, new growth business is 10 times greater if the innovators pursue a disruptive strategy rather than a sustaining one. Genuinely disruptive innovations are the ones that result in the creation of entirely new markets and business models. Few companies have introduced these innovations. Disruptive inno...

  9. Engineering analysis of TFTR disruption

    Energy Technology Data Exchange (ETDEWEB)

    Murray, J.G.; Rothe, K.E.; Bronner, G.

    1984-09-01

    This report covers an engineering approach quantifying the currents, forces, and times, as well as plasma position, for the worst-case disruption based on engineerign circuit assumptions for the plasma. As the plasma moves toward the wall during the current-decay phase of disruption, the wall currents affect the rate of movement and, hence, the decay time. The calculated structure-induced currents differ considerably from those calculated using a presently available criterion, which specifies that the plasma remains stationary in the center of the torus while decaying in 10 ms. This report outlines the method and basis for the engineering calculation used to determine the current and forces as a function of the circuit characteristics. It provides specific calculations for the Tokamak Fusion Test Reactor (TFTR) with variations in parameters such as the thermal decay time, the torus resistance, and plasma temperature during the current decay. The study reviews possible ways to reduce the disruption damage of TFTR by reducing the magnitude of the plasma external field energy that is absorbed by the plasma during the current decay.

  10. LYSOSOMAL DISRUPTION BY BACTERIAL TOXINS

    Science.gov (United States)

    Bernheimer, Alan W.; Schwartz, Lois L.

    1964-01-01

    Bernheimer, Alan W. (New York University School of Medicine, New York), and Lois L. Schwartz. Lysosomal disruption by bacterial toxins. J. Bacteriol. 87:1100–1104. 1964.—Seventeen bacterial toxins were examined for capacity (i) to disrupt rabbit leukocyte lysosomes as indicated by decrease in turbidity of lysosomal suspensions, and (ii) to alter rabbit liver lysosomes as measured by release of β-glucuronidase and acid phosphatase. Staphylococcal α-toxin, Clostridium perfringens α-toxin, and streptolysins O and S affected lysosomes in both systems. Staphylococcal β-toxin, leucocidin and enterotoxin, Shiga neurotoxin, Serratia endotoxin, diphtheria toxin, tetanus neurotoxin, C. botulinum type A toxin, and C. perfringens ε-toxin were not active in either system. Staphylococcal δ-toxin, C. histolyticum collagenase, crude C. perfringens β-toxin, and crude anthrax toxin caused lysosomal damage in only one of the test systems. There is a substantial correlation between the hemolytic property of a toxin and its capacity to disrupt lysosomes, lending support to the concept that erythrocytes and lysosomes are bounded by similar membranes. PMID:5874534

  11. Thyroid Hormone-disrupting Effects and the Amphibian Metamorphosis Assay.

    Science.gov (United States)

    Miyata, Kaori; Ose, Keiko

    2012-03-01

    There are continued concerns about endocrine-disrupting chemical effects, and appropriate vertebrate models for assessment of risk are a high priority. Frog tadpoles are very sensitive to environmental substances because of their habitat and the complex processes of metamorphosis regulated by the endocrine system, mainly thyroid hormones. During metamorphosis, marked alteration in hormonal factors occurs, as well as dramatic structural and functional changes in larval tissues. There are a variety of mechanisms determining thyroid hormone balance or disruption directly or indirectly. Direct-acting agents can cause changes in thyroxine synthesis and/or secretion in thyroid through effects on peroxidases, thyroidal iodide uptake, deiodinase, and proteolysis. At the same time, indirect action may result from biochemical processes such as sulfation, deiodination and glucuronidation. Because their potential to disrupt thyroid hormones has been identified as an important consideration for the regulation of chemicals, the OECD and the EPA have each established guidelines that make use of larval African clawed frogs (Xenopus laevis) and frog metamorphosis for screening and testing of potential endocrine disrupters. The guidelines are based on evaluation of alteration in the hypothalamic-pituitary-thyroid axis. One of the primary endpoints is thyroid gland histopathology. Others are mortality, developmental stage, hind limb length, snout-vent length and wet body weight. Regarding histopathological features, the guidelines include core criteria and additional qualitative parameters along with grading. Taking into account the difficulties in evaluating amphibian thyroid glands, which change continuously throughout metamorphosis, histopathological examination has been shown to be a very sensitive approach.

  12. American Samoa: Energy Action Plan

    Energy Technology Data Exchange (ETDEWEB)

    Ness, J. Erik [National Renewable Energy Lab. (NREL), Golden, CO (United States); Haase, Scott [National Renewable Energy Lab. (NREL), Golden, CO (United States); Conrad, Misty [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2016-09-01

    This document outlines actions being taken to reduce American Samoa's petroleum consumption. It describes the four near-term strategies selected by the American Samoa Renewable Energy Committee during action-planning workshops conducted in May 2016, and describes the steps that will need to be taken to implement those strategies.

  13. Disruptive innovation as an entrepreneurial process

    NARCIS (Netherlands)

    Chandra, Y.; Yang, S.-J.S.; Singh, P.; Prajogo, D.; O'Neill, P.; Rahman, S.

    2008-01-01

    Research on conditions and causal mechanisms that influence disruptive innovation has been relatively unexplored in the extant research in disruptive innovation. By re-conceptualizing disruptive innovation as an entrepreneurial process at product, firm and industry levels, this paper draws on emergi

  14. Disruption and Distinctiveness in Higher Education

    Science.gov (United States)

    Purcell, Wendy

    2014-01-01

    "Disruption"--while an evocative word triggering feelings of anxiety and perhaps even fear--also signals renewal and growth. The Higher Education (HE) sector in England has experienced some profound disruption over the years, and yet has emerged stronger and renewed in many ways. The impact of recent disruptive forces, from fees to the…

  15. Dealing with Disruptive Behavior of Adult Learners

    Science.gov (United States)

    Dobmeier, Robert; Moran, Joseph

    2008-01-01

    The adult education literature on disruptive behavior of adult learners was reviewed and a survey on disruptive behavior of adult learners was conducted with adult educators. The findings are synthesized in a conceptual framework for understanding the types and causes of disruptive behavior, which fall into the categories of inattention,…

  16. Disruptive innovation as an entrepreneurial process

    NARCIS (Netherlands)

    Chandra, Y.; Yang, S.-J.S.; Singh, P.; Prajogo, D.; O'Neill, P.; Rahman, S.

    2008-01-01

    Research on conditions and causal mechanisms that influence disruptive innovation has been relatively unexplored in the extant research in disruptive innovation. By re-conceptualizing disruptive innovation as an entrepreneurial process at product, firm and industry levels, this paper draws on

  17. Modelling the interaction of steroid receptors with endocrine disrupting chemicals.

    Science.gov (United States)

    D'Ursi, Pasqualina; Salvi, Erika; Fossa, Paola; Milanesi, Luciano; Rovida, Ermanna

    2005-12-01

    The organic polychlorinated compounds like dichlorodiphenyltrichloroethane with its metabolites and polychlorinated biphenyls are a class of highly persistent environmental contaminants. They have been recognized to have detrimental health effects both on wildlife and humans acting as endocrine disrupters due to their ability of mimicking the action of the steroid hormones, and thus interfering with hormone response. There are several experimental evidences that they bind and activate human steroid receptors. However, despite the growing concern about the toxicological activity of endocrine disrupters, molecular data of the interaction of these compounds with biological targets are still lacking. We have used a flexible docking approach to characterize the molecular interaction of seven endocrine disrupting chemicals with estrogen, progesterone and androgen receptors in the ligand-binding domain. All ligands docked in the buried hydrophobic cavity corresponding to the hormone steroid pocket. The interaction was characterized by multiple hydrophobic contacts involving a different number of residues facing the binding pocket, depending on ligands orientation. The EDC ligands did not display a unique binding mode, probably due to their lipophilicity and flexibility, which conferred them a great adaptability into the hydrophobic and large binding pocket of steroid receptors. Our results are in agreement with toxicological data on binding and allow to describe a pattern of interactions for a group of ECD to steroid receptors suggesting the requirement of a hydrophobic cavity to accommodate these chlorine carrying compounds. Although the affinity is lower than for hormones, their action can be brought about by a possible synergistic effect.

  18. Activity and mechanism of action of HDVD, a novel pyrimidine nucleoside derivative with high levels of selectivity and potency against gammaherpesviruses.

    Science.gov (United States)

    Coen, N; Singh, U; Vuyyuru, V; Van den Oord, J J; Balzarini, J; Duraffour, S; Snoeck, R; Cheng, Y C; Chu, C K; Andrei, G

    2013-04-01

    A novel nucleoside analogue, 1-[(2S,4S-2-(hydroxymethyl)-1,3-dioxolan-4-yl]5-vinylpyrimidine-2,4(1H,3H)-dione, or HDVD, was evaluated against a wide variety of herpesviruses and was found to be a highly selective inhibitor of replication of the gammaherpesviruses Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). HDVD had also a pronounced inhibitory activity against murine herpesvirus 68 (MHV-68) and herpes simplex virus 1 (HSV-1). In contrast, replication of herpesvirus saimiri (HVS), HSV-2, and varicella-zoster virus (VZV) was weakly inhibited by the compound, and no antiviral activity was determined against human cytomegalovirus (HCMV) and rhesus rhadinovirus (RRV). The HDVD-resistant virus phenotype contained point mutations in the viral thymidine kinase (TK) of HSV-1, MHV-68, and HVS isolates. These mutations conferred cross-resistance to other TK-dependent drugs, with the exception of an MHV-68 mutant (E358D) that exhibited resistance only to HDVD. HSV-1 and HVS TK-mutants isolated under selective pressure with bromovinyldeoxyuridine (BVDU) also showed reduced sensitivity to HDVD. Oral treatment with HDVD and BVDU was assessed in an intranasal model of MHV-68 infection in BALB/c mice. In contrast to BVDU treatment, HDVD-treated animals showed a reduction in viral DNA loads and diminished viral gene expression during acute viral replication in the lungs in comparison to levels in untreated controls. The valyl ester prodrug of HDVD (USS-02-71-44) suppressed the latent infection in the spleen to a greater extent than HDVD. In the present study, HDVD emerged as a highly potent antiviral with a unique spectrum of activity against herpesviruses, in particular, gammaherpesviruses, and may be of interest in the treatment of virus-associated diseases.

  19. Combination of interferon alpha with either Ara-C or ATRA in vitro reduces the selective action of interferon against CML CFU-GM.

    Science.gov (United States)

    Marley, S B; Davidson, R J; Goldman, J M; Gordon, M Y

    2000-08-01

    Although interferon (IFN)-alpha has no specific inhibitory effect on the plating efficiency of granulocyte-macrophage colony-forming cells (CFU-GM) from patients with chronic myeloid leukaemia (CML), it does selectively inhibit the replating ability (secondary colony formation) of CML CFU-GM. Thus, amplification of CFU-GM may be a target for IFN-alpha and other agents used in the treatment of CML. Here we examined whether cytarabine (Ara-C) or all-trans retinoic acid (ATRA) exert similar effects and whether they might in combination with IFN-alpha enhance its efficacy. We found that Ara-C preferentially inhibits the formation of CML CFU-GM compared to normal CFU-GM, but this inhibition was not increased by addition of IFN-alpha. When Ara-C was added to cultures containing IFN-alpha, the inhibition of replating by CML progenitors was abrogated. ATRA increased significantly the plating efficiency of normal CFU-GM. The addition of IFN-alpha to ATRA had no effect on CML or normal colony numbers. However, addition of ATRA to cultures containing IFN-alpha reversed the selective inhibition of CML CFU-GM replating seen in cultures containing IFN-alpha alone. In four IFN-alpha/Ara-C experiments, secondary CML patient-derived colonies were examined by fluorescence in situ hybridisation (FISH). All of them were Ph chromosome positive. No significant effects on CFU-GM production were observed when CML primitive haemopoietic progenitor cells were investigated in a delta (delta) assay. Thus we conclude that combining IFN-alpha with Ara-C or ATRA neutralises the effect of IFN-alpha on CML CFU-GM. This observation provides a rationale for treating patients with alternating courses of IFN-alpha and Ara-C or ATRA, rather than giving either of these two agents in combination with IFN-alpha.

  20. Reliability of Search and Rescue Action

    Science.gov (United States)

    Burciu, Zbigniew

    2012-06-01

    Determination of the reliability of Search and Rescue action system allows the SAR Mission Coordinator to increase the effectiveness of the action through the proper selection of operational characteristics of the system elements, in particular the selection of the rescue units and auxiliary units. The paper presents the example of the influence of water temperature and time of the action on the reliability of search and rescue action in the case of rescuing a survivor in the water.

  1. Endocrine-disrupting chemicals and public health protection

    DEFF Research Database (Denmark)

    Zoeller, R Thomas; Brown, T R; Doan, L L

    2012-01-01

    exposures to have potent and irreversible effects. Finally, with regard to the current program designed to detect putative EDC, namely, the Endocrine Disruptor Screening Program, we offer recommendations for strengthening this program through the incorporation of basic endocrine principles to promote......An endocrine-disrupting chemical (EDC) is an exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action. The potential for deleterious effects of EDC must be considered relative to the regulation of hormone synthesis, secretion, and actions and the variability...... in regulation of these events across the life cycle. The developmental age at which EDC exposures occur is a critical consideration in understanding their effects. Because endocrine systems exhibit tissue-, cell-, and receptor-specific actions during the life cycle, EDC can produce complex, mosaic effects...

  2. Lytic polysaccharide monooxygenases disrupt the cellulose fibers structure

    Science.gov (United States)

    Villares, Ana; Moreau, Céline; Bennati-Granier, Chloé; Garajova, Sona; Foucat, Loïc; Falourd, Xavier; Saake, Bodo; Berrin, Jean-Guy; Cathala, Bernard

    2017-01-01

    Lytic polysaccharide monooxygenases (LPMOs) are a class of powerful oxidative enzymes that breakdown recalcitrant polysaccharides such as cellulose. Here we investigate the action of LPMOs on cellulose fibers. After enzymatic treatment and dispersion, LPMO-treated fibers show intense fibrillation. Cellulose structure modifications visualized at different scales indicate that LPMO creates nicking points that trigger the disintegration of the cellulose fibrillar structure with rupture of chains and release of elementary nanofibrils. Investigation of LPMO action using solid-state NMR provides direct evidence of modification of accessible and inaccessible surfaces surrounding the crystalline core of the fibrils. The chains breakage likely induces modifications of the cellulose network and weakens fibers cohesion promoting their disruption. Besides the formation of new initiation sites for conventional cellulases, this work provides the first evidence of the direct oxidative action of LPMOs with the mechanical weakening of the cellulose ultrastructure. LPMOs can be viewed as promising biocatalysts for enzymatic modification or degradation of cellulose fibers. PMID:28071716

  3. Fourier transform infra-red spectroscopy and flow cytometric assessment of the antibacterial mechanism of action of aqueous extract of garlic (Allium sativum) against selected probiotic Bifidobacterium strains.

    Science.gov (United States)

    Booyens, Jemma; Thantsha, Mapitsi Silvester

    2014-08-06

    It is generally reported that garlic (Allium sativum) harms pathogenic but not beneficial bacteria. Although numerous studies supporting the alleged garlic effects on pathogens are available, there are limited studies to prove this claim for beneficial bacteria. We have recently shown that garlic exhibits antibacterial activity against probiotic bifidobacteria. The aim of the current study was to elucidate the mechanism of action of garlic clove extract (GCE) on Bifidobacterium bifidum LMG 11041, B. longum LMG 13197 and B. lactis Bb12 using Fourier transform infrared (FT-IR) spectroscopy and flow cytometry. Cultures (1 × 108 CFU ml-1) were individually incubated for 6 h at 37°C in garlic clove extract containing allicin at a corresponding predetermined minimum bactericidal concentration for each strain. For FTIR, an aliquot of each culture was deposited on CaF2 slide and vacuum dried. The slides were immediately viewed using a Bruker Vertex 70 V FT-IR spectrometer equipped with a Hyperion microscope and data analyzed using OPUS software (version 6, Bruker). Spectra were smoothed with a Savitsky-Goly function algorithim, base-line corrected and normalized. Samples for flow cytometry were stained using the Live/Dead BacLight bacterial viability kit L7012. Data compensation and analysis was performed using a BD FACSAria and FlowJo (version 7.6.1). Fourier transform infrared spectroscopy showed changes in spectral features of lipids and fatty acids in cell membranes, proteins, polysaccharides and nucleic acids. Spectral data as per principle component analysis (PCA) revealed segregation of control and GCE-treated cells for all the tested bifidobacteria. Flow cytometry not only showed increase in numbers of membrane damaged and possibly lysed cells after GCE treatment, but also displayed diffuse light scatter patterns for GCE treated cells, which is evidence for changes to the size, granularity and molecular content of the cells. Garlic has multiple target sites in

  4. Disrupted neuronal maturation in Angelman syndrome-derived induced pluripotent stem cells.

    Science.gov (United States)

    Fink, James J; Robinson, Tiwanna M; Germain, Noelle D; Sirois, Carissa L; Bolduc, Kaitlyn A; Ward, Amanda J; Rigo, Frank; Chamberlain, Stormy J; Levine, Eric S

    2017-04-24

    Angelman syndrome (AS) is a neurogenetic disorder caused by deletion of the maternally inherited UBE3A allele and is characterized by developmental delay, intellectual disability, ataxia, seizures and a happy affect. Here, we explored the underlying pathophysiology using induced pluripotent stem cell-derived neurons from AS patients and unaffected controls. AS-derived neurons showed impaired maturation of resting membrane potential and action potential firing, decreased synaptic activity and reduced synaptic plasticity. These patient-specific differences were mimicked by knocking out UBE3A using CRISPR/Cas9 or by knocking down UBE3A using antisense oligonucleotides. Importantly, these phenotypes could be rescued by pharmacologically unsilencing paternal UBE3A expression. Moreover, selective effects of UBE3A disruption at late stages of in vitro development suggest that changes in action potential firing and synaptic activity may be secondary to altered resting membrane potential. Our findings provide a cellular phenotype for investigating pathogenic mechanisms underlying AS and identifying novel therapeutic strategies.

  5. Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions.

    Science.gov (United States)

    Schopfer, Francisco J; Cole, Marsha P; Groeger, Alison L; Chen, Chen-Shan; Khoo, Nicholas K H; Woodcock, Steven R; Golin-Bisello, Franca; Motanya, U Nkiru; Li, Yong; Zhang, Jifeng; Garcia-Barrio, Minerva T; Rudolph, Tanja K; Rudolph, Volker; Bonacci, Gustavo; Baker, Paul R S; Xu, H Eric; Batthyany, Carlos I; Chen, Y Eugene; Hallis, Tina M; Freeman, Bruce A

    2010-04-16

    The peroxisome proliferator-activated receptor-gamma (PPARgamma) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPARgamma include lipids and anti-hyperglycemic drugs such as thiazolidinediones (TZDs). Recently, TZDs have raised concern after being linked with increased risk of peripheral edema, weight gain, and adverse cardiovascular events. Most reported endogenous PPARgamma ligands are intermediates of lipid metabolism and oxidation that bind PPARgamma with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO(2)-FA) are endogenous products of nitric oxide ((*)NO) and nitrite (NO(2)(-))-mediated redox reactions that activate PPARgamma at nanomolar concentrations. We report that NO(2)-FA act as partial agonists of PPARgamma and covalently bind PPARgamma at Cys-285 via Michael addition. NO(2)-FA show selective PPARgamma modulator characteristics by inducing coregulator protein interactions, PPARgamma-dependent expression of key target genes, and lipid accumulation is distinctively different from responses induced by the TZD rosiglitazone. Administration of this class of signaling mediators to ob/ob mice revealed that NO(2)-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.

  6. Design and synthesis of new benzimidazole-carbazole conjugates for the stabilization of human telomeric DNA, telomerase inhibition, and their selective action on cancer cells.

    Science.gov (United States)

    Maji, Basudeb; Kumar, Krishan; Kaulage, Mangesh; Muniyappa, K; Bhattacharya, Santanu

    2014-08-28

    Cell-permeable small molecules that enhance the stability of the G-quadruplex (G4) DNA structures are currently among the most intensively pursued ligands for inhibition of the telomerase activity. Herein we report the design and syntheses of four novel benzimidazole-carbazole conjugates and demonstrate their high binding affinity to G4 DNA. S1 nuclease assay confirmed the ligand mediated G-quadruplex DNA protection. Additional evidence from Telomeric Repeat Amplification Protocol (TRAP-LIG) assay demonstrated efficient telomerase inhibition activity by the ligands. Two of the ligands showed IC50 values in the sub-micromolar range in the TRAP-LIG assay, which are the best among the benzimidazole derivatives reported so far. The ligands also exhibited cancer cell selective nuclear internalization, nuclear condensation, fragmentation, and eventually antiproliferative activity in long-term cell viability assays. Annexin V-FITC/PI staining assays confirm that the cell death induced by the ligands follows an apoptotic pathway. An insight into the mode of ligand binding was obtained from the molecular dynamics simulations.

  7. Changing perspectives in medical practice: disruptive innovation.

    Science.gov (United States)

    Paterick, Zachary R; Pradhan, Sala R; Paterick, Timothy E; Waterhouse, Blake E

    2009-01-01

    Disruptive innovation represents a business model that identifies a market location and increases consumer options. Retail clinics may represent a disruptive healthcare innovation that identifies strategies to reduce the cost of healthcare at the primary care level. The future of healthcare demands disruptive innovation that will allow for the 50 million uninsured members of our society to receive medical care. Disruptive innovative solutions need to ensure access, quality, and reasonable cost. Retail clinics represent the tip of the iceberg in disruptive innovative thinking. The obstacles that retail clinics must solve will be lessons learned for those that identify future innovative techniques.

  8. From Digital Disruption to Business Model Scalability

    DEFF Research Database (Denmark)

    Nielsen, Christian; Lund, Morten; Thomsen, Peter Poulsen

    2017-01-01

    This article discusses the terms disruption, digital disruption, business models and business model scalability. It illustrates how managers should be using these terms for the benefit of their business by developing business models capable of achieving exponentially increasing returns to scale...... will seldom lead to business model scalability capable of competing with digital disruption(s)....... as a response to digital disruption. A series of case studies illustrate that besides frequent existing messages in the business literature relating to the importance of creating agile businesses, both in growing and declining economies, as well as hard to copy value propositions or value propositions that take...

  9. Effect of membrane structure on the action of polyenes: I. Nystatin action in cholesterol- and ergosterol-containing membranes.

    Science.gov (United States)

    Récamier, K S; Hernández-Gómez, A; González-Damián, J; Ortega-Blake, I

    2010-09-01

    A detailed and thorough characterization of nystatin-induced permeability on lipid bilayers of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)-containing ergosterol or cholesterol is presented. The results show that the same collection of transmembrane pores appears in membranes containing either sterol. The concentration range for the appearance of these pores is sterol-dependent. Another mechanism of action, membrane disruption, is also observed in ergosterol-POPC membranes. The greater potency of nystatin present in ergosterol-containing membranes cannot be explained simply by the longer opening times of its pores, as has been suggested; it is also due to an increased number of events in these membranes. The present results and those of a companion paper lead us to propose that membrane structure is the determining factor for drug selectivity in membranes with different sterols.

  10. Action Emulation

    NARCIS (Netherlands)

    D.J.N. van Eijck (Jan); J. Ruan; T. Sadzik

    2012-01-01

    textabstractThe effects of public announcements, private communications, deceptive messages to groups, and so on, can all be captured by a general mechanism of updating multi-agent models with update action models, now in widespread use. There is a natural extension of the definition of

  11. China's Actions

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    @@ China's National Development and Reform Commission publicized the country's policies and actions for addressing climate change in a report released on November 26,2009.The report highlighted China's efforts in cutting greenhouse gas emissions in 2009 by: (1)Rigorously checking the blind expansion of its energy-and pollution-intensive industries.

  12. Bird populations as sentinels of endocrine disrupting chemicals

    Directory of Open Access Journals (Sweden)

    Claudio Carere

    2010-03-01

    Full Text Available Exposure to endocrine disrupting chemicals (EDCs is a widespread phenomenon in nature. Although the mechanisms of action of EDCs are actively studied, the consequences of endocrine disruption (ED at the population level and the adaptations evolved to cope with chronic EDC exposure have been overlooked. Birds probably represent the animal taxon most successfully adapted to synanthropic life. Hence, birds share with humans a similar pattern of exposure to xenobiotics. In this article, we review case studies on patterns of behaviour that deviate from the expectation in bird species exposed to EDCs. We provide behavioural and ecological parameters to be used as endpoints of ED; methodological requirements and caveats based on species-specific life-history traits, behavioural repertoires, developmental styles, and possibility of captive breeding; a list of species that could be used as sentinels to assess the quality of man-made environment.

  13. Node of Ranvier Disruption as a Cause of Neurological Diseases

    Directory of Open Access Journals (Sweden)

    Keiichiro Susuki

    2013-07-01

    Full Text Available Dysfunction and/or disruption of nodes of Ranvier are now recognized as key contributors to the pathophysiology of various neurological diseases. One reason is that the excitable nodal axolemma contains a high density of Nav (voltage-gated Na+ channels that are required for the rapid and efficient saltatory conduction of action potentials. Nodal physiology is disturbed by altered function, localization, and expression of voltage-gated ion channels clustered at nodes and juxtaparanodes, and by disrupted axon–glial interactions at paranodes. This paper reviews recent discoveries in molecular/cellular neuroscience, genetics, immunology, and neurology that highlight the critical roles of nodes of Ranvier in health and disease.

  14. Multimodal responsive action

    DEFF Research Database (Denmark)

    Oshima, Sae

    While a first pair part projects a limited set of second pair parts to be provided next, responders select different types and formats for second pair parts to assemble activities (Schegloff 2007). Accordingly, various ways of shaping responses have been extensively studied (e.g. Pomerantz 1984......; Raymond 2003; Schegloff and Lerner 2009), including those with multimodal actions (e.g. Olsher 2004; Fasulo & Monzoni 2009). Some responsive actions can also be completed with bodily behavior alone, such as: when an agreement display is achieved by using only nonvocal actions (Jarmon 1996), when...... both verbal and body-behavioral elements. This paper explores one such situation in professional-client interaction, during the event of evaluating a service outcome in a haircutting session. In general, a haircutting session is brought to its closure through the service-assessment sequence, in which...

  15. Action-based flood forecasting for triggering humanitarian action

    Science.gov (United States)

    Coughlan de Perez, Erin; van den Hurk, Bart; van Aalst, Maarten K.; Amuron, Irene; Bamanya, Deus; Hauser, Tristan; Jongma, Brenden; Lopez, Ana; Mason, Simon; Mendler de Suarez, Janot; Pappenberger, Florian; Rueth, Alexandra; Stephens, Elisabeth; Suarez, Pablo; Wagemaker, Jurjen; Zsoter, Ervin

    2016-09-01

    Too often, credible scientific early warning information of increased disaster risk does not result in humanitarian action. With financial resources tilted heavily towards response after a disaster, disaster managers have limited incentive and ability to process complex scientific data, including uncertainties. These incentives are beginning to change, with the advent of several new forecast-based financing systems that provide funding based on a forecast of an extreme event. Given the changing landscape, here we demonstrate a method to select and use appropriate forecasts for specific humanitarian disaster prevention actions, even in a data-scarce location. This action-based forecasting methodology takes into account the parameters of each action, such as action lifetime, when verifying a forecast. Forecasts are linked with action based on an understanding of (1) the magnitude of previous flooding events and (2) the willingness to act "in vain" for specific actions. This is applied in the context of the Uganda Red Cross Society forecast-based financing pilot project, with forecasts from the Global Flood Awareness System (GloFAS). Using this method, we define the "danger level" of flooding, and we select the probabilistic forecast triggers that are appropriate for specific actions. Results from this methodology can be applied globally across hazards and fed into a financing system that ensures that automatic, pre-funded early action will be triggered by forecasts.

  16. Professional Disruption in Health Regulation

    DEFF Research Database (Denmark)

    Hasselbalch, Jacob

    2016-01-01

    How do professions respond to fast-moving technological changes? Disruptive innovations overturn expectations about how markets function and develop, and they often raise moral, legal and scientific concerns among professionals. Sudden technological changes can result in a state of professional...... recent revision to the Tobacco Products Directive. Medical and public health professionals that control tobacco issues were challenged by a coalition of e-cigarette industry representatives, e-cigarette users, and liberal politicians. The challengers drew on the contending norm of harm reduction...

  17. Disruptive Innovation in Numerical Hydrodynamics

    Energy Technology Data Exchange (ETDEWEB)

    Waltz, Jacob I. [Los Alamos National Laboratory

    2012-09-06

    We propose the research and development of a high-fidelity hydrodynamic algorithm for tetrahedral meshes that will lead to a disruptive innovation in the numerical modeling of Laboratory problems. Our proposed innovation has the potential to reduce turnaround time by orders of magnitude relative to Advanced Simulation and Computing (ASC) codes; reduce simulation setup costs by millions of dollars per year; and effectively leverage Graphics Processing Unit (GPU) and future Exascale computing hardware. If successful, this work will lead to a dramatic leap forward in the Laboratory's quest for a predictive simulation capability.

  18. Incumbent response to disruptive innovation

    DEFF Research Database (Denmark)

    Kaulio, Matti; Thorén, Kent; Rohrbeck, René

    changes, however successful in minor business model adaptions. An implication hereof is that the business model concept as such has low predictive power in explaining success and failure and is in the need of an operationalization. In addition, the article discusses the relationship between technological...... in relation to disruptive change. In relation to technical change the case company has successfully in transferred its technology from one generation to the next during more than 20 years. In relation to business model change the case company has been proactive but not successful in major business model...... innovation and business innovation....

  19. Disruptive innovation for social change.

    Science.gov (United States)

    Christensen, Clayton M; Baumann, Heiner; Ruggles, Rudy; Sadtler, Thomas M

    2006-12-01

    Countries, organizations, and individuals around the globe spend aggressively to solve social problems, but these efforts often fail to deliver. Misdirected investment is the primary reason for that failure. Most of the money earmarked for social initiatives goes to organizations that are structured to support specific groups of recipients, often with sophisticated solutions. Such organizations rarely reach the broader populations that could be served by simpler alternatives. There is, however, an effective way to get to those underserved populations. The authors call it "catalytic innovation." Based on Clayton Christensen's disruptive-innovation model, catalytic innovations challenge organizational incumbents by offering simpler, good-enough solutions aimed at underserved groups. Unlike disruptive innovations, though, catalytic innovations are focused on creating social change. Catalytic innovators are defined by five distinct qualities. First, they create social change through scaling and replication. Second, they meet a need that is either overserved (that is, the existing solution is more complex than necessary for many people) or not served at all. Third, the products and services they offer are simpler and cheaper than alternatives, but recipients view them as good enough. Fourth, they bring in resources in ways that initially seem unattractive to incumbents. And fifth, they are often ignored, put down, or even encouraged by existing organizations, which don't see the catalytic innovators' solutions as viable. As the authors show through examples in health care, education, and economic development, both nonprofit and for-profit groups are finding ways to create catalytic innovation that drives social change.

  20. The antimicrobial polymer PHMB enters cells and selectively condenses bacterial chromosomes

    DEFF Research Database (Denmark)

    Chindera, Kantaraja; Mahato, Manohar; Sharma, Ashwani Kumar

    2016-01-01

    To combat infection and antimicrobial resistance, it is helpful to elucidate drug mechanism(s) of action. Here we examined how the widely used antimicrobial polyhexamethylene biguanide (PHMB) kills bacteria selectively over host cells. Contrary to the accepted model of microbial membrane disruption...... by PHMB, we observed cell entry into a range of bacterial species, and treated bacteria displayed cell division arrest and chromosome condensation, suggesting DNA binding as an alternative antimicrobial mechanism. A DNA-level mechanism was confirmed by observations that PHMB formed nanoparticles when...... to bacterial and mammalian cellular DNA and selectively binds and condenses bacterial chromosomes. Because acquired resistance to PHMB has not been reported, selective chromosome condensation provides an unanticipated paradigm for antimicrobial action that may not succumb to resistance....

  1. Endocrine disrupting compounds and echinoderms: new ecotoxicological sentinels for the marine ecosystem.

    Science.gov (United States)

    Sugni, Michela; Mozzi, Daniela; Barbaglio, Alice; Bonasoro, Francesco; Candia Carnevali, Maria Daniela

    2007-02-01

    Echinoderms are valuable test species in marine ecotoxicology and offer a wide range of biological processes appropriate for this approach. In spite of this potential, available data in literature are still rather limited, particularly with regard to the possible effects of endocrine disrupter compounds (EDCs). This review presents echinoderms as useful models for ecotoxicological tests and gives a brief overview of the most significant results obtained in recent years, particularly in the context of the COMPRENDO EU project. In this research project two different aspects of echinoderm physiology, plausibly regulated by humoral mechanisms, were investigated: reproductive biology and regenerative development. Selected EDCs suspected for their androgenic or antiandrogenic action were tested at low concentrations. The results obtained so far showed that different parameters such as regenerative growth, histological pattern, egg diameter and gonad maturation were affected by the exposure to the selected compounds. These results substantiate that reproductive and regenerative phenomena of echinoderms can be considered valuable alternative models for studies on EDCs and confirm that these compounds interfere with fundamental physiological processes, including growth, development and reproductive competence.

  2. Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors

    Science.gov (United States)

    Sukhai, Mahadeo A.; Prabha, Swayam; Hurren, Rose; Rutledge, Angela C.; Lee, Anna Y.; Sriskanthadevan, Shrivani; Sun, Hong; Wang, Xiaoming; Skrtic, Marko; Seneviratne, Ayesh; Cusimano, Maria; Jhas, Bozhena; Gronda, Marcela; MacLean, Neil; Cho, Eunice E.; Spagnuolo, Paul A.; Sharmeen, Sumaiya; Gebbia, Marinella; Urbanus, Malene; Eppert, Kolja; Dissanayake, Dilan; Jonet, Alexia; Dassonville-Klimpt, Alexandra; Li, Xiaoming; Datti, Alessandro; Ohashi, Pamela S.; Wrana, Jeff; Rogers, Ian; Sonnet, Pascal; Ellis, William Y.; Corey, Seth J.; Eaves, Connie; Minden, Mark D.; Wang, Jean C.Y.; Dick, John E.; Nislow, Corey; Giaever, Guri; Schimmer, Aaron D.

    2012-01-01

    Despite efforts to understand and treat acute myeloid leukemia (AML), there remains a need for more comprehensive therapies to prevent AML-associated relapses. To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the antimalarial agent mefloquine as a compound that selectively kills AML cells and AML stem cells in a panel of leukemia cell lines and in mice. Using a yeast genome-wide functional screen for mefloquine sensitizers, we identified genes associated with the yeast vacuole, the homolog of the mammalian lysosome. Consistent with this, we determined that mefloquine disrupts lysosomes, directly permeabilizes the lysosome membrane, and releases cathepsins into the cytosol. Knockdown of the lysosomal membrane proteins LAMP1 and LAMP2 resulted in decreased cell viability, as did treatment of AML cells with known lysosome disrupters. Highlighting a potential therapeutic rationale for this strategy, leukemic cells had significantly larger lysosomes compared with normal cells, and leukemia-initiating cells overexpressed lysosomal biogenesis genes. These results demonstrate that lysosomal disruption preferentially targets AML cells and AML progenitor cells, providing a rationale for testing lysosomal disruption as a novel therapeutic strategy for AML. PMID:23202731

  3. Disruption of overshadowing and latent inhibition in high schizotypy individuals.

    Science.gov (United States)

    Granger, K T; Prados, J; Young, A M J

    2012-07-15

    Deficits in selective attention are seen in positively symptomatic schizophrenia sufferers, and in normal people displaying schizotypal traits. We investigated the relationship between selective attention and schizotypy in undergraduate students, by comparing participants' performance in two models of selective attention, overshadowing and latent inhibition, with psychoticism scores derived from the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). Using a novel within-subject overshadowing task, we showed that the unusual experiences dimension of schizotypy, but not the other three O-LIFE dimensions, was negatively related to overshadowing score. We also replicated findings that the unusual experiences dimension of schizotypy was negatively related to latent inhibition score. These experiments provide evidence that selective attention is disrupted in normal individuals showing traits relating to positive-like schizophrenic symptoms, and has implications for interpreting selective attention deficits measured in schizophrenia patients.

  4. Synergistic Disruption of External Male Sex Organ Development by a Mixture of Four Antiandrogens

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Scholze, Martin; Dalgaard, Majken;

    2009-01-01

    are not well described, especially when they exert their actions by differing molecular mechanisms. Objectives: To fill this gap, we investigated the effects of mixtures of a widely used plasticizer, di(2-ethylhexyl) phthalate (DEHP), two fungicides present in food, vinclozolin and prochloraz......By disrupting the action of androgens during gestation, certain chemicals present in food, consumer products and the environment can induce irreversible demasculinisation and malformations of sex organs among male offspring. However, the consequences of simultaneous exposure to such chemicals...

  5. Manufacturing doubt about endocrine disrupter science

    DEFF Research Database (Denmark)

    Bergman, Åke; Becher, Georg; Blumberg, Bruce;

    2015-01-01

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption...... not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity....

  6. Catastrophic Disruption of Comet ISON

    Science.gov (United States)

    Keane, Jacqueline V.; Milam, Stefanie N.; Coulson, Iain M.; Kleyna, Jan T.; Sekanina, Zdenek; Kracht, Rainer; Riesen, Timm-Emmanuel; Meech, Karen J.; Charnley, Steven B.

    2016-01-01

    We report submillimeter 450 and 850 microns dust continuum observations for comet C/2012 S1 (ISON) obtained at heliocentric distances 0.31-0.08 au prior to perihelion on 2013 November 28 (rh?=?0.0125 au). These observations reveal a rapidly varying dust environment in which the dust emission was initially point-like. As ISON approached perihelion, the continuum emission became an elongated dust column spread out over as much as 60? (greater than 10(exp 5) km in the anti-solar direction. Deconvolution of the November 28.04 850 microns image reveals numerous distinct clumps consistent with the catastrophic disruption of comet ISON, producing approximately 5.2?×?10(exp 10) kg of submillimeter-sized dust. Orbital computations suggest that the SCUBA-2 emission peak coincides with the comet's residual nucleus.

  7. Disrupting Entanglement of Black Holes

    CERN Document Server

    Leichenauer, Stefan

    2014-01-01

    We study entanglement in thermofield double states of strongly coupled CFTs by analyzing two-sided Reissner-Nordstrom solutions in AdS. The central object of study is the mutual information between a pair of regions, one on each asymptotic boundary of the black hole. For large regions the mutual information is positive and for small ones it vanishes; we compute the critical length scale, which goes to infinity for extremal black holes, of the transition. We also generalize the butterfly effect of Shenker and Stanford to a wide class of charged black holes, showing that mutual information is disrupted upon perturbing the system and waiting for a time of order $\\log E/\\delta E$ in units of the temperature. We conjecture that the parametric form of this timescale is universal.

  8. The quality and economic impact of disruptive behaviors on clinical outcomes of patient care.

    Science.gov (United States)

    Rosenstein, Alan H

    2011-01-01

    Disruptive behaviors have been shown to have a negative impact on work relationships, team collaboration, communication efficiency, and process flow, all of which can adversely affect patient safety and quality of care. Despite the growing recognition of the damage that can be done, there are still pockets of resistance to taking action to address the issue head-on. Given the new call to action from the Joint Commission accreditation standard and the growing public accountability for patient safety, organizations need to recognize the full impact of disruptive behaviors and implement appropriate policies, procedures, and educational programs to raise levels of awareness regarding the seriousness of the issue, hold individuals accountable for their behavior, and provide training and support not only to reduce the incidence and consequences of disruptive events but also to improve efficiency of communication and team collaboration in an effort to improve outcomes of care.

  9. Action priors for learning domain invariances

    CSIR Research Space (South Africa)

    Rosman, Benjamin S

    2015-04-01

    Full Text Available , defined as distributions over the action space, conditioned on environment state, and show how these can be learnt from a set of value functions. We apply action priors in the setting of reinforcement learning, to bias action selection during exploration...

  10. Resistance to disruption in a classroom setting.

    Science.gov (United States)

    Parry-Cruwys, Diana E; Neal, Carrie M; Ahearn, William H; Wheeler, Emily E; Premchander, Raseeka; Loeb, Melissa B; Dube, William V

    2011-01-01

    Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple variable-interval (VI) 7-s VI 30-s schedule for 6 participants with developmental disabilities. Resistance to disruption was measured by presenting a distracting item. Response rates in the disruption components were compared to within-session response rates in prior baseline components. Results were consistent with the predictions of behavioral momentum theory for 5 of 6 participants.

  11. Tumor vascular disruption using various radiation types

    Directory of Open Access Journals (Sweden)

    JJ Bevelacqua

    2014-04-01

    Full Text Available The feasibility of disrupting a tumor’s vascular structure with various radiation types and radionuclides is investigated. Calculated absorbed dose profiles for photons and 4He ions suggest that low-energy beta-gamma and alpha emitting radionuclides can deposit sufficient absorbed dose to disrupt a tumor’s vascular structure while minimizing the dose outside the blood vessel. Candidate radionuclides uniformly distributed in microspheres are theoretically investigated with respect to their vascular disruption potential and to offer an alternative to 90Y microsphere therapy. Requisite activities of candidate low-energy beta-gamma and alpha emitting radionuclides to facilitate vascular disruption are calculated.

  12. Automatic location of disruption times in JET.

    Science.gov (United States)

    Moreno, R; Vega, J; Murari, A

    2014-11-01

    The loss of stability and confinement in tokamak plasmas can induce critical events known as disruptions. Disruptions produce strong electromagnetic forces and thermal loads which can damage fundamental components of the devices. Determining the disruption time is extremely important for various disruption studies: theoretical models, physics-driven models, or disruption predictors. In JET, during the experimental campaigns with the JET-C (Carbon Fiber Composite) wall, a common criterion to determine the disruption time consisted of locating the time of the thermal quench. However, with the metallic ITER-like wall (JET-ILW), this criterion is usually not valid. Several thermal quenches may occur previous to the current quench but the temperature recovers. Therefore, a new criterion has to be defined. A possibility is to use the start of the current quench as disruption time. This work describes the implementation of an automatic data processing method to estimate the disruption time according to this new definition. This automatic determination allows both reducing human efforts to locate the disruption times and standardizing the estimates (with the benefit of being less vulnerable to human errors).

  13. Dipolarization front and current disruption

    Science.gov (United States)

    Lui, A. T. Y.

    2016-10-01

    The modification of current density on the dawn-dusk cross section of the magnetotail with the earthward approach of a dipolarization front (DF) is examined through the recently published results of a three-dimensional (3-D) particle-in-cell (PIC) simulation. It is found that the current density intensifies by 37% abruptly within 1.5 ion gyrotime as the DF approaches and shows localized regions with north-south extrusions. After reaching its peak value, it undergoes a drastic current reduction (DCR) by 65% within 2 ion gyrotime. Breakdown of the frozen-in condition occurs in the neutral sheet region in association with DCR, demonstrating the non-MHD behavior of the phenomenon. The evolution of current density from this 3-D PIC simulation bears several similarities to those observed for the current disruption (CD) phenomenon, such as explosive growth and disruption of the current density leading to a breakdown of the frozen-in condition. The evolution is also similar to those from a previous two-dimensional (2-D) PIC simulation specially designed to investigate the nonlinear evolution of the cross-field current instability for CD. One interpretation of these findings is that CD and substorm triggering can be associated with earthward intrusion of a DF into the near-Earth plasma sheet as indicated by previous Cluster and Time History of Events and Macroscale Interactions during Substorms observations. An alternative interpretation is that both DF and CD are consequences of a global evolution from an ion-tearing-like instability of the magnetotail.

  14. In vitro profiling of the endocrine-disrupting potency of brominated flame retardants

    NARCIS (Netherlands)

    Hamers, T.H.M.; Kamstra, J.H.; Sonneveld, E.; Murk, A.J.; Kester, M.H.A.; Andersson, P.L.; Legler, J.; Brouwer, A.

    2006-01-01

    Over the last years, increasing evidence has become available that some brominated flame retardants (BFRs) may have endocrine disrupting (ED) potencies. The goal of the current study was to perform a systematic in vitro screening of the ED potencies of BFRs (1) to elucidate possible modes of action

  15. In vitro profiling of the endocrine-disrupting potency of brominated flame retardants

    NARCIS (Netherlands)

    Hamers, T.H.M.; Kamstra, J.H.; Sonneveld, E.; Murk, A.J.; Kester, M.H.A.; Andersson, P.L.; Legler, J.; Brouwer, A.

    2006-01-01

    Over the last years, increasing evidence has become available that some brominated flame retardants (BFRs) may have endocrine disrupting (ED) potencies. The goal of the current study was to perform a systematic in vitro screening of the ED potencies of BFRs (1) to elucidate possible modes of action

  16. Action Learning: Avoiding Conflict or Enabling Action

    Science.gov (United States)

    Corley, Aileen; Thorne, Ann

    2006-01-01

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

  17. Deiodinases and thyroid metabolism disruption in teleost fish.

    Science.gov (United States)

    Jarque, Sergio; Piña, Benjamin

    2014-11-01

    Many xenobiotic compounds with endocrine disrupting activity have been described since the late eighties. These compounds are able to interact with natural hormone systems and potentially induce deleterious effects in wildlife, notably piscine species. However, while the characterization of endocrine disruptors with "dioxin-like", estrogenic or androgenic activities is relatively well established, little is known about environmentally relevant pollutants that may act at thyroid system level. Iodothyronine deiodinases, the key enzymes in the activation and inactivation of thyroid hormones, have been suggested as suitable biomarkers for thyroid metabolism disruption. The present article reviews the biotic and abiotic factors that are able to modulate deiodinases in teleosts, a representative model organism for vertebrates. Data show that deiodinases are highly sensitive to several physiological and physical variables, so they should be taken into account to establish natural basal deiodination patterns to further understand responses under chemical exposure. Among xenobiotic compounds, brominated flame retardants are postulated as chemicals of major concern because of their similar structure shared with thyroid hormones. More ambiguous results are shown for the rest of compounds, i.e. polychlorinated biphenyls, perfluorinated chemicals, pesticides, metals and synthetic drugs, in part due to the limited information available. The different mechanisms of action still remain unknown for most of those compounds, although several hypothesis based on observed effects are discussed. Future tasks are also suggested with the aim of moving forward in the full characterization of chemical compounds with thyroid disrupting activity. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Perceptual and performance biases in action selection

    NARCIS (Netherlands)

    Wilson, A.; van Bergen, E.; van Swieten, L.; Kent, S.; Mon-Williams, M.

    2008-01-01

    When we see an object in the world, there may be a large number of different ways to interact with that object. This large 'visuomotor space' can be constrained through affordances (perceptually available object properties defining potential uses), task demands and the actor's intentions. The effect

  19. Perceptual and performance biases in action selection

    OpenAIRE

    2008-01-01

    When we see an object in the world, there may be a large number of different ways to interact with that object. This large 'visuomotor space' can be constrained through affordances (perceptually available object properties defining potential uses), task demands and the actor's intentions. The effects of perceptual biases can be modified by performance factors, such as a limb's end-state-comfort (ESC; Rosenbaum et al. 1990). We investigated how two other potential performance biases affected i...

  20. Organizational and activational effects of estrogenic endocrine disrupting chemicals

    Directory of Open Access Journals (Sweden)

    Silbergeld Ellen K.

    2002-01-01

    Full Text Available Endocrine disruption is a hypothesis of common mode of action that may define a set of structurally varied chemicals, both natural and synthetic. Their common mode of action may suggest that they produce or contribute to similar toxic effects, although this has been difficult to demonstrate. Insights from developmental biology suggest that development of hormone sensitive systems, such as the brain and the genitourinary tract, may be particularly sensitive to EDCs. Because these systems are both organized and later activated by hormones, the brain and vagina may be valuable model systems to study the toxicity of EDCs in females and to elucidate mechanisms whereby early exposures appear to affect long term function.

  1. Substances that disrupt thyroid hormone biosynthesis (in Romanian

    Directory of Open Access Journals (Sweden)

    Pap, Andreea

    2015-06-01

    Full Text Available Endocrine disrupters are natural or synthetic chemical substances that have the possibility to alter the endocrine functions leading to serious metabolic changes especially in newborns. The accumulation and persistence over long periods of time became a priority in terms of health and environment. The mechanism of action is represented by blocking, mimicking or modifying the effects of thyroid hormones. In this review, the main purpose was to determine what effects have the endocrine disruptors on the thyroid gland, especially on the thyroid hormone biosynthesis and setting the stage involved by it. We focused on the action of perchlorates, phthalates, BPC, PDPEs, soy, isoflavones, nitrates, thiocyanates, bisphenol A and triclorsan and came to the conclusion that their intervention can result in either hyperthyroidism or hypothyroidism.

  2. Altering sensorimotor feedback disrupts visual discrimination of facial expressions.

    Science.gov (United States)

    Wood, Adrienne; Lupyan, Gary; Sherrin, Steven; Niedenthal, Paula

    2016-08-01

    Looking at another person's facial expression of emotion can trigger the same neural processes involved in producing the expression, and such responses play a functional role in emotion recognition. Disrupting individuals' facial action, for example, interferes with verbal emotion recognition tasks. We tested the hypothesis that facial responses also play a functional role in the perceptual processing of emotional expressions. We altered the facial action of participants with a gel facemask while they performed a task that involved distinguishing target expressions from highly similar distractors. Relative to control participants, participants in the facemask condition demonstrated inferior perceptual discrimination of facial expressions, but not of nonface stimuli. The findings suggest that somatosensory/motor processes involving the face contribute to the visual perceptual-and not just conceptual-processing of facial expressions. More broadly, our study contributes to growing evidence for the fundamentally interactive nature of the perceptual inputs from different sensory modalities.

  3. Memory Disrupting Effects of Nonmuscle Myosin II Inhibition Depend on the Class of Abused Drug and Brain Region

    Science.gov (United States)

    Briggs, Sherri B.; Blouin, Ashley M.; Young, Erica J.; Rumbaugh, Gavin; Miller, Courtney A.

    2017-01-01

    Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared…

  4. Memory Disrupting Effects of Nonmuscle Myosin II Inhibition Depend on the Class of Abused Drug and Brain Region

    Science.gov (United States)

    Briggs, Sherri B.; Blouin, Ashley M.; Young, Erica J.; Rumbaugh, Gavin; Miller, Courtney A.

    2017-01-01

    Depolymerizing actin in the amygdala through nonmuscle myosin II inhibition (NMIIi) produces a selective, lasting, and retrieval-independent disruption of the storage of methamphetamine-associated memories. Here we report a similar disruption of memories associated with amphetamine, but not cocaine or morphine, by NMIIi. Reconsolidation appeared…

  5. Small is useful in endocrine disrupter assessment--four key recommendations for aquatic invertebrate research.

    Science.gov (United States)

    Hutchinson, Thomas H

    2007-02-01

    As we enter the 21st "biocentury", with issues such as biodiversity and biotechnology growing in public profile, it is important to reflect on the immense ecological, medical and economic importance of invertebrates. Efforts to understand the diverse biology of invertebrates come from many directions, including Nobel Prize winning developmental biology, research to control insects that threaten human health and food supplies, aquaculture opportunities and also within ecotoxicology. In the latter context, this special journal volume highlights the importance of addressing endocrine disruption in aquatic invertebrates, from molecular and cellular biomarkers to population-relevant adverse effects. The contributors to this special volume have provided an excellent assessment of both the fundamental endocrinology and applied ecotoxicology of many aquatic invertebrate groups. On the premise that reproductive success is ultimately the vital population parameter, this chapter gives a personal view of key gaps in knowledge in invertebrate reproductive and developmental endocrinology and ecotoxicology. Based on current knowledge, there are four key issues that need to be prioritised within aquatic ecotoxicology: (1) a wider assessment of the reproductive status of invertebrates in both freshwater and coastal ecosystems; (2) prioritisation of laboratory studies in OECD and other regulatory test organisms, including basic endocrinology and ADME (absorption, distribution, metabolism and excretion) research; (3) development and validation of mechanistic biomarkers that can be used as "signposts" to help prioritise species and chronic test endpoint selection, and help link data from laboratory and field studies; and (4) develop a comparative invertebrate toxicology database utilising the prioritised reference chemicals from the EDIETA workshop, encompassing the diverse modes-of-action pertinent to endocrine disrupter testing in both aquatic arthropod and non

  6. Generation of gene disruptions by transcription activator-like effector nucleases (TALENs) in Xenopus tropicalis embryos

    OpenAIRE

    Lei, Yong; Guo, Xiaogang; Deng, Yi; Chen, Yonglong; Zhao, Hui

    2013-01-01

    Transcription activator-like effector nucleases (TALENs) are novel engineered DNA nucleases, and have been proven to be effective for gene specific targeting in various species. Recently we reported gene disruptions in Xenopus embryos by using TALENs. Here we summarize the protocol that is used in our studies for gene disruption. This protocol covers selection of TALEN targeting sites, TALEN assembly with a modified Golden Gate method, and injection of TALEN mRNAs into Xenopus tropicalis embr...

  7. Classroom discipline skills and disruption rate: A correlational study

    Science.gov (United States)

    Dropik, Melonie Jane

    Very little has been done to quantify the relationship between the frequency with which teachers use discipline skills and disruption rate in high school settings. Most of the available research that examined this relationship empirically was done in elementary schools, while a few studies examined the junior high school setting. The present research examined whether the use of ten specific discipline skills were related to the rate of disruption in suburban high school science classrooms. The ten skills were selected based on their prevalence in the theoretical literature and the strength of the relationships reported in empirical studies of elementary and junior high classrooms. Each relationship was tested directionally at alpha = .01. The maximum experimentwise Type I error rate was .10. Disruption rate was measured by trained observers over five class periods in the Fall of the school year. The frequency of performing the ten skills was assessed using a student survey developed for this study. The ten skills were: (1) beginning class on time, (2) using routines, (3) waiting for student attention before speaking, (4) giving clear directions, (5) presenting material fast enough to hold students' attention, (6) requiring students to remain seated, (7) appearing confident, (8) stopping misbehavior quickly, (9) checking for student attentiveness, and (10) teaching to the bell. Appearing confident (r = --.697, p = .004) and quickly stopping misbehavior (r = --.709, p = .003) were significantly negatively related to disruption rate. The effect sizes for the confidence and stopping misbehavior variables were .49 and .50, respectively. At least half of the variation in disruption rate was attributable to the difference in the frequency of appearing confident and stopping misbehavior quickly. The eight other relationships produced nonsignificant results. The results raise questions about whether theories developed from observational and anecdotal evidence gathered in

  8. Action-effect bindings and ideomotor learning in intention- and stimulus-based actions

    Directory of Open Access Journals (Sweden)

    Arvid eHerwig

    2012-10-01

    Full Text Available According to ideomotor theory, action-effect associations are crucial for voluntary action control. Recently, a number of studies started to investigate the conditions that mediate the acquisition and application of action-effect associations by comparing actions carried out in response to exogenous stimuli (stimulus-based with actions selected endogenously (intention-based. There is evidence that the acquisition and/or application of action-effect associations is boosted when acting in an intention-based action mode. For instance, bidirectional action-effect associations were diagnosed in a forced choice test phase if participants previously experienced action-effect couplings in an intention-based but not in a stimulus-based action mode. The present study aims at investigating effects of the action mode on action-effect associations in more detail. In a series of experiments, we compared the strength and durability of short-term action-effect associations (binding immediately following intention- as well as stimulus-based actions. Moreover, long-term action-effect associations (learning were assessed in a subsequent test phase. Our results show short-term action-effect associations of equal strength and durability for both action modes. However, replicating previous results, long-term associations were observed only following intention-based actions. These findings indicate that the effect of the action mode on long-term associations cannot merely be a result of accumulated short-term action-effect bindings. Instead, only those episodic bindings are selectively perpetuated or retrieved that integrate action-relevant aspects of the processing event, i.e., in case of intention-based actions, the link between action and ensuing effect.

  9. Endocrine disrupting pesticides: implications for risk assessment.

    Science.gov (United States)

    McKinlay, R; Plant, J A; Bell, J N B; Voulvoulis, N

    2008-02-01

    Endocrine disrupting (ED) chemicals are compounds that alter the normal functioning of the endocrine system, potentially causing disease or deformity in organisms and their offspring. Pesticides are used widely to kill unwanted organisms in crops, public areas, homes and gardens and medicinally to kill parasites. Many are proven or suspected to be EDs. Ancient physiological similarities between different vertebrate groups suggest that disorders observed in wildlife may indicate risks to humans. This makes accurate risk assessment and effective legislation difficult. In this paper, the hazardous properties of pesticides which are known to have ED properties are reviewed in order to assess the implications for risk assessment. As well as data on sources of exposure in the United Kingdom (UK) an assessment of the evidence on the health effects of ED pesticides is also included. In total, 127 have been identified from the literature and their effects and modes of action are listed in this paper. Using the UK as a case study, the types and quantities of pesticides used, and their methods of application are assessed, along with their potential pathways to humans. In the UK reliable data are available only for agricultural use, so non-agricultural routes of pesticide exposure have been poorly quantified. The exposure of people resident in or visiting rural areas could also have been grossly under-estimated. Material links between ED pesticide use and specific illnesses or deformities are complicated by the multifactorial nature of disease, which can be affected by factors such as diet. Despite these difficulties, a large body of evidence has accumulated linking specific conditions to ED pesticides in wildlife and humans. A more precautionary approach to the use of ED pesticides, especially for non-essential purposes is proposed.

  10. Neuroimaging findings in disruptive behavior disorders.

    Science.gov (United States)

    Baker, Rosalind H; Clanton, Roberta L; Rogers, Jack C; De Brito, Stéphane A

    2015-08-01

    Decades of research have shown that youths with disruptive behavior disorders (DBD) are a heterogeneous population. Over the past 20 years, researchers have distinguished youths with DBD as those displaying high (DBD/HCU) versus low (DBD/LCU) callous-unemotional (CU) traits. These traits include flat affect and reduced empathy and remorse, and are associated with more severe, varied, and persistent patterns of antisocial behavior and aggression. Conduct problems in youths with HCU and LCU are thought to reflect distinct causal vulnerabilities, with antisocial behavior in youths with DBD/HCU reflecting a predominantly genetic etiology, while antisocial behavior in youths with DBD/LCU is associated primarily with environmental influences. Here we selectively review recent functional (fMRI) and structural (sMRI) magnetic resonance imaging research on DBD, focusing particularly on the role of CU traits. First, fMRI studies examining the neural correlates of affective stimuli, emotional face processing, empathy, theory of mind, morality, and decision-making in DBD are discussed. This is followed by a review of the studies investigating brain structure and structural connectivity in DBD. Next, we highlight the need to further investigate females and the role of sex differences in this population. We conclude the review by identifying potential clinical implications of this research.

  11. Manufacturing doubt about endocrine disrupter science

    DEFF Research Database (Denmark)

    Bergman, Åke; Becher, Georg; Blumberg, Bruce

    2015-01-01

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is b...

  12. Thyroid effects of endocrine disrupting chemicals

    DEFF Research Database (Denmark)

    Boas, Malene; Feldt-Rasmussen, Ulla; Main, Katharina M

    2012-01-01

    In recent years, many studies of thyroid-disrupting effects of environmental chemicals have been published. Of special concern is the exposure of pregnant women and infants, as thyroid disruption of the developing organism may have deleterious effects on neurological outcome. Chemicals may exert ...

  13. Disruption Management in Passenger Railway Transportation

    DEFF Research Database (Denmark)

    Groth, Julie Jespersen; Potthoff, Daniel; Clausen, Jens

    2009-01-01

    This paper deals with disruption management in passenger railway transportation. In the disruption management process, many actors belonging to different organizations play a role. In this paper we therefore describe the process itself and the roles of the different actors. Furthermore, we discuss...

  14. Resistance to Disruption in a Classroom Setting

    Science.gov (United States)

    Parry-Cruwys, Diana E.; Neal, Carrie M.; Ahearn, William H.; Wheeler, Emily E.; Premchander, Raseeka; Loeb, Melissa B.; Dube, William V.

    2011-01-01

    Substantial experimental evidence indicates that behavior reinforced on a denser schedule is more resistant to disruption than is behavior reinforced on a thinner schedule. The present experiment studied resistance to disruption in a natural educational environment. Responding during familiar activities was reinforced on a multiple…

  15. Filial attachment and its disruption: insights from the guinea pig.

    Science.gov (United States)

    Hennessy, Michael B

    2014-12-01

    Guinea pigs are precocial rodents that show evidence of a selective attachment to the mother who, in turn, exhibits little active maternal care. Effects of separation in guinea pigs are, therefore, more likely to reflect the disruption of attachment than the removal of, or alterations in, patterns of maternal care. Here, effects in guinea pigs of the presence or absence of the mother on psychobiological endpoints and of maternal separation on depressive-like behavior are reviewed. It is argued that results with guinea pigs often align more closely with those of nonhuman primates than those of laboratory rats and mice, and that the guinea pig offers a valuable translational model for studies of the consequences of attachment and its disruption.

  16. Antimicrobial peptide action on parasites.

    Science.gov (United States)

    Torrent, Marc; Pulido, David; Rivas, Luis; Andreu, David

    2012-08-01

    Diseases caused by protozoan parasites can pose a severe thread to human health and are behind some serious neglected tropical diseases like malaria and leishmaniasis. Though several different drugs have been developed in order to eradicate these diseases, a successful candidate has not yet been discovered. Among the most active compounds tested, antimicrobial peptides (AMPs) are particularly appealing because of their wide spectrum of action. AMPs have been described to perturb protozoan homeostasis by disrupting the cellular membranes but also by interfering with key processes in the parasite metabolism. In this review we describe the diverse mechanisms of action of AMPs on protozoan targets and how they can be exploited to treat diseases. Moreover, we describe with detail the antimicrobial action of AMPs on two major parasitical infections: leishmaniasis and malaria. All the features reviewed here show that AMPs are promising drugs to target protozoan parasites and that further understanding of the mechanism of action of these compounds will lead to improved drugs that could be worth to test in a clinical phase.

  17. American Samoa Energy Action Plan

    Energy Technology Data Exchange (ETDEWEB)

    Haase, Scott [National Renewable Energy Lab. (NREL), Golden, CO (United States); Esterly, Sean [National Renewable Energy Lab. (NREL), Golden, CO (United States); Herdrich, David [National Renewable Energy Lab. (NREL), Golden, CO (United States); Bodell, Tim [National Renewable Energy Lab. (NREL), Golden, CO (United States); Visser, Charles [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2013-08-01

    Describes the five near-term strategies selected by the American Samoa Renewable Energy Committee (ASREC) during action planning workshops conducted in May 2013, and outlines the actions being taken to implement those strategies. Each option is tied to a priority identified in the earlier draft American Samoa Strategic Energy Plan as being an essential component of reducing American Samoa'spetroleum energy consumption. The actions described for each strategy provide a roadmap to facilitate the implementation of each strategy. This document is intended to evolve along with the advancement of the projects, and will be updated to reflect progress.

  18. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2

    Directory of Open Access Journals (Sweden)

    Lan eYe

    2012-09-01

    Full Text Available Rapamycin, an inhibitor of mTOR complex 1 (mTORC1, improves insulin sensitivity in acute studies in vitro and in vivo by disrupting a negative feedback loop mediated by S6 kinase. We find that rapamycin has a clear biphasic effect on insulin sensitivity in C2C12 myotubes, with enhanced responsiveness during the first hour that declines to almost complete insulin resistance by 24-48 hours. We and others have recently observed that chronic rapamycin treatment induces insulin resistance in rodents, at least in part due to disruption of mTORC2, an mTOR-containing complex that is not acutely sensitive to the drug. Chronic rapamycin treatment may also impair insulin action via the inhibition of mTORC1-dependent mitochondrial biogenesis and activity, which could result in a buildup of lipid intermediates that are known to trigger insulin resistance. We confirmed that rapamycin inhibits expression of PGC-1α, a key mitochondrial transcription factor, and acutely reduces respiration rate in myotubes. However, rapamycin did not stimulate phosphorylation of PKCθ, a central mediator of lipid-induced insulin resistance. Instead, we found dramatic disruption of mTORC2, which coincided with the onset of insulin resistance. Selective inhibition of mTORC1 or mTORC2 by shRNA-mediated knockdown of specific components (Raptor and Rictor, respectively confirmed that mitochondrial effects of rapamycin are mTORC1-dependent, whereas insulin resistance was recapitulated only by knockdown of mTORC2. Thus, mTORC2 disruption, rather than inhibition of mitochondria, causes insulin resistance in rapamycin-treated myotubes, and this system may serve as a useful model to understand the effects of rapamycin on mTOR signaling in vivo.

  19. Microalgal cell disruption via ultrasonic nozzle spraying.

    Science.gov (United States)

    Wang, M; Yuan, W

    2015-01-01

    The objective of this study was to understand the effect of operating parameters, including ultrasound amplitude, spraying pressure, nozzle orifice diameter, and initial cell concentration on microalgal cell disruption and lipid extraction in an ultrasonic nozzle spraying system (UNSS). Two algal species including Scenedesmus dimorphus and Nannochloropsis oculata were evaluated. Experimental results demonstrated that the UNSS was effective in the disruption of microalgal cells indicated by significant changes in cell concentration and Nile red-stained lipid fluorescence density between all treatments and the control. It was found that increasing ultrasound amplitude generally enhanced cell disruption and lipid recovery although excessive input energy was not necessary for best results. The effect of spraying pressure and nozzle orifice diameter on cell disruption and lipid recovery was believed to be dependent on the competition between ultrasound-induced cavitation and spraying-generated shear forces. Optimal cell disruption was not always achieved at the highest spraying pressure or biggest nozzle orifice diameter; instead, they appeared at moderate levels depending on the algal strain and specific settings. Increasing initial algal cell concentration significantly reduced cell disruption efficiency. In all UNSS treatments, the effectiveness of cell disruption and lipid recovery was found to be dependent on the algal species treated.

  20. Plasma current asymmetries during disruptions in JET

    Science.gov (United States)

    Gerasimov, S. N.; Hender, T. C.; Morris, J.; Riccardo, V.; Zakharov, L. E.; EFDA Contributors, JET

    2014-07-01

    A key feature of disruptions during vertical displacement events, discovered in JET in 1996, is the toroidal variation in the measured plasma current Ip, i.e. the plasma current asymmetries, lasting for almost the entire current quench. The unique magnetic diagnostics at JET (full set of poloidal coils and saddle loops recorded either from two toroidally opposite or from four toroidally orthogonal locations) allow for a comprehensive analysis of asymmetrical disruptions with a large scale database. This paper presents an analysis of 4854 disruptions over an 18 year period that includes both the JET carbon (C) wall and the ITER-like (IL) wall (a mixed beryllium/tungsten first wall). In spite of the Ip quench time significantly increasing for the IL-wall compared to C-wall disruptions, the observed toroidal asymmetry time integral (˜ sideways force impulse), did not increase for IL-wall disruptions. The Ip asymmetry has a dominantly n = 1 structure. Its motion in the toroidal direction has a sporadic behaviour, in general. The distributions of the number of rotation periods are found to be very similar for both C- and IL-wall disruptions, and multi-turn rotation was sometimes observed. The Ip asymmetry amplitude has no degradation with rotation frequency for either the C- or IL-wall disruption. Therefore dynamic amplification remains a potentially serious issue for ITER due to possible mechanical resonance of the machine components with the rotating asymmetry.

  1. Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury.

    Science.gov (United States)

    Kumar, Hemant; Ropper, Alexander E; Lee, Soo-Hong; Han, Inbo

    2016-05-18

    The blood-spinal cord barrier (BSCB) is a specialized protective barrier that regulates the movement of molecules between blood vessels and the spinal cord parenchyma. Analogous to the blood-brain barrier (BBB), the BSCB plays a crucial role in maintaining the homeostasis and internal environmental stability of the central nervous system (CNS). After spinal cord injury (SCI), BSCB disruption leads to inflammatory cell invasion such as neutrophils and macrophages, contributing to permanent neurological disability. In this review, we focus on the major proteins mediating the BSCB disruption or BSCB repair after SCI. This review is composed of three parts. Section 1. SCI and the BSCB of the review describes critical events involved in the pathophysiology of SCI and their correlation with BSCB integrity/disruption. Section 2. Major proteins involved in BSCB disruption in SCI focuses on the actions of matrix metalloproteinases (MMPs), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), angiopoietins (Angs), bradykinin, nitric oxide (NO), and endothelins (ETs) in BSCB disruption and repair. Section 3. Therapeutic approaches discusses the major therapeutic compounds utilized to date for the prevention of BSCB disruption in animal model of SCI through modulation of several proteins.

  2. Asymmetry in patient-related information disrupts pre-anesthetic patient briefing.

    Science.gov (United States)

    Schnoor, Joerg; Kupfer, Anja; Jurack, Babette; Reuter, Ulrike; Wrigge, Herrmann; Friese, Steffen; Thieme, Volker

    2013-10-04

    If one party has more or better information than the other, an information asymmetry can be assumed. The aim of the study was to identify the origin of incomplete patient-related preoperative information, which led to disruptions and losses of time during pre-anaesthetic patient briefing. We hypothesized that lower employees' educational level increases the amount of disruptive factors. A prospective observational study design was used. Patient selection was depending on the current patient flow in the area of the clinic for pre-anesthetic patient briefing. Data were collected over a period of 8 weeks. A stopwatch was used to record the time of disruptive factors. Various causes of time losses were grouped to facilitate statistical evaluation, which was performed by using the U-test of Mann and Whitney, Chi-square test or the Welch-t-test, as required. Out of 221 patients, 130 patient briefings (58.8%) had been disrupted. Residents were affected more often than consultants (66% vs. 47%, p = 0.008). Duration of disruptions was independent of the level of training and lasted about 2,5 minutes and 10% of the total time of patient briefing. Most time-consuming disruptive factors were missing study results, incomplete case histories, and limited patient compliance. Disruptions during pre-anesthetic patient briefings that were caused by patient-related information asymmetry are common and account for a significant loss of time. The resultant costs justify investments in appropriate personnel allocation.

  3. DISRUPTIVE BEHAVIOUR AMONGST DOCTORS, MYTH OR REALITY?

    Directory of Open Access Journals (Sweden)

    Avtar Singh

    2014-01-01

    Full Text Available BACKGROUND : Disruptive behavior in a medical setting is defined as objectionable or offensive interpersonal behavior that leads to disruption of professional activities in the workplace. 1 It has been observed that majority of doctors do not show disruptive behavior in their day today conduct and only few doctors are identified for their disruptive behavior . Special commi ttee on professional conduct and ethics defines disruptive behavior in physicians as aberrant behavior manifested through personal interaction with physicians , hospital personnel , health care professionals , patients , family members or others which interferes with patient care or could reasonably be expected to interfere with the process of delivering quality care. 2 Common forms of disruptive behaviors generally seen amongst young doctors are use of abusive language , yelling or shouting at patients , colleagues and subordinate staff , showing in disciplined behavior and at times indulging in physical abuse. 3 - 4 STUDY DESIGN : Study was conducted at a tertiary care hospital where 614 health care professionals participated which included 108 doctors 432 nurs ing staff and 74 paramedical staff METHOD : Data collection was done by semi structured pretested questionnaire and was entered in Microsoft Excel and analyzed for frequency and percentages . RESULTS : 64 % doctor , 66% nursing staff and 50% of the paramedicals answered that they have seen doctors showing disruptive behavior at one time or the other . Not all the doctors show disruptive behavior but this type of aberrant behavior is seen mainly in2 - 3 percent of doctors only. While answering to the que stion as to the type of disruptive behavior , 57% health care professionals reported that commonest form of disruptive behavior noticed by them amongst doctors was yelling or shouting on junior staff , patients and colleagues . 47% answered that doctors with disruptive behavior do not follow laid down orders or

  4. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. Grøne; Krægpøth, Morten; Nielsen, Helena Skyt

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  5. School-based interventions for disruptive behavior.

    Science.gov (United States)

    Lee, Terry

    2012-01-01

    Youth disruptive behavior is a concern for youth, school personnel,families, and society. Early childhood disruptive behaviors negatively impact the classroom, and are associated with negative academic, social, behavioral, emotional, substance use, health, and justice system outcomes in adolescence and adulthood. Effective, comprehensive, multicomponent interventions targeting risk/protective factors and pathways associated with antisocial behavior reduce and/or mitigate these negative outcomes. Positive effects have been demonstrated for universal and indicated programs for participating youth and families in early childhood, and for high-risk youth in adolescence and young adulthood. These empirically supported programs inform the treatment of complex and difficult-to-treat disruptive behavior.

  6. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten; Nielsen, Helena Skyt

    2015-01-01

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving school-cohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  7. Disruptive School Peers and Student Outcomes

    DEFF Research Database (Denmark)

    Kristoffersen, Jannie H. G.; Krægpøth, Morten Visby; Skyt Nielsen, Helena

    This paper estimates how peers’ achievement gains are affected by the presence of potentially disruptive and emotionally sensitive children in the school-cohort. We exploit that some children move between schools and thus generate variation in peer composition in the receiving schoolcohort. We...... identify three groups of potentially disruptive and emotionally sensitive children from detailed Danish register data: children with divorced parents, children with parents convicted of crime, and children with a psychiatric diagnosis. We find that adding potentially disruptive children lowers the academic...

  8. Understanding your supply chain to reduce the risk of supply chain disruption.

    Science.gov (United States)

    Wildgoose, Nick; Brennan, Patrick; Thompson, Simon

    2012-01-01

    Supply chains are at the heart of the way in which organisations operate and compete today; they also play a critical role in overall organisation performance. In the context of increasingly complex and global supply chains, the actions taken to drive down costs are likely to drive risk into the supply chain. The frequency of supply chain disruptions is high and this paper offers practical advice to help reduce the frequency and cost associated with these. There is advice to help with the understanding of how to identify critical suppliers. The reader is guided through comprehensive risk assessment and mitigation approaches and a selection of practical risk solutions and tools that you can use is described. There is a section on the 'dos and don'ts' relating to supplier due diligence. For those organisations facing the challenge of drawing up a business case relating to investment in improving supply chain resiliency, there is also a section outlining some of the business benefits of improving supply chain resiliency.

  9. Guam Energy Action Plan

    Energy Technology Data Exchange (ETDEWEB)

    Conrad, M. D.; Ness, J. E.

    2013-07-01

    Describes the four near-term strategies selected by the Guam Energy Task Force during action planning workshops conducted in March 2013, and outlines the steps being taken to implement those strategies. Each strategy addresses one of the energy sectors identified in the earlier Guam strategic energy plan as being an essential component of diversifying Guam's fuel sources and reducing fossil energy consumption 20% by 2020. The four energy strategies selected are: (1) expanding public outreach on energy efficiency and conservation, (2) establishing a demand-side management revolving loan program, (3) exploring waste-to-energy options, and (4) influencing the transportation sector via anti-idling legislation, vehicle registration fees, and electric vehicles.

  10. An analysis and reduction of disruptive behavior on school buses.

    Science.gov (United States)

    Greene, B F; Bailey, J S; Barber, F

    1981-01-01

    Thousands of children are injured or killed each year in school bus accidents. A significant number of these tragic incidents is precipitated by disruptive child behavior that distracts the drivers from their difficult task. Two experiments were conducted which addressed this problem. For both experiments an automated sound recording device (referred to as a Noise Guard) selectively responsive to frequencies above 500 Hz (i.e., unresponsive to bus drone) recorded both the duration and frequency of noise outbursts above a tolerable threshold. Additionally, an observer made in situ measurements of other disruptions including roughhousing and getting-out-of-seat. In the first experiment, following baseline measurements of these behaviors, middle-school students received feedback for noise outbursts. That is, when "Noise Guard" was activated, it in turn operated one of several lights on a panel visible to all passengers. Each day students were allowed to listen to high-appeal taped music while riding the bus and to participate in a raffle for prizes, provided the number of outbursts on the preceding day remained below a specified criterion indicated on the light panel. This intervention resulted in drastic reductions of noise outbursts with a concomitant reduction in other disruptive behaviors. Comparable results were obtained in the second experiment which eliminated the raffle from the intervention.

  11. Neutronic analysis of LMFBRs during severe core disruptive accidents

    Energy Technology Data Exchange (ETDEWEB)

    Tomlinson, E.T.

    1979-01-01

    A number of numerical experiments were performed to assess the validity of diffusion theory and various perturbation methods for calculating the reactivity state of a severely disrupted liquid metal cooled fast breeder reactor (LMFBR). The disrupted configurations correspond, in general, to phases through which an LMFBR core could pass during a core disruptive accident (CDA). Two-reactor models were chosen for this study, the two zone, homogeneous Clinch River Breeder Reactor and the Large Heterogeneous Reactor Design Study Core. The various phases were chosen to approximate the CDA results predicted by the safety analysis code SAS3D. The calculational methods investigated in this study include the eigenvalue difference technique based on both discrete ordinate transport theory and diffusion theory, first-order perturbation theory, exact perturbation theory, and a new hybrid perturbation theory. Selected cases were analyzed using Monte Carlo methods. It was found that in all cases, diffusion theory and perturbation theory yielded results for the change in reactivity that significantly disagreed with both the discrete ordinate and Monte Carlo results. These differences were, in most cases, in a nonconservative direction.

  12. Development and validation of the Johns Hopkins Disruptive Clinician Behavior Survey.

    Science.gov (United States)

    Dang, Deborah; Nyberg, Dorothy; Walrath, Jo M; Kim, Miyong T

    2015-01-01

    Although the negative impact of disruptive clinician behavior on quality health care delivery has gained attention recently, little systematic effort to address this issue has been reported. To facilitate empirical research to reduce disruptive clinician behaviors, an assessment tool (Johns Hopkins Disruptive Clinician Behavior Survey [JH-DCBS]) with 5 discrete subscales was developed using a 2-step design. First a pool of items was generated from focus group studies and the literature, and then a psychometric evaluation of the survey was conducted with a sample of clinicians (N = 1198) practicing in a large urban academic medical center. The results indicated that the tool was reliable (Cronbach α = .79-.91), showed high content validity (Content Validity Index = .97), and had significantly high correlations with theoretically selected variables. The study team concluded that the JH-DCBS provides a valid empirical assessment of disruptive behavior. Assessment results may be used to design strategies to improve the health and safety of practice environments.

  13. Inhibition of prostate carcinogenesis in probasin/SV40 T antigen transgenic rats by raloxifene, an antiestrogen with anti-androgen action, but not nimesulide, a selective cyclooxygenase-2 inhibitor.

    Science.gov (United States)

    Zeng, Yu; Yokohira, Masanao; Saoo, Kousuke; Takeuchi, Hijiri; Chen, Yan; Yamakawa, Keiko; Matsuda, Yoko; Kakehi, Yoshiyuki; Imaida, Katsumi

    2005-06-01

    The chemopreventive efficacies of raloxifene and nimesulide, an anti-estrogen but with anti-androgen action and a cyclooxygenase-2 (COX-2) selective inhibitor, respectively, were evaluated in probasin/SV40 T antigen (Tag) transgenic (TG) rats. The treatment groups were placebo, nimesulide (400 p.p.m. in basal diet p.o.), raloxifene (slow-release pellets implanted s.c., 5 mg/kg/day), raloxifene (5 mg/kg/day) plus nimesulide (400 p.p.m.), and raloxifene (10 mg/kg/day) plus nimesulide (400 p.p.m.). Animals were killed at 17 weeks of age, and prostate tissues were harvested and weighed by lobes. Tissues were evaluated by histology, immunohistochemistry, and western blot analyses and blood was collected to measure the testosterone levels. All the animals in the placebo group had tumors in each lobe compared with only 43% each in the dorsolateral (DLP) and anterior prostate (AP) of the animals treated with raloxifene (10 mg/kg/day) plus nimesulide. The total prostate weights and adenocarcinoma portions were significantly reduced in the three raloxifene-treated groups, whereas atrophic glands were increased. There were no significant differences between the nimesulide alone and placebo groups or between the raloxifene (5 mg/kg/day) alone and raloxifene (5 mg/kg/day) plus nimesulide group, suggesting a lack of cancer preventive effects of the COX-2 inhibitor in this animal model. PCNA positive rates in ventral prostate (VP) and DLP, and androgen receptor (AR) levels in VP were significantly reduced in the three raloxifene-treated groups. Furthermore, circulating testosterone was decreased after raloxifene (10 mg/kg/day) plus nimesulide treatment. These results demonstrate that raloxifene, but not nimesulide, inhibits prostate carcinogenesis in SV40 Tag TG rats associated with a decline in circulating testosterone levels and a loss of AR expression, as well as an inhibition of cell proliferation.

  14. Shell Galaxies, Dynamical Friction, and Dwarf Disruption

    CERN Document Server

    Ebrova, Ivana; Canalizo, Gabriela; Bennert, Nicola; Jilkova, Lucie

    2009-01-01

    Using N-body simulations of shell galaxies created in nearly radial minor mergers, we investigate the error of collision dating, resulting from the neglect of dynamical friction and of gradual disruption of the cannibalized dwarf.

  15. Towards a Framework of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    2014-01-01

    Digital platforms are disruptive information technology (IT) artifacts that erode conventional business logic associated with traditional market structures. This paper presents a framework for examining the disruptive potential of digital platforms whereby we postulate that the strategic interplay...... of governance regimes and platform layers is deterministic of whether disruptive derivatives are permitted to flourish. This framework has been employed in a comparative case study between centralized (i.e., PayPal) and decentralized (i.e., Coinkite) digital payment platforms to illustrate its applicability...... and yield propositions on the nature and impact of digital platform disruptions. Preliminary findings indicate that centralized digital platforms attempt to create unique configurals to obtain monopolistic power by tightly coupling platform layers, which are difficult to replicate. Conversely, decentralized...

  16. The Logic of Digital Platform Disruption

    DEFF Research Database (Denmark)

    Kazan, Erol; Tan, Chee-Wee; Lim, Eric T. K.

    Digital platforms are disruptive IT artifacts, because they facilitate the quick release of innovative platform derivatives from third parties (e.g., apps). This study endeavours to unravel the disruptive potential, caused by distinct designs and configurations of digital platforms on market...... environments. We postulate that the disruptive potential of digital platforms is determined by the degree of alignment among the business, technology and platform profiles. Furthermore, we argue that the design and configuration of the aforementioned three elements dictates the extent to which open innovation...... is permitted. To shed light on the disruptive potential of digital platforms, we opted for payment platforms as our unit of analysis. Through interviews with experts and payment providers, we seek to gain an in-depth appreciation of how contemporary digital payment platforms are designed and configured...

  17. Report on Criteria for Endocrine Disrupters

    DEFF Research Database (Denmark)

    Holbech, Henrik

    2011-01-01

    This report has been prepared by the Danish Centre on Endocrine Disrupters as a project contracted by the Danish Environmental Protection Agency. The Danish Centre on Endocrine Disrupters is an interdisciplinary scientific network without walls. The main purpose of the Centre is to build and gather...... new knowledge on endocrine disrupters with the focus on providing information requested for the preventive work of the regulatory authorities. The Centre is financed by the Ministry of the Environment and the scientific work programme is followed by an international scientific advisory board....... The overall aim of this project is to provide a science based proposal for criteria for endocrine disrupters. The terms of reference for the project specify elements to be included and/or addressed when developing the criteria (Annex 1). Also, several international reports and papers dealing with assessment...

  18. Magnetic field evolution in tidal disruption events

    CERN Document Server

    Bonnerot, Clément; Lodato, Giuseppe; Rossi, Elena M

    2016-01-01

    When a star gets tidally disrupted by a supermassive black hole, its magnetic field is expected to be transmitted to the debris. In this paper, we study this process via smoothed particle magnetohydrodynamical simulations of the disruption and early debris evolution including the stellar magnetic field. As the gas stretches into a stream, we show that the magnetic field evolution is strongly dependent on its orientation with respect to the stretching direction. In particular, an alignment of the field lines with the direction of stretching induces an increase of the magnetic energy. For disruptions happening well within the tidal radius, the star compression causes the magnetic field strength to sharply increase by an order of magnitude at the time of pericentre passage. If the disruption is partial, we find evidence for a dynamo process occurring inside the surviving core due to the formation of vortices. This causes an amplification of the magnetic field strength by a factor of $\\sim 10$. However, this valu...

  19. Endocrine disruption in aquatic insects: a review.

    Science.gov (United States)

    Soin, Thomas; Smagghe, Guy

    2007-02-01

    There is mounting evidence that a wide variety of compounds can have endocrine disrupting effects on humans and wildlife. However, investigations so far have focused primarily on exposure to human and other vertebrates, with invertebrate findings largely restricted to marine mollusks or to the ecdysteroid and juvenile hormone agonists as purposely synthesized endocrine disrupters for the pest management of insects. This article provides a brief description of the insect hormone system, a short sum-up of the relevant insect groups with aquatic life stages, and an overview of the additional evidence for endocrine disruption in aquatic insects from laboratory and field studies since 1999. In addition, the suitability of insects as sentinels for endocrine disrupting chemicals in aquatic ecosystems is discussed. Conclusions are drawn and research needs are defined.

  20. Double tidal disruptions in galactic nuclei

    CERN Document Server

    Mandel, Ilya

    2015-01-01

    A star on a nearly radial trajectory approaching a massive black hole (MBH) gets tidally disrupted if it comes sufficiently close to the MBH. Here we explore what happens to binary stars whose centers of mass approach the MBH on nearly radial orbits. The interaction with the MBH often leads to both stars being disrupted in sequence. We argue that such events could produce light curves that are substantially different from those of the single disruptions, with possible features such as two local maxima. Tidal forces from the MBH can also lead the binary components to collide; these merger products can form highly magnetized stars, whose subsequent tidal disruption may enable prompt jet formation.