WorldWideScience

Sample records for targeted electrode-based modulation

  1. Striatal activity is modulated by target probability.

    Science.gov (United States)

    Hon, Nicholas

    2017-06-14

    Target probability has well-known neural effects. In the brain, target probability is known to affect frontal activity, with lower probability targets producing more prefrontal activation than those that occur with higher probability. Although the effect of target probability on cortical activity is well specified, its effect on subcortical structures such as the striatum is less well understood. Here, I examined this issue and found that the striatum was highly responsive to target probability. This is consistent with its hypothesized role in the gating of salient information into higher-order task representations. The current data are interpreted in light of that fact that different components of the striatum are sensitive to different types of task-relevant information.

  2. Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes.

    NARCIS (Netherlands)

    de Groote, M.L.; Verschure, P.J.; Rots, M.G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  3. Epigenetic Editing : targeted rewriting of epigenetic marks to modulate expression of selected target genes

    NARCIS (Netherlands)

    de Groote, Marloes L.; Verschure, Pernette J.; Rots, Marianne G.

    2012-01-01

    Despite significant advances made in epigenetic research in recent decades, many questions remain unresolved, especially concerning cause and consequence of epigenetic marks with respect to gene expression modulation (GEM). Technologies allowing the targeting of epigenetic enzymes to predetermined

  4. Targeted modulation of reactive oxygen species in the vascular endothelium.

    Science.gov (United States)

    Shuvaev, Vladimir V; Muzykantov, Vladimir R

    2011-07-15

    'Endothelial cells lining vascular luminal surface represent an important site of signaling and injurious effects of reactive oxygen species (ROS) produced by other cells and endothelium itself in ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules (vascular immunotargeting) provides site-specific interventions in the endothelial ROS, unattainable by other formulations including PEG-modified enzymes. Targeting of ROS generating enzymes (e.g., glucose oxidase) provides ROS- and site-specific models of endothelial oxidative stress, whereas targeting of antioxidant enzymes SOD and catalase offers site-specific quenching of superoxide anion and H(2)O(2). These targeted antioxidant interventions help to clarify specific role of endothelial ROS in vascular and pulmonary pathologies and provide basis for design of targeted therapeutics for treatment of these pathologies. In particular, antibody/catalase conjugates alleviate acute lung ischemia/reperfusion injury, whereas antibody/SOD conjugates inhibit ROS-mediated vasoconstriction and inflammatory endothelial signaling. Encapsulation in protease-resistant, ROS-permeable carriers targeted to endothelium prolongs protective effects of antioxidant enzymes, further diversifying the means for targeted modulation of endothelial ROS. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Targeted modulation of reactive oxygen species in the vascular endothelium

    OpenAIRE

    Shuvaev, Vladimir V.; Muzykantov, Vladimir R.

    2011-01-01

    Endothelial cells lining vascular luminal surface represent an important site of signaling and injurious effects of reactive oxygen species (ROS) produced by other cells and endothelium itself in ischemia, inflammation and other pathological conditions. Targeted delivery of ROS modulating enzymes conjugated with antibodies to endothelial surface molecules (vascular immunotargeting) provides site-specific interventions in the endothelial ROS, unattainable by other formulations including PEG-mo...

  6. Phase-modulation interferometer for ICF-target characterization

    International Nuclear Information System (INIS)

    Cooper, D.E.

    1981-01-01

    Characterization requirements for high gain laser fusion targets are severe. We are required to detect defects on the surfaces of opaque and transparent shells with an amplitude resolution of +- 5 nm and a spatial resolution of 1 to 10 μm. To achieve this we have developed a laser-illuminated phase-modulation interferometer. This instrument is based on a photoelastic polarization modulation technique which allows one to convert phase information into an intensity modulation which can be easily and sensitively measured using ac signal processing techniques. This interferometer has detected path length changes as small as 1 nm and the required spatial resolution is assured by using a microscope objective to focus the probe laser beam down to a small (approx. 1 μm) spot on the surface of a microballoon. The interferometer will soon be coupled to an LSI-11 controlled 4π sphere manipulator which will allow us to automatically inspect the entire surface area of a target sphere

  7. B cells as a target of immune modulation

    Directory of Open Access Journals (Sweden)

    Hawker Kathleen

    2009-01-01

    Full Text Available B cells have recently been identified as an integral component of the immune system; they play a part in autoimmunity through antigen presentation, antibody secretion, and complement activation. Animal models of multiple sclerosis (MS suggest that myelin destruction is partly mediated through B cell activation (and plasmablasts. MS patients with evidence of B cell involvement, as compared to those without, tend to have a worse prognosis. Finally, the significant decrease in new gadolinium-enhancing lesions, new T2 lesions, and relapses in MS patients treated with rituximab (a monoclonal antibody against CD20 on B cells leads us to the conclusion that B cells play an important role in MS and that immune modulation of these cells may ameliorate the disease. This article will explore the role of B cells in MS and the rationale for the development of B cell-targeted therapeutics. MS is an immune-mediated disease that affects over 2 million people worldwide and is the number one cause of disability in young patients. Most therapeutic targets have focused on T cells; however, recently, the focus has shifted to the role of B cells in the pathogenesis of MS and the potential of B cells as a therapeutic target.

  8. Calcium channel modulation as a target in chronic pain control.

    Science.gov (United States)

    Patel, Ryan; Montagut-Bordas, Carlota; Dickenson, Anthony H

    2018-06-01

    Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first-in-class synthetic version of ω-conotoxin MVIIA, a peptide blocker of Ca v 2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use-dependent block of Ca v 2.2 channels; activation state-dependent blockers were hypothesized to circumvent the side effects of state-independent blockers by selectively targeting high-frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state-dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus-evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant-based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench-to-bedside translation of calcium channel modulators. This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175

  9. Syndecans as modulators and potential pharmacological targets in cancer progression

    Directory of Open Access Journals (Sweden)

    Despoina eBarbouri

    2014-02-01

    Full Text Available Extracellular matrix (ECM components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs, a family of transmembrane heparan sulfate proteoglycans (HSPGs. Specifically, heparan sulfate (HS chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases (MMPs, ADAM as well as ADΑMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble syndecans shed syndecans in the extracellular matrix interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed syndecans, upon binding to several matrix effectors, such as growth factors, chemokines and cytokines, have the ability to act as competitive inhibitors for membrane PGs, and modulate the inflammatory microenvironment of cancer cells. It is notable that syndecans and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of syndecans in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma.

  10. Target Probability Modulates Neuronal Activity in the Primate Saccadic System

    National Research Council Canada - National Science Library

    Basso, M

    2001-01-01

    The brain has a limited capacity to process information, so perceptual discriminations made when viewing natural visual scenes require that individual stimuli be singled out as targets for further analysis...

  11. Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

    OpenAIRE

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-01-01

    Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform ...

  12. Programmable type III-A CRISPR-Cas DNA targeting modules.

    Directory of Open Access Journals (Sweden)

    H Travis Ichikawa

    Full Text Available The CRISPR-Cas systems provide invader defense in a wide variety of prokaryotes, as well as technologies for many powerful applications. The Type III-A or Csm CRISPR-Cas system is one of the most widely distributed across prokaryotic phyla, and cleaves targeted DNA and RNA molecules. In this work, we have constructed modules of Csm systems from 3 bacterial species and heterologously expressed the functional modules in E. coli. The modules include a Cas6 protein and a CRISPR locus for crRNA production, and Csm effector complex proteins. The expressed modules from L. lactis, S. epidermidis and S. thermophilus specifically eliminate invading plasmids recognized by the crRNAs of the systems. Characteristically, activation of plasmid targeting activity depends on transcription of the plasmid sequence recognized by the crRNA. Activity was not observed when transcription of the crRNA target sequence was blocked, or when the opposite strand or a non-target sequence was transcribed. Moreover, the Csm module can be programmed to recognize plasmids with novel target sequences by addition of appropriate crRNA coding sequences to the module. These systems provide a platform for investigation of Type III-A CRISPR-Cas systems in E. coli, and for introduction of programmable transcription-activated DNA targeting into novel organisms.

  13. Gene Targeting and Expression Modulation by Peptide Nucleic Acids (PNA)

    DEFF Research Database (Denmark)

    Nielsen, Peter E

    2010-01-01

    Peptide nucleic acids (PNA) are artificial structural mimics of nucleic acids capable of sequence specific hybridization to both RNA and DNA. Thus they have obvious potential as gene targeting agents for drug discovery approaches. An overview with emphasis on recent progress on RNA "interference...

  14. Personalising e-learning modules: targeting Rasmussen levels using XML.

    Science.gov (United States)

    Renard, J M; Leroy, S; Camus, H; Picavet, M; Beuscart, R

    2003-01-01

    The development of Internet technologies has made it possible to increase the number and the diversity of on-line resources for teachers and students. Initiatives like the French-speaking Virtual Medical University Project (UMVF) try to organise the access to these resources. But both teachers and students are working on a partly redundant subset of knowledge. From the analysis of some French courses we propose a model for knowledge organisation derived from Rasmussen's stepladder. In the context of decision-making Rasmussen has identified skill-based, rule-based and knowledge-based levels for the mental process. In the medical context of problem-solving, we apply these three levels to the definition of three students levels: beginners, intermediate-level learners, experts. Based on our model, we build a representation of the hierarchical structure of data using XML language. We use XSLT Transformation Language in order to filter relevant data according to student level and to propose an appropriate display on students' terminal. The model and the XML implementation we define help to design tools for building personalised e-learning modules.

  15. Impedance modulation and feedback corrections in tracking targets of variable size and frequency.

    Science.gov (United States)

    Selen, Luc P J; van Dieën, Jaap H; Beek, Peter J

    2006-11-01

    Humans are able to adjust the accuracy of their movements to the demands posed by the task at hand. The variability in task execution caused by the inherent noisiness of the neuromuscular system can be tuned to task demands by both feedforward (e.g., impedance modulation) and feedback mechanisms. In this experiment, we studied both mechanisms, using mechanical perturbations to estimate stiffness and damping as indices of impedance modulation and submovement scaling as an index of feedback driven corrections. Eight subjects tracked three differently sized targets (0.0135, 0.0270, and 0.0405 rad) moving at three different frequencies (0.20, 0.25, and 0.33 Hz). Movement variability decreased with both decreasing target size and movement frequency, whereas stiffness and damping increased with decreasing target size, independent of movement frequency. These results are consistent with the theory that mechanical impedance acts as a filter of noisy neuromuscular signals but challenge stochastic theories of motor control that do not account for impedance modulation and only partially for feedback control. Submovements during unperturbed cycles were quantified in terms of their gain, i.e., the slope between their duration and amplitude in the speed profile. Submovement gain decreased with decreasing movement frequency and increasing target size. The results were interpreted to imply that submovement gain is related to observed tracking errors and that those tracking errors are expressed in units of target size. We conclude that impedance and submovement gain modulation contribute additively to tracking accuracy.

  16. Bacterial Multidrug Efflux Pumps of the Major Facilitator Superfamily as Targets for Modulation.

    Science.gov (United States)

    Kumar, Sanath; He, Guixin; Kakarla, Prathusha; Shrestha, Ugina; Ranjana, K C; Ranaweera, Indrika; Willmon, T Mark; Barr, Sharla R; Hernandez, Alberto J; Varela, Manuel F

    2016-01-01

    Causative agents of infectious disease that are multidrug resistant bacterial pathogens represent a serious public health concern due to the increasingly difficult nature of achieving efficacious clinical treatments. Of the various acquired and intrinsic antimicrobial agent resistance determinants, integral-membrane multidrug efflux pumps of the major facilitator superfamily constitute a major mechanism of bacterial resistance. The major facilitator superfamily (MFS) encompasses thousands of known related secondary active and passive solute transporters, including multidrug efflux pumps, from bacteria to humans. This review article addresses recent developments involving the targeting by various modulators of bacterial multidrug efflux pumps from the major facilitator superfamily. It is currently of tremendous interest to modulate bacterial multidrug efflux pumps in order to eventually restore the clinical efficacy of therapeutic agents against recalcitrant bacterial infections. Such MFS multidrug efflux pumps are good targets for modulation.

  17. Translational PK-PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576.

    Science.gov (United States)

    Bursi, Roberta; Erdemli, Gul; Campbell, Robert; Hutmacher, Matthew M; Kerbusch, Thomas; Spanswick, David; Jeggo, Ross; Nations, Kari R; Dogterom, Peter; Schipper, Jacques; Shahid, Mohammed

    2011-12-01

    The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor potentiator Org 26576 represents an interesting pharmacological tool to evaluate the utility of glutamatergic enhancement towards the treatment of psychiatric disorders. In this study, a rat-human translational pharmacokinetic-pharmacodynamic (PK-PD) model of AMPA receptor modulation was used to predict human target engagement and inform dose selection in efficacy clinical trials. Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC(80)) for AMPA receptor modulation. Human plasma pharmacokinetics was determined from 33 healthy volunteers and eight major depressive disorder patients. From four out of these eight patients, CSF PK was also determined. Simulations of human CSF levels were performed for several doses of Org 26576. Org 26576 (0.1-10 mg/kg, i.v.) potentiated rat hippocampal AMPA receptor responses in an exposure-dependant manner. The rat plasma and CSF PK data were fitted by one-compartment model each. The rat CSF PK-PD model yielded an EC(80) value of 593 ng/ml (90% confidence interval 406.8, 1,264.1). The human plasma and CSF PK data were simultaneously well described by a two-compartment model. Simulations showed that in humans at 100 mg QD, CSF levels of Org 26576 would exceed the EC(80) target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h. The modelling approach provided useful insight on the likely human dose-molecular target engagement relationship for Org 26576. Based on the current analysis, 100 and 400 mg BID would be suitable to provide 'phasic' and 'continuous' AMPA receptor engagement, respectively.

  18. Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling*

    Science.gov (United States)

    Moreno, Estefanía; Andradas, Clara; Medrano, Mireia; Caffarel, María M.; Pérez-Gómez, Eduardo; Blasco-Benito, Sandra; Gómez-Cañas, María; Pazos, M. Ruth; Irving, Andrew J.; Lluís, Carme; Canela, Enric I.; Fernández-Ruiz, Javier; Guzmán, Manuel; McCormick, Peter J.; Sánchez, Cristina

    2014-01-01

    The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology. PMID:24942731

  19. Modulation of calmodulin lobes by different targets: an allosteric model with hemiconcerted conformational transitions.

    Directory of Open Access Journals (Sweden)

    Massimo Lai

    2015-01-01

    Full Text Available Calmodulin is a calcium-binding protein ubiquitous in eukaryotic cells, involved in numerous calcium-regulated biological phenomena, such as synaptic plasticity, muscle contraction, cell cycle, and circadian rhythms. It exibits a characteristic dumbell shape, with two globular domains (N- and C-terminal lobe joined by a linker region. Each lobe can take alternative conformations, affected by the binding of calcium and target proteins. Calmodulin displays considerable functional flexibility due to its capability to bind different targets, often in a tissue-specific fashion. In various specific physiological environments (e.g. skeletal muscle, neuron dendritic spines several targets compete for the same calmodulin pool, regulating its availability and affinity for calcium. In this work, we sought to understand the general principles underlying calmodulin modulation by different target proteins, and to account for simultaneous effects of multiple competing targets, thus enabling a more realistic simulation of calmodulin-dependent pathways. We built a mechanistic allosteric model of calmodulin, based on an hemiconcerted framework: each calmodulin lobe can exist in two conformations in thermodynamic equilibrium, with different affinities for calcium and different affinities for each target. Each lobe was allowed to switch conformation on its own. The model was parameterised and validated against experimental data from the literature. In spite of its simplicity, a two-state allosteric model was able to satisfactorily represent several sets of experiments, in particular the binding of calcium on intact and truncated calmodulin and the effect of different skMLCK peptides on calmodulin's saturation curve. The model can also be readily extended to include multiple targets. We show that some targets stabilise the low calcium affinity T state while others stabilise the high affinity R state. Most of the effects produced by calmodulin targets can be

  20. Cytokines and cytokine networks target neurons to modulate long-term potentiation.

    Science.gov (United States)

    Prieto, G Aleph; Cotman, Carl W

    2017-04-01

    Cytokines play crucial roles in the communication between brain cells including neurons and glia, as well as in the brain-periphery interactions. In the brain, cytokines modulate long-term potentiation (LTP), a cellular correlate of memory. Whether cytokines regulate LTP by direct effects on neurons or by indirect mechanisms mediated by non-neuronal cells is poorly understood. Elucidating neuron-specific effects of cytokines has been challenging because most brain cells express cytokine receptors. Moreover, cytokines commonly increase the expression of multiple cytokines in their target cells, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Here, we review evidence on both direct and indirect-mediated modulation of LTP by cytokines. We also describe novel approaches based on neuron- and synaptosome-enriched systems to identify cytokines able to directly modulate LTP, by targeting neurons and synapses. These approaches can test multiple samples in parallel, thus allowing the study of multiple cytokines simultaneously. Hence, a cytokine networks perspective coupled with neuron-specific analysis may contribute to delineation of maps of the modulation of LTP by cytokines. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Targeting brain cells with glutathione-modulated nanoliposomes: in vitro and in vivo study

    Directory of Open Access Journals (Sweden)

    Salem HF

    2015-07-01

    Full Text Available Heba F Salem,1 Sayed M Ahmed,2 Ashraf E Hassaballah,3 Mahmoud M Omar1,4 1Department of Pharmaceutics and Industrial Pharmacy, Beni-suef University, 2Department of Industrial Pharmacy, Assiut University, 3Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assuit, 4Department of Pharmaceutics and Industrial Pharmacy, Deraya University, Egypt Background: The blood–brain barrier prevents many drug moieties from reaching the central nervous system. Therefore, glutathione-modulated nanoliposomes have been engineered to enhance the targeting of flucytosine to the brain. Methods: Glutathione-modulated nanoliposomes were prepared by thin-film hydration technique and evaluated in the primary brain cells of rats. Lecithin, cholesterol, and span 65 were mixed at 1:1:1 molar ratio. The molar percentage of PEGylated glutathione varied from 0 mol% to 0.75 mol%. The cellular binding and the uptake of the targeted liposomes were both monitored by epifluorescent microscope and flow cytometry techniques. A biodistribution and a pharmacokinetic study of flucytosine and flucytosine-loaded glutathione–modulated liposomes was carried out to evaluate the in vivo brain-targeting efficiency. Results: The size of glutathione-modulated nanoliposomes was <100 nm and the zeta potential was more than -65 mV. The cumulative release reached 70% for certain formulations. The cellular uptake increased as molar percent of glutathione increased to reach the maximum at 0.75 mol%. The uptake of the targeted liposomes by brain cells of the rats was three times greater than that of the nontargeted liposomes. An in vivo study showed that the relative efficiency was 2.632±0.089 and the concentration efficiency was 1.590±0.049, and also, the drug-targeting index was 3.670±0.824. Conclusion: Overall, these results revealed that glutathione-PEGylated nanoliposomes enhance the effective delivery of flucytosine to brain and could become a promising new

  2. ROMA: representation and quantification of module activity from target expression data

    Directory of Open Access Journals (Sweden)

    Loredana eMartignetti

    2016-02-01

    Full Text Available In many analysis of high-throughput data in systems biology, there is a need to quantify the activity of a set of genes in individual samples. A typical example is the case where it is necessary to estimate the activity of a transcription factor (which is often not directly measurable from the expression of its target genes. We present here ROMA (Representation and quantification Of Module Activities Java software, designed for fast and robust computation of the activity of gene sets (or modules with coordinated expression. ROMA activity quantification is based on the simplest uni-factor linear model of gene regulation that approximates the expression data of a gene set by its first principal component.The proposed algorithm implements novel functionalities: it provides several method modifications for principal components computation, including weighted, robust and centered methods; it distinguishes overdispersed modules (based on the variance explained by the first principal component and coordinated modules (based on the significance of the spectral gap; finally, it computes statistical significance of the estimated module overdispersion or coordination.ROMA can be applied in many contexts, from estimating differential activities of transcriptional factors to findingoverdispersed pathways in single-cell transcriptomics data. We describe here the principles of ROMA providing several practical examples of its use.ROMA source code is available at https://github.com/sysbio-curie/Roma.

  3. Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors.

    Science.gov (United States)

    Ojha, Tarun; Pathak, Vertika; Shi, Yang; Hennink, Wim E; Moonen, Chrit T W; Storm, Gert; Kiessling, Fabian; Lammers, Twan

    2017-09-15

    The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Ivy and neurogliaform interneurons are a major target of μ opioid receptor modulation

    Science.gov (United States)

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-01-01

    Mu opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous, but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABAB response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Further, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR-activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking PV basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR-activation. Together these findings identify a major, previously unrecognized, target of μOR-modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications. PMID:22016519

  5. Ivy and neurogliaform interneurons are a major target of μ-opioid receptor modulation.

    Science.gov (United States)

    Krook-Magnuson, Esther; Luu, Lillian; Lee, Sang-Hun; Varga, Csaba; Soltesz, Ivan

    2011-10-19

    μ-Opioid receptors (μORs) are selectively expressed on interneurons in area CA1 of the hippocampus. Fast-spiking, parvalbumin-expressing, basket cells express μORs, but circumstantial evidence suggests that another major, unidentified, GABAergic cell class must also be modulated by μORs. Here we report that the abundant, dendritically targeting, neurogliaform family of cells (Ivy and neurogliaform cells) is a previously unrecognized target of direct modulation by μORs. Ivy and neurogliaform cells are not only numerous but also have unique properties, including promiscuous gap junctions formed with various interneuronal subtypes, volume transmission, and the ability to produce a postsynaptic GABA(B) response after a single presynaptic spike. Using a mouse line expressing green fluorescent protein under the neuropeptide Y promoter, we find that, across all layers of CA1, activation of μORs hyperpolarizes Ivy and neurogliaform cells. Furthermore, paired recordings between synaptically coupled Ivy and pyramidal cells show that Ivy cell terminals are dramatically inhibited by μOR activation. Effects in Ivy and neurogliaform cells are seen at similar concentrations of agonist as those producing inhibition in fast-spiking parvalbumin basket cells. We also report that Ivy cells display the recently described phenomenon of persistent firing, a state of continued firing in the absence of continued input, and that induction of persistent firing is inhibited by μOR activation. Together, these findings identify a major, previously unrecognized, target of μOR modulation. Given the prominence of this cell type in and beyond CA1, as well as its unique role in microcircuitry, opioid modulation of neurogliaform cells has wide implications.

  6. Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

    Directory of Open Access Journals (Sweden)

    Nico Derichs

    2013-03-01

    Full Text Available Cystic fibrosis (CF is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.

  7. Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction.

    Directory of Open Access Journals (Sweden)

    Stéphanie eOlière

    2013-09-01

    Full Text Available Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamine. Interestingly, recent accumulating evidence points toward the involvement of the endocannabinoid system (ECBS in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep-insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. The aims of this article are to: 1 review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and 2 evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoid in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants.

  8. Targeting accuracy of single-isocenter intensity-modulated radiosurgery for multiple lesions

    Energy Technology Data Exchange (ETDEWEB)

    Calvo-Ortega, J.F., E-mail: jfcdrr@yahoo.es; Pozo, M.; Moragues, S.; Casals, J.

    2017-07-01

    To investigate the targeting accuracy of intensity-modulated SRS (IMRS) plans designed to simultaneously treat multiple brain metastases with a single isocenter. A home-made acrylic phantom able to support a film (EBT3) in its coronal plane was used. The phantom was CT scanned and three coplanar small targets (a central and two peripheral) were outlined in the Eclipse system. Peripheral targets were 6 cm apart from the central one. A reference IMRS plan was designed to simultaneously treat the three targets, but only a single isocenter located at the center of the central target was used. After positioning the phantom on the linac using the room lasers, a CBCT scan was acquired and the reference plan were mapped on it, by placing the planned isocenter at the intersection of the landmarks used in the film showing the linac isocenter. The mapped plan was then recalculated and delivered. The film dose distribution was derived using a cloud computing application ( (www.radiochromic.com)) that uses a triple-channel dosimetry algorithm. Comparison of dose distributions using the gamma index (5%/1 mm) were performed over a 5 × 5 cm{sup 2} region centered over each target. 2D shifts required to get the best gamma passing rates on the peripheral target regions were compared with the reported ones for the central target. The experiment was repeated ten times in different sessions. Average 2D shifts required to achieve optimal gamma passing rates (99%, 97%, 99%) were 0.7 mm (SD: 0.3 mm), 0.8 mm (SD: 0.4 mm) and 0.8 mm (SD: 0.3 mm), for the central and the two peripheral targets, respectively. No statistical differences (p > 0.05) were found for targeting accuracy between the central and the two peripheral targets. The study revealed a targeting accuracy within 1 mm for off-isocenter targets within 6 cm of the linac isocenter, when a single-isocenter IMRS plan is designed.

  9. Presenilin is the molecular target of acidic γ-secretase modulators in living cells.

    Directory of Open Access Journals (Sweden)

    Thorsten Jumpertz

    Full Text Available The intramembrane-cleaving protease γ-secretase catalyzes the last step in the generation of toxic amyloid-β (Aβ peptides and is a principal therapeutic target in Alzheimer's disease. Both preclinical and clinical studies have demonstrated that inhibition of γ-secretase is associated with prohibitive side effects due to suppression of Notch processing and signaling. Potentially safer are γ-secretase modulators (GSMs, which are small molecules that selectively lower generation of the highly amyloidogenic Aβ42 peptides but spare Notch processing. GSMs with nanomolar potency and favorable pharmacological properties have been described, but the molecular mechanism of GSMs remains uncertain and both the substrate amyloid precursor protein (APP and subunits of the γ-secretase complex have been proposed as the molecular target of GSMs. We have generated a potent photo-probe based on an acidic GSM that lowers Aβ42 generation with an IC(50 of 290 nM in cellular assays. By combining in vivo photo-crosslinking with affinity purification, we demonstrated that this probe binds the N-terminal fragment of presenilin (PSEN, the catalytic subunit of the γ-secretase complex, in living cells. Labeling was not observed for APP or any of the other γ-secretase subunits. Binding was readily competed by structurally divergent acidic and non-acidic GSMs suggesting a shared mode of action. These findings indicate that potent acidic GSMs target presenilin to modulate the enzymatic activity of the γ-secretase complex.

  10. Metal cofactor modulated folding and target recognition of HIV-1 NCp7.

    Science.gov (United States)

    Ren, Weitong; Ji, Dongqing; Xu, Xiulian

    2018-01-01

    The HIV-1 nucleocapsid 7 (NCp7) plays crucial roles in multiple stages of HIV-1 life cycle, and its biological functions rely on the binding of zinc ions. Understanding the molecular mechanism of how the zinc ions modulate the conformational dynamics and functions of the NCp7 is essential for the drug development and HIV-1 treatment. In this work, using a structure-based coarse-grained model, we studied the effects of zinc cofactors on the folding and target RNA(SL3) recognition of the NCp7 by molecular dynamics simulations. After reproducing some key properties of the zinc binding and folding of the NCp7 observed in previous experiments, our simulations revealed several interesting features in the metal ion modulated folding and target recognition. Firstly, we showed that the zinc binding makes the folding transition states of the two zinc fingers less structured, which is in line with the Hammond effect observed typically in mutation, temperature or denaturant induced perturbations to protein structure and stability. Secondly, We showed that there exists mutual interplay between the zinc ion binding and NCp7-target recognition. Binding of zinc ions enhances the affinity between the NCp7 and the target RNA, whereas the formation of the NCp7-RNA complex reshapes the intrinsic energy landscape of the NCp7 and increases the stability and zinc affinity of the two zinc fingers. Thirdly, by characterizing the effects of salt concentrations on the target RNA recognition, we showed that the NCp7 achieves optimal balance between the affinity and binding kinetics near the physiologically relevant salt concentrations. In addition, the effects of zinc binding on the inter-domain conformational flexibility and folding cooperativity of the NCp7 were also discussed.

  11. Metal cofactor modulated folding and target recognition of HIV-1 NCp7.

    Directory of Open Access Journals (Sweden)

    Weitong Ren

    Full Text Available The HIV-1 nucleocapsid 7 (NCp7 plays crucial roles in multiple stages of HIV-1 life cycle, and its biological functions rely on the binding of zinc ions. Understanding the molecular mechanism of how the zinc ions modulate the conformational dynamics and functions of the NCp7 is essential for the drug development and HIV-1 treatment. In this work, using a structure-based coarse-grained model, we studied the effects of zinc cofactors on the folding and target RNA(SL3 recognition of the NCp7 by molecular dynamics simulations. After reproducing some key properties of the zinc binding and folding of the NCp7 observed in previous experiments, our simulations revealed several interesting features in the metal ion modulated folding and target recognition. Firstly, we showed that the zinc binding makes the folding transition states of the two zinc fingers less structured, which is in line with the Hammond effect observed typically in mutation, temperature or denaturant induced perturbations to protein structure and stability. Secondly, We showed that there exists mutual interplay between the zinc ion binding and NCp7-target recognition. Binding of zinc ions enhances the affinity between the NCp7 and the target RNA, whereas the formation of the NCp7-RNA complex reshapes the intrinsic energy landscape of the NCp7 and increases the stability and zinc affinity of the two zinc fingers. Thirdly, by characterizing the effects of salt concentrations on the target RNA recognition, we showed that the NCp7 achieves optimal balance between the affinity and binding kinetics near the physiologically relevant salt concentrations. In addition, the effects of zinc binding on the inter-domain conformational flexibility and folding cooperativity of the NCp7 were also discussed.

  12. Target tracking using DMLC for volumetric modulated arc therapy: A simulation study

    Energy Technology Data Exchange (ETDEWEB)

    Sun Baozhou; Rangaraj, Dharanipathy; Papiez, Lech; Oddiraju, Swetha; Yang Deshan; Li, H. Harold [Department of Radiation Oncology, School of Medicine, Washington University, 4921 Parkview Place, St. Louis, Missouri 63110 (United States); Department of Radiation Oncology, Southwestern Medical Center, University of Texas, Dallas, Texas 75390 (United States); Department of Radiation Oncology, School of Medicine, Washington University, 4921 Parkview Place, St. Louis, Missouri 63110 (United States)

    2010-12-15

    Purpose: Target tracking using dynamic multileaf collimator (DMLC) is a promising approach for intrafraction motion management in radiation therapy. The purpose of this work is to develop a DMLC tracking algorithm capable of delivering volumetric-modulated arc therapy (VMAT) to the targets that experience two-dimensional (2D) rigid motion in the beam's eye view. Methods: The problem of VMAT delivery to moving targets is formulated as a control problem with constraints. The relationships between gantry speed, gantry acceleration, MLC leaf-velocity, dose rate, and target motion are derived. An iterative search algorithm is developed to find numerical solutions for efficient delivery of a specific VMAT plan to the moving target using 2D DMLC tracking. The delivery of five VMAT lung plans is simulated. The planned and delivered fluence maps in the target-reference frame are calculated and compared. Results: The simulation demonstrates that the 2D tracking algorithm is capable of delivering the VMAT plan to a moving target fast and accurately without violating the machine constraints and the integrity of the treatment plan. The average delivery time is only 29 s longer than that of no-tracking delivery, 101 versus 72 s, respectively. The fluence maps are normalized to 200 MU and the average root-mean-square error between the desired and the delivered fluence is 2.1 MU, compared to 14.8 MU for no-tracking and 3.6 MU for one-dimensional tracking. Conclusions: A locally optimal MLC tracking algorithm for VMAT delivery is proposed, aiming at shortest delivery time while maintaining treatment plan invariant. The inconsequential increase of treatment time due to DMLC tracking is clinically desirable, which makes VMAT with DMLC tracking attractive in treating moving tumors.

  13. MFP scanner diagnostics using a self-printed target to measure the modulation transfer function

    Science.gov (United States)

    Wang, Weibao; Bauer, Peter; Wagner, Jerry; Allebach, Jan P.

    2014-01-01

    In the current market, reduction of warranty costs is an important avenue for improving profitability by manufacturers of printer products. Our goal is to develop an autonomous capability for diagnosis of printer and scanner caused defects with mid-range laser multifunction printers (MFPs), so as to reduce warranty costs. If the scanner unit of the MFP is not performing according to specification, this issue needs to be diagnosed. If there is a print quality issue, this can be diagnosed by printing a special test page that is resident in the firmware of the MFP unit, and then scanning it. However, the reliability of this process will be compromised if the scanner unit is defective. Thus, for both scanner and printer image quality issues, it is important to be able to properly evaluate the scanner performance. In this paper, we consider evaluation of the scanner performance by measuring its modulation transfer function (MTF). The MTF is a fundamental tool for assessing the performance of imaging systems. Several ways have been proposed to measure the MTF, all of which require a special target, for example a slanted-edge target. It is unacceptably expensive to ship every MFP with such a standard target, and to expect that the customer can keep track of it. To reduce this cost, in this paper, we develop new approach to this task. It is based on a self-printed slanted-edge target. Then, we propose algorithms to improve the results using a self-printed slanted-edge target. Finally, we present experimental results for MTF measurement using self-printed targets and compare them to the results obtained with standard targets.

  14. Intensity-Modulated Radiotherapy for Craniospinal Irradiation: Target Volume Considerations, Dose Constraints, and Competing Risks

    International Nuclear Information System (INIS)

    Parker, William; Filion, Edith; Roberge, David; Freeman, Carolyn R.

    2007-01-01

    Purpose: To report the results of an analysis of dose received to tissues and organs outside the target volume, in the setting of spinal axis irradiation for the treatment of medulloblastoma, using three treatment techniques. Methods and Materials: Treatment plans (total dose, 23.4 Gy) for a standard two-dimensional (2D) technique, a three-dimensional (3D) technique using a 3D imaging-based target volume, and an intensity-modulated radiotherapy (IMRT) technique, were compared for 3 patients in terms of dose-volume statistics for target coverage, as well as organ at risk (OAR) and overall tissue sparing. Results: Planning target volume coverage and dose homogeneity was superior for the IMRT plans for V 95% (IMRT, 100%; 3D, 96%; 2D, 98%) and V 107% (IMRT, 3%; 3D, 38%; 2D, 37%). In terms of OAR sparing, the IMRT plan was better for all organs and whole-body contour when comparing V 10Gy , V 15Gy , and V 20Gy . The 3D plan was superior for V 5Gy and below. For the heart and liver in particular, the IMRT plans provided considerable sparing in terms of V 10Gy and above. In terms of the integral dose, the IMRT plans were superior for liver (IMRT, 21.9 J; 3D, 28.6 J; 2D, 38.6 J) and heart (IMRT, 9 J; 3D, 14.1J; 2D, 19.4 J), the 3D plan for the body contour (IMRT, 349 J; 3D, 337 J; 2D, 555 J). Conclusions: Intensity-modulated radiotherapy is a valid treatment option for spinal axis irradiation. We have shown that IMRT results in sparing of organs at risk without a significant increase in integral dose

  15. Lmx1b-targeted cis-regulatory modules involved in limb dorsalization.

    Science.gov (United States)

    Haro, Endika; Watson, Billy A; Feenstra, Jennifer M; Tegeler, Luke; Pira, Charmaine U; Mohan, Subburaman; Oberg, Kerby C

    2017-06-01

    Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b in mouse limbs at embryonic day 12.5 followed by next-generation sequencing (ChIP-seq). Nearly 84% ( n =617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential cis -regulatory modules (PCRMs). In addition, 73 LBIs mapped to CRMs that are known to be active during limb development. We compared Lmx1b-bound PCRMs with genes regulated by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontological analysis suggests that Lmx1b targets extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related Gdf5 that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with Lmx1b that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization. © 2017. Published by The Company of Biologists Ltd.

  16. Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

    Directory of Open Access Journals (Sweden)

    Mallory E. Harden

    2017-01-01

    Full Text Available The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs. While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects the expression of cellular noncoding RNAs. The goal of our study was to investigate HPV16 E6/E7 modulation of cellular microRNA (miR levels and to determine the potential consequences for cellular gene expression. We performed deep sequencing of small and large cellular RNAs in primary undifferentiated cultures of human foreskin keratinocytes (HFKs with stable expression of HPV16 E6/E7 or a control vector. After integration of the two data sets, we identified 51 differentially expressed cellular miRs associated with the modulation of 1,456 potential target mRNAs in HPV16 E6/E7-expressing HFKs. We discovered that the degree of differential miR expression in HFKs expressing HPV16 E6/E7 was not necessarily predictive of the number of corresponding mRNA targets or the potential impact on gene expression. Additional analyses of the identified miR-mRNA pairs suggest modulation of specific biological activities and biochemical pathways. Overall, our study supports the model that perturbation of cellular miR expression by HPV16 E6/E7 importantly contributes to the rewiring of cellular regulatory circuits by the high-risk HPV E6 and E7 proteins that contribute to oncogenic transformation.

  17. A multi-pad electrode based functional electrical stimulation system for restoration of grasp

    Directory of Open Access Journals (Sweden)

    Malešević Nebojša M

    2012-09-01

    Full Text Available Abstract Background Functional electrical stimulation (FES applied via transcutaneous electrodes is a common rehabilitation technique for assisting grasp in patients with central nervous system lesions. To improve the stimulation effectiveness of conventional FES, we introduce multi-pad electrodes and a new stimulation paradigm. Methods The new FES system comprises an electrode composed of small pads that can be activated individually. This electrode allows the targeting of motoneurons that activate synergistic muscles and produce a functional movement. The new stimulation paradigm allows asynchronous activation of motoneurons and provides controlled spatial distribution of the electrical charge that is delivered to the motoneurons. We developed an automated technique for the determination of the preferred electrode based on a cost function that considers the required movement of the fingers and the stabilization of the wrist joint. The data used within the cost function come from a sensorized garment that is easy to implement and does not require calibration. The design of the system also includes the possibility for fine-tuning and adaptation with a manually controllable interface. Results The device was tested on three stroke patients. The results show that the multi-pad electrodes provide the desired level of selectivity and can be used for generating a functional grasp. The results also show that the procedure, when performed on a specific user, results in the preferred electrode configuration characteristics for that patient. The findings from this study are of importance for the application of transcutaneous stimulation in the clinical and home environments.

  18. Light-reflection random-target method for measurement of the modulation transfer function of a digital video-camera

    Czech Academy of Sciences Publication Activity Database

    Pospíšil, Jaroslav; Jakubík, P.; Machala, L.

    2005-01-01

    Roč. 116, - (2005), s. 573-585 ISSN 0030-4026 Institutional research plan: CEZ:AV0Z10100522 Keywords : random-target measuring method * light-reflection white - noise target * digital video camera * modulation transfer function * power spectral density Subject RIV: BH - Optics, Masers, Lasers Impact factor: 0.395, year: 2005

  19. Dosimetric feasibility of an “off-target isocenter” technique for cranial intensity-modulated radiosurgery

    International Nuclear Information System (INIS)

    Calvo-Ortega, Juan Francisco; Moragues, Sandra; Pozo, Miquel; Delgado, David; Casals, Joan

    2015-01-01

    To evaluate the dosimetric effect of placing the isocenter away from the planning target volume (PTV) on intensity-modulated radiosurgery (IMRS) plans to treat brain lesions. A total of 15 patients who received cranial IMRS at our institution were randomly selected. Each patient was treated with an IMRS plan designed with the isocenter located at the target center (plan A). A second off-target isocenter plan (plan B) was generated for each case. In all the plans,100% of the prescription dose covered 99% of the target volume. The plans A and B were compared for the target dosage (conformity index [CI] and homogeneity index) and organs-at-risk (OAR) dose sparing. Peripheral dose falloff was compared by using the metrics volume of normal brain receiving more than 12-Gy dose (V12) and CI at the level of the 50% of the prescription dose (CI 50%). The values found for each metric (plan B vs plan A) were (mean ± standard deviation [SD]) as follows—CI: 1.28 ± 0.15 vs 1.28 ± 0.15, p = 0.978; homogeneity index (HI): 1.29 ± 0.14 vs 1.34 ± 0.17, p = 0.079; maximum dose to the brainstem: 2.95 ± 2.11 vs 2.89 ± 1.88 Gy, p = 0.813; maximum dose to the optical pathway: 2.65 ± 4.18 vs 2.44 ± 4.03 Gy, p = 0.195; and maximum dose to the eye lens: 0.33 ± 0.73 vs 0.33 ± 0.53 Gy, p = 0.970. The values of the peripheral dose falloff were (plan B vs plan A) as follows—V12: 5.98 ± 4.95 vs 6.06 ± 4.92 cm"3, p = 0.622, and CI 50%: 6.08 ± 2.77 vs 6.28 ± 3.01, p = 0.119. The off-target isocenter solution resulted in dosimetrically comparable plans as the center-target isocenter technique, by avoiding the risk of gantry-couch collision during the cone beam computed tomography (CBCT) acquisition.

  20. Assessing potential targets of calcium action in light-modulated gravitropism

    Science.gov (United States)

    Roux, S. J.

    1995-01-01

    Light, through the mediation of the pigment phytochrome, modulates the gravitropic response of the shoots and roots of many plants. The transduction of both light and gravity stimuli appears to involve Ca(2+)-regulated steps, one or more of which may represent points of intersection between the two transduction chains. To be confident that Ca2+ plays a critical role in stimulus-response coupling for gravitropism, it will be important to identify specific targets of Ca2+ action whose function can be clearly linked to the regulation of growth. Calcium typically exerts its influence on cell metabolism through binding to and activating key regulatory proteins. The three best characterized of these proteins in plants are the calmodulins, calcium-dependent protein kinases, and annexins. In this review we summarize what is known about the structure and function of these proteins and speculate on how their activation by Ca2+ could influence the differential growth response of gravitropism.

  1. Tumor trailing strategy for intensity-modulated radiation therapy of moving targets

    International Nuclear Information System (INIS)

    Trofimov, Alexei; Vrancic, Christian; Chan, Timothy C. Y.; Sharp, Gregory C.; Bortfeld, Thomas

    2008-01-01

    Internal organ motion during the course of radiation therapy of cancer affects the distribution of the delivered dose and, generally, reduces its conformality to the targeted volume. Previously proposed approaches aimed at mitigating the effect of internal motion in intensity-modulated radiation therapy (IMRT) included expansion of the target margins, motion-correlated delivery (e.g., respiratory gating, tumor tracking), and adaptive treatment plan optimization employing a probabilistic description of motion. We describe and test the tumor trailing strategy, which utilizes the synergy of motion-adaptive treatment planning and delivery methods. We regard the (rigid) target motion as a superposition of a relatively fast cyclic component (e.g., respiratory) and slow aperiodic trends (e.g., the drift of exhalation baseline). In the trailing approach, these two components of motion are decoupled and dealt with separately. Real-time motion monitoring is employed to identify the 'slow' shifts, which are then corrected by applying setup adjustments. The delivery does not track the target position exactly, but trails the systematic trend due to the delay between the time a shift occurs, is reliably detected, and, subsequently, corrected. The ''fast'' cyclic motion is accounted for with a robust motion-adaptive treatment planning, which allows for variability in motion parameters (e.g., mean and extrema of the tidal volume, variable period of respiration, and expiratory duration). Motion-surrogate data from gated IMRT treatments were used to provide probability distribution data for motion-adaptive planning and to test algorithms that identified systematic trends in the character of motion. Sample IMRT fields were delivered on a clinical linear accelerator to a programmable moving phantom. Dose measurements were performed with a commercial two-dimensional ion-chamber array. The results indicate that by reducing intrafractional motion variability, the trailing strategy

  2. Task relevance modulates the cortical representation of feature conjunctions in the target template.

    Science.gov (United States)

    Reeder, Reshanne R; Hanke, Michael; Pollmann, Stefan

    2017-07-03

    Little is known about the cortical regions involved in representing task-related content in preparation for visual task performance. Here we used representational similarity analysis (RSA) to investigate the BOLD response pattern similarity between task relevant and task irrelevant feature dimensions during conjunction viewing and target template maintenance prior to visual search. Subjects were cued to search for a spatial frequency (SF) or orientation of a Gabor grating and we measured BOLD signal during cue and delay periods before the onset of a search display. RSA of delay period activity revealed that widespread regions in frontal, posterior parietal, and occipitotemporal cortices showed general representational differences between task relevant and task irrelevant dimensions (e.g., orientation vs. SF). In contrast, RSA of cue period activity revealed sensory-related representational differences between cue images (regardless of task) at the occipital pole and additionally in the frontal pole. Our data show that task and sensory information are represented differently during viewing and during target template maintenance, and that task relevance modulates the representation of visual information across the cortex.

  3. The application of leak before break concept to W7-X target module

    Energy Technology Data Exchange (ETDEWEB)

    Dundulis, G., E-mail: gintas@mail.lei.lt; Janulionis, R.; Karalevičius, R.

    2013-11-15

    Highlights: • LBB application to Wendelstein 7-X fusion reactor. • R6 method application to crack analysis. • Through wall crack opening analysis. • Determination of leak rate function. • Crack growth analysis. -- Abstract: Fusion is the energy production technology, which could potentially solve problems with growing energy demand of population in the future. Wendelstein 7-X (W7-X) is an experimental stellarator of the helias type fusion reactor currently being built in Greifswald, Germany. This experimental stellarator is a complex structure, such as nuclear power plants and high level of safety requirements should be used for structural integrity analysis. It is thus not possible to obtain simple solutions for general cases, therefore sophisticated methods are necessary for the analysis. Inside the Plasma Vessel (PV) of W7-X there is a number of different components such as pipes, divertors, baffles and targets. A guillotine failure of one component is very dangerous for structural integrity of surrounding components located in PV. For this reason it is very important to evaluate possibility to apply “leak before break” (LBB) concept for W7-X. The LBB concept is widely used in the nuclear industry to describe the idea that in the piping carrying the coolant of a power reactor a leak will occur before a catastrophic break will occurred. LBB allows to conduct the structural design without considering the loads due to postulated line breaks. The LBB analysis was made for the case when plasma vessel is operating in “baking” mode. “Baking” is the mode, when the cooling system is working as a warming system and it heats the plasma vessel structures up to 160 °C in order to release the absorbed gases from the surfaces and to pump them out of the plasma vessel before plasma operation. The LBB analysis was performed for most loaded component of target module. According to the results of the analysis it is possible to conclude that target module 1H

  4. Versatile and Tunable Transparent Conducting Electrodes Based on Doped Graphene

    KAUST Repository

    Mansour, Ahmed

    2016-01-01

    Herein, we explore non-covalent doping routes of CVD FLG, such as surface doping, intercalation and combination thereof, through in-depth and systematic characterization of the electrical transport properties and energy levels shifts. The intercalation of FLG with Br2 and FeCl3 is demonstrated, showing the highest improvements of the figure of merit of TCEs of any doping scheme, which results from up to a five-fold increase in conductivity while maintaining the transmittance within 3% of that for the pristine value. Importantly the intercalation yields TCEs that are air-stable, due to encapsulation of the intercalant in the bulk of FLG. Surface doping with novel solution-processed metal-organic molecular species (n- and p-type) is demonstrated with an unprecedented range of work function modulation, resulting from electron transfer and the formation of molecular surface dipoles. However, the conductivity increases compared modestly to intercalation as the electron transfer is limited to the uppermost graphene layers. Finally, a novel and universal multi-modal doping strategy is developed, thanks to the unique platform offered by FLG, where surface and intercalation doping are combined to mutually achieve high conductivity with an extended tunability of the work function. This work presents doped-FLG as a prospective and versatile candidate among emerging TCEs, given the need for efficient and stable doping routes capable of controllably tuning its properties to meet the criteria of a broad range of applications.

  5. Pharmacologic Targeting of Chromatin Modulators As Therapeutics of Acute Myeloid Leukemia.

    Science.gov (United States)

    Lu, Rui; Wang, Gang Greg

    2017-01-01

    Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently "hit" genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event. Increasing body of evidence demonstrates that chromatin modification aberrations underlying the formation of blood cancer can be reversed by pharmacological targeting of the responsible epigenetic modulators, thus providing new mechanism-based treatment strategies. Here, we summarize recent advances in development of small-molecule inhibitors specific to chromatin factors and their potential applications in the treatment of genetically defined AMLs. These compounds selectively inhibit various subclasses of "epigenetic writers" (such as histone methyltransferases MLL/KMT2A, G9A/KMT1C, EZH2/KMT6A, DOT1L/KMT4, and PRMT1), "epigenetic readers" (such as BRD4 and plant homeodomain finger proteins), and "epigenetic erasers" (such as histone demethylases LSD1/KDM1A and JMJD2C/KDM4C). We also discuss about the molecular mechanisms underpinning therapeutic effect of these epigenetic compounds in AML and favor their potential usage for combinational therapy and treatment of pre-leukemia diseases.

  6. Pharmacologic Targeting of Chromatin Modulators As Therapeutics of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Rui Lu

    2017-10-01

    Full Text Available Acute myeloid leukemia (AML, a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently “hit” genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event. Increasing body of evidence demonstrates that chromatin modification aberrations underlying the formation of blood cancer can be reversed by pharmacological targeting of the responsible epigenetic modulators, thus providing new mechanism-based treatment strategies. Here, we summarize recent advances in development of small-molecule inhibitors specific to chromatin factors and their potential applications in the treatment of genetically defined AMLs. These compounds selectively inhibit various subclasses of “epigenetic writers” (such as histone methyltransferases MLL/KMT2A, G9A/KMT1C, EZH2/KMT6A, DOT1L/KMT4, and PRMT1, “epigenetic readers” (such as BRD4 and plant homeodomain finger proteins, and “epigenetic erasers” (such as histone demethylases LSD1/KDM1A and JMJD2C/KDM4C. We also discuss about the molecular mechanisms underpinning therapeutic effect of these epigenetic compounds in AML and favor their potential usage for combinational therapy and treatment of pre-leukemia diseases.

  7. Versatile and Tunable Transparent Conducting Electrodes Based on Doped Graphene

    KAUST Repository

    Mansour, Ahmed E.

    2016-11-25

    The continued growth of the optoelectronics industry and the emergence of wearable and flexible electronics will continue to place an ever increasing pressure on replacing ITO, the most widely used transparent conducting electrode (TCE). Among the various candidates, graphene shows the highest optical transmittance in addition to promising electrical transport properties. The currently available large-scale synthesis routes of graphene result in polycrystalline samples rife with grain boundaries and other defects which limit its transport properties. Chemical doping of graphene is a viable route towards increasing its conductivity and tuning its work function. However, dopants are typically present at the surface of the graphene sheet, making them highly susceptible to degradation in environmental conditions. Few-layers graphene (FLG) is a more resilient form of graphene exhibiting higher conductivity and performance stability under stretching and bending as contrasted to single-layer graphene. In addition FLG presents the advantage of being amenable bulk doping by intercalation. Herein, we explore non-covalent doping routes of CVD FLG, such as surface doping, intercalation and combination thereof, through in-depth and systematic characterization of the electrical transport properties and energy levels shifts. The intercalation of FLG with Br2 and FeCl3 is demonstrated, showing the highest improvements of the figure of merit of TCEs of any doping scheme, which results from up to a five-fold increase in conductivity while maintaining the transmittance within 3% of that for the pristine value. Importantly the intercalation yields TCEs that are air-stable, due to encapsulation of the intercalant in the bulk of FLG. Surface doping with novel solution-processed metal-organic molecular species (n- and p-type) is demonstrated with an unprecedented range of work function modulation, resulting from electron transfer and the formation of molecular surface dipoles. However

  8. Uvrag targeting by Mir125a and Mir351 modulates autophagy associated with Ewsr1 deficiency.

    Science.gov (United States)

    Kim, Yunha; Kang, Young-Sook; Lee, Na-Young; Kim, Ki Yoon; Hwang, Yu Jin; Kim, Hyun-Wook; Rhyu, Im Joo; Her, Song; Jung, Min-Kyung; Kim, Sun; Lee, Chai-Jin; Ko, Seyoon; Kowall, Neil W; Lee, Sean Bong; Lee, Junghee; Ryu, Hoon

    2015-01-01

    The EWSR1 (EWS RNA-binding protein 1/Ewing Sarcoma Break Point Region 1) gene encodes a RNA/DNA binding protein that is ubiquitously expressed and involved in various cellular processes. EWSR1 deficiency leads to impairment of development and accelerated senescence but the mechanism is not known. Herein, we found that EWSR1 modulates the Uvrag (UV radiation resistance associated) gene at the post-transcription level. Interestingly, EWSR1 deficiency led to the activation of the DROSHA-mediated microprocessor complex and increased the level of Mir125a and Mir351, which directly target Uvrag. Moreover, the Mir125a- and Mir351-mediated reduction of Uvrag was associated with the inhibition of autophagy that was confirmed in ewsr1 knockout (KO) MEFs and ewsr1 KO mice. Taken together, our data indicate that EWSR1 is involved in the post-transcriptional regulation of Uvrag via a miRNA-dependent pathway, resulting in the deregulation of autophagy inhibition. The mechanism of Uvrag and autophagy regulation by EWSR1 provides new insights into the role of EWSR1 deficiency-related cellular dysfunction.

  9. Targeting S1P in Inflammatory bowel disease: new avenues for modulating intestinal leukocyte migration.

    Science.gov (United States)

    Danese, Silvio; Furfaro, Federica; Vetrano, Stefania

    2017-07-28

    Sphingosine 1 phosphate (S1P) is a bioactive lipid mediator involved in the regulation of several cellular processes though the activation of a G protein-coupled receptor family known as the S1P receptors (S1PRs). Advances in the understanding of the biological activities mediated by S1PRs have sparked great interest in the S1P/S1PRs axes as new therapeutic targets for the modulation of several cellular processes. In particular, S1P/ S1PR1 axis has been identified as key regulator for the lymphocyte migration from lymph nodes. The blockade of this axis is emerging as a new therapeutic approach to control the aberrant leukocytes migration into the mucosa in inflammatory bowel disease (IBD). This review briefly summarizes the current evidence coming from clinical studies and discusses the future prospects of S1P inhibitors for treatment of inflammatory bowel disease. Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  10. A novel fibronectin binding motif in MSCRAMMs targets F3 modules.

    Directory of Open Access Journals (Sweden)

    Sabitha Prabhakaran

    Full Text Available BBK32 is a surface expressed lipoprotein and fibronectin (Fn-binding microbial surface component recognizing adhesive matrix molecule (MSCRAMM of Borrelia burgdorferi, the causative agent of Lyme disease. Previous studies from our group showed that BBK32 is a virulence factor in experimental Lyme disease and located the Fn-binding region to residues 21-205 of the lipoprotein.Studies aimed at identifying interacting sites between BBK32 and Fn revealed an interaction between the MSCRAMM and the Fn F3 modules. Further analysis of this interaction showed that BBK32 can cause the aggregation of human plasma Fn in a similar concentration-dependent manner to that of anastellin, the superfibronectin (sFn inducing agent. The resulting Fn aggregates are conformationally distinct from plasma Fn as indicated by a change in available thermolysin cleavage sites. Recombinant BBK32 and anastellin affect the structure of Fn matrices formed by cultured fibroblasts and inhibit endothelial cell proliferation similarly. Within BBK32, we have located the sFn-forming activity to a region between residues 160 and 175 which contains two sequence motifs that are also found in anastellin. Synthetic peptides mimicking these motifs induce Fn aggregation, whereas a peptide with a scrambled sequence motif was inactive, suggesting that these motifs represent the sFn-inducing sequence.We conclude that BBK32 induces the formation of Fn aggregates that are indistinguishable from those formed by anastellin. The results of this study provide evidence for how bacteria can target host proteins to manipulate host cell activities.

  11. Locoregional control after intensity-modulated radiotherapy for nasopharyngeal carcinoma with an anatomy-based target definition

    International Nuclear Information System (INIS)

    Kawashima, Mitsuhiko; Ariji, Takaki; Kameoka, Satoru

    2013-01-01

    The objective of the study was to evaluate locoregional control after intensity-modulated radiotherapy for nasopharyngeal cancer using a target definition along with anatomical boundaries. Forty patients with biopsy-proven squamous cell or non-keratinizing carcinoma of the nasopharynx who underwent intensity-modulated radiotherapy between April 2006 and November 2009 were reviewed. There were 10 females and 30 males with a median age of 48 years (range, 17-74 years). More than half of the patients had T3/4 (n=21) and/or N2/3 (n=24) disease. Intensity-modulated radiotherapy was administered as 70 Gy/33 fractions with or without concomitant chemotherapy. The clinical target volume was contoured along with muscular fascia or periosteum, and the prescribed radiotherapy dose was determined for each anatomical compartment and lymph node level in the head and neck. One local recurrence was observed at Meckel's cave on the periphery of the high-risk clinical target volume receiving a total dose of <63 Gy. Otherwise, six locoregional failures were observed within irradiated volume receiving 70 Gy. Local and nodal control rates at 3 years were 91 and 89%, respectively. Adverse events were acceptable, and 25 (81%) of 31 patients who were alive without recurrence at 2 years had xerostomia of ≤ Grade 1. The overall survival rate at 3 years was 87%. Target definition along with anatomically defined boundaries was feasible without compromise of the therapeutic ratio. It is worth testing this method further to minimize the unnecessary irradiated volume and to standardize the target definition in intensity-modulated radiotherapy for nasopharyngeal cancer. (author)

  12. Detection of Metallic and Electronic Radar Targets by Acoustic Modulation of Electromagnetic Waves

    Science.gov (United States)

    2017-07-01

    by Acoustic Modulation of Electromagnetic Waves 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Gregory J... Program 13 List of Symbols, Abbreviations, and Acronyms 18 Distribution List 19 Approved for public release; distribution is...4 Fig. 4 Flowchart of wireless experiment to receive acoustically modulated radar waveforms

  13. Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma.

    Science.gov (United States)

    Boro, Aleksandar; Prêtre, Kathya; Rechfeld, Florian; Thalhammer, Verena; Oesch, Susanne; Wachtel, Marco; Schäfer, Beat W; Niggli, Felix K

    2012-11-01

    Ewing's sarcoma family of tumors (EFT) is characterized by the presence of chromosomal translocations leading to the expression of oncogenic transcription factors such as, in the majority of cases, EWS/FLI1. Because of its key role in Ewing's sarcoma development and maintenance, EWS/FLI1 represents an attractive therapeutic target. Here, we characterize PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Using this gene and additional specific well-characterized target genes such as NROB1, NKX2.2 and CAV1, all activated by EWS/FLI1, as a read-out system, we screened a small-molecule compound library enriched for FDA-approved drugs that modulated the expression of EWS/FLI1 target genes. Among a hit-list of nine well-known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of six Ewing's sarcoma cell lines in vitro and can significantly suppress xenograft tumor growth in vivo. These results suggest that midostaurin might be a novel drug that is active against Ewing's cells, which might act by modulating the expression of EWS/FLI1 target genes. Copyright © 2012 UICC.

  14. Priming of pop-out modulates attentional target selection in visual search: Behavioural and electrophysiological evidence

    OpenAIRE

    Eimer, Martin; Kiss, Monika; Cheung, Theodore

    2009-01-01

    Previous behavioural studies have shown that the repetition of target or distractor features across trials speeds pop-out visual search. We obtained behavioural and event-related brain potential (ERP) measures in two experiments where participants searched for a colour singleton target among homogeneously coloured distractors. An ERP marker of spatially selective attention (N2pc component) was delayed when either target or distractor colours were swapped across successive trials, demonstratin...

  15. Post-translational regulation of Foxp3 : identification of novel molecular targets for immune modulation

    NARCIS (Netherlands)

    van Loosdregt, J.

    2011-01-01

    Maintenance of immune homeostasis is a complex process allowing the immune system to be both aggressive enough to eradicate cells that express foreign antigens, and yet provide sensitivity to tolerate cells expressing self antigens. Key modulators allowing tolerance of host antigens, thereby

  16. Impedance modulation and feedback corrections in tracking targets of variable size and frequency

    NARCIS (Netherlands)

    Selen, L.P.J.; van Dieen, J.H.; Beek, P.J.

    2006-01-01

    Humans are able to adjust the accuracy of their movements to the demands posed by the task at hand. The variability in task execution caused by the inherent noisiness of the neuromuscular system can be tuned to task demands by both feedforward (e.g., impedance modulation) and feedback mechanisms. In

  17. Visual working memory modulates low-level saccade target selection: Evidence from rapidly generated saccades in the global effect paradigm

    Science.gov (United States)

    Hollingworth, Andrew; Matsukura, Michi; Luck, Steven J.

    2013-01-01

    In three experiments, we examined the influence of visual working memory (VWM) on the metrics of saccade landing position in a global effect paradigm. Participants executed a saccade to the more eccentric object in an object pair appearing on the horizontal midline, to the left or right of central fixation. While completing the saccade task, participants maintained a color in VWM for an unrelated memory task. Either the color of the saccade target matched the memory color (target match), the color of the distractor matched the memory color (distractor match), or the colors of neither object matched the memory color (no match). In the no-match condition, saccades tended to land at the midpoint between the two objects: the global, or averaging, effect. However, when one of the two objects matched VWM, the distribution of landing position shifted toward the matching object, both for target match and for distractor match. VWM modulation of landing position was observed even for the fastest quartile of saccades, with a mean latency as low as 112 ms. Effects of VWM on such rapidly generated saccades, with latencies in the express-saccade range, indicate that VWM interacts with the initial sweep of visual sensory processing, modulating perceptual input to oculomotor systems and thereby biasing oculomotor selection. As a result, differences in memory match produce effects on landing position similar to the effects generated by differences in physical salience. PMID:24190909

  18. Visual working memory modulates low-level saccade target selection: evidence from rapidly generated saccades in the global effect paradigm.

    Science.gov (United States)

    Hollingworth, Andrew; Matsukura, Michi; Luck, Steven J

    2013-11-04

    In three experiments, we examined the influence of visual working memory (VWM) on the metrics of saccade landing position in a global effect paradigm. Participants executed a saccade to the more eccentric object in an object pair appearing on the horizontal midline, to the left or right of central fixation. While completing the saccade task, participants maintained a color in VWM for an unrelated memory task. Either the color of the saccade target matched the memory color (target match), the color of the distractor matched the memory color (distractor match), or the colors of neither object matched the memory color (no match). In the no-match condition, saccades tended to land at the midpoint between the two objects: the global, or averaging, effect. However, when one of the two objects matched VWM, the distribution of landing position shifted toward the matching object, both for target match and for distractor match. VWM modulation of landing position was observed even for the fastest quartile of saccades, with a mean latency as low as 112 ms. Effects of VWM on such rapidly generated saccades, with latencies in the express-saccade range, indicate that VWM interacts with the initial sweep of visual sensory processing, modulating perceptual input to oculomotor systems and thereby biasing oculomotor selection. As a result, differences in memory match produce effects on landing position similar to the effects generated by differences in physical salience.

  19. Platforms for the identification of GPCR targets, and of orthosteric and allosteric modulators.

    Science.gov (United States)

    Franco, Rafael; Canela, Enric I; Casado, Vicent; Ferre, Sergi

    2010-04-01

    The review provides a summary of old and new approaches for GPCR target identification and for the screening of molecules acting on GPCR targets. The new findings in the field are presented as well as an opinion about how these developments may help GPCR drug discovery. Importance in the field: GPCRs have been the most useful family of proteins in terms of targets for drug discovery. The expectations for GPCR target identification and discovery of new drugs acting on 'old' or 'new' GPCR targets are very high. Given the fact that the pace at which new 'GPCR drugs' appear in the market is decreasing and since the new developments in the field are not being translated into drug discovery there is a need to review the field from a critical perspective. To overcome the limitation of the old approaches used in GPCR target identification and drugs discovery new approaches are required. In particular successful approaches in GPCR drug discovery should take into account that the real GPCR targets for a given disease are not GPCR monomers but GPCR heteromers. The reader will gain an overview of the strategies currently used and their pros and cons. The reader will also understand that new strategies may help in accelerating the access of GPCR into the market, and also notice that successful strategies should take advantage of the new findings in the field of GPCRs.

  20. Improved bioavailability of targeted Curcumin delivery efficiently regressed cardiac hypertrophy by modulating apoptotic load within cardiac microenvironment

    International Nuclear Information System (INIS)

    Ray, Aramita; Rana, Santanu; Banerjee, Durba; Mitra, Arkadeep; Datta, Ritwik; Naskar, Shaon; Sarkar, Sagartirtha

    2016-01-01

    Cardiomyocyte apoptosis acts as a prime modulator of cardiac hypertrophy leading to heart failure, a major cause of human mortality worldwide. Recent therapeutic interventions have focussed on translational applications of diverse pharmaceutical regimes among which, Curcumin (from Curcuma longa) is known to have an anti-hypertrophic potential but with limited pharmacological efficacies due to low aqueous solubility and poor bioavailability. In this study, Curcumin encapsulated by carboxymethyl chitosan (CMC) nanoparticle conjugated to a myocyte specific homing peptide was successfully delivered in bioactive form to pathological myocardium for effective regression of cardiac hypertrophy in a rat (Rattus norvegicus) model. Targeted nanotization showed higher cardiac bioavailability of Curcumin at a low dose of 5 mg/kg body weight compared to free Curcumin at 35 mg/kg body weight. Moreover, Curcumin/CMC-peptide treatment during hypertrophy significantly improved cardiac function by downregulating expression of hypertrophy marker genes (ANF, β-MHC), apoptotic mediators (Bax, Cytochrome-c) and activity of apoptotic markers (Caspase 3 and PARP); whereas free Curcumin in much higher dose showed minimal improvement during compromised cardiac function. Targeted Curcumin treatment significantly lowered p53 expression and activation in diseased myocardium via inhibited interaction of p53 with p300-HAT. Thus attenuated acetylation of p53 facilitated p53 ubiquitination and reduced the apoptotic load in hypertrophied cardiomyocytes; thereby limiting cardiomyocytes' need to enter the regeneration cycle during hypertrophy. This study elucidates for the first time an efficient targeted delivery regimen for Curcumin and also attributes towards probable mechanistic insight into its therapeutic potential as a cardio-protective agent for regression of cardiac hypertrophy. - Highlights: • Cardiomyocyte targeted Curcumin/CMC-peptide increases bioavailability of the drug.

  1. Mathematical modeling and measurement of electric fields of electrode-based through-the-earth (TTE) communication

    OpenAIRE

    Yan, Lincan; Zhou, Chenming; Reyes, Miguel; Whisner, Bruce; Damiano, Nicholas

    2017-01-01

    There are two types of through-the-earth (TTE) wireless communication in the mining industry: magnetic loop TTE and electrode-based (or linear) TTE. While the magnetic loop systems send signal through magnetic fields, the transmitter of an electrode-based TTE system sends signal directly through the mine overburden by driving an extremely low frequency (ELF) or ultralow frequency (ULF) AC current into the earth. The receiver at the other end (underground or surface) detects the resultant curr...

  2. Treatment planning with intensity modulated particle therapy for multiple targets in stage IV non-small cell lung cancer

    Science.gov (United States)

    Anderle, Kristjan; Stroom, Joep; Vieira, Sandra; Pimentel, Nuno; Greco, Carlo; Durante, Marco; Graeff, Christian

    2018-01-01

    Intensity modulated particle therapy (IMPT) can produce highly conformal plans, but is limited in advanced lung cancer patients with multiple lesions due to motion and planning complexity. A 4D IMPT optimization including all motion states was expanded to include multiple targets, where each target (isocenter) is designated to specific field(s). Furthermore, to achieve stereotactic treatment planning objectives, target and OAR weights plus objective doses were automatically iteratively adapted. Finally, 4D doses were calculated for different motion scenarios. The results from our algorithm were compared to clinical stereotactic body radiation treatment (SBRT) plans. The study included eight patients with 24 lesions in total. Intended dose regimen for SBRT was 24 Gy in one fraction, but lower fractionated doses had to be delivered in three cases due to OAR constraints or failed plan quality assurance. The resulting IMPT treatment plans had no significant difference in target coverage compared to SBRT treatment plans. Average maximum point dose and dose to specific volume in OARs were on average 65% and 22% smaller with IMPT. IMPT could also deliver 24 Gy in one fraction in a patient where SBRT was limited due to the OAR vicinity. The developed algorithm shows the potential of IMPT in treatment of multiple moving targets in a complex geometry.

  3. Design, simulation and manufacture of a multi leaf collimator to confirm the target volumes in intensity modulated radiation therapy

    International Nuclear Information System (INIS)

    Kamali-Asl, A.; Batooli, A. H.; Harriri, S.; Salman-Rezaee, F.; Shahmardan, F.; Yavari, L.

    2010-01-01

    Intensity modulated radiation therapy is one of the cancer treatment methods. It is important to selectively aim at the target in this way, which can be performed using a multi leaf collimator. Materials and Methods: In order to specifically irradiate the target volume in radiotherapy to reduce the patient absorbed dose, the use of multi leaf collimator has been investigated in this work. Design and simulation of an multi leaf collimator was performed by a Monte Carlo method and the optimum material for manufacturing the leaves was determined using MCNP4C. After image processing (CT or MRI) in this system, the tumor configuration is determined. Then the linear accelerator is switched on and the beam irradiates the cancerous cells. When the multi leaf collimator leaves receive a command from the micro controller, they start to move and absorb the radiation and modulate its intensity. Consequently, the tumor receives maximum intensity of radiation but minimum intensity is delivered to healthy tissues. Results: According to the simulations and calculations, the best material to manufacture the leaves from is tungsten alloy containing copper and nickel which absorbs a large amount of the radiation; by using a 8.65 cm thickness of alloy, 10.55% of radiation will transmit through the leaves. Discussion and Conclusion: Lead blocks are conventionally used in radiotherapy. However, they have some problems like cost, storage and manufacture for every patient. Certainly, the multi leaf collimator is the most efficient device to specifically irradiate the tumor in Intensity modulated radiation therapy. Furthermore, it facilitates treating the target in different views by rotation around the patient. Thus the patient's absorbed dose will decrease and the tumor will receive maximum dose.

  4. Mathematical modeling and measurement of electric fields of electrode-based through-the-earth (TTE) communication

    Science.gov (United States)

    Yan, Lincan; Zhou, Chenming; Reyes, Miguel; Whisner, Bruce; Damiano, Nicholas

    2017-06-01

    There are two types of through-the-earth (TTE) wireless communication in the mining industry: magnetic loop TTE and electrode-based (or linear) TTE. While the magnetic loop systems send signal through magnetic fields, the transmitter of an electrode-based TTE system sends signal directly through the mine overburden by driving an extremely low frequency (ELF) or ultralow frequency (ULF) AC current into the earth. The receiver at the other end (underground or surface) detects the resultant current and receives it as a voltage. A wireless communication link between surface and underground is then established. For electrode-based TTE communications, the signal is transmitted through the established electric field and is received as a voltage detected at the receiver. It is important to understand the electric field distribution within the mine overburden for the purpose of designing and improving the performance of the electrode-based TTE systems. In this paper, a complete explicit solution for all three electric field components for the electrode-based TTE communication was developed. An experiment was conducted using a prototype electrode-based TTE system developed by National Institute for Occupational Safety and Health. The mathematical model was then compared and validated with test data. A reasonable agreement was found between them.

  5. Spatiotemporal Relationships among Audiovisual Stimuli Modulate Auditory Facilitation of Visual Target Discrimination.

    Science.gov (United States)

    Li, Qi; Yang, Huamin; Sun, Fang; Wu, Jinglong

    2015-03-01

    Sensory information is multimodal; through audiovisual interaction, task-irrelevant auditory stimuli tend to speed response times and increase visual perception accuracy. However, mechanisms underlying these performance enhancements have remained unclear. We hypothesize that task-irrelevant auditory stimuli might provide reliable temporal and spatial cues for visual target discrimination and behavioral response enhancement. Using signal detection theory, the present study investigated the effects of spatiotemporal relationships on auditory facilitation of visual target discrimination. Three experiments were conducted where an auditory stimulus maintained reliable temporal and/or spatial relationships with visual target stimuli. Results showed that perception sensitivity (d') to visual target stimuli was enhanced only when a task-irrelevant auditory stimulus maintained reliable spatiotemporal relationships with a visual target stimulus. When only reliable spatial or temporal information was contained, perception sensitivity was not enhanced. These results suggest that reliable spatiotemporal relationships between visual and auditory signals are required for audiovisual integration during a visual discrimination task, most likely due to a spread of attention. These results also indicate that auditory facilitation of visual target discrimination follows from late-stage cognitive processes rather than early stage sensory processes. © 2015 SAGE Publications.

  6. Amplitude modulation in δ Sct stars: statistics from an ensemble of Kepler targets

    Science.gov (United States)

    Bowman, Dominic M.; Kurtz, Donald W.; Breger, Michel; Murphy, Simon J.; Holdsworth, Daniel L.

    2017-10-01

    The results of a search for amplitude modulation of pulsation modes in 983 δ Sct stars, which have effective temperatures between 6400 ⩽ Teff ⩽ 10 000 K in the Kepler Input Catalogue and were continuously observed by the Kepler Space Telescope for 4 yr, are presented. A total of 603 δ Sct stars (61.3 per cent) are found to exhibit at least one pulsation mode that varies significantly in amplitude over 4 yr. Furthermore, it is found that amplitude modulation is not restricted to a specific region within the classical instability strip in the HR diagram, therefore its cause is not necessarily dependent on stellar parameters such as Teff or log g. On the other hand, many δ Sct stars show constant pulsation amplitudes demonstrating that the cause of pulsational non-linearity in these stars is not well understood.

  7. Pharmacologic Targeting of Chromatin Modulators As Therapeutics of Acute Myeloid Leukemia

    OpenAIRE

    Rui Lu; Rui Lu; Gang Greg Wang; Gang Greg Wang

    2017-01-01

    Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently “hit” genes encoding epigenetic modulators, a wide range of chromatin-modifyin...

  8. MiR-155 modulates the progression of neuropathic pain through targeting SGK3.

    Science.gov (United States)

    Liu, Shaoxing; Zhu, Bo; Sun, Yan; Xie, Xianfeng

    2015-01-01

    This study aimed to illustrate the potential effects of miR-155 in neuropathic pain and its potential mechanism. Spragure-Dawley (SD) rats were used for neuropathic pain model of bilateral chronic constriction injury (bCCI) construction. Effects of miR-155 expression on pain threshold of mechanical stimuli (MWT), paw withdrawal threshold latency (PMTL) and cold threshold were analyzed. Target for miR-155 was analyzed using bioinformatics methods. Moreover, effects of miR-155 target gene expression on pain thresholds were also assessed. Compared with the controls and sham group, miR-155 was overexpressed in neuropathic pain rats (P<0.05), but miR-155 slicing could significantly decreased the pain thresholds (P<0.05). Serum and glucocorticoid regulated protein kinase 3 (SGK3) was predicted as the target gene for miR-155, and miR-155 expression was negatively correlated to SGK3 expression. Furthermore, SGK3 overexpression could significantly decreased the pain thresholds which was the same as miR-155 (P<0.05). Moreover, miR-155 slicing and SGK3 overexpression could significantly decrease the painthreshold. The data presented in this study suggested that miR-155 slicing could excellently alleviate neuropathic pain in rats through targeting SGK3 expression. miR-155 may be a potential therapeutic target for neuropathic pain treatment.

  9. HER2-Targeted Polyinosine/Polycytosine Therapy Inhibits Tumor Growth and Modulates the Tumor Immune Microenvironment.

    Science.gov (United States)

    Zigler, Maya; Shir, Alexei; Joubran, Salim; Sagalov, Anna; Klein, Shoshana; Edinger, Nufar; Lau, Jeffrey; Yu, Shang-Fan; Mizraji, Gabriel; Globerson Levin, Anat; Sliwkowski, Mark X; Levitzki, Alexander

    2016-08-01

    The development of targeted therapies that affect multiple signaling pathways and stimulate antitumor immunity is greatly needed. About 20% of patients with breast cancer overexpress HER2. Small molecules and antibodies targeting HER2 convey some survival benefits; however, patients with advanced disease succumb to the disease under these treatment regimens, possibly because HER2 is not completely necessary for the survival of the targeted cancer cells. In the present study, we show that a polyinosine/polycytosine (pIC) HER2-homing chemical vector induced the demise of HER2-overexpressing breast cancer cells, including trastuzumab-resistant cells. Targeting pIC to the tumor evoked a number of cell-killing mechanisms, as well as strong bystander effects. These bystander mechanisms included type I IFN induction, immune cell recruitment, and activation. The HER2-targeted pIC strongly inhibited the growth of HER2-overexpressing tumors in immunocompetent mice. The data presented here could open additional avenues in the treatment of HER2-positive breast cancer. Cancer Immunol Res; 4(8); 688-97. ©2016 AACR. ©2016 American Association for Cancer Research.

  10. Cell signaling heterogeneity is modulated by both cell-intrinsic and -extrinsic mechanisms: An integrated approach to understanding targeted therapy.

    Science.gov (United States)

    Kim, Eunjung; Kim, Jae-Young; Smith, Matthew A; Haura, Eric B; Anderson, Alexander R A

    2018-03-01

    During the last decade, our understanding of cancer cell signaling networks has significantly improved, leading to the development of various targeted therapies that have elicited profound but, unfortunately, short-lived responses. This is, in part, due to the fact that these targeted therapies ignore context and average out heterogeneity. Here, we present a mathematical framework that addresses the impact of signaling heterogeneity on targeted therapy outcomes. We employ a simplified oncogenic rat sarcoma (RAS)-driven mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase-protein kinase B (PI3K-AKT) signaling pathway in lung cancer as an experimental model system and develop a network model of the pathway. We measure how inhibition of the pathway modulates protein phosphorylation as well as cell viability under different microenvironmental conditions. Training the model on this data using Monte Carlo simulation results in a suite of in silico cells whose relative protein activities and cell viability match experimental observation. The calibrated model predicts distributional responses to kinase inhibitors and suggests drug resistance mechanisms that can be exploited in drug combination strategies. The suggested combination strategies are validated using in vitro experimental data. The validated in silico cells are further interrogated through an unsupervised clustering analysis and then integrated into a mathematical model of tumor growth in a homogeneous and resource-limited microenvironment. We assess posttreatment heterogeneity and predict vast differences across treatments with similar efficacy, further emphasizing that heterogeneity should modulate treatment strategies. The signaling model is also integrated into a hybrid cellular automata (HCA) model of tumor growth in a spatially heterogeneous microenvironment. As a proof of concept, we simulate tumor responses to targeted therapies in a spatially segregated tissue structure containing tumor

  11. A charge-pump 60kV modulator for the ISOLDE target extraction voltage

    CERN Document Server

    Barlow, R A; Fowler, A; Gaudillet, H; Gharsa, T; Schipper, J

    2015-01-01

    The ISOLDE facility at CERN provides radioactive ion beams to a number of experimental stations. These ions are produced by a metal target, floating at 60 kV, which is impacted by a 1.4 GeV high intensity proton beam. The ions are then accelerated by a grounded extraction electrode to 60 keV, before transport to the experimental area. During proton beam impact extremely high ionisation of the volume around the target gives rise to significant leakage current which results in loss of charge on the effective target capacitance of approximately 6 nF. If short life-time isotopes are to be studied, the 60 kV must be re-established within a maximum of 10 ms. Recharging the target capacitance to 60 kV and to the required stability of better than 10-4 precludes a direct charging system and an alternative method of re-establishing the 60 kV is used. The present system [1], in operation since 1991, employs a resonant circuit which is triggered 35 µs prior to beam impact. This circuit transfers the charge on the effec...

  12. Unconscious Congruency Priming from Unpracticed Words Is Modulated by Prime-Target Semantic Relatedness

    Science.gov (United States)

    Ortells, Juan J.; Mari-Beffa, Paloma; Plaza-Ayllon, Vanesa

    2013-01-01

    Participants performed a 2-choice categorization task on visible word targets that were preceded by novel (unpracticed) prime words. The prime words were presented for 33 ms and followed either immediately (Experiments 1-3) or after a variable delay (Experiments 1 and 4) by a pattern mask. Both subjective and objective measures of prime visibility…

  13. Targeted Therapy Combined with Immune Modulation Using Gold Nanoparticles for Treating Metastatic Colorectal Cancer

    Science.gov (United States)

    2017-09-01

    stimulate the body’s immune system to target and attack cancer cells. Another part of our research includes coating these gold nanoparticles with...change in animal care is the introduction of doxycycline through food chow in addition to drinking water. The dose of doxycycline from the drinking water

  14. Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting.

    Directory of Open Access Journals (Sweden)

    Ann-Marie Chacko

    Full Text Available Antibodies to platelet endothelial cell adhesion molecule-1 (PECAM-1 facilitate targeted drug delivery to endothelial cells by "vascular immunotargeting." To define the targeting quantitatively, we investigated the endothelial binding of monoclonal antibodies (mAbs to extracellular epitopes of PECAM-1. Surprisingly, we have found in human and mouse cell culture models that the endothelial binding of PECAM-directed mAbs and scFv therapeutic fusion protein is increased by co-administration of a paired mAb directed to an adjacent, yet distinct PECAM-1 epitope. This results in significant enhancement of functional activity of a PECAM-1-targeted scFv-thrombomodulin fusion protein generating therapeutic activated Protein C. The "collaborative enhancement" of mAb binding is affirmed in vivo, as manifested by enhanced pulmonary accumulation of intravenously administered radiolabeled PECAM-1 mAb when co-injected with an unlabeled paired mAb in mice. This is the first demonstration of a positive modulatory effect of endothelial binding and vascular immunotargeting provided by the simultaneous binding a paired mAb to adjacent distinct epitopes. The "collaborative enhancement" phenomenon provides a novel paradigm for optimizing the endothelial-targeted delivery of therapeutic agents.

  15. Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

    International Nuclear Information System (INIS)

    Wada, Takeyoshi; Asahi, Toru; Sawamura, Naoya

    2016-01-01

    The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.

  16. Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

    Energy Technology Data Exchange (ETDEWEB)

    Wada, Takeyoshi [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Asahi, Toru [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Sawamura, Naoya, E-mail: naoya.sawamura@gmail.com [Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan); Research Organization for Nano & Life Innovation, Waseda University #03C309, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo, 162-8480 (Japan)

    2016-08-26

    The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin. - Highlights: • We found that CRBN is a nucleocytoplasmic shutting protein and identified the key domain for nucleocytoplasmic shuttling. • CRBN associates with the transcription factor Ikaros via the N-terminal domain. • CRBN modulates Ikaros-mediated transcriptional regulation and its downstream target, enkephalin.

  17. The Endocannabinoid System as a Potential Therapeutic Target for Pain Modulation

    Directory of Open Access Journals (Sweden)

    Ahmet Ulugöl

    2014-06-01

    Full Text Available Although cannabis has been used for pain management for millennia, very few approved cannabinoids are indicated for the treatment of pain and other medical symptoms. Cannabinoid therapy re-gained attention only after the discovery of endocannabinoids and fatty acid amide hydrolase (FAAH and monoacylglycerol lipase (MAGL, the enzymes playing a role in endocannabinoid metabolism. Nowadays, research has focused on the inhibition of these degradative enzymes and the elevation of endocannabinoid tonus locally; special emphasis is given on multi-target analgesia compounds, where one of the targets is the endocannabinoid degrading enzyme. In this review, I provide an overview of the current understanding about the processes accounting for the biosynthesis, transport and metabolism of endocannabinoids, and pharmacological approaches and potential therapeutic applications in this area, regarding the use of drugs elevating endocannabinoid levels in pain conditions.

  18. DMLC motion tracking of moving targets for intensity modulated arc therapy treatment

    DEFF Research Database (Denmark)

    Zimmerman, Jens; Korreman, Stine; Persson, Gitte

    2009-01-01

    (DMLC). The aim of this work was to evaluate the dose delivered to moving targets using the RapidArc (Varian Medical Systems, Inc.) technology with and without a DMLC tracking algorithm. MATERIAL AND METHODS: A Varian Clinac iX was equipped with a preclinical RapidArc and a 3D DMLC tracking application......) and state (1). CONCLUSIONS: DMLC tracking together with RapidArc make a feasible combination and is capable of improving the dose distribution delivered to a moving target. It seems to be of importance to minimize noise influencing the tracking, to gain the full benefit from the application........ A motion platform was placed on the couch, with the detectors on top: a PTW seven29 and a Scandidos Delta4. One lung plan and one prostate plan were delivered. Motion was monitored using a Real-time Position Management (RPM) system. Reference measurements were performed for both plans with both detectors...

  19. Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea

    OpenAIRE

    Lapp, T.; Zaher, S. S.; Haas, C. T.; Becker, D. L.; Thrasivoulou, C.; Chain, B. M.; Larkin, D. F. P.; Noursadeghi, M.

    2015-01-01

    Purpose: We sought to test the hypothesis that monocytes contribute to the immunopathogenesis of corneal allograft rejection and identify therapeutic targets to inhibit monocyte recruitment. Methods: Monocytes and proinflammatory mediators within anterior chamber samples during corneal graft rejection were quantified by flow cytometry and multiplex protein assays. Lipopolysaccharide or IFN-γ stimulation of monocyte-derived macrophages (MDMs) was used to generate inflammatory conditioned me...

  20. MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation

    Directory of Open Access Journals (Sweden)

    Thomas J. Kean

    2013-01-01

    Full Text Available Mesenchymal stem cells (MSCs are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the “first-pass” accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC therapeutic dose.

  1. A Targeted Attack For Enhancing Resiliency of Intelligent Intrusion Detection Modules in Energy Cyber Physical Systems

    Energy Technology Data Exchange (ETDEWEB)

    Youssef, Tarek [Florida Intl Univ., Miami, FL (United States); El Hariri, Mohammad [Florida Intl Univ., Miami, FL (United States); Habib, Hani [Florida Intl Univ., Miami, FL (United States); Mohammed, Osama [Florida Intl Univ., Miami, FL (United States); Harmon, E [Florida Intl Univ., Miami, FL (United States)

    2017-02-28

    Abstract— Secure high-speed communication is required to ensure proper operation of complex power grid systems and prevent malicious tampering activities. In this paper, artificial neural networks with temporal dependency are introduced for false data identification and mitigation for broadcasted IEC 61850 SMV messages. The fast responses of such intelligent modules in intrusion detection make them suitable for time- critical applications, such as protection. However, care must be taken in selecting the appropriate intelligence model and decision criteria. As such, this paper presents a customizable malware script to sniff and manipulate SMV messages and demonstrates the ability of the malware to trigger false positives in the neural network’s response. The malware developed is intended to be as a vaccine to harden the intrusion detection system against data manipulation attacks by enhancing the neural network’s ability to learn and adapt to these attacks.

  2. Effect of interfractional shoulder motion on low neck nodal targets for patients treated using volume modulated arc therapy (VMAT

    Directory of Open Access Journals (Sweden)

    Kevin Casey

    2014-03-01

    Full Text Available Purpose: To quantify the dosimetric impact of interfractional shoulder motion on targets in the low neck for head and neck patients treated with volume modulated arc therapy (VMAT.Methods: Three patients with head and neck cancer were selected. All three required treatment to nodal regions in the low neck in addition to the primary tumor site. The patients were immobilized during simulation and treatment with a custom thermoplastic mask covering the head and shoulders. One VMAT plan was created for each patient utilizing two full 360° arcs and a second plan was created consisting of two superior VMAT arcs matched to an inferior static AP supraclavicular field. A CT-on-rails alignment verification was performed weekly during each patient’s treatment course. The weekly CT images were registered to the simulation CT and the target contours were deformed and applied to the weekly CT. The two VMAT plans were copied to the weekly CT datasets and recalculated to obtain the dose to the deformed low neck contours.Results: The average observed shoulder position shift in any single dimension relative to simulation was 2.5 mm. The maximum shoulder shift observed in a single dimension was 25.7 mm. Low neck target mean doses, normalized to simulation and averaged across all weekly recalculations were 0.996, 0.991, and 1.033 (Full VMAT plan and 0.986, 0.995, and 0.990 (Half-Beam VMAT plan for the three patients, respectively. The maximum observed deviation in target mean dose for any individual weekly recalculation was 6.5%, occurring with the Full VMAT plan for Patient 3.Conclusion: Interfractional variation in dose to low neck nodal regions was quantified for three head and neck patients treated with VMAT. Mean dose was 3.3% higher than planned for one patient using a Full VMAT plan. A Half-Beam technique is likely a safer choice when treating the supraclavicular region with VMAT.-------------------------------------------Cite this article as: Casey K

  3. The Salmonella Effector Protein SopA Modulates Innate Immune Responses by Targeting TRIM E3 Ligase Family Members.

    Directory of Open Access Journals (Sweden)

    Jana Kamanova

    2016-04-01

    Full Text Available Salmonella Typhimurium stimulates inflammatory responses in the intestinal epithelium, which are essential for its ability to replicate within the intestinal tract. Stimulation of these responses is strictly dependent on the activity of a type III secretion system encoded within its pathogenicity island 1, which through the delivery of effector proteins, triggers signaling pathways leading to inflammation. One of these effectors is SopA, a HECT-type E3 ligase, which is required for the efficient stimulation of inflammation in an animal model of Salmonella Typhimurium infection. We show here that SopA contributes to the stimulation of innate immune responses by targeting two host E3 ubiquitin ligases, TRIM56 and TRIM65. We also found that TRIM65 interacts with the innate immune receptor MDA5 enhancing its ability to stimulate interferon-β signaling. Therefore, by targeting TRIM56 and TRIM65, SopA can stimulate signaling through two innate immune receptors, RIG-I and MDA5. These findings describe a Salmonella mechanism to modulate inflammatory responses by directly targeting innate immune signaling mechanisms.

  4. Light-reflection random-target method for measurement of the modulation transfer function of a digital video-camera

    Science.gov (United States)

    Pospisil, J.; Jakubik, P.; Machala, L.

    2005-11-01

    This article reports the suggestion, realization and verification of the newly developed measuring means of the noiseless and locally shift-invariant modulation transfer function (MTF) of a digital video camera in a usual incoherent visible region of optical intensity, especially of its combined imaging, detection, sampling and digitizing steps which are influenced by the additive and spatially discrete photodetector, aliasing and quantization noises. Such means relates to the still camera automatic working regime and static two-dimensional spatially continuous light-reflection random target of white-noise property. The introduced theoretical reason for such a random-target method is also performed under exploitation of the proposed simulation model of the linear optical intensity response and possibility to express the resultant MTF by a normalized and smoothed rate of the ascertainable output and input power spectral densities. The random-target and resultant image-data were obtained and processed by means of a processing and evaluational PC with computation programs developed on the basis of MATLAB 6.5E The present examples of results and other obtained results of the performed measurements demonstrate the sufficient repeatability and acceptability of the described method for comparative evaluations of the performance of digital video cameras under various conditions.

  5. Target volume delineation and field setup. A practical guide for conformal and intensity-modulated radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Nancy Y. [Memorial Sloan-Kettering Cancer Center, New York, NY (United States). Radiation Oncology; Lu, Jiade J. (eds.) [National Univ. Health System, Singapore (Singapore). Dept. of Radiation Oncology; National Univ. of Singapore (Singapore). Dept. of Medicine

    2013-03-01

    Practical handbook on selection and delineation of tumor volumes and fields for conformal radiation therapy, including IMRT. Helpful format facilitating use on a step-by-step basis in daily practice. Designed to ensure accurate coverage of commonly encountered tumors along their routes of spread. This handbook is designed to enable radiation oncologists to appropriately and confidently delineate tumor volumes/fields for conformal radiation therapy, including intensity-modulated radiation therapy (IMRT), in patients with commonly encountered cancers. The orientation of this handbook is entirely practical, in that the focus is on the illustration of clinical target volume (CTV) delineation for each major malignancy. Each chapter provides guidelines and concise knowledge on CTV selection for a particular disease, explains how the anatomy of lymphatic drainage shapes the selection of the target volume, and presents detailed illustrations of volumes, slice by slice, on planning CT images. While the emphasis is on target volume delineation for three-dimensional conformal therapy and IMRT, information is also provided on conventional radiation therapy field setup and planning for certain malignancies for which IMRT is not currently suitable.

  6. Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy.

    Science.gov (United States)

    Pergola, Carlo; Schubert, Katrin; Pace, Simona; Ziereisen, Jana; Nikels, Felix; Scherer, Olga; Hüttel, Stephan; Zahler, Stefan; Vollmar, Angelika M; Weinigel, Christina; Rummler, Silke; Müller, Rolf; Raasch, Martin; Mosig, Alexander; Koeberle, Andreas; Werz, Oliver

    2017-01-30

    Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells.

  7. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. | Office of Cancer Genomics

    Science.gov (United States)

    Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition.

  8. The Attentional Blink is Modulated by First Target Contrast: Implications of an Attention Capture Hypothesis

    DEFF Research Database (Denmark)

    Nielsen, Simon; Andersen, Tobias

    2011-01-01

    When two targets (T1 & T2) are presented in rapid succession, observers often fail to report T2 if they attend to T1. The bottleneck theory proposes that this attentional blink (AB) is due to T1 occupying a slow processing stage when T2 is presented. Accordingly, if increasing T1 difficulty...... increases T1 processing time, this should cause a greater AB. The attention capture hypothesis suggests that T1 captures attention, which cannot be reallocated to T2 in time. Accordingly, if increasing T1 difficulty decreases T1 saliency, this should cause a smaller AB. In two experiments we find support...... for an attention capture hypothesis. In Experiment 1 we find that AB magnitude increases with T1 contrast – but only when T1 is unmasked. In Experiment 2 we add Gaussian noise to targets and vary T1 contrast but keep T1 ‘s SNR constant. Again we find that AB magnitude increases with T1 contrast....

  9. The attentional blink is modulated by first target contrast: Implications of an attention capture hypothesis

    DEFF Research Database (Denmark)

    Nielsen, Simon; Andersen, Tobias S

    2011-01-01

    When two targets (T1 & T2) are presented in rapid succession, observers often fail to report T2 if they attend to T1. The bottleneck theory proposes that this attentional blink (AB) is due to T1 occupying a slow processing stage when T2 is presented. Accordingly, if increasing T1 difficulty...... increases T1 processing time, this should cause a greater AB. The attention capture hypothesis suggests that T1 captures attention, which cannot be reallocated to T2 in time. Accordingly, if increasing T1 difficulty decreases T1 saliency, this should cause a smaller AB. In two experiments we find support...... for an attention capture hypothesis. In Experiment 1 we find that AB magnitude increases with T1 contrast – but only when T1 is unmasked. In Experiment 2 we add Gaussian noise to targets and vary T1 contrast but keep T1 ‘s SNR constant. Again we find that AB magnitude increases with T1 contrast....

  10. Nanomedicine targeting the tumor microenvironment: Therapeutic strategies to inhibit angiogenesis, remodel matrix, and modulate immune responses

    Directory of Open Access Journals (Sweden)

    Elizabeth L. Siegler

    2016-11-01

    Full Text Available Increasing attention has been given to the tumor microenvironment (TME, which includes cellular and structural components such as fibroblasts, immune cells, vasculature, and extracellular matrix (ECM that surround tumor sites. These components contribute to tumor growth and metastasis and are one reason why traditional chemotherapy often is insufficient to eradicate the tumor completely. Newer treatments that target aspects of the TME, such as antiangiogenic and immunostimulatory therapies, have seen limited clinical success despite promising preclinical results. This can be attributed to a number of reasons, including a lack of drug penetration deeper into the necrotic tumor core, nonspecific delivery, rapid clearance from serum, or toxic side effects at high doses. Nanoparticles offer a potential solution to all of these obstacles, and many recent studies have shown encouraging results using nanomedicine to target TME vasculature, ECM, and immune response. While few of these platforms have made it to clinical trials to date, these strategies are relatively new and may offer a way to improve the effects of anticancer therapies.

  11. Honey Bee Allatostatins Target Galanin/Somatostatin-Like Receptors and Modulate Learning: A Conserved Function?

    Directory of Open Access Journals (Sweden)

    Elodie Urlacher

    Full Text Available Sequencing of the honeybee genome revealed many neuropeptides and putative neuropeptide receptors, yet functional characterization of these peptidic systems is scarce. In this study, we focus on allatostatins, which were first identified as inhibitors of juvenile hormone synthesis, but whose role in the adult honey bee (Apis mellifera brain remains to be determined. We characterize the bee allatostatin system, represented by two families: allatostatin A (Apime-ASTA and its receptor (Apime-ASTA-R; and C-type allatostatins (Apime-ASTC and Apime-ASTCC and their common receptor (Apime-ASTC-R. Apime-ASTA-R and Apime-ASTC-R are the receptors in bees most closely related to vertebrate galanin and somatostatin receptors, respectively. We examine the functional properties of the two honeybee receptors and show that they are transcriptionally expressed in the adult brain, including in brain centers known to be important for learning and memory processes. Thus we investigated the effects of exogenously applied allatostatins on appetitive olfactory learning in the bee. Our results show that allatostatins modulate learning in this insect, and provide important insights into the evolution of somatostatin/allatostatin signaling.

  12. HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation

    International Nuclear Information System (INIS)

    Okumura, Atsushi; Alce, Tim; Lubyova, Barbora; Ezelle, Heather; Strebel, Klaus; Pitha, Paula M.

    2008-01-01

    The activation of IRF-3 during the early stages of viral infection is critical for the initiation of the antiviral response; however the activation of IRF-3 in HIV-1 infected cells has not yet been characterized. We demonstrate that the early steps of HIV-1 infection do not lead to the activation and nuclear translocation of IRF-3; instead, the relative levels of IRF-3 protein are decreased due to the ubiquitin-associated proteosome degradation. Addressing the molecular mechanism of this effect we show that the degradation is independent of HIV-1 replication and that virion-associated accessory proteins Vif and Vpr can independently degrade IRF-3. The null mutation of these two genes reduced the capacity of the HIV-1 virus to down modulate IRF-3 levels. The degradation was associated with Vif- and Vpr-mediated ubiquitination of IRF-3 and was independent of the activation of IRF-3. N-terminal lysine residues were shown to play a critical role in the Vif- and Vpr-mediated degradation of IRF-3. These data implicate Vif and Vpr in the disruption of the initial antiviral response and point to the need of HIV-1 to circumvent the antiviral response during the very early phase of replication

  13. Change of tumor target volume during waiting time for intensity-modulated radiotherapy (IMRT) in nasopharyngeal carcinoma

    International Nuclear Information System (INIS)

    Chen Bo; Yi Junlin; Gao Li; Xu Guozhen; Huang Xiaodong; Zhang Zhong; Luo Jingwei; Li Suyan

    2007-01-01

    Objective: To determine the influence of change in tumor target volume of nasopharyngeal carcinoma (NPC) while waiting for intensity modulated radiation therapy (IMRT). Methods: From March 2005 to December 2005, 31 patients with nasopharyngeal carcinoma received IMRT as the initial treatment at the Cancer Hospital of Chinese Academic of Medical Sciences. The original simulation CT scan was acquired before IMRT planning. A second CT scan was acquired before the start of radiotherapy. Wait- ing time was defined as the duration between CT simulation and start of radiotherapy. CT-CT fusion was used to minimize the error of delineation between the first tumor target volume (GTV) and the second tumor target volume (sGTV). Tumor target volume was calculated by treatment planning system. T test was carried out to analyse the difference between GTV and sGTV. Pearson correlation and multivariate linear regression was used to analyse the influence factor of the change betweent GTV and sGTV. Results: Median waiting time was 18 days (range, 9-27 days). There were significant differences between GTV and sGTV of both primary tumor (P=0.009) and metastatic lymphoma (P=0.005 ). Both Pearson correlation and multivariate linear regression showed that the change of primary tumor target volume had significant correlation with the first tumor target volume but had no significant correlation with the waiting time, sex, age, T stage and N stage (1992 Chinese Fuzhou Staging Classification). Conclusions: Within the range of the waiting time ob- served in our study, large volume primary tumor would have had a significant increase in volume, but whether the therapeutic effect would be influenced or not would need to be proved by study of large number of cases. Patients with large volume tumor should be considered to reduce the influence of waiting time by enlarging gross target volume and clinical targe volume and by neoadjuveant chemotherapy. For avoiding the unnecessary high-dose to normal

  14. Modified gold electrodes based on thiocytosine/guanine-gold nanoparticles for uric and ascorbic acid determination

    International Nuclear Information System (INIS)

    Vulcu, Adriana; Grosan, Camelia; Muresan, Liana Maria; Pruneanu, Stela; Olenic, Liliana

    2013-01-01

    The present paper describes the preparation of new modified surfaces for electrodes based on guanine/thiocytosine and gold nanoparticles. The gold nanoparticles were analyzed by UV–vis spectroscopy and transmission electron microscopy (TEM) and it was found that they have diameters between 30 and 40 nm. The layers were characterized by specular reflectance infrared spectroscopy (FTIR-RAS) and by atomic force microscopy (AFM). The thickness of layers was found to be approximately 30 nm for TC layers and 300 nm for GU layers. Every layer was characterized as electrochemical sensor (by cyclic voltammetry) both for uric acid and ascorbic acid determinations, separately and in their mixture. The modified sensors have good calibration functions with good sensitivity (between 1.145 and 1.406 mA cm −2 /decade), reproducibility ( t hiocytosine (Au T C) and gold g uanine (Au G U) layers

  15. Enantioanalysis of S-deprenyl using enantioselective, potentiometric membrane electrodes based on C60 derivatives

    International Nuclear Information System (INIS)

    Stefan-van Staden, Raluca-Ioana

    2010-01-01

    Enantioselective, potentiometric membrane electrodes based on (1,2-methanofullerene C 60 )-61-carboxylic acid, diethyl (1,2-methanofullerene C 60 )-61-61-dicarboxylate and tert-butyl (1,2-methanofullerene C 60 )-61-carboxylic acid were proposed for the enantioanalysis of S-deprenyl in pharmaceutical compounds. Molecular modeling calculations were performed to prove the reliability of the proposed electrodes. The different characteristics involved in this analysis were explained, namely (i) the stability of each molecule using total energy, hardness and dipole moment, and (ii) the explanation of the mechanism of interaction using intermolecular forces (moderate hydrogen bond interactions), atomic charges and electrostatic potential. Electronic structures as well as molecular interaction have been investigated using Hartree-Fock theory, 3-21G(*) basis set. Stability and feasibility of all the generated structures were supported by their respective energy minima and fundamental frequencies.

  16. Graphitic carbon nitride nanosheet electrode-based high-performance ionic actuator

    Science.gov (United States)

    Wu, Guan; Hu, Ying; Liu, Yang; Zhao, Jingjing; Chen, Xueli; Whoehling, Vincent; Plesse, Cédric; Nguyen, Giao T. M.; Vidal, Frédéric; Chen, Wei

    2015-01-01

    Ionic actuators have attracted attention due to their remarkably large strain under low-voltage stimulation. Because actuation performance is mainly dominated by the electrochemical and electromechanical processes of the electrode layer, the electrode material and structure are crucial. Here, we report a graphitic carbon nitride nanosheet electrode-based ionic actuator that displays high electrochemical activity and electromechanical conversion abilities, including large specific capacitance (259.4 F g−1) with ionic liquid as the electrolyte, fast actuation response (0.5±0.03% in 300 ms), large electromechanical strain (0.93±0.03%) and high actuation stability (100,000 cycles) under 3 V. The key to the high performance lies in the hierarchical pore structure with dominant size actuation performance. PMID:26028354

  17. WNT-mediated Modulation of Bone Metabolism: Implications for WNT Targeting to Treat Extraskeletal Disorders.

    Science.gov (United States)

    Bullock, Whitney A; Robling, Alexander G

    2017-10-01

    The WNT-signaling pathway is involved in cellular and tissue functions that control such diverse processes as body axis patterning, cellular proliferation, differentiation, and life span. The long list of molecules that can participate or modify WNT signaling makes this pathway one of the most complex in cell biology. In bone tissues, WNT signaling is required for proper skeletal development, and human mutations in various components of the cascade revealed insights into pharmacologic targeting that can be harnessed to improve skeletal health. In particular, mutations in genes that code for the WNT-signaling inhibitor sclerostin or the WNT coreceptor lipoprotein receptor-related protein 5 have highlighted the potential therapeutic value of recapitulating those effects in patients with low bone mass. A constant challenge in this area is selectively modifying WNT components in the tissue of interest, as WNT has manifold effects in nearly every tissue.

  18. The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine.

    Science.gov (United States)

    Syeda, Ruhma; Santos, Jose S; Montal, Mauricio

    2016-02-05

    KCNQ (voltage-gated K(+) channel family 7 (Kv7)) channels control cellular excitability and underlie the K(+) current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K(+) current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  19. The Pseudomonas aeruginosa N-acylhomoserine lactone quorum sensing molecules target IQGAP1 and modulate epithelial cell migration.

    Directory of Open Access Journals (Sweden)

    Thommie Karlsson

    Full Text Available Quorum sensing (QS signaling allows bacteria to control gene expression once a critical population density is achieved. The Gram-negative human pathogen Pseudomonas aeruginosa uses N-acylhomoserine lactones (AHL as QS signals, which coordinate the production of virulence factors and biofilms. These bacterial signals can also modulate human cell behavior. Little is known about the mechanisms of the action of AHL on their eukaryotic targets. Here, we found that N-3-oxo-dodecanoyl-L-homoserine lactone 3O-C(12-HSL modulates human intestinal epithelial Caco-2 cell migration in a dose- and time-dependent manner. Using new 3O-C(12-HSL biotin and fluorescently-tagged probes for LC-MS/MS and confocal imaging, respectively, we demonstrated for the first time that 3O-C(12-HSL interacts and co-localizes with the IQ-motif-containing GTPase-activating protein IQGAP1 in Caco-2 cells. The interaction between IQGAP1 and 3O-C(12-HSL was further confirmed by pull-down assay using a GST-tagged protein with subsequent Western blot of IQGAP1 and by identifying 3O-C(12-HSL with a sensor bioassay. Moreover, 3O-C(12-HSL induced changes in the phosphorylation status of Rac1 and Cdc42 and the localization of IQGAP1 as evidenced by confocal and STED microscopy and Western blots. Our findings suggest that the IQGAP1 is a novel partner for P. aeruginosa 3O-C(12-HSL and likely the integrator of Rac1 and Cdc42- dependent altered cell migration. We propose that the targeting of IQGAP1 by 3O-C(12-HSL can trigger essential changes in the cytoskeleton network and be an essential component in bacterial--human cell communication.

  20. Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.

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    Vitor Coutinho Carneiro

    2014-05-01

    Full Text Available Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitment of two histone acetyltransferases (HATs, SmGCN5 and SmCBP1. The treatment of HEK293 cells with histone deacetylase (HDAC inhibitors (NaB or TSA produced an 8-fold activation of the SmRXR1/SmNR1-mediated Smp14 promoter activity. Incubation with synthetic HAT inhibitors, including PU139, significantly impaired the Smp14 promoter activity in these cells. Worm pairs cultivated in the presence of PU139 exhibited limited expression of Smp14 mRNA and protein. ChIP analysis demonstrated chromatin condensation at the Smp14 promoter site in worms treated with PU139. ChIP also revealed the presence of H3K27me3 and the absence of RNA Pol II at the Smp14 promoter region in the PU139-treated worms. Most significantly, the PU139-mediated inhibition of Smp14 expression resulted in a significant number of abnormal eggs as well as defective eggs within the ootype. In addition, scanning electron microscopy revealed structural defects and unformed eggshells, and vitelline cell leakage was apparent. The dsRNAi-targeting of SmGCN5 or SmCBP1 significantly decreased Smp14 transcription and protein synthesis, which compromised the reproductive system of mature female worms, egg-laying and egg morphology. Our data strongly suggest that the inhibition of Smp14 expression targeting SmGCN5 and/or SmCBP1 represents a novel and effective strategy to control S. mansoni egg development.

  1. Cytokine-Modulating Strategies and Newer Cytokine Targets for Arthritis Therapy

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    Shivaprasad H. Venkatesha

    2014-12-01

    Full Text Available Cytokines are the key mediators of inflammation in the course of autoimmune arthritis and other immune-mediated diseases. Uncontrolled production of the pro-inflammatory cytokines such as interferon-γ (IFN-γ, tumor necrosis factor α (TNFα, interleukin-6 (IL-6, and IL-17 can promote autoimmune pathology, whereas anti-inflammatory cytokines including IL-4, IL-10, and IL-27 can help control inflammation and tissue damage. The pro-inflammatory cytokines are the prime targets of the strategies to control rheumatoid arthritis (RA. For example, the neutralization of TNFα, either by engineered anti-cytokine antibodies or by soluble cytokine receptors as decoys, has proven successful in the treatment of RA. The activity of pro-inflammatory cytokines can also be downregulated either by using specific siRNA to inhibit the expression of a particular cytokine or by using small molecule inhibitors of cytokine signaling. Furthermore, the use of anti-inflammatory cytokines or cytokine antagonists delivered via gene therapy has proven to be an effective approach to regulate autoimmunity. Unexpectedly, under certain conditions, TNFα, IFN-γ, and few other cytokines can display anti-inflammatory activities. Increasing awareness of this phenomenon might help develop appropriate regimens to harness or avoid this effect. Furthermore, the relatively newer cytokines such as IL-32, IL-34 and IL-35 are being investigated for their potential role in the pathogenesis and treatment of arthritis.

  2. Modulation of Lipid Droplet Metabolism—A Potential Target for Therapeutic Intervention in Flaviviridae Infections

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    Jingshu Zhang

    2017-11-01

    Full Text Available Lipid droplets (LDs are endoplasmic reticulum (ER-related dynamic organelles that store and regulate fatty acids and neutral lipids. They play a central role in cellular energy storage, lipid metabolism and cellular homeostasis. It has become evident that viruses have co-evolved in order to exploit host lipid metabolic pathways. This is especially characteristic of the Flaviviridae family, including hepatitis C virus (HCV and several flaviviruses. Devoid of an appropriate lipid biosynthetic machinery of their own, these single-strand positive-sense RNA viruses can induce dramatic changes in host metabolic pathways to establish a favorable environment for viral multiplication and acquire essential components to facilitate their assembly and traffic. Here we have reviewed the current knowledge on the intracellular life cycle of those from the Flaviviridae family, with particular emphasis on HCV and dengue virus (DENV, and their association with the biosynthesis and metabolism of LDs, with the aim to identify potential antiviral targets for development of novel therapeutic interventions.

  3. Fluorinated Nucleotide Modifications Modulate Allele Selectivity of SNP-Targeting Antisense Oligonucleotides

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    Michael E. Østergaard

    2017-06-01

    Full Text Available Antisense oligonucleotides (ASOs have the potential to discriminate between subtle RNA mismatches such as SNPs. Certain mismatches, however, allow ASOs to bind at physiological conditions and result in RNA cleavage mediated by RNase H. We showed that replacing DNA nucleotides in the gap region of an ASO with other chemical modification can improve allele selectivity. Herein, we systematically substitute every position in the gap region of an ASO targeting huntingtin gene (HTT with fluorinated nucleotides. Potency is determined in cell culture against mutant HTT (mtHTT and wild-type HTT (wtHTT mRNA and RNase H cleavage intensities, and patterns are investigated. This study profiled five different fluorinated nucleotides and showed them to have predictable, site-specific effects on RNase H cleavage, and the cleavage patterns were rationalized from a published X-ray structure of human RNase H1. The results herein can be used as a guide for future projects where ASO discrimination of SNPs is important.

  4. EMT blockage strategies: Targeting Akt dependent mechanisms for breast cancer metastatic behaviour modulation.

    Science.gov (United States)

    Rafael, D; Doktorovová, S; Florindo, H F; Gener, P; Abasolo, I; Schwartz, S; Videira, M A

    2015-01-01

    Epithelial Mesenchymal Transition (EMT) is an event where epithelial cells acquire mesenchymal-like phenotype. EMT can occur as a physiological phenomenon during tissue development and wound healing, but most importantly, EMT can confer highly invasive properties to epithelial carcinoma cells. The impairment of E-cadherin expression, an essential cell-cell adhesion protein, together with an increase in the expression of mesenchymal markers, such as N-cadherin, vimentin, and fibronectin, characterize the EMT process and are usually correlated with tumor migration, and metastization. A wide range of micro-environmental and intracellular factors regulate tumor development and progression. The dynamic cross-talk between the adhesion-related proteins such as E-cadherin and the EMT-related transcription factors, with special focus on TWIST, will be discussed here, with the aim of finding a suitable biological pathway to be used as potential target for cancer therapy. Emerging concepts such as the role of the PI3K/AKT/TWIST pathway in the regulation of the E-cadherin expression will be highlighted, since it seems to be consistently involved in cells EMT. The well-known efficacy of the RNA interference as a tool to silence the expression of specific proteins has come into focus as a strategy to control different tumor sub-populations. Despite the oligonucleotides enormous sensitivity and low in vivo stability, new (nano)technological solutions are expected to enable RNAi clinical application in cancer therapy.

  5. Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy

    Directory of Open Access Journals (Sweden)

    Catarina Roma-Rodrigues

    2017-01-01

    Full Text Available Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes’ release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs make them suitable vehicles to pursuit this goal. AuNPs’ properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs’ role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.

  6. Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy.

    Science.gov (United States)

    Roma-Rodrigues, Catarina; Raposo, Luís R; Cabral, Rita; Paradinha, Fabiana; Baptista, Pedro V; Fernandes, Alexandra R

    2017-01-14

    Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes' release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs' properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs' role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.

  7. New Pharmacotherapy Targeting Cognitive Dysfunction of Schizophrenia via Modulation of GABA Neuronal Function.

    Science.gov (United States)

    Uehara, Takashi; Sumiyoshi, Tomiki; Kurachi, Masayoshi

    2015-01-01

    Schizophrenia is considered a neurodevelopmental and neurodegenerative disorder. Cognitive impairment is a core symptom in patients with the illness, and has been suggested a major predictor of functional outcomes. Reduction of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) interneurons has been associated with the pathophysiology of schizophrenia, in view of the link between the abnormality of GABA neurons and cognitive impairments of the disease. It is assumed that an imbalance of excitatory and inhibitory (E-I) activity induced by low activity of glutamatergic projections and PV-positive GABA interneurons in the prefrontal cortex resulted in sustained neural firing and gamma oscillation, leading to impaired cognitive function. Therefore, it is important to develop novel pharmacotherapy targeting GABA neurons and their activities. Clinical evidence suggests serotonin (5-HT) 1A receptor agonist improves cognitive disturbances of schizophrenia, consistent with results from preclinical studies, through mechanism that corrects E-I imbalance via the suppression of GABA neural function. On the other hand, T-817MA, a novel neurotrophic agent, ameliorated loss of PV-positive GABA neurons in the medial prefrontal cortex and reduction of gamma-band activity, as well as cognitive dysfunction in animal model of schizophrenia. In conclusion, a pharmacotherapy to alleviate abnormalities in GABA neurons through 5-HT1A agonists and T-817MA is expected to prevent the onset and/or progression of schizophrenia.

  8. A novel spiroindoline targets cell cycle and migration via modulation of microtubule cytoskeleton.

    Science.gov (United States)

    Kumar, Naveen; Hati, Santanu; Munshi, Parthapratim; Sen, Subhabrata; Sehrawat, Seema; Singh, Shailja

    2017-05-01

    Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound. Herein we report the subcellular studies performed for this molecule on breast cancer cells. Our investigation revealed that it repositions microtubule cytoskeleton and displaces AKAP9 located at the microtubule organization centre. DNA ladder assay and cell cycle experiments further established the molecule as an apoptotic agent. This work further substantiated the amalgamation of DOS-phenotypic screening-sub-cellular studies as a consolidated blueprint for the discovery of potential pharmaceutical drug candidates.

  9. Amylin and GLP-1 target different populations of area postrema neurons that are both modulated by nutrient stimuli.

    Science.gov (United States)

    Züger, Daniela; Forster, Karoline; Lutz, Thomas A; Riediger, Thomas

    2013-03-15

    The area postrema mediates the hypophagic effect of the pancreatic hormone amylin and is also sensitive to glucagon-like peptide 1 (GLP-1). Protein seems to modulate amylin responsiveness because amylin seems to produce a stronger hypophagic effect and a stronger c-Fos expression when protein is absent from the diet. Accordingly, amylin induces a stronger c-Fos expression in the AP when injected in fasted compared to ad libitum fed rats. Here we tested the hypothesis that diet-derived protein attenuates the amylin dependent suppression of feeding and AP activation using isocaloric diets that differed in their protein content. Moreover, we investigated whether peripheral amino acid injection attenuates amylin-induced c-Fos expression in fasted rats. Since recent evidence suggests that GLP-1 may also reduce eating via the AP we tested whether 24 h fasting also increases neuronal AP responsiveness to GLP-1 similar to the fasting-induced increase in amylin responsiveness. Finally, we used the calcitonin receptor (CTR) as an immunohistochemical marker for amylin-receptive AP neurons to investigate whether amylin's target neurons differ from GLP-1 responsive AP neurons. We also dissociated amylin responsive cells from neurons implicated in other AP-mediated functions such as aversion or blood pressure regulation. For this purpose, we conducted c-Fos/CTR double staining after LiCl or angiotensin II treatment, respectively. Amylin (5 μg/kg s.c.) was more effective to reduce the intake of a 1% vs. an 8% or 18% protein diet and to induce c-Fos expression in the AP in rats receiving 1% vs. 18% protein diet. Increased protein intake was associated with increased blood amino acid levels. Peripheral injection of amino acids (1 g/kg i.p.) attenuated the amylin-induced AP activation in 24 h fasted rats. Similar to amylin, GLP-1 (100 μg/kg i.p.) elicited a significant c-Fos response only in fasted but not in ad libitum fed rats. However, in contrast to a high co-localization of

  10. Novel Antibiofilm Chemotherapy Targets Exopolysaccharide Synthesis and Stress Tolerance in Streptococcus mutans To Modulate Virulence Expression In Vivo

    Science.gov (United States)

    Falsetta, Megan L.; Klein, Marlise I.; Lemos, José A.; Silva, Bruno B.; Agidi, Senyo; Scott-Anne, Kathy K.

    2012-01-01

    Fluoride is the mainstay of dental caries prevention, and yet current applications offer incomplete protection and may not effectively address the infectious character of the disease. Therefore, we evaluated the effectiveness of a novel combination therapy (CT; 2 mM myricetin, 4 mM tt-farnesol, 250 ppm of fluoride) that supplements fluoride with naturally occurring, food-derived, antibiofilm compounds. Treatment regimens simulating those experienced clinically (twice daily for ≤60 s) were used both in vitro over a saliva-coated hydroxyapatite biofilm model and in vivo with a rodent model of dental caries. The effectiveness of CT was evaluated based on the incidence and severity of carious lesions (compared to fluoride or vehicle control). We found that CT was superior to fluoride (positive control, P plaque. We subsequently identified the underlying mechanisms through which applications of CT modulate biofilm virulence. CT targets expression of key Streptococcus mutans genes during biofilm formation in vitro and in vivo. These are associated with exopolysaccharide matrix synthesis (gtfB) and the ability to tolerate exogenous stress (e.g., sloA), which are essential for cariogenic biofilm assembly. We also identified a unique gene (SMU.940) that was severely repressed and may represent a potentially novel target; its inactivation disrupted exopolysaccharide accumulation and matrix development. Altogether, CT may be clinically more effective than current anticaries modalities, targeting expression of bacterial virulence associated with pathogenesis of the disease. These observations may have relevance for development of enhanced therapies against other biofilm-dependent infections. PMID:22985885

  11. Rescuing cholinergic neurons from apoptotic degeneration by targeting of serotonin modulator- and apolipoprotein E-conjugated liposomes to the hippocampus

    Directory of Open Access Journals (Sweden)

    Kuo YC

    2016-12-01

    Full Text Available Yung-Chih Kuo, Yin-Jung Lee Department of Chemical Engineering, National Chung Cheng University, Chia-Yi, Taiwan, Republic of China Abstract: β-Amyloid (Aβ-targeting liposomes (LIP with surface serotonin modulator (SM and apolipoprotein E (ApoE were utilized to facilitate the delivery of nerve growth factor (NGF across the blood–brain barrier (BBB for neuroprotection in the hippocampus. The therapeutic efficacy of SM- and ApoE-grafted LIP carrying NGF (NGF-SM-ApoE-LIP was assessed by an in vitro Alzheimer’s disease (AD model of degenerated SK-N-MC cells and an in vivo AD model of Aβ-insulted Wistar rats. The experimental evidences revealed that the modified SM and ApoE on the surface of LIP increased the permeation of NGF across the BBB without serious damage to structural integrity of tight junction. When compared with free NGF, NGF-SM-ApoE-LIP upregulated the expression of phosphorylated neurotrophic tyrosine kinase receptor type 1 on cholinergic neurons and significantly improved their survival. In addition, NGF-SM-ApoE-LIP could reduce the secretion of acetylcholinesterase and malondialdehyde and rescue hippocampal neurons from apoptosis in rat brains. The synergistic effect of SM and ApoE is promising in the induction of NGF to inhibit the neurotoxicity of Aβ and NGF-SM-ApoE-LIP can be a potent antiapoptotic pharmacotherapy for clinical care of patients with AD. Keywords: Alzheimer’s disease, blood–brain barrier, serotonin modulator, apolipoprotein E, nerve growth factor, liposome

  12. Dosimetric effects of sectional adjustments of collimator angles on volumetric modulated arc therapy for irregularly-shaped targets.

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    Beom Seok Ahn

    Full Text Available To calculate an optimal collimator angle at each of sectional arcs in a full-arc volumetric modulated arc therapy (VMAT plan and evaluate dosimetric quality of these VMAT plans comparing full-arc VMAT plans with a fixed collimator angle.Seventeen patients who had irregularly-shaped target in abdominal, head and neck, and chest cases were selected retrospectively. To calculate an optimal collimator angle at each of sectional arcs in VMAT, integrated MLC apertures which could cover all shapes of target determined by beam's-eye view (BEV within angular sections were obtained for each VMAT plan. The angular sections were 40°, 60°, 90° and 120°. When the collimator settings were rotated at intervals of 2°, we obtained the optimal collimator angle to minimize area size difference between the integrated MLC aperture and collimator settings with 5 mm-margins to the integrated MLC aperture. The VMAT plans with the optimal collimator angles (Colli-VMAT were generated in the EclipseTM. For comparison purposes, one full-arc VMAT plans with a fixed collimator angles (Std-VMAT were generated. The dose-volumetric parameters and total MUs were evaluated.The mean dose-volumetric parameters for target volume of Colli-VMAT were comparable to Std-VMAT. Colli-VMAT improved sparing of most normal organs but for brain stem, compared to Std-VMAT for all cases. There were decreasing tendencies in mean total MUs with decreasing angular section. The mean total MUs for Colli-VMAT with the angular section of 40° (434 ± 95 MU, 317 ± 81 MU, and 371 ± 43 MU for abdominal, head and neck, and chest cases, respectively were lower than those for Std-VMAT (654 ± 182 MU, 517 ± 116 MU, and 533 ± 25 MU, respectively.For an irregularly-shaped target, Colli-VMAT with the angular section of 40° reduced total MUs and improved sparing of normal organs, compared to Std-VMAT.

  13. Dosimetric evaluation of a moving tumor target in intensity-modulated radiation therapy (IMRT) for lung cancer patients

    Science.gov (United States)

    Kim, Sung Kyu; Kang, Min Kyu; Yea, Ji Woon; Oh, Se An

    2013-07-01

    Immobilization plays an important role in intensity-modulated radiation therapy (IMRT). The application of IMRT in lung cancer patients is very difficult due to the movement of the tumor target. Patient setup in radiation treatment demands high accuracy because IMRT employs a treatment size of a 1mm pixel unit. Hence, quality assurance of the dose delivered to patients must be at its highest. The radiation dose was evaluated for breathing rates of 9, 14, and 18 breaths per minute (bpm) for tumor targets moving up and down by 1.0 cm and 1.5 cm. The dose of the moving planned target volume (PTV) was measured by using a thermo-luminescent dosimeter (TLD) and Gafchromic™ EBT film. The measurement points were 1.0 cm away from the top, the bottom and the left and the right sides of the PTV center. The evaluated dose differences ranged from 94.2 to 103.8%, from 94.4 to 105.4%, and from 90.7 to 108.5% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.0 cm. The mean values of the doses were 101.4, 99.9, and 99.5% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.0 cm. Meanwhile, the evaluated dose differences ranged from 93.6 to 105.8%, from 95.9 to 111.5%, and from 96.2 to 111.7% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.5 cm. The mean values of the doses were 102.3, 103.4, and 103.1% for 9, 14 and 18 bpm, respectively, for a tumor movement of 1.5 cm. Therefore, we suggest that IMRT can be used in the treatment of lung cancer patients with vertical target movements within the range of 1.0 to 1.5 cm.

  14. Numerical simulation of diffuse double layer around microporous electrodes based on the Poisson–Boltzmann equation

    International Nuclear Information System (INIS)

    Kitazumi, Yuki; Shirai, Osamu; Yamamoto, Masahiro; Kano, Kenji

    2013-01-01

    Graphical abstract: - Highlights: • Diffuse double layers overlap with each other in the micropore. • The overlapping of the diffuse double layer affects the double layer capacitance. • The electric field becomes weak in the micropore. • The electroneutrality is unsatisfactory in the micropore. - Abstract: The structure of the diffuse double layer around a nm-sized micropore on porous electrodes has been studied by numerical simulation using the Poisson–Boltzmann equation. The double layer capacitance of the microporous electrode strongly depends on the electrode potential, the electrolyte concentration, and the size of the micropore. The potential and the electrolyte concentration dependence of the capacitance is different from that of the planner electrode based on the Gouy's theory. The overlapping of the diffuse double layer becomes conspicuous in the micropore. The overlapped diffuse double layer provides the mild electric field. The intensified electric field exists at the rim of the orifice of the micropore because of the expansion of the diffuse double layers. The characteristic features of microporous electrodes are caused by the heterogeneity of the electric field around the micropores

  15. All-solid-state carbonate-selective electrode based on screen-printed carbon paste electrode

    International Nuclear Information System (INIS)

    Li, Guang; Lyu, Xiaofeng; Wang, Zhan; Rong, Yuanzhen; Hu, Ruifen; Wang, You; Luo, Zhiyuan

    2017-01-01

    A novel disposable all-solid-state carbonate-selective electrode based on a screen-printed carbon paste electrode using poly(3-octylthiophene-2,5-diyl) (POT) as an ion-to-electron transducer has been developed. The POT was dropped onto the reaction area of the carbon paste electrode covered by the poly(vinyl chloride) (PVC) membrane, which contains N,N-Dioctyl-3 α ,12 α -bis(4-trifluoroacetylbenzoyloxy)-5 β -cholan-24-amide as a carbonate ionophore. The electrode showed a near-Nernstian slope of  −27.5 mV/decade with a detection limit of 3.6 * 10 −5 mol l −1 . Generally, the detection time was 30 s. Because these electrodes are fast, convenient and low in cost, they have the potential to be mass produced and used in on-site testing as disposable sensors. Furthermore, the repeatability, reproducibility and stability have been studied to evaluate the properties of the electrodes. Measurement of the carbonate was also conducted in a human blood solution and achieved good performance. (paper)

  16. Lanthanum(IlI) PVC membrane electrodes based on 1,3,5-trithiacyclohexane.

    Science.gov (United States)

    Shamsipur, Mojtaba; Yousefi, Mohammad; Hosseini, Morteza; Ganjali, Mohammad Reza

    2002-11-01

    Novel plasticized polymeric membrane (PPME) and membrane-coated graphite (MCGE) electrodes based on 1,3,5-trithiacyclohexane for highly selective determination of La3+ ion have been developed. The electrodes exhibit Nernstian responses over very wide concentration ranges (8.0 x 10(-6)-5.0 x 10(-2) M for PPME and 4.0 x 10(-8)-1.0 x 10(-2) M for MCGE). The limit of detections were 5.0 x 10(-6) and 2.0 x 10(-8) M for PPME and MCGE, respectively. The electrodes possess a fast response time of approximately 10 s and can be used for at least 6 months without observing any deviation. The proposed electrodes revealed excellent selectivities for La3+ over a wide variety of alkali, alkaline earth, transition, and heavy metal ions and could be used in a pH range of 5.0-8.0. The practical utility of the electrodes has been demonstrated by their use as indicator electrodes in the potentiometric titration of La3+ ions with EDTA and in determination of F- in some mouthwash preparations.

  17. High Operating Voltage Supercapacitor Using PPy/AC Composite Electrode Based on Simple Dipping Method

    Directory of Open Access Journals (Sweden)

    Kyoungho Kim

    2015-01-01

    Full Text Available As various wearable devices are emerging, self-generated power sources, such as piezoelectric generators, triboelectric generators, and thermoelectric generators, are of interest. To adapt self-generated power sources for application devices, a supercapacitor is necessary because of the short generation times (1–10 ms and low generated power (1–100 μW of self-generated power sources. However, to date, supercapacitors are too large to be adapted for wearable devices. There have been many efforts to reduce the size of supercapacitors by using polypyrrole (PPy for high energy supercapacitor electrodes. However, these supercapacitors have several disadvantages, such as a low operating voltage due to the use of an aqueous electrolyte, and complex manufacturing methods, such as the hydrogel and aerosol methods. In particular, the low operating voltage (~1.0 V is a significant issue because most electronic components operate above 3.0 V. In this study, we successfully demonstrated the high operating voltage (3.0 V of a supercapacitor using a PPy/activated carbon (AC composite electrode based on the chemical polymerization of the PPy by simple dipping. In addition, a twofold enhancement of its energy density was achieved compared with conventional supercapacitors using AC electrodes.

  18. Cadmium-sensitive electrode based on tetracetone derivatives of p-tert-butylcalix[8]arene

    Energy Technology Data Exchange (ETDEWEB)

    Dernane, C. [Université de Jijel, Laboratoire de Matériaux: Elaborations-Propriétés-Applications, BP 98, Ouled Aissa, 18000 Jijel (Algeria); Zazoua, A., E-mail: azazoua@yahoo.fr [Université de Jijel, Laboratoire de Matériaux: Elaborations-Propriétés-Applications, BP 98, Ouled Aissa, 18000 Jijel (Algeria); Kazane, I. [Université de Jijel, Laboratoire de Matériaux: Elaborations-Propriétés-Applications, BP 98, Ouled Aissa, 18000 Jijel (Algeria); Jaffrezic-Renault, N. [Université de Lyon, LSA-UMR 5180 CNRS, Université Claude Bernard Lyon 1, 69622 Villeurbanne cedex (France)

    2013-10-15

    The performance of a cadmium-sensitive electrode based on the tetracetone derivatives of p-tert butylcalix[8]arene was investigated. The ion-sensitivity of the calix[8]arene was examined via cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectrometry, UV/Vis spectroscopy and FT-IR spectroscopy. The sensitive membrane containing the active ionophore was cast onto the surface of a gold electrode. The electrode exhibited a linear relationship between the charge transfer resistance (R{sub ct}) and the logarithm of the detected ion concentration. The cathodic peak at a potential of 0.56 V increased linearly as the Cd{sup 2+} ion concentration increased. The detection limit of the device reached 10{sup −7} M with high sensitivity toward cadmium. - Highlights: • The performances of cadmium-sensitive electrode were investigated. • The sensitive membrane was casted on the surface of a gold electrode. • The electrode showed a linear relationship between the R{sub ct} and the ion concentration. • The detection limit of the device was 10{sup −7} M with high sensitivity toward cadmium.

  19. Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells

    International Nuclear Information System (INIS)

    Born, E J; Hartman, S V; Holstein, S A

    2013-01-01

    Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways

  20. Analysis of Maneuvering Targets with Complex Motions by Two-Dimensional Product Modified Lv's Distribution for Quadratic Frequency Modulation Signals.

    Science.gov (United States)

    Jing, Fulong; Jiao, Shuhong; Hou, Changbo; Si, Weijian; Wang, Yu

    2017-06-21

    For targets with complex motion, such as ships fluctuating with oceanic waves and high maneuvering airplanes, azimuth echo signals can be modeled as multicomponent quadratic frequency modulation (QFM) signals after migration compensation and phase adjustment. For the QFM signal model, the chirp rate (CR) and the quadratic chirp rate (QCR) are two important physical quantities, which need to be estimated. For multicomponent QFM signals, the cross terms create a challenge for detection, which needs to be addressed. In this paper, by employing a novel multi-scale parametric symmetric self-correlation function (PSSF) and modified scaled Fourier transform (mSFT), an effective parameter estimation algorithm is proposed-referred to as the Two-Dimensional product modified Lv's distribution (2D-PMLVD)-for QFM signals. The 2D-PMLVD is simple and can be easily implemented by using fast Fourier transform (FFT) and complex multiplication. These measures are analyzed in the paper, including the principle, the cross term, anti-noise performance, and computational complexity. Compared to the other three representative methods, the 2D-PMLVD can achieve better anti-noise performance. The 2D-PMLVD, which is free of searching and has no identifiability problems, is more suitable for multicomponent situations. Through several simulations and analyses, the effectiveness of the proposed estimation algorithm is verified.

  1. The role of verbal memory in regressions during reading is modulated by the target word's recency in memory.

    Science.gov (United States)

    Guérard, Katherine; Saint-Aubin, Jean; Maltais, Marilyne; Lavoie, Hugo

    2014-10-01

    During reading, a number of eye movements are made backward, on words that have already been read. Recent evidence suggests that such eye movements, called regressions, are guided by memory. Several studies point to the role of spatial memory, but evidence for the role of verbal memory is more limited. In the present study, we examined the factors that modulate the role of verbal memory in regressions. Participants were required to make regressions on target words located in sentences displayed on one or two lines. Verbal interference was shown to affect regressions, but only when participants executed a regression on a word located in the first part of the sentence, irrespective of the number of lines on which the sentence was displayed. Experiments 2 and 3 showed that the effect of verbal interference on words located in the first part of the sentence disappeared when participants initiated the regression from the middle of the sentence. Our results suggest that verbal memory is recruited to guide regressions, but only for words read a longer time ago.

  2. Using four-dimensional computed tomography images to optimize the internal target volume when using volume-modulated arc therapy to treat moving targets.

    Science.gov (United States)

    Yakoumakis, Nikolaos; Winey, Brian; Killoran, Joseph; Mayo, Charles; Niedermayr, Thomas; Panayiotakis, George; Lingos, Tania; Court, Laurence

    2012-11-08

    In this work we used 4D dose calculations, which include the effects of shape deformations, to investigate an alternative approach to creating the ITV. We hypothesized that instead of needing images from all the breathing phases in the 4D CT dataset to create the outer envelope used for treatment planning, it is possible to exclude images from the phases closest to the inhale phase. We used 4D CT images from 10 patients with lung cancer. For each patient, we drew a gross tumor volume on the exhale-phase image and propagated this to the images from other phases in the 4D CT dataset using commercial image registration software. We created four different ITVs using the N phases closest to the exhale phase (where N = 10, 8, 7, 6). For each ITV contour, we created a volume-modulated arc therapy plan on the exhale-phase CT and normalized it so that the prescribed dose covered at least 95% of the ITV. Each plan was applied to CT images from each CT phase (phases 1-10), and the calculated doses were then mapped to the exhale phase using deformable registration. The effect of the motion was quantified using the dose to 95% of the target on the exhale phase (D95) and tumor control probability. For the three-dimensional and 4D dose calculations of the plan where N = 10, differences in the D95 value varied from 3% to 14%, with an average difference of 7%. For 9 of the 10 patients, the reduction in D95 was less than 5% if eight phases were used to create the ITV. For three of the 10 patients, the reduction in the D95 was less than 5% if seven phases were used to create the ITV. We were unsuccessful in creating a general rule that could be used to create the ITV. Some reduction (8/10 phases) was possible for most, but not all, of the patients, and the ITV reduction was small.

  3. Using four‐dimensional computed tomography images to optimize the internal target volume when using volume‐modulated arc therapy to treat moving targets

    Science.gov (United States)

    Yakoumakis, Nikolaos; Winey, Brian; Killoran, Joseph; Mayo, Charles; Niedermayr, Thomas; Panayiotakis, George; Lingos, Tania; Court, Laurence

    2012-01-01

    In this work we used 4D dose calculations, which include the effects of shape deformations, to investigate an alternative approach to creating the ITV. We hypothesized that instead of needing images from all the breathing phases in the 4D CT dataset to create the outer envelope used for treatment planning, it is possible to exclude images from the phases closest to the inhale phase. We used 4D CT images from 10 patients with lung cancer. For each patient, we drew a gross tumor volume on the exhale‐phase image and propagated this to the images from other phases in the 4D CT dataset using commercial image registration software. We created four different ITVs using the N phases closest to the exhale phase (where N=10, 8, 7, 6). For each ITV contour, we created a volume‐modulated arc therapy plan on the exhale‐phase CT and normalized it so that the prescribed dose covered at least 95% of the ITV. Each plan was applied to CT images from each CT phase (phases 1–10), and the calculated doses were then mapped to the exhale phase using deformable registration. The effect of the motion was quantified using the dose to 95% of the target on the exhale phase (D95) and tumor control probability. For the three‐dimensional and 4D dose calculations of the plan where N=10, differences in the D95 value varied from 3% to 14%, with an average difference of 7%. For 9 of the 10 patients, the reduction in D95 was less than 5% if eight phases were used to create the ITV. For three of the 10 patients, the reduction in the D95 was less than 5% if seven phases were used to create the ITV. We were unsuccessful in creating a general rule that could be used to create the ITV. Some reduction (8/10 phases) was possible for most, but not all, of the patients, and the ITV reduction was small. PACS number: 87.55.D‐ PMID:23149778

  4. miR-21 modulates resistance of HR-HPV positive cervical cancer cells to radiation through targeting LATS1

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shikai; Song, Lili, E-mail: commasll@163.com; Zhang, Liang; Zeng, Saitian; Gao, Fangyuan

    2015-04-17

    Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3′-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity. - Highlights: • miR-21 is highly expressed in HR-HPV (+) radioresistant cervical cancer patients. • miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells. • miR-21 can decrease radiation induced G2/M block and increase S phase accumulation. • miR-21 modulates radiosensitivity cervical cancer cell by directly targeting LATS1.

  5. Imaginary Worlds and the Institute for Clinical and Economic Review (ICER Evidence Report: Targeted Immune Modulators for Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Paul C Langley

    2017-05-01

    Full Text Available In April 2017, the Institute for Clinical and Economic Review (ICER issued its evidence report on the value of targeted immune modulators (TIMs in rheumatoid arthritis. The report made the case that for the TIMs to be accepted for formulary placement in the US, where notional willingness-to-pay thresholds are the ICER gateway criteria, manufacturers should be prepared to offer substantial unit price discounts. The purpose of this commentary is to make the case that the methodology underpinning the ICER claims for value assessment does not meet the required standards of normal science. None of the claims made for clinical and comparative cost-effectiveness are credible, evaluable and replicable. As such, formulary committees have no idea whether ICER recommendations are right or even if they are wrong. They are, in fact, immune to failure and should be rejected. Utilizing ICER claims generated by simulated projections, this review points out that it is entirely possible to justify the current WAC or net pricing structure of TIMS. The review concludes that if ICER is to contribute to the successful formulary placement of drugs and devices the methodology for pricing recommendation should be re-assessed. As it stands, questions must be raised regarding recommendations for, possibly unnecessary, price discounts. ICER needs to develop an assessment framework that focuses on developing claims for competing therapies that are robust, evaluable and replicable together with recommendations on how these claims are to be evaluated in a timeframe meaningful to health care decision makers.   Type: Commentary

  6. Individualized planning target volumes for intrafraction motion during hypofractionated intensity-modulated radiotherapy boost for prostate cancer

    International Nuclear Information System (INIS)

    Cheung, Patrick; Sixel, Katharina; Morton, Gerard; Loblaw, D. Andrew; Tirona, Romeo; Pang, Geordi; Choo, Richard; Szumacher, Ewa; DeBoer, Gerrit; Pignol, Jean-Philippe

    2005-01-01

    Purpose: The objective of the study was to access toxicities of delivering a hypofractionated intensity-modulated radiotherapy (IMRT) boost with individualized intrafraction planning target volume (PTV) margins and daily online correction for prostate position. Methods and materials: Phase I involved delivering 42 Gy in 21 fractions using three-dimensional conformal radiotherapy, followed by a Phase II IMRT boost of 30 Gy in 10 fractions. Digital fluoroscopy was used to measure respiratory-induced motion of implanted fiducial markers within the prostate. Electronic portal images were taken of fiducial marker positions before and after each fraction of radiotherapy during the first 9 days of treatment to calculate intrafraction motion. A uniform 10-mm PTV margin was used for the first phase of treatment. PTV margins for Phase II were patient-specific and were calculated from the respiratory and intrafraction motion data obtained from Phase I. The IMRT boost was delivered with daily online correction of fiducial marker position. Acute toxicity was measured using National Cancer Institute Common Toxicity Criteria, version 2.0. Results: In 33 patients who had completed treatment, the average PTV margin used during the hypofractionated IMRT boost was 3 mm in the lateral direction, 3 mm in the superior-inferior direction, and 4 mm in the anteroposterior direction. No patients developed acute Grade 3 rectal toxicity. Three patients developed acute Grade 3 urinary frequency and urgency. Conclusions: PTV margins can be reduced significantly with daily online correction of prostate position. Delivering a hypofractionated boost with this high-precision IMRT technique resulted in acceptable acute toxicity

  7. Contribution of the residue at position 4 within classical nuclear localization signals to modulating interaction with importins and nuclear targeting.

    Science.gov (United States)

    Smith, Kate M; Di Antonio, Veronica; Bellucci, Luca; Thomas, David R; Caporuscio, Fabiana; Ciccarese, Francesco; Ghassabian, Hanieh; Wagstaff, Kylie M; Forwood, Jade K; Jans, David A; Palù, Giorgio; Alvisi, Gualtiero

    2018-08-01

    Nuclear import involves the recognition by importin (IMP) superfamily members of nuclear localization signals (NLSs) within protein cargoes destined for the nucleus, the best understood being recognition of classical NLSs (cNLSs) by the IMPα/β1 heterodimer. Although the cNLS consensus [K-(K/R)-X-(K/R) for positions P2-P5] is generally accepted, recent studies indicated that the contribution made by different residues at the P4 position can vary. Here, we apply a combination of microscopy, molecular dynamics, crystallography, in vitro binding, and bioinformatics approaches to show that the nature of residues at P4 indeed modulates cNLS function in the context of a prototypical Simian Virus 40 large tumor antigen-derived cNLS (KKRK, P2-5). Indeed, all hydrophobic substitutions in place of R impaired binding to IMPα and nuclear targeting, with the largest effect exerted by a G residue at P4. Substitution of R with neutral hydrophobic residues caused the loss of electrostatic and van der Waals interactions between the P4 residue side chains and IMPα. Detailed bioinformatics analysis confirmed the importance of the P4 residue for cNLS function across the human proteome, with specific residues such as G being associated with low activity. Furthermore, we validate our findings for two additional cNLSs from human cytomegalovirus (HCMV) DNA polymerase catalytic subunit UL54 and processivity factor UL44, where a G residue at P4 results in a 2-3-fold decrease in NLS activity. Our results thus showed that the P4 residue makes a hitherto poorly appreciated contribution to nuclear import efficiency, which is essential to determining the precise nuclear levels of cargoes. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. miR-21 modulates resistance of HR-HPV positive cervical cancer cells to radiation through targeting LATS1

    International Nuclear Information System (INIS)

    Liu, Shikai; Song, Lili; Zhang, Liang; Zeng, Saitian; Gao, Fangyuan

    2015-01-01

    Although multiple miRNAs are found involved in radioresistance development in HR-HPV positive (+) cervical cancer, only limited studies explored the regulative mechanism of the miRNAs. miR-21 is one of the miRNAs significantly upregulated in HR-HPV (+) cervical cancer is also significantly associated with radioresistance. However, the detailed regulative network of miR-21 in radioresistance is still not clear. In this study, we confirmed that miR-21 overexpression was associated with higher level of radioresistance in HR-HPV (+) cervical cancer patients and thus decided to further explore its role. Findings of this study found miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells and decrease radiation induced G2/M block and increase S phase accumulation. By using dual luciferase assay, we verified a binding site between miR-21 and 3′-UTR of large tumor suppressor kinase 1 (LATS1). Through direct binding, miR-21 can regulate LATS1 expression in cervical cancer cells. LATS1 overexpression can reverse miR-21 induced higher colony formation rate and also reduced miR-21 induced S phase accumulation and G2/M phase block reduction under radiation treatment. These results suggested that miR-21-LATS1 axis plays an important role in regulating radiosensitivity. - Highlights: • miR-21 is highly expressed in HR-HPV (+) radioresistant cervical cancer patients. • miR-21 can negatively affect radiosensitivity of HR-HPV (+) cervical cancer cells. • miR-21 can decrease radiation induced G2/M block and increase S phase accumulation. • miR-21 modulates radiosensitivity cervical cancer cell by directly targeting LATS1

  9. The study of target delineation and target movement of whole breast assisted by active breathing control in intensity modulated radiotherapy after breast conservative surgery

    International Nuclear Information System (INIS)

    Li Jianbing; Yu Jinming; Ma Zhifang; Lu Jie; Sun Tao; Guo Shoufang; Wang Jingguo

    2009-01-01

    Objective: To explore the influence of different delineators and different delineating time on target determination of the whole breast and to explore intrafraction and interfraction target displacements of the breast on moderate deep inspiration breathing hold (mDIBH) assisted by active breathing control (ABC) alter breast conservative surgery. Methods: Twenty patients received primary CT-simulation assisted by ABC to get five sets of CT image on the three breathing condition which included one set from free breath (FB), two sets from mDIBH and two sets from deep expiration breathing control (DEBH). After radiotherapy with ten to fifteen fractions, the repeat CT-simulation was carried out to get the same five sets of CT image as the primary CT- simulation. The whole breast target were delineated at different time by the same delineator and delineated respectively by five delineators on the first set of CT images got with mDIBH from the primary CT-simulation, and to compare the influence of delineator and delineating time on the whole breast target. The total silver clips in the cavity were marked respectively on the two sets of CT images got with mDIBH from the primary CT-simulation, and to compare the intrafraction displacement of geometric body structured by the total of silver clips. The two ribs near the isocentric plane of the breast target were delineated respectively on two sets of the mDIBH CT image from the primary CT-simulation and on one set of the mDIBH CT image from the repeat CT-simulation, and comparing the movement of the point of interest (POI) of the ribs delineated to get the value of intrafraction and interfraction thoracic expansion. Results: There was not statistically significant between the four volumes of whole breast targets delineated by the same delineator at different time, but with statistics significant between the volumes of whole breast target delineated by the different delineators ( F=19.681, P=0.000). There was not statistically

  10. MicroRNA-31 controls phenotypic modulation of human vascular smooth muscle cells by regulating its target gene cellular repressor of E1A-stimulated genes

    International Nuclear Information System (INIS)

    Wang, Jie; Yan, Cheng-Hui; Li, Yang; Xu, Kai; Tian, Xiao-Xiang; Peng, Cheng-Fei; Tao, Jie; Sun, Ming-Yu; Han, Ya-Ling

    2013-01-01

    Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. The cellular repressor of E1A-stimulated genes (CREG) has been shown to play an important role in phenotypic modulation of VSMCs. However, the mechanism regulating CREG upstream signaling remains unclear. MicroRNAs (miRNAs) have recently been found to play a critical role in cell differentiation via target-gene regulation. This study aimed to identify a miRNA that binds directly to CREG, and may thus be involved in CREG-mediated VSMC phenotypic modulation. Computational analysis indicated that miR-31 bound to the CREG mRNA 3′ untranslated region (3′-UTR). miR-31 was upregulated in quiescent differentiated VSMCs and downregulated in proliferative cells stimulated by platelet-derived growth factor and serum starvation, demonstrating a negative relationship with the VSMC differentiation marker genes, smooth muscle α-actin, calponin and CREG. Using gain-of-function and loss-of-function approaches, CREG and VSMC differentiation marker gene expression levels were shown to be suppressed by a miR-31 mimic, but increased by a miR-31 inhibitor at both protein and mRNA levels. Notably, miR-31 overexpression or inhibition affected luciferase expression driven by the CREG 3′-UTR containing the miR-31 binding site. Furthermore, miR-31-mediated VSMC phenotypic modulation was inhibited in CREG-knockdown human VSMCs. We also determined miR-31 levels in the serum of patients with coronary artery disease (CAD), with or without in stent restenosis and in healthy controls. miR-31 levels were higher in the serum of CAD patients with restenosis compared to CAD patients without restenosis and in healthy controls. In summary, these data demonstrate that miR-31 not only directly binds to its target gene CREG and modulates the VSMC phenotype through this interaction, but also can be an important biomarker in diseases involving VSMC

  11. The need for rotational margins in intensity-modulated radiotherapy and a new method for planning target volume design

    International Nuclear Information System (INIS)

    Langer, Mark Peter; Papiez, Lech; Spirydovich, Siarhei; Thai, Van

    2005-01-01

    Purpose: The effect of rotational errors on the coverage of clinical target volumes (CTVs) is examined. A new planning target volume (PTV) construction that considers the individual paths traced by movements of the target boundary points is developed. Methods and Materials: A standard uniform margin expansion was compared with a PTV constructed from the space swept out by a concave moving target. A new method formed the PTV by aggregating the separate convex hulls taken of the positions of the individual target boundary points in a sampling of CTV displacements. Results: A 0.5-cm uniform margin adequate for translations was inadequate given CTV rotation about a fixed off-center axis. A PTV formed of the target's swept-out area was 22% smaller than needed for coverage by a uniform margin, but computationally is not readily extended to translations combined with rotations about a shifting axis. Forming instead the union of convex hulls of the boundary points in a sampling of CTV displacements represented these movements in the PTV design and retained the target's concave shape. Conclusions: Planning target volumes should accommodate target rotation. The union of convex hulls of the boundary point positions in a sampling of displacements can effectively represent multiple sources of deviations while preserving target concavities

  12. Modulation of mdm2 pre-mRNA splicing by 9-aminoacridine-PNA (peptide nucleic acid conjugates targeting intron-exon junctions

    Directory of Open Access Journals (Sweden)

    Nielsen Peter E

    2010-06-01

    Full Text Available Abstract Background Modulation of pre-mRNA splicing by antisense molecules is a promising mechanism of action for gene therapeutic drugs. In this study, we have examined the potential of peptide nucleic acid (PNA 9-aminoacridine conjugates to modulate the pre-mRNA splicing of the mdm2 human cancer gene in JAR cells. Methods We screened 10 different 15 mer PNAs targeting intron2 at both the 5' - and the 3'-splice site for their effects on the splicing of mdm2 using RT-PCR analysis. We also tested a PNA (2512 targeting the 3'-splice site of intron3 with a complementarity of 4 bases to intron3 and 11 bases to exon4 for its splicing modulation effect. This PNA2512 was further tested for the effects on the mdm2 protein level as well as for inhibition of cell growth in combination with the DNA damaging agent camptothecin (CPT. Results We show that several of these PNAs effectively inhibit the splicing thereby producing a larger mRNA still containing intron2, while skipping of exon3 was not observed by any of these PNAs. The most effective PNA (PNA2406 targeting the 3'-splice site of intron2 had a complementarity of 4 bases to intron2 and 11 bases to exon3. PNA (2512 targeting the 3'-splice site of intron3 induced both splicing inhibition (intron3 skipping and skipping of exon4. Furthermore, treatment of JAR cells with this PNA resulted in a reduction in the level of MDM2 protein and a concomitant increase in the level of tumor suppressor p53. In addition, a combination of this PNA with CPT inhibited cell growth more than CPT alone. Conclusion We have identified several PNAs targeting the 5'- or 3'-splice sites in intron2 or the 3'-splice site of intron3 of mdm2 pre-mRNA which can inhibit splicing. Antisense targeting of splice junctions of mdm2 pre-mRNA may be a powerful method to evaluate the cellular function of MDM2 splice variants as well as a promising approach for discovery of mdm2 targeted anticancer drugs.

  13. BRCA1, FANCD2 and Chk1 are potential molecular targets for the modulation of a radiation-induced DNA damage response in bystander cells.

    Science.gov (United States)

    Burdak-Rothkamm, Susanne; Rothkamm, Kai; McClelland, Keeva; Al Rashid, Shahnaz T; Prise, Kevin M

    2015-01-28

    Radiotherapy is an important treatment option for many human cancers. Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers. The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects. This study aims to elucidate radiation-induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting. Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine (BrdU) nuclear foci detection at sites of single stranded DNA. γH2AX co-localised with these BrdU foci. BRCA1 and FANCD2 foci formed in T98G bystander cells. Using ATR mutant F02-98 hTERT and ATM deficient GM05849 fibroblasts it could be shown that ATR but not ATM was required for the recruitment of FANCD2 to sites of replication associated DNA damage in bystander cells whereas BRCA1 bystander foci were ATM-dependent. Phospho-Chk1 foci formation was observed in T98G bystander cells. Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor UCN-01 but increased radioresistance of bystander cells. This study identifies BRCA1, FANCD2 and Chk1 as potential targets for the modulation of radiation response in bystander cells. It adds to our understanding of the key molecular events propagating out-of-field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Transcranial Direct Current Stimulation (tDCS) Targeting Left Dorsolateral Prefrontal Cortex Modulates Task-Induced Acute Pain in Healthy Volunteers.

    Science.gov (United States)

    Mariano, Timothy Y; Van't Wout, Mascha; Garnaat, Sarah L; Rasmussen, Steven A; Greenberg, Benjamin D

    2016-04-01

    Current chronic pain treatments target nociception rather than affective "suffering" and its associated functional and psychiatric comorbidities. The left dorsolateral prefrontal cortex (DLPFC) has been implicated in affective, cognitive, and attentional aspects of pain and is a primary target of neuromodulation for affective disorders. Transcranial direct current stimulation (tDCS) can non-invasively modulate cortical activity. The present study tests whether anodal tDCS targeting the left DLPFC will increase tolerability of acute painful stimuli vs cathodal tDCS. Forty tDCS-naive healthy volunteers received anodal and cathodal stimulation targeting the left DLPFC in two randomized and counterbalanced sessions. During stimulation, each participant performed cold pressor (CP) and breath holding (BH) tasks. We measured pain intensity with the Defense and Veterans Pain Rating Scale (DVPRS) before and after each task. Mixed ANOVA revealed no main effect of stimulation polarity for mean CP threshold, tolerance, or endurance, or mean BH time (allP > 0.27). However, DVPRS rise associated with CP was significantly smaller with anodal vs cathodal tDCS (P = 0.024). We further observed a significant tDCS polarity × stimulation order interaction (P = 0.042) on CP threshold, suggesting task sensitization. Although our results do not suggest that polarity of tDCS targeting the left DLPFC differentially modulates the tolerability of CP- and BH-related pain distress in healthy volunteers, there was a significant effect on DVPRS pain ratings. This contrasts with our previous findings that tDCS targeting the left dorsal anterior cingulate cortex showed a trend toward higher mean CP tolerance with cathodal vs anodal stimulation. The present results may suggest tDCS-related effects on nociception or DLPFC-mediated attention, or preferential modulation of the affective valence of pain as captured by the DVPRS. Sham-controlled clinical studies are needed. © 2015

  15. SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

    OpenAIRE

    Tajima, Ken; Yae, Toshifumi; Javaid, Sarah; Tam, Oliver; Comaills, Valentine; Morris, Robert; Wittner, Ben S.; Liu, Mingzhu; Engstrom, Amanda; Takahashi, Fumiyuki; Black, Joshua C.; Ramaswamy, Sridhar; Shioda, Toshihiro; Hammell, Molly; Haber, Daniel A.

    2015-01-01

    Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead t...

  16. Emotional Intent Modulates The Neural Substrates Of Creativity: An fMRI Study of Emotionally Targeted Improvisation in Jazz Musicians.

    Science.gov (United States)

    McPherson, Malinda J; Barrett, Frederick S; Lopez-Gonzalez, Monica; Jiradejvong, Patpong; Limb, Charles J

    2016-01-04

    Emotion is a primary motivator for creative behaviors, yet the interaction between the neural systems involved in creativity and those involved in emotion has not been studied. In the current study, we addressed this gap by using fMRI to examine piano improvisation in response to emotional cues. We showed twelve professional jazz pianists photographs of an actress representing a positive, negative or ambiguous emotion. Using a non-ferromagnetic thirty-five key keyboard, the pianists improvised music that they felt represented the emotion expressed in the photographs. Here we show that activity in prefrontal and other brain networks involved in creativity is highly modulated by emotional context. Furthermore, emotional intent directly modulated functional connectivity of limbic and paralimbic areas such as the amygdala and insula. These findings suggest that emotion and creativity are tightly linked, and that the neural mechanisms underlying creativity may depend on emotional state.

  17. [Pharmacological characteristics of drugs targeted on calcium-sensing receptor.-properties of cinacalcet hydrochloride as allosteric modulator].

    Science.gov (United States)

    Nagano, Nobuo; Tsutsui, Takaaki

    2016-06-01

    Calcimimetics act as positive allosteric modulators of the calcium-sensing receptor (CaSR), thereby decreasing parathyroid hormone (PTH) secretion from the parathyroid glands. On the other hand, negative allosteric modulators of the CaSR with stimulatory effect on PTH secretion are termed calcilytics. The calcimimetic cinacalcet hydrochloride (cinacalcet) is the world's first allosteric modulator of G protein-coupled receptor to enter the clinical market. Cinacalcet just tunes the physiological effects of Ca(2+), an endogenous ligand, therefore, shows high selectivity and low side effects. Calcimimetics also increase cell surface CaSR expression by acting as pharmacological chaperones (pharmacoperones). It is considered that the cinacalcet-induced upper gastrointestinal problems are resulted from enhanced physiological responses to Ca(2+) and amino acids via increased sensitivity of digestive tract CaSR by cinacalcet. While clinical developments of calcilytics for osteoporosis were unfortunately halted or terminated due to paucity of efficacy, it is expected that calcilytics may be useful for the treatment of patients with activating CaSR mutations, asthma, and idiopathic pulmonary artery hypertension.

  18. Dosimetric impact of inter-observer variability for 3D conformal radiotherapy and volumetric modulated arc therapy: the rectal tumor target definition case

    International Nuclear Information System (INIS)

    Lobefalo, Francesca; Cozzi, Luca; Scorsetti, Marta; Mancosu, Pietro; Bignardi, Mario; Reggiori, Giacomo; Tozzi, Angelo; Tomatis, Stefano; Alongi, Filippo; Fogliata, Antonella; Gaudino, Anna; Navarria, Piera

    2013-01-01

    To assess the dosimetric effect induced by inter-observer variability in target definition for 3D-conformal RT (3DCRT) and volumetric modulated arc therapy by RapidArc (RA) techniques for rectal cancer treatment. Ten patients with rectal cancer subjected to neo-adjuvant RT were randomly selected from the internal database. Four radiation oncologists independently contoured the clinical target volume (CTV) in blind mode. Planning target volume (PTV) was defined as CTV + 7 mm in the three directions. Afterwards, shared guidelines between radiation oncologists were introduced to give general criteria for the contouring of rectal target and the four radiation oncologists defined new CTV following the guidelines. For each patient, six intersections (I) and unions (U) volumes were calculated coupling the contours of the various oncologists. This was repeated for the contours drawn after the guidelines. Agreement Index (AI = I/U) was calculated pre and post guidelines. Two RT plans (one with 3DCRT technique using 3–4 fields and one with RA using a single modulated arc) were optimized on each radiation oncologist’s PTV. For each plan the PTV volume receiving at least 95% of the prescribed dose (PTV V95%) was calculated for both target and non-target PTVs. The inter-operator AI pre-guidelines was 0.57 and was increased up to 0.69 post-guidelines. The maximum volume difference between the various CTV couples, drawn for each patient, passed from 380 ± 147 cm 3 to 137 ± 83 cm 3 after the introduction of guidelines. The mean percentage for the non-target PTV V95% was 93.7 ± 9.2% before and 96.6 ± 4.9%after the introduction of guidelines for the 3DCRT, for RA the increase was more relevant, passing from 86.5 ± 13.8% (pre) to 94.5 ± 7.5% (post). The OARs were maximally spared with VMAT technique while the variability between pre and post guidelines was not relevant in both techniques. The contouring inter-observer variability has dosimetric effects in the PTV coverage

  19. Consensus Guidelines for Delineation of Clinical Target Volume for Intensity-Modulated Pelvic Radiotherapy for the Definitive Treatment of Cervix Cancer

    International Nuclear Information System (INIS)

    Lim, Karen; Small, William; Portelance, Lorraine; Creutzberg, Carien; Juergenliemk-Schulz, Ina M.; Mundt, Arno; Mell, Loren K.; Mayr, Nina; Viswanathan, Akila; Jhingran, Anuja; Erickson, Beth; De Los Santos, Jennifer; Gaffney, David; Yashar, Catheryn; Beriwal, Sushil; Wolfson, Aaron

    2011-01-01

    Purpose: Accurate target definition is vitally important for definitive treatment of cervix cancer with intensity-modulated radiotherapy (IMRT), yet a definition of clinical target volume (CTV) remains variable within the literature. The aim of this study was to develop a consensus CTV definition in preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group. Methods and Materials: A guidelines consensus working group meeting was convened in June 2008 for the purposes of developing target definition guidelines for IMRT for the intact cervix. A draft document of recommendations for CTV definition was created and used to aid in contouring a clinical case. The clinical case was then analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with kappa statistics as a measure of agreement between participants. Results: Nineteen experts in gynecological radiation oncology generated contours on axial magnetic resonance images of the pelvis. Substantial STAPLE agreement sensitivity and specificity values were seen for gross tumor volume (GTV) delineation (0.84 and 0.96, respectively) with a kappa statistic of 0.68 (p < 0.0001). Agreement for delineation of cervix, uterus, vagina, and parametria was moderate. Conclusions: This report provides guidelines for CTV definition in the definitive cervix cancer setting for the purposes of IMRT, building on previously published guidelines for IMRT in the postoperative setting.

  20. NO2 inhalation promotes Alzheimer’s disease-like progression: cyclooxygenase-2-derived prostaglandin E2 modulation and monoacylglycerol lipase inhibition-targeted medication

    Science.gov (United States)

    Yan, Wei; Yun, Yang; Ku, Tingting; Li, Guangke; Sang, Nan

    2016-03-01

    Air pollution has been reported to be associated with increased risks of cognitive impairment and neurodegenerative diseases. Because NO2 is a typical primary air pollutant and an important contributor to secondary aerosols, NO2-induced neuronal functional abnormalities have attracted greater attention, but the available experimental evidence, modulating mechanisms, and targeting medications remain ambiguous. In this study, we exposed C57BL/6J and APP/PS1 mice to dynamic NO2 inhalation and found for the first time that NO2 inhalation caused deterioration of spatial learning and memory, aggravated amyloid β42 (Aβ42) accumulation, and promoted pathological abnormalities and cognitive defects related to Alzheimer’s disease (AD). The microarray and bioinformation data showed that the cyclooxygenase-2 (COX-2)-mediated arachidonic acid (AA) metabolism of prostaglandin E2 (PGE2) played a key role in modulating this aggravation. Furthermore, increasing endocannabinoid 2-arachidonoylglycerol (2-AG) by inhibiting monoacylglycerol lipase (MAGL) prevented PGE2 production, neuroinflammation-associated Aβ42 accumulation, and neurodegeneration, indicating a therapeutic target for relieving cognitive impairment caused by NO2 exposure.

  1. Target volume delineation for head and neck cancer intensity-modulated radiotherapy; Delineation des volumes cibles des cancers des voies aerodigestives superieures en radiotherapie conformationnelle avec modulation d'intensite

    Energy Technology Data Exchange (ETDEWEB)

    Lapeyre, M.; Toledano, I.; Bourry, N. [Departement de radiotherapie, centre Jean-Perrin, 58, rue Montalembert, BP 5026, 63011 Clermont-Ferrand cedex 1 (France); Bailly, C. [Unite de radiodiagnostic, centre Jean-Perrin, 58, rue Montalembert, BP 5026, 63011 Clermont-Ferrand cedex 1 (France); Cachin, F. [Unite de medecine nucleaire, centre Jean-Perrin, 58, rue Montalembert, BP 5026, 63011 Clermont-Ferrand cedex 1 (France)

    2011-10-15

    This article describes the determination and the delineation of the target volumes for head-and-neck cancers treated with intensity-modulated radiotherapy (IMRT). The delineation of the clinical target volumes (CTV) on the computerized tomography scanner (CT scan) requires a rigorous methodology due to the complexity of head-and-neck anatomy. The clinical examination with a sketch of pretreatment tumour extension, the surgical and pathological reports and the adequate images (CT scan, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography) are necessary for the delineation. The target volumes depend on the overall strategy: sequential IMRT or simultaneous integrated boost-IMRT (SIB-IMRT). The concept of selectivity of the potential subclinical disease near the primary tumor and the selection of neck nodal targets are described according to the recommendations and the literature. The planing target volume (PTV), mainly reflecting setup errors (random and systematic), results from a uniform 4-5 mm expansion around the CTV. We propose the successive delineation of: (1) the gross volume tumour (GTV); (2) the 'high risk' CTV1 around the GTV or including the postoperative tumour bed in case of positive margins or nodal extra-capsular spread (65-70 Gy in 30-35 fractions); (3) the CTV2 'intermediate risk' around the CTV1 for SIB-IMRT (59-63 Gy in 30-35 fractions); (4) the 'low-risk' CTV3 (54-56 Gy in 30-35 fractions); (5) the PTVs. (authors)

  2. High-performance flexible electrode based on electrodeposition of polypyrrole/MnO2 on carbon cloth for supercapacitors

    Science.gov (United States)

    Fan, Xingye; Wang, Xiaolei; Li, Ge; Yu, Aiping; Chen, Zhongwei

    2016-09-01

    A highly flexible electrodes based on electrodeposited MnO2 and polypyrrole composite on carbon cloth is designed and developed by a facile in-situ electrodeposition technique. Such flexible composite electrodes with multiply layered structure possess a high specific capacitance of 325 F g-1 at a current density of 0.2 A g-1, and an excellent rate capability with a capacitance retention of 70% at a high current density of 5.0 A g-1. The superior electrochemical performance is mainly due to the unique electrode with improved ion- and electron-transportation pathways as well as the efficient utilization of active materials and electrode robustness. The excellent electrochemical performance and the low cost property endow this flexible nanocomposite electrode with great promise in applications of flexible supercapacitors.

  3. Poly(vinyl chloride) membrane alkali metal ion-selective electrodes based on crystalline synthetic zeolite of the Faujasite type

    International Nuclear Information System (INIS)

    Aghai, H.; Giahi, M.; Arvand Barmehi, M.

    2002-01-01

    Potentiometric electrodes based on the incorporation of zeolite particle in to poly (vinyl chloride) (pvc) membranes are described. The electrodes characteristics are evaluated regarding the response towards alkali ions. Pvc membranes plasticised with dibutyl phthalate and without lipophilic additives (co-exchanger) were used throughout this study. The electrode exhibits a Nernst ion response over the alkali metal cations concentration a range of 1.0x10 - 4 - 1.0 x 10 1 M with a slop of 57.0 ± 0.9 mV per decade of concentration a working ph range (3.0- 9.0) and a fast response time (≤15 c). The selective coefficients for cesium ion as test species with respect to alkaline earth, ammonium and some heavy metal ions were determined. Zeolite-PVC electrodes were applied to the determination of ionic surfactant

  4. Operando studies of all-vanadium flow batteries: Easy-to-make reference electrode based on silver-silver sulfate

    Science.gov (United States)

    Ventosa, Edgar; Skoumal, Marcel; Vázquez, Francisco Javier; Flox, Cristina; Morante, Joan Ramon

    2014-12-01

    In-depth evaluation of the electrochemical performance of all-vanadium redox flow batteries (VRFBs) under operando conditions requires the insertion of a reliable reference electrode in the battery cell. In this work, an easy-to-make reference electrode based on silver-silver sulfate is proposed and described for VRFBs. The relevance and feasibility of the information obtained by inserting the reference electrode is illustrated with the study of ammoxidized graphite felts. In this case, we show that the kinetic of the electrochemical reaction VO2+/VO2+ is slower than that of V2+/V3+ at the electrode. While the slow kinetics at the positive electrode limits the voltage efficiency, the operating potential of the negative electrode, which is outside the stability widow of water, reduces the coulombic efficiency due to the hydrogen evolution.

  5. miR-17-5p targets the p300/CBP-associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells

    International Nuclear Information System (INIS)

    Gong, Ai-Yu; Eischeid, Alex N; Xiao, Jing; Zhao, Jian; Chen, Dongqing; Wang, Zhao-Yi; Young, Charles YF; Chen, Xian-Ming

    2012-01-01

    Androgen receptor (AR) signalling is critical to the initiation and progression of prostate cancer (PCa). Transcriptional activity of AR involves chromatin recruitment of co-activators, including the p300/CBP-associated factor (PCAF). Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease. Whether miRNAs regulate PCAF expression in PCa cells to regulate AR transcriptional activity is still unclear. Expression of PCAF was investigated in several PCa cell lines by qRT-PCR, Western blot, and immunocytochemistry. The effects of PCAF expression on AR-regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation, reporter gene construct analysis, and MTS assay. Targeting of PCAF by miR-17-5p was evaluated using the luciferase reporter assay. PCAF was upregulated in several PCa cell lines. Upregulation of PCAF promoted AR transcriptional activation and cell growth in cultured PCa cells. Expression of PCAF in PCa cells was associated with the downregulation of miR-17-5p. Targeting of the 3’-untranslated region of PCAF mRNA by miR-17-5p caused translational suppression and RNA degradation, and, consequently, modulation of AR transcriptional activity in PCa cells. PCAF is upregulated in cultured PCa cells, and upregulation of PCAF is associated with the downregulation of miR-17-5p. Targeting of PCAF by miR-17-5p modulates AR transcriptional activity and cell growth in cultured PCa cells

  6. Estrogen induced metastatic modulators MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in thyroid cancer.

    Directory of Open Access Journals (Sweden)

    Shilpi Rajoria

    2011-01-01

    Full Text Available Thyroid cancer is the most common endocrine related cancer with increasing incidences during the past five years. Current treatments for thyroid cancer, such as surgery or radioactive iodine therapy, often require patients to be on lifelong thyroid hormone replacement therapy and given the significant recurrence rates of thyroid cancer, new preventive modalities are needed. The present study investigates the property of a natural dietary compound found in cruciferous vegetables, 3,3'-diindolylmethane (DIM, to target the metastatic phenotype of thyroid cancer cells through a functional estrogen receptor.Thyroid cancer cell lines were treated with estrogen and/or DIM and subjected to in vitro adhesion, migration and invasion assays to investigate the anti-metastatic and anti-estrogenic effects of DIM. We observed that DIM inhibits estrogen mediated increase in thyroid cell migration, adhesion and invasion, which is also supported by ER-α downregulation (siRNA studies. Western blot and zymography analyses provided direct evidence for this DIM mediated inhibition of E(2 enhanced metastasis associated events by virtue of targeting essential proteolytic enzymes, namely MMP-2 and MMP-9.Our data reports for the first time that DIM displays anti-estrogenic like activity by inhibiting estradiol enhanced thyroid cancer cell proliferation and in vitro metastasis associated events, namely adhesion, migration and invasion. Most significantly, MMP-2 and MMP-9, which are known to promote and enhance metastasis, were determined to be targets of DIM. This anti-estrogen like property of DIM may lead to the development of a novel preventive and/or therapeutic dietary supplement for thyroid cancer patients by targeting progression of the disease.

  7. Laminar Module Cascade from Layer 5 to 6 Implementing Cue-to-Target Conversion for Object Memory Retrieval in the Primate Temporal Cortex.

    Science.gov (United States)

    Koyano, Kenji W; Takeda, Masaki; Matsui, Teppei; Hirabayashi, Toshiyuki; Ohashi, Yohei; Miyashita, Yasushi

    2016-10-19

    The cerebral cortex computes through the canonical microcircuit that connects six stacked layers; however, how cortical processing streams operate in vivo, particularly in the higher association cortex, remains elusive. By developing a novel MRI-assisted procedure that reliably localizes recorded single neurons at resolution of six individual layers in monkey temporal cortex, we show that transformation of representations from a cued object to a to-be-recalled object occurs at the infragranular layer in a visual cued-recall task. This cue-to-target conversion started in layer 5 and was followed by layer 6. Finally, a subset of layer 6 neurons exclusively encoding the sought target became phase-locked to surrounding field potentials at theta frequency, suggesting that this coordinated cell assembly implements cortical long-distance outputs of the recalled target. Thus, this study proposes a link from local computation spanning laminar modules of the temporal cortex to the brain-wide network for memory retrieval in primates. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1

    International Nuclear Information System (INIS)

    Zhuang, Ming; Gao, Wen; Xu, Jing; Wang, Ping; Shu, Yongqian

    2014-01-01

    Graphical abstract: - Highlights: • H19 regulates gastric cancer cell proliferation phenotype via miR-675. • MiR-675 modulates cell proliferation of gastric cancer cells by targeting tumor suppressor RUNX1. • The H19/miR-675/RUNX1 axis plays an important role in the tumorigenesis of gastric cancer. - Abstract: The lncRNA H19 has been recently shown to be upregulated and play important roles in gastric cancer tumorigenesis. However, the precise molecular mechanism of H19 and its mature product miR-675 in the carcinogenesis of gastric cancer remains unclear. In this study, we found that miR-675 was positively expressed with H19 and was a pivotal mediator in H19-induced gastric cancer cell growth promotion. Subsequently, the tumor suppressor Runt Domain Transcription Factor1 (RUNX1) was confirmed to be a direct target of miR-675 using a luciferase reporter assay and Western blotting analyses. A series of rescue assays indicated that RUNX1 mediated H19/miR-67-induced gastric cancer cell phenotypic changes. Moreover, the inverse relationship between the expression of RUNX1 and H19/miR-675 was also revealed in gastric cancer tissues and gastric cancer cell lines. Taken together, our study demonstrated that the novel pathway H19/miR-675/RUNX1 regulates gastric cancer development and may serve as a potential target for gastric cancer therapy

  9. A new module in neural differentiation control: two microRNAs upregulated by retinoic acid, miR-9 and -103, target the differentiation inhibitor ID2.

    Directory of Open Access Journals (Sweden)

    Daniela Annibali

    Full Text Available The transcription factor ID2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. MicroRNAs (miRNAs are increasingly involved in differentiation control and cancer development. Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells--miR-9 and miR-103--restrain ID2 expression by directly targeting the coding sequence and 3' untranslated region of the ID2 encoding messenger RNA, respectively. Notably, the two miRNAs show an inverse correlation with ID2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR-103 in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID2 inhibition. Conversely, an ID2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID2. These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID2, suggesting that its alteration may be involved in neural cancer development.

  10. Sodium modulates opioid receptors through a membrane component different from G-proteins. Demonstration by target size analysis

    International Nuclear Information System (INIS)

    Ott, S.; Costa, T.; Herz, A.

    1988-01-01

    The target size for opioid receptor binding was studied after manipulations known to affect the interactions between receptor and GTP-binding regulatory proteins (G-proteins). Addition of GTP or its analogs to the binding reaction, exposure of intact cells to pertussis toxin prior to irradiation, or treatment of irradiated membranes with N-ethylmaleimide did not change the target size (approximately equal to 100 kDa) for opioid receptors in NG 108-15 cells and rat brain. These data suggest that the 100-kDa species does not include an active subunit of a G-protein or alternatively that GTP does not promote the dissociation of the receptor-G-protein complex. The presence of Na+ (100 mM) in the radioligand binding assay induced a biphasic decay curve for agonist binding and a flattening of the monoexponential decay curve for a partial agonist. In both cases the effect was explained by an irradiation-induced loss of the low affinity state of the opioid receptor produced by the addition of Na+. This suggests that an allosteric inhibitor that mediates the effect of sodium on the receptor is destroyed at low doses of irradiation, leaving receptors which are no longer regulated by sodium. The effect of Na+ on target size was slightly increased by the simultaneous addition of GTP but was not altered by pertussis toxin treatment. Thus, the sodium unit is distinct from G-proteins and may represent a new component of the opioid receptor complex. Assuming a simple bimolecular model of one Na+ unit/receptor, the size of this inhibitor can be measured as 168 kDa

  11. MiR-19a targets suppressor of cytokine signaling 1 to modulate the progression of neuropathic pain.

    Science.gov (United States)

    Wang, Conghui; Jiang, Qi; Wang, Min; Li, Dong

    2015-01-01

    We aimed to investigate whether miR-19a is associated with neuropathic pain and elucidate the underlying regulatory mechanism. We established a neuropathic pain model of bilateral chronic constriction injury (bCCI). Then bCCI rats were injected with mo-miR-19a, siR-SOCS1 or blank expression vector through a microinjection syringe via an intrathecal catheter on 3 day before surgery and after surgery. Behavioral tests, such as mechanical allodynia, thermal hyperalgesia and acetone induced cold allodynia, were performed to evaluate the pain threshold. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the expression of miR-19a and western blotting was carried out to measure the expression of SOCS1. miR-19a expression levels were markedly increased in neuropathic pain models. Moreover, miR-19a significantly attenuated mechanical allodynia and thermal hyperalgesia, and similar results were obtained after knockdown of SOCS1 expression. However, miR-19a markedly increased the times that the rats appeared a sign of cold allodynia, and knockdown of SOCS1 expression had similar effects. Besides, the results of bioinformatics analysis and western blotting analysis were all confirmed that SOCS1 was a direct target of miR-19a in neuropathic pain models. Our finding indicate that SOCS1 is a direct target of miR-19a in neuropathic pain rats and miR-19a may play a critical role in regulating of neuropathic pain via targeting SOCS1.

  12. Novel anti-cancer strategy in bone tumors by targeting molecular and cellular modulators of bone resorption.

    Science.gov (United States)

    Brounais, Bénédicte; Ruiz, Carmen; Rousseau, Julie; Lamoureux, François; Blanchard, Frédéric; Heymann, Dominique; Redini, Françoise

    2008-11-01

    Tumor cells alter the balanced process of bone formation and bone resorption mediated respectively by osteoblasts and osteoclasts, leading to the disruption of the normal equilibrium and resulting in a spectrum of osteolytic to osteoblastic lesions. This review will summarize research on molecules that play direct and essential roles in the differentiation and activity of osteoclasts, and the role of these molecules in bone destruction caused by cancer. Results from experimental models suggest that the Receptor Activator of NF-kB Ligand (RANKL), a member of the TNF superfamily is a common effector of bony lesions in osteolysis caused by primary and secondary bone tumors. Therefore, osteoclast represents an attractive target across a broad range of tumors that develop in bone. Elucidation of the mechanisms of RANKL interactions with its activator (RANK) and decoy (osteoprotegerin: OPG) receptors has enable the development of pharmacological inhibitors of RANKL (and of its signalling pathway) which have been recently patented, with potential for the treatment of cancer-induced bone disease. Blocking bone resorption by specific other drugs such as bisphosphonates, inhibitors of cathepsin K (the main enzyme involved in bone resorption mechanisms) or signalling pathways regulating osteoclast differentiation and activation is also a promising target for the treatment of osteolysis associated to bone tumors.

  13. Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

    Science.gov (United States)

    Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

    2010-05-14

    Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

  14. Two rhodamine lactam modulated lysosome-targetable fluorescence probes for sensitively and selectively monitoring subcellular organelle pH change

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hongmei [Ministry of Education Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, College of Chemistry & Materials Science, Northwest University, Xi' an 710069 (China); Wang, Cuiling [Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Science, Northwest University, Xi' an 710069 (China); She, Mengyao; Zhu, Yuelu; Zhang, Jidong; Yang, Zheng [Ministry of Education Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, College of Chemistry & Materials Science, Northwest University, Xi' an 710069 (China); Liu, Ping, E-mail: liuping@nwu.edu.cn [Ministry of Education Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, College of Chemistry & Materials Science, Northwest University, Xi' an 710069 (China); Wang, Yaoyu [Ministry of Education Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, College of Chemistry & Materials Science, Northwest University, Xi' an 710069 (China); Li, Jianli, E-mail: lijianli@nwu.edu.cn [Ministry of Education Key Laboratory of Synthetic and Natural Functional Molecule Chemistry, College of Chemistry & Materials Science, Northwest University, Xi' an 710069 (China)

    2015-11-05

    Be a powerful technique for convenient detection of pH change in living cells, especially at subcellular level, fluorescent probes has attracted more and more attention. In this work, we designed and synthesized three rhodamine lactam modulated fluorescent probes RS1, RS2 and RS3, which all respond sensitively toward weak acidity (pH range 4–6) via the photophysical property in buffer solution without interference from the other metal ions, and they also show ideal pKa values and excellent reversibility. Particularly, by changing the lone pair electrons distribution of lactam-N atom with different conjugations, RS2 and RS3 exhibit high quantum yield, negligible cytotoxicity and excellent permeability. They are suitable to stain selectively lysosomes of tumor cells and monitor its pH changes sensitively via optical molecular imaging. The above findings suggest that the probes we designed could act as ideal and easy method for investigating the pivotal role of H{sup +} in lysosomes and are potential pH detectors in disease diagnosis through direct intracellular imaging. - Highlights: • Two probes for sensitively and selectively monitoring weak acidic pH change. • The pKa of the probes was highly suitable for staining lysosomes in tumor cells. • The properties of those probes were changed by different conjugate system. • These probes have negligible cytotoxicity and good sensitivity in vivo.

  15. Two rhodamine lactam modulated lysosome-targetable fluorescence probes for sensitively and selectively monitoring subcellular organelle pH change

    International Nuclear Information System (INIS)

    Li, Hongmei; Wang, Cuiling; She, Mengyao; Zhu, Yuelu; Zhang, Jidong; Yang, Zheng; Liu, Ping; Wang, Yaoyu; Li, Jianli

    2015-01-01

    Be a powerful technique for convenient detection of pH change in living cells, especially at subcellular level, fluorescent probes has attracted more and more attention. In this work, we designed and synthesized three rhodamine lactam modulated fluorescent probes RS1, RS2 and RS3, which all respond sensitively toward weak acidity (pH range 4–6) via the photophysical property in buffer solution without interference from the other metal ions, and they also show ideal pKa values and excellent reversibility. Particularly, by changing the lone pair electrons distribution of lactam-N atom with different conjugations, RS2 and RS3 exhibit high quantum yield, negligible cytotoxicity and excellent permeability. They are suitable to stain selectively lysosomes of tumor cells and monitor its pH changes sensitively via optical molecular imaging. The above findings suggest that the probes we designed could act as ideal and easy method for investigating the pivotal role of H + in lysosomes and are potential pH detectors in disease diagnosis through direct intracellular imaging. - Highlights: • Two probes for sensitively and selectively monitoring weak acidic pH change. • The pKa of the probes was highly suitable for staining lysosomes in tumor cells. • The properties of those probes were changed by different conjugate system. • These probes have negligible cytotoxicity and good sensitivity in vivo.

  16. In situ targeting TEM8 via immune response and polypeptide recognition by wavelength-modulated surface plasmon resonance biosensor

    Science.gov (United States)

    Wang, Yimin; Luo, Zewei; Liu, Kunping; Wang, Jie; Duan, Yixiang

    2016-01-01

    There is an increasing interest in real-time and in situ monitoring of living cell activities in life science and medicine. This paper reports a whole cell sensing protocol over the interface of Au film coupled in a wavelength-modulated surface plasmon resonance (WMSPR) biosensor. With dual parabolic mirrors integrated in the sensor, the compact and miniaturized instrument shows satisfactory refractive index sensitivity (2220 nm/RIU) and a high resolution of resonance wavelength shift of 0.3 nm to liquid samples. The affinity interactions between the biomarker of human tumor endothelial marker 8 (TEM8) and antibody (Ab) or specific polypeptide (PEP) were firstly introduced to WMSPR biosensor analysis. Both the interaction events of Ab-cell and PEP-cell over the Au film interface can be recognized by the sensor and the balance time of interactions is about 20 min. The concentration range of Ab for quantitative monitoring of the TEM8 expression on human colon carcinoma SW620 cells was investigated. The present low-cost and time-saving method provides a time resolution of binding specificity between Ab/PEP and TEM8 for real-time analysis of antigen on living tumor cell surface. PMID:26822761

  17. Modulation of telomere binding proteins: a future area of research for skin protection and anti-aging target.

    Science.gov (United States)

    Imbert, Isabelle; Botto, Jean-Marie; Farra, Claude D; Domloge, Nouha

    2012-06-01

    Telomere shortening is considered as one of the main characteristics of cellular aging by limiting cellular division. Besides the fundamental advances through the discoveries of telomere and telomerase, which were recognized by a Nobel Prize, telomere protection remains an essential area of research. Recently, it was evidenced that studying the cross-talks between the proteins associated with telomere should provide a better understanding of the mechanistic basis for telomere-associated aging phenotypes. In this review, we discuss the current knowledge on telomere shortening, telomerase activity, and the essential role of telomere binding proteins in telomere stabilization and telomere-end protection. This review highlights the capacity of telomere binding proteins to limit cellular senescence and to maintain skin tissue homeostasis, which is of key importance to reduce accelerated tissue aging. Future studies addressing telomere protection and limitation of DNA damage response in human skin should include investigations on telomere binding proteins. As little is known about the expression of telomere binding proteins in human skin and modulation of their expression with aging, it remains an interesting field of skin research and a key area for future skin protection and anti-aging developments. © 2012 Wiley Periodicals, Inc.

  18. Chimeric peptides as modulators of CK2-dependent signaling: Mechanism of action and off-target effects.

    Science.gov (United States)

    Zanin, Sofia; Sandre, Michele; Cozza, Giorgio; Ottaviani, Daniele; Marin, Oriano; Pinna, Lorenzo A; Ruzzene, Maria

    2015-10-01

    Protein kinase CK2 is a tetrameric enzyme composed of two catalytic (α/α') and two regulatory (β) subunits. It has a global prosurvival function, especially in cancer, and represents an attractive therapeutic target. Most CK2 inhibitors available so far are ATP-competitive compounds; however, the possibility to block only the phosphorylation of few substrates has been recently explored, and a compound composed of a Tat cell-penetrating peptide and an active cyclic peptide, selected for its ability to bind to the CK2 substrate E7 protein of human papilloma virus, has been developed [Perea et al., Cancer Res. 2004; 64:7127-7129]. By using a similar chimeric peptide (CK2 modulatory chimeric peptide, CK2-MCP), we performed a study to dissect its molecular mechanism of action and the signaling pathways that it affects in cells. We found that it directly interacts with CK2 itself, counteracting the regulatory and stabilizing functions of the β subunit. Cell treatment with CK2-MCP induces a rapid decrease of the amount of CK2 subunits, as well as of other signaling proteins. Concomitant cell death is observed, more pronounced in tumor cells and not accompanied by apoptotic events. CK2 relocalizes to lysosomes, whose proteases are activated, while the proteasome machinery is inhibited. Several sequence variants of the chimeric peptide have been also synthesized, and their effects compared to those of the parental peptide. Intriguingly, the Tat moiety is essential not only for cell penetration but also for the in vitro efficacy of the peptide. We conclude that this class of chimeric peptides, in addition to altering some properties of CK2 holoenzyme, affects several other cellular targets, causing profound perturbations of cell biology. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Development of mannose functionalized dendrimeric nanoparticles for targeted delivery to macrophages: use of this platform to modulate atherosclerosis.

    Science.gov (United States)

    He, Hongliang; Yuan, Quan; Bie, Jinghua; Wallace, Ryan L; Yannie, Paul J; Wang, Jing; Lancina, Michael G; Zolotarskaya, Olga Yu; Korzun, William; Yang, Hu; Ghosh, Shobha

    2018-03-01

    Dysfunctional macrophages underlie the development of several diseases including atherosclerosis where accumulation of cholesteryl esters and persistent inflammation are 2 of the critical macrophage processes that regulate the progression as well as stability of atherosclerotic plaques. Ligand-dependent activation of liver-x-receptor (LXR) not only enhances mobilization of stored cholesteryl ester but also exerts anti-inflammatory effects mediated via trans-repression of proinflammatory transcription factor nuclear factor kappa B. However, increased hepatic lipogenesis by systemic administration of LXR ligands (LXR-L) has precluded their therapeutic use. The objective of the present study was to devise a strategy to selectively deliver LXR-L to atherosclerotic plaque-associated macrophages while limiting hepatic uptake. Mannose-functionalized dendrimeric nanoparticles (mDNP) were synthesized to facilitate active uptake via the mannose receptor expressed exclusively by macrophages using polyamidoamine dendrimer. Terminal amine groups were used to conjugate mannose and LXR-L T091317 via polyethylene glycol spacers. mDNP-LXR-L was effectively taken up by macrophages (and not by hepatocytes), increased expression of LXR target genes (ABCA1/ABCG1), and enhanced cholesterol efflux. When administered intravenously to LDLR-/- mice with established plaques, significant accumulation of fluorescently labeled mDNP-LXR-L was seen in atherosclerotic plaque-associated macrophages. Four weekly injections of mDNP-LXR-L led to significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation as assessed by expression of nuclear factor kappa B target gene matrix metalloproteinase 9; no increase in hepatic lipogenic genes or plasma lipids was observed. These studies validate the development of a macrophage-specific delivery platform for the delivery of anti-atherosclerotic agents directly to the plaque-associated macrophages to attenuate plaque

  20. Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model.

    Science.gov (United States)

    van Vliet, Danique; Bruinenberg, Vibeke M; Mazzola, Priscila N; van Faassen, Martijn Hjr; de Blaauw, Pim; Pascucci, Tiziana; Puglisi-Allegra, Stefano; Kema, Ido P; Heiner-Fokkema, M Rebecca; van der Zee, Eddy A; van Spronsen, Francjan J

    2016-11-01

    Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus

  1. miR-130b-3p Modulates Epithelial-Mesenchymal Crosstalk in Lung Fibrosis by Targeting IGF-1.

    Science.gov (United States)

    Li, Shuhong; Geng, Jing; Xu, Xuefeng; Huang, Xiaoxi; Leng, Dong; Jiang, Dingyuan; Liang, Jiurong; Wang, Chen; Jiang, Dianhua; Dai, Huaping

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease with largely unknown etiology and pathogenesis. Evidence suggests microRNAs (miRNA) contribute to pathogenesis of IPF. In this study, we sought to identify miRNA expression signatures and determine the role of miR-130b-3p in lung fibrosis. The miRNA expression profile of the lungs from patients with IPF and normal donors was determined by Affymetrix microarray, and transcriptome with Affymetrix array. The functions and signal pathways as well as miRNA-mRNA networks were established by bioinformatics analysis. Luciferase assays and ELISA were used to confirm the miRNA target gene. The effect of miRNA-transfected epithelium on fibroblast activities was assessed using a co-culture system. The fibroblast activities were determined by qRT-PCR, western blotting, Transwell and BrdU assays. Seven miRNAs were significantly decreased in IPF lungs, with miR-130b-3p being the highest in the miRNA-mRNA network. Insulin-like growth factor (IGF-1) was a target gene of miR-130b-3p in the epithelium. miR-130b-3p inhibition in the epithelium induced collagen I expression and enhanced the proliferation and migration ability of fibroblast in co-culture systems, which mimicked the functions of exogenous IGF-1 on fibroblasts. Neutralizing IGF-1 with an antibody significantly reduced the modulatory effects of miR-130b-3p inhibitor-transfected epithelium on the activation of fibroblasts. Our results show that miR-130b-3p was downregulated in IPF lungs. miR-130b-3p downregulation contributed to the activation of fibroblasts and the dysregulated epithelial-mesenchymal crosstalk by promoting IGF-1 secretion from lung epithelium, suggesting a key regulatory role for this miRNA in preventing lung fibrosis.

  2. Mitochondrial targeted curcumin exhibits anticancer effects through disruption of mitochondrial redox and modulation of TrxR2 activity.

    Science.gov (United States)

    Jayakumar, Sundarraj; Patwardhan, Raghavendra S; Pal, Debojyoti; Singh, Babita; Sharma, Deepak; Kutala, Vijay Kumar; Sandur, Santosh Kumar

    2017-12-01

    Mitocurcumin is a derivative of curcumin, which has been shown to selectively enter mitochondria. Here we describe the anti-tumor efficacy of mitocurcumin in lung cancer cells and its mechanism of action. Mitocurcumin, showed 25-50 fold higher efficacy in killing lung cancer cells as compared to curcumin as demonstrated by clonogenic assay, flow cytometry and high throughput screening assay. Treatment of lung cancer cells with mitocurcumin significantly decreased the frequency of cancer stem cells. Mitocurcumin increased the mitochondrial reactive oxygen species (ROS), decreased the mitochondrial glutathione levels and induced strand breaks in the mitochondrial DNA. As a result, we observed increased BAX to BCL-2 ratio, cytochrome C release into the cytosol, loss of mitochondrial membrane potential and increased caspase-3 activity suggesting that mitocurcumin activates the intrinsic apoptotic pathway. Docking studies using mitocurcumin revealed that it binds to the active site of the mitochondrial thioredoxin reductase (TrxR2) with high affinity. In corroboration with the above finding, mitocurcumin decreased TrxR activity in cell free as well as the cellular system. The anti-cancer activity of mitocurcumin measured in terms of apoptotic cell death and the decrease in cancer stem cell frequency was accentuated by TrxR2 overexpression. This was due to modulation of TrxR2 activity to NADPH oxidase like activity by mitocurcumin, resulting in higher ROS accumulation and cell death. Thus, our findings reveal mitocurcumin as a potent anticancer agent with better efficacy than curcumin. This study also demonstrates the role of TrxR2 and mitochondrial DNA damage in mitocurcumin mediated killing of cancer cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.

    Science.gov (United States)

    Snider, Kaitlin H; Dziema, Heather; Aten, Sydney; Loeser, Jacob; Norona, Frances E; Hoyt, Kari; Obrietan, Karl

    2016-07-15

    A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Lactobacillus rhamnosus ATCC 7469 exopolysaccharides synergizes with low level ionizing radiation to modulate signaling molecular targets in colorectal carcinogenesis in rats.

    Science.gov (United States)

    Zahran, Walid E; Elsonbaty, Sawsan M; Moawed, Fatma S M

    2017-08-01

    Combination therapy that targets cellular signaling pathway represents an alternative therapy for the treatment of colon cancer (CRC). The present study was therefore aimed to investigate the probable interaction of Lactobacillus rhamnosus ATCC 7469 exopolysaccharides (EPS) with low level ionizing γ radiation (γ-R) exposure against dimethylhydrazine (DMH)- induced colorectal carcinogenesis in rats. Colon cancer was induced with 20mg DMH/kg BW. Rats received daily by gastric gavage 100mg EPS/Kg BW concomitant with 1Gy γ-R over two months. Colonic oxidative and inflammatory stresses were assessed. The change in the expression of p-p38 MAPK, p-STAT3, β-catenin, NF-kB, COX-2 and iNOS was evaluated by western blotting and q-PCR. It was found that DMH treatment significantly induced colon oxidative injury accompanied by inflammatory disturbance along with increased protein expression of the targeted signaling factors p-p38 MAPK, p-STAT3 and β-catenin. The mRNA gene expression of NF-kB, COX-2 and iNOS was significantly higher in DMH-treated animals. It's worthy to note that colon tissues with DMH treatment showed significant dysplasia and anaplasia of the glandular mucosal lining epithelium with loses of goblet cells formation, pleomorphism in the cells and hyperchromachia in nuclei. Interestingly, EPS treatment with γ-R exposure showed statistically significant amelioration of the oxidative and inflammatory biomarkers with modulated signaling molecular factors accompanied by improved histological structure against DMH-induced CRC. In conclusion, our findings showed that Lactobacillus rhamnosus ATCC 7469 EPS with low level γ-R in synergistic interaction are efficacious control against CRC progression throughout the modulation of key signaling growth factors associated with inflammation via antioxidant mediated anti-inflammatory and anti-proliferative activities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  5. The impact of rectal and bladder variability on target coverage during post-prostatectomy intensity modulated radiotherapy

    International Nuclear Information System (INIS)

    Bell, Linda J.; Cox, Jennifer; Eade, Thomas; Rinks, Marianne; Kneebone, Andrew

    2014-01-01

    Background and purpose: Accuracy when delivering post-prostatectomy intensity modulated radiotherapy (IMRT) is crucial. The aims of this study were to quantify prostate bed movement and determine what amount of bladder or rectum size variation creates the potential for geographic miss. Methods and materials: The Cone Beam CT (CBCT) images (n = 377) of forty patients who received post-prostatectomy IMRT with daily on-line alignment to bony anatomy were reviewed. Prostate bed movement was estimated using the location of surgical clips in the upper and lower sections of the PTV and correlated with rectal and bladder filling (defined as changes in the cross sectional diameter at defined levels). The number of potential geographic misses caused by bladder and rectum variation was calculated assuming a uniform CTV to PTV expansion of 1 cm except 0.5 cm posteriorly. Results: Variations in bladder filling of >2 cm larger, ±1 cm, or >2 cm smaller occurred in 3.4%, 56.2%, and 15.1% of images respectively with potential geographic misses in the upper prostate bed of 61.5%, 9.9% and 26.3% respectively. Variations in rectal filling in the upper prostate bed of >1.5 cm larger, 1.5 cm larger to 1 cm smaller, and >1 cm smaller occurred in 17.2%, 75.6%, and 7.2% of images respectively. These variations resulted in geographic misses in the upper prostate bed in 29.2%, 12.3%, and 63.0% of images respectively. Variations in bladder and rectal filling in the lower prostate bed region had minimal impact on geographic misses. Conclusions: Bladder and rectal size changes at treatment affect prostate bed coverage, especially in the upper aspect of the prostate bed. The greatest potential for geographic miss occurred when either the bladder increased in size or when the rectum became smaller. Ensuring a full bladder and empty rectum at simulation will minimise this risk. Our data also support anisotropic PTV margins with larger margins superiorly than inferiorly

  6. let-7 Modulates Chromatin Configuration and Target Gene Repression through Regulation of the ARID3B Complex

    Directory of Open Access Journals (Sweden)

    Tsai-Tsen Liao

    2016-01-01

    Full Text Available Let-7 is crucial for both stem cell differentiation and tumor suppression. Here, we demonstrate a chromatin-dependent mechanism of let-7 in regulating target gene expression in cancer cells. Let-7 directly represses the expression of AT-rich interacting domain 3B (ARID3B, ARID3A, and importin-9. In the absence of let-7, importin-9 facilitates the nuclear import of ARID3A, which then forms a complex with ARID3B. The nuclear ARID3B complex recruits histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and promotes the transcription of stemness factors. Functionally, expression of ARID3B is critical for the tumor initiation in let-7-depleted cancer cells. An inverse association between let-7 and ARID3A/ARID3B and prognostic significance is demonstrated in head and neck cancer patients. These results highlight a chromatin-dependent mechanism where let-7 regulates cancer stemness through ARID3B.

  7. Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells

    Science.gov (United States)

    Drube, Sebastian; Beyer, Mandy; Rothe, Mandy; Rabenhorst, Anja; Göpfert, Christiane; Meininger, Isabel; Diamanti, Michaela A.; Stegner, David; Häfner, Norman; Böttcher, Martin; Reinecke, Kirstin; Herdegen, Thomas; Greten, Florian R.; Nieswandt, Bernhard; Hartmann, Karin; Krämer, Oliver H.; Kamradt, Thomas

    2015-01-01

    Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2+-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term “subthreshold IKK activation”. This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33. We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo. Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure. PMID:25749030

  8. Down-Regulation of Neuropathy Target Esterase in Preeclampsia Placenta Inhibits Human Trophoblast Cell Invasion via Modulating MMP-9 Levels

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    Ting Zhong

    2018-02-01

    Full Text Available Background/Aims: Neuropathy target esterase (NTE, also known as neurotoxic esterase is proven to deacylate phosphatidylcholine (PC to glycerophosphocholine as a phospholipase B. Recently; studies showed that artificial phosphatidylserine/PC microvesicles can induce preeclampsia (PE-like changes in pregnant mice. However, it is unclear whether NTE plays a key role in the pathology of PE, a pregnancy-related disease, which was characterized by deficient trophoblast invasion and reduced trophoblast-mediated remodeling of spiral arteries. The aim of this study was to investigate the expression pattern of NTE in the placenta from women with PE and normal pregnancy, and the molecular mechanism of NTE involved in the development of PE. Methods: NTE expression levels in placentas from 20 pregnant women with PE and 20 healthy pregnant women were detected using quantitative PCR and immunohistochemistry staining. The effect of NTE on trophoblast migration and invasion and the underlying mechanisms were examined in HTR-8/SVneo cell lines by transfection method. Results: NTE mRNA and protein expression levels were significantly decreased in preeclamptic placentas than normal control. Over-expression of NTE in HTR-8/SVneo cells significantly promoted trophoblast cells migration and invasion and was associated with increased MMP-9 levels. Conversely, shRNA-mediated down-regulation of NTE markedly inhibited the cell migration and invasion. In addition, silencing NTE reduced the MMP-9 activity and phosphorylated Erk1/2 and AKT levels. Conclusions: Our results suggest that the decreased NTE may contribute to the development of PE through impairing trophoblast invasion by down-regulating MMP-9 via the Erk1/2 and AKT signaling pathway.

  9. Mas-related G protein coupled receptor-X2: A potential new target for modulating mast cell-mediated allergic and inflammatory diseases.

    Science.gov (United States)

    Ali, Hydar

    2016-12-01

    Mast cells (MCs) are tissue resident immune cells that are best known for their roles in allergic and inflammatory diseases. In addition to the high affinity IgE receptor (FcεRI), MCs express numerous G protein coupled receptors (GPCRs), which are the most common targets of drug therapy. Neurokinin 1 receptor (NK-1R) is expressed on MCs and contributes to IgE and non-IgE-mediated responses in mice. Although NK-1R antagonists are highly effective in modulating experimental allergic and inflammatory responses in mice they lack efficacy in humans. This article reviews recent findings that demonstrate that while neuropeptides (NPs) activate murine MCs via NK-1R and Mas related G protein coupled receptor B2 (MrgprB2), they activate human MCs via Mas-related G protein coupled receptor X2 (MRGPRX2). Interestingly, conventional NK-1R antagonists have off-target activity against mouse MrgprB2 but not human MRGPRX2. These findings suggest that the failure to translate studies with NK-1R antagonists from in vivo mouse studies to the clinic likely reflects their lack of effect on human MRGPRX2. A unique feature of MRGPRX2 that distinguishes it from other GPCRs is that it is activated by a diverse group of ligands that include; neuropeptides, cysteine proteases, antimicrobial peptides and cationic proteins released from activated eosinophils. Thus, the development of small molecule MRGPRX2-specific antagonists or neutralizing antibodies may provide new targets for the treatment of MC-mediated allergic and inflammatory diseases.

  10. Planning magnetic resonance imaging for prostate cancer intensity-modulated radiation therapy: Impact on target volumes, radiotherapy dose and androgen deprivation administration.

    Science.gov (United States)

    Horsley, Patrick J; Aherne, Noel J; Edwards, Grace V; Benjamin, Linus C; Wilcox, Shea W; McLachlan, Craig S; Assareh, Hassan; Welshman, Richard; McKay, Michael J; Shakespeare, Thomas P

    2015-03-01

    Magnetic resonance imaging (MRI) scans are increasingly utilized for radiotherapy planning to contour the primary tumors of patients undergoing intensity-modulated radiation therapy (IMRT). These scans may also demonstrate cancer extent and may affect the treatment plan. We assessed the impact of planning MRI detection of extracapsular extension, seminal vesicle invasion, or adjacent organ invasion on the staging, target volume delineation, doses, and hormonal therapy of patients with prostate cancer undergoing IMRT. The records of 509 consecutive patients with planning MRI scans being treated with IMRT for prostate cancer between January 2010 and July 2012 were retrospectively reviewed. Tumor staging and treatment plans before and after MRI were compared. Of the 509 patients, 103 (20%) were upstaged and 44 (9%) were migrated to a higher risk category as a result of findings at MRI. In 94 of 509 patients (18%), the MRI findings altered management. Ninety-four of 509 patients (18%) had a change to their clinical target volume (CTV) or treatment technique, and in 41 of 509 patients (8%) the duration of hormone therapy was changed because of MRI findings. The use of radiotherapy planning MRI altered CTV design, dose and/or duration of androgen deprivation in 18% of patients in this large, single institution series of men planned for dose-escalated prostate IMRT. This has substantial implications for radiotherapy target volumes and doses, as well as duration of androgen deprivation. Further research is required to investigate whether newer MRI techniques can simultaneously fulfill staging and radiotherapy contouring roles. © 2014 Wiley Publishing Asia Pty Ltd.

  11. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity.

    Science.gov (United States)

    Monceau, Virginie; Pasinetti, Nadia; Schupp, Charlotte; Pouzoulet, Fred; Opolon, Paule; Vozenin, Marie-Catherine

    2010-11-01

    The medical options available to prevent or treat radiation-induced injury are scarce and developing effective countermeasures is still an open research field. In addition, more than half of cancer patients are treated with radiation therapy, which displays a high antitumor efficacy but can cause, albeit rarely, disabling long-term toxicities including radiation fibrosis. Progress has been made in the definition of molecular pathways associated with normal tissue toxicity that suggest potentially effective therapeutic targets. Targeting the Rho/ROCK pathway seems a promising anti-fibrotic approach, at least in the gut; the current study was performed to assess whether this target was relevant to the prevention and/or treatment of injury to the main thoracic organs, namely heart and lungs. First, we showed activation of two important fibrogenic pathways (Smad and Rho/ROCK) in response to radiation-exposure to adult cardiomyocytes; we extended these observations in vivo to the heart and lungs of mice, 15 and 30 weeks post-irradiation. We correlated this fibrogenic molecular imprint with alteration of heart physiology and long-term remodelling of pulmonary and cardiac histological structures. Lastly, cardiac and pulmonary radiation injury and bleomycin-induced pulmonary fibrosis were successfully modulated using Rho/ROCK inhibitors (statins and Y-27632) and this was associated with a normalization of fibrogenic markers. In conclusion, the present paper shows for the first time, activation of Rho/ROCK and Smad pathways in pulmonary and cardiac radiation-induced delayed injury. Our findings thereby reveal a safe and efficient therapeutic opportunity for the abrogation of late thoracic radiation injury, potentially usable either before or after radiation exposure; this approach is especially attractive in (1) the radiation oncology setting, as it does not interfere with prior anti-cancer treatment and in (2) radioprotection, as applicable to the treatment of established

  12. Modulation of the ρ/rock pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity

    International Nuclear Information System (INIS)

    Monceau, V.; Pasinetti, N.; Schupp, C.; Pouzoulet, F.; Opolon, P.; Vozenin, M.C.

    2010-01-01

    The medical options available to prevent or treat radiation-induced injury are scarce and developing effective countermeasures is still an open research field. In addition, more than half of cancer patients are treated with radiation therapy, which displays a high antitumor efficacy but can cause, albeit rarely, disabling long-term toxicities including radiation fibrosis. Progress has been made in the definition of molecular pathways associated with normal tissue toxicity that suggest potentially effective therapeutic targets. Targeting the Rho/ROCK pathway seems a promising anti-fibrotic approach, at least in the gut; the current study was performed to assess whether this target was relevant to the prevention and/or treatment of injury to the main thoracic organs, namely heart and lungs. First, we showed activation of two important fibro-genic pathways (Smad and Rho/ROCK) in response to radiation-exposure to adult cardio-myocytes; we extended these observations in vivo to the heart and lungs of mice, 15 and 30 weeks post-irradiation. We correlated this fibro-genic molecular imprint with alteration of heart physiology and long-term remodelling of pulmonary and cardiac histological structures. Lastly, cardiac and pulmonary radiation injury and bleomycin-induced pulmonary fibrosis were successfully modulated using Rho/ROCK inhibitors (statins and Y-27632) and this was associated with a normalization of fibro-genic markers. In conclusion, the present paper shows for the first time, activation of Rho/ROCK and Smad pathways in pulmonary and cardiac radiation-induced delayed injury. Our findings thereby reveal a safe and efficient therapeutic opportunity for the abrogation of late thoracic radiation injury, potentially usable either before or after radiation exposure; this approach is especially attractive in (1) the radiation oncology setting, as it does not interfere with prior anti-cancer treatment and in (2) radioprotection, as applicable to the treatment of

  13. A highly sensitive PVC membrane iodide electrode based on complexes of mercury(II) as neutral carrier.

    Science.gov (United States)

    Chai, Y-Q; Yuan, R; Xu, L; Xu, W-J; Dai, J-Y; Jiang, F

    2004-09-01

    A novel solvent polymeric membrane electrode based on bis(1,3,4-thiadiazole) complexes of Hg(II) is described which has excellent selectivity and sensitivity toward iodide ion. The electrode, containing 1,4-bis(5-methyl-1,3,4-thiadiazole-2-yl-thio)butanemercury(II) [Hg(II)BMTB(NO3)4], has a Nernstian potentiometric response from 2.0 x 10(-8) to 2.0 x 10(-2) mol L(-1) with a detection limit of 8.0 x 10(-9) mol L(-1) and a slope of -59.0+/-0.5 mV/decade in 0.01 mol L(-1) phosphate buffer solution (pH 3.0, 20 degrees C). The selectivity sequence observed is iodide>bromide>thiocyanate>nitrite>nitrate>chloride>perchlorate>acetate>sulfate. The selectivity behavior is discussed in terms of the UV-Vis spectrum, and the process of transfer of iodide across the membrane interface is investigated by use of the AC impedance technique. The electrode was successfully applied to the determination of iodide in Jialing River and Spring in Jinyun Mountains, with satisfactory results.

  14. Prostate Tumor Growth Can Be Modulated by Dietarily Targeting the 15-Lipoxygenase-1 and Cyclooxygenase-2 Enzymes

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    Uddhav P. Kelavkar

    2009-07-01

    Full Text Available The main objectives of our study were to determine the bioavailability of omega-3 (ω-3 to the tumor, to understand its mechanisms, and to determine the feasibility of targeting the ω-6 polyunsaturated fatty acids (PUFAs metabolizing 15-lipoxygenase-1 (15-LO-1 and cyclooxygenase-2 (COX-2 pathways. Nude mice injected subcutaneously with LAPC-4 prostate cancer cells were randomly divided into three different isocaloric (and same percent [%] of total fat diet groups: high ω-6 linoleic acid (LA, high ω-3 stearidonic acid (SDA PUFAs, and normal (control diets. Tumor growth and apoptosis were examined as end points after administration of short-term (5 weeks ω-3 and ω-6 fatty acid diets. Tumor tissue membranes were examined for growth, lipids, enzyme activities, apoptosis, and proliferation. Tumors from the LA diet-fed mice exhibited the most rapid growth compared with tumors from the control and SDA diet-fed mice. Moreover, a diet switch from LA to SDA caused a dramatic decrease in the growth of tumors in 5 weeks, whereas tumors grew more aggressively when mice were switched from an SDA to an LA diet. Evaluating tumor proliferation (Ki-67 and apoptosis (caspase-3 in mice fed the LA and SDA diets suggested increased percentage proliferation index from the ω-6 diet-fed mice compared with the tumors from the ω-3 SDA-fed mice. Further, increased apoptosis was observed in tumors from ω-3 SDA diet-fed mice versus tumors from ω-6 diet-fed mice. Levels of membrane phospholipids of red blood cells reflected dietary changes and correlated with the levels observed in tumors. Linoleic or arachidonic acid and metabolites (eicosanoid/prostaglandins were analyzed for 15-LO-1 and COX-2 activities by high-performance liquid chromatography. We also examined the percent unsaturated or saturated fatty acids in the total phospholipids, PUFA ω-6/ω-3 ratios, and other major enzymes (elongase, Delta [Δ]-5-desaturase, and Δ-6-desaturase of ω-6 catabolic

  15. A platform to screen for C-type lectin receptor-binding carbohydrates and their potential for cell-specific targeting and immune modulation.

    Science.gov (United States)

    Maglinao, Maha; Eriksson, Magdalena; Schlegel, Mark K; Zimmermann, Stephanie; Johannssen, Timo; Götze, Sebastian; Seeberger, Peter H; Lepenies, Bernd

    2014-02-10

    Myeloid C-type lectin receptors (CLRs) in innate immunity represent a superfamily of pattern recognition receptors that recognize carbohydrate structures on pathogens and self-antigens. The primary interaction of an antigen-presenting cell and a pathogen shapes the following immune response. Therefore, the identification of CLR ligands that can either enhance or modulate the immune response is of interest. We have developed a screening platform based on glycan arrays to identify immune modulatory carbohydrate ligands of CLRs. A comprehensive library of CLRs was expressed by fusing the extracellular part of each respective CLR, the part containing the carbohydrate-recognition domain (CRD), to the Fc fragment of human IgG1 molecules. CLR-Fc fusion proteins display the CRD in a dimeric form, are properly glycosylated, and can be detected by a secondary antibody with a conjugated fluorophore. Thus, they are valuable tools for high-throughput screening. We were able to identify novel carbohydrate binders of CLRs using the glycan array technology. These CLR-binding carbohydrates were then covalently attached to the model antigen ovalbumin. The ovalbumin neoglycoconjugates were used in a dendritic cell/T cell co-culture assay to stimulate transgenic T cells in vitro. In addition, mice were immunized with these conjugates to analyze the immune modulatory properties of the CLR ligands in vivo. The CLR ligands induced an increased Th1 cytokine production in vitro and modulated the humoral response in vivo. The platform described here allows for the identification of CLR ligands, as well as the evaluation of each ligand's cell-specific targeting and immune modulatory properties. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Eukaryotic initiation factor 2α--a downstream effector of mammalian target of rapamycin--modulates DNA repair and cancer response to treatment.

    Directory of Open Access Journals (Sweden)

    Liron Tuval-Kochen

    Full Text Available In an effort to circumvent resistance to rapamycin--an mTOR inhibitor--we searched for novel rapamycin-downstream-targets that may be key players in the response of cancer cells to therapy. We found that rapamycin, at nM concentrations, increased phosphorylation of eukaryotic initiation factor (eIF 2α in rapamycin-sensitive and estrogen-dependent MCF-7 cells, but had only a minimal effect on eIF2α phosphorylation in the rapamycin-insensitive triple-negative MDA-MB-231 cells. Addition of salubrinal--an inhibitor of eIF2α dephosphorylation--decreased expression of a surface marker associated with capacity for self renewal, increased senescence and induced clonogenic cell death, suggesting that excessive phosphorylation of eIF2α is detrimental to the cells' survival. Treating cells with salubrinal enhanced radiation-induced increase in eIF2α phosphorylation and clonogenic death and showed that irradiated cells are more sensitive to increased eIF2α phosphorylation than non-irradiated ones. Similar to salubrinal--the phosphomimetic eIF2α variant--S51D--increased sensitivity to radiation, and both abrogated radiation-induced increase in breast cancer type 1 susceptibility gene, thus implicating enhanced phosphorylation of eIF2α in modulation of DNA repair. Indeed, salubrinal inhibited non-homologous end joining as well as homologous recombination repair of double strand breaks that were induced by I-SceI in green fluorescent protein reporter plasmids. In addition to its effect on radiation, salubrinal enhanced eIF2α phosphorylation and clonogenic death in response to the histone deacetylase inhibitor--vorinostat. Finally, the catalytic competitive inhibitor of mTOR--Ku-0063794--increased phosphorylation of eIF2α demonstrating further the involvement of mTOR activity in modulating eIF2α phosphorylation. These experiments suggest that excessive phosphorylation of eIF2α decreases survival of cancer cells; making eIF2α a worthy target for

  17. The C-terminus of H-Ras as a target for the covalent binding of reactive compounds modulating Ras-dependent pathways.

    Directory of Open Access Journals (Sweden)

    Clara L Oeste

    2011-01-01

    Full Text Available Ras proteins are crucial players in differentiation and oncogenesis and constitute important drug targets. The localization and activity of Ras proteins are highly dependent on posttranslational modifications at their C-termini. In addition to an isoprenylated cysteine, H-Ras, but not other Ras proteins, possesses two cysteine residues (C181 and C184 in the C-terminal hypervariable domain that act as palmitoylation sites in cells. Cyclopentenone prostaglandins (cyPG are reactive lipidic mediators that covalently bind to H-Ras and activate H-Ras dependent pathways. Dienone cyPG, such as 15-deoxy-Δ(12,14-PGJ(2 (15d-PGJ(2 and Δ(12-PGJ(2 selectively bind to the H-Ras hypervariable domain. Here we show that these cyPG bind simultaneously C181 and C184 of H-Ras, thus potentially altering the conformational tendencies of the hypervariable domain. Based on these results, we have explored the capacity of several bifunctional cysteine reactive small molecules to bind to the hypervariable domain of H-Ras proteins. Interestingly, phenylarsine oxide (PAO, a widely used tyrosine phosphatase inhibitor, and dibromobimane, a cross-linking agent used for cysteine mapping, effectively bind H-Ras hypervariable domain. The interaction of PAO with H-Ras takes place in vitro and in cells and blocks modification of H-Ras by 15d-PGJ(2. Moreover, PAO treatment selectively alters H-Ras membrane partition and the pattern of H-Ras activation in cells, from the plasma membrane to endomembranes. These results identify H-Ras as a novel target for PAO. More importantly, these observations reveal that small molecules or reactive intermediates interacting with spatially vicinal cysteines induce intramolecular cross-linking of H-Ras C-terminus potentially contributing to the modulation of Ras-dependent pathways.

  18. Requirement for the Phospho-H2AX Binding Module of Crb2 in Double-Strand Break Targeting and Checkpoint Activation▿

    Science.gov (United States)

    Sanders, Steven L.; Arida, Ahmad R.; Phan, Funita P.

    2010-01-01

    Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability. PMID:20679488

  19. Requirement for the phospho-H2AX binding module of Crb2 in double-strand break targeting and checkpoint activation.

    Science.gov (United States)

    Sanders, Steven L; Arida, Ahmad R; Phan, Funita P

    2010-10-01

    Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability.

  20. Postoperative Intensity-Modulated Radiotherapy for Squamous Cell Carcinoma of the External Auditory Canal and Middle Ear: Treatment Outcomes, Marginal Misses, and Perspective on Target Delineation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Wan-Yu [Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Kuo, Sung-Hsin [Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan (China); Chen, Yu-Hsuan; Lu, Szu-Huai; Tsai, Chiao-Ling [Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Chia-Hsien Cheng, Jason [Division of Radiation Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan (China); Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan (China); Hong, Ruey-Long [Division of Medical Oncology, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan (China); Chen, Ya-Fang [Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan (China); Hsu, Chuan-Jen; Lin, Kai-Nan; Ko, Jenq-Yuh; Lou, Pei-Jen; Wang, Cheng-Ping [Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan (China); Chong, Fok-Ching [Graduate Institute of Electrical Engineering, National Taiwan University, Taipei, Taiwan (China); Wang, Chun-Wei, E-mail: cwwang@ntuh.gov.tw [Graduate Institute of Electrical Engineering, National Taiwan University, Taipei, Taiwan (China)

    2012-03-15

    Purpose: To report outcomes of the rare disease of squamous cell carcinoma (SCC) of the external auditory canal (EAC) and middle ear treated with surgery and postoperative intensity-modulated radiotherapy (IMRT). Failure patterns related to spatial dose distribution were also analyzed to provide insight into target delineation. Methods and Materials: A retrospective review was conducted of the records of 11 consecutive patients with SCC of the EAC and middle ear who were treated with curative surgery and postoperative IMRT at one institution between January 2007 and February 2010. The prescribed IMRT dose was 60 to 66 Gy at 2 Gy per fraction. Three patients also received concurrent cisplatin-based chemotherapy, and 1 patient received concurrent oral tegafur/uracil. The median follow-up time was 19 months (range, 6-33 months). Results: Four patients had locoregional recurrence, yielding an estimated 2-year locoregional control rate of 70.7%. Among them, 1 patient had persistent disease after treatment, and 3 had marginal recurrence. Distant metastasis occurred in 1 patient after extensive locoregional recurrence, yielding an estimated 2-year distant control rate of 85.7%. The estimated 2-year overall survival was 67.5%. The three cases of marginal recurrence were near the preauricular space and glenoid fossa of the temporomandibular joint, adjacent to the apex of the ear canal and glenoid fossa of the temporomandibular joint, and in the postauricular subcutaneous area and ipsilateral parotid nodes, respectively. Conclusions: Marginal misses should be recognized to improve target delineation. When treating SCC of the EAC and middle ear, care should be taken to cover the glenoid fossa of the temporomandibular joint and periauricular soft tissue. Elective ipsilateral parotid irradiation should be considered. The treatment planning procedure should also be refined to balance subcutaneous soft-tissue dosimetry and toxicity.

  1. Postoperative Intensity-Modulated Radiotherapy for Squamous Cell Carcinoma of the External Auditory Canal and Middle Ear: Treatment Outcomes, Marginal Misses, and Perspective on Target Delineation

    International Nuclear Information System (INIS)

    Chen, Wan-Yu; Kuo, Sung-Hsin; Chen, Yu-Hsuan; Lu, Szu-Huai; Tsai, Chiao-Ling; Chia-Hsien Cheng, Jason; Hong, Ruey-Long; Chen, Ya-Fang; Hsu, Chuan-Jen; Lin, Kai-Nan; Ko, Jenq-Yuh; Lou, Pei-Jen; Wang, Cheng-Ping; Chong, Fok-Ching; Wang, Chun-Wei

    2012-01-01

    Purpose: To report outcomes of the rare disease of squamous cell carcinoma (SCC) of the external auditory canal (EAC) and middle ear treated with surgery and postoperative intensity-modulated radiotherapy (IMRT). Failure patterns related to spatial dose distribution were also analyzed to provide insight into target delineation. Methods and Materials: A retrospective review was conducted of the records of 11 consecutive patients with SCC of the EAC and middle ear who were treated with curative surgery and postoperative IMRT at one institution between January 2007 and February 2010. The prescribed IMRT dose was 60 to 66 Gy at 2 Gy per fraction. Three patients also received concurrent cisplatin-based chemotherapy, and 1 patient received concurrent oral tegafur/uracil. The median follow-up time was 19 months (range, 6–33 months). Results: Four patients had locoregional recurrence, yielding an estimated 2-year locoregional control rate of 70.7%. Among them, 1 patient had persistent disease after treatment, and 3 had marginal recurrence. Distant metastasis occurred in 1 patient after extensive locoregional recurrence, yielding an estimated 2-year distant control rate of 85.7%. The estimated 2-year overall survival was 67.5%. The three cases of marginal recurrence were near the preauricular space and glenoid fossa of the temporomandibular joint, adjacent to the apex of the ear canal and glenoid fossa of the temporomandibular joint, and in the postauricular subcutaneous area and ipsilateral parotid nodes, respectively. Conclusions: Marginal misses should be recognized to improve target delineation. When treating SCC of the EAC and middle ear, care should be taken to cover the glenoid fossa of the temporomandibular joint and periauricular soft tissue. Elective ipsilateral parotid irradiation should be considered. The treatment planning procedure should also be refined to balance subcutaneous soft-tissue dosimetry and toxicity.

  2. Expression of trypsin modulating oostatic factor (TMOF in an entomopathogenic fungus increases its virulence towards Anopheles gambiae and reduces fecundity in the target mosquito

    Directory of Open Access Journals (Sweden)

    Kamareddine Layla

    2013-01-01

    Full Text Available Abstract Background Adult and larval mosquitoes regulate food digestion in their gut with trypsin modulating oostatic factor (TMOF, a decapeptide hormone synthesized by the ovaries and the neuroendocrine system. TMOF is currently being developed as a mosquitocide, however, delivery of the peptide to the mosquito remains a significant challenge. Entomopathogenic fungi offer a means for targeting mosquitoes with TMOF. Findings The efficacy of wild type and transgenic Beauveria bassiana strains expressing Aedes aegypti TMOF (Bb-Aa1 were evaluated against larvae and sugar- and blood-fed adult Anopheles gambiae mosquitoes using insect bioassays. Bb-Aa1 displayed increased virulence against larvae, and sugar and blood fed adult A. gambiae when compared to the wild type parent strain. Median lethal dose (LD50 values decreased by ~20% for larvae, and ~40% for both sugar and blood-fed mosquitoes using Bb-Aa1 relative to the wild type parent. Median lethal time (LT50 values were lower for blood-fed compared to sugar-fed mosquitoes in infections with both wild type and Bb-Aa1. However, infection using Bb-Aa1 resulted in 15% to 25% reduction in LT50 values for sugar- and blood fed mosquitoes, and ~27% for larvae, respectively, relative to the wild type parent. In addition, infection with Bb-Aa1 resulted in a dramatic reduction in fecundity of the target mosquitoes. Conclusions B. bassiana expressing Ae. aegypti TMOF exhibited increased virulence against A. gambiae compared to the wild type strain. These data expand the range and utility of entomopathogenic fungi expressing mosquito-specific molecules to improve their biological control activities against mosquito vectors of disease.

  3. Highly selective direct determination of chlorate ions by using a newly developed potentiometric electrode based on modified smectite.

    Science.gov (United States)

    Topcu, Cihan

    2016-12-01

    A novel polyvinyl chloride membrane chlorate (ClO 3 - ) selective electrode based on modified smectite was developed for the direct determination of chlorate ions and the potentiometric performance characteristics of its were examined. The best selectivity and sensitivity for chlorate ions were obtained for the electrode membrane containing ionophore/polyvinylchloride/o-nitrophenyloctylether in composition of 12/28/60 (w/w%). The proposed electrode showed a Nernstian response toward chlorate ions at pH=7 in the concentration range of 1×10 -7 -1×10 -1 M and the limit of detection was calculated as 9×10 -8 M from the constructed response plot. The linear slope of the electrode was -61±1mVdecade -1 for chlorate activity in the mentioned linear working range. The selectivity coefficients were calculated according to both the matched potential method and the separate solution method. The calculated selectivity coefficients showed that the electrode performed excellent selectivity for chlorate ions. The potentiometric response of electrode toward chlorate ions was found to be highly reproducible. The electrode potential was stable between pH=4-10 and it had a dynamic response time of <5s. The potentiometric behavior of the electrode in partial non-aqueous medium was also investigated and the obtained results (up to 5% (v/v) alcohol) were satisfactory. The proposed electrode was used during 15 weeks without any significant change in its potential response. Additionally, the electrode was very useful in water analysis studies such as dam water, river water, tap water, and swimming pool water where the direct determination of chlorate ions was required. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. A comprehensive survey of 3' animal miRNA modification events and a possible role for 3' adenylation in modulating miRNA targeting effectiveness.

    Science.gov (United States)

    Burroughs, A Maxwell; Ando, Yoshinari; de Hoon, Michiel J L; Tomaru, Yasuhiro; Nishibu, Takahiro; Ukekawa, Ryo; Funakoshi, Taku; Kurokawa, Tsutomu; Suzuki, Harukazu; Hayashizaki, Yoshihide; Daub, Carsten O

    2010-10-01

    Animal microRNA sequences are subject to 3' nucleotide addition. Through detailed analysis of deep-sequenced short RNA data sets, we show adenylation and uridylation of miRNA is globally present and conserved across Drosophila and vertebrates. To better understand 3' adenylation function, we deep-sequenced RNA after knockdown of nucleotidyltransferase enzymes. The PAPD4 nucleotidyltransferase adenylates a wide range of miRNA loci, but adenylation does not appear to affect miRNA stability on a genome-wide scale. Adenine addition appears to reduce effectiveness of miRNA targeting of mRNA transcripts while deep-sequencing of RNA bound to immunoprecipitated Argonaute (AGO) subfamily proteins EIF2C1-EIF2C3 revealed substantial reduction of adenine addition in miRNA associated with EIF2C2 and EIF2C3. Our findings show 3' addition events are widespread and conserved across animals, PAPD4 is a primary miRNA adenylating enzyme, and suggest a role for 3' adenine addition in modulating miRNA effectiveness, possibly through interfering with incorporation into the RNA-induced silencing complex (RISC), a regulatory role that would complement the role of miRNA uridylation in blocking DICER1 uptake.

  5. A comprehensive survey of 3′ animal miRNA modification events and a possible role for 3′ adenylation in modulating miRNA targeting effectiveness

    Science.gov (United States)

    Burroughs, A. Maxwell; Ando, Yoshinari; de Hoon, Michiel J.L.; Tomaru, Yasuhiro; Nishibu, Takahiro; Ukekawa, Ryo; Funakoshi, Taku; Kurokawa, Tsutomu; Suzuki, Harukazu; Hayashizaki, Yoshihide; Daub, Carsten O.

    2010-01-01

    Animal microRNA sequences are subject to 3′ nucleotide addition. Through detailed analysis of deep-sequenced short RNA data sets, we show adenylation and uridylation of miRNA is globally present and conserved across Drosophila and vertebrates. To better understand 3′ adenylation function, we deep-sequenced RNA after knockdown of nucleotidyltransferase enzymes. The PAPD4 nucleotidyltransferase adenylates a wide range of miRNA loci, but adenylation does not appear to affect miRNA stability on a genome-wide scale. Adenine addition appears to reduce effectiveness of miRNA targeting of mRNA transcripts while deep-sequencing of RNA bound to immunoprecipitated Argonaute (AGO) subfamily proteins EIF2C1–EIF2C3 revealed substantial reduction of adenine addition in miRNA associated with EIF2C2 and EIF2C3. Our findings show 3′ addition events are widespread and conserved across animals, PAPD4 is a primary miRNA adenylating enzyme, and suggest a role for 3′ adenine addition in modulating miRNA effectiveness, possibly through interfering with incorporation into the RNA-induced silencing complex (RISC), a regulatory role that would complement the role of miRNA uridylation in blocking DICER1 uptake. PMID:20719920

  6. Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice

    Science.gov (United States)

    Durieux, Alice M. S.; Fernandes, Cathy; Murphy, Declan; Labouesse, Marie Anais; Giovanoli, Sandra; Meyer, Urs; Li, Qi; So, Po-Wah; McAlonan, Grainne

    2015-01-01

    An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span. PMID:26696857

  7. Analysis of Maneuvering Targets with Complex Motions by Two-Dimensional Product Modified Lv’s Distribution for Quadratic Frequency Modulation Signals

    Directory of Open Access Journals (Sweden)

    Fulong Jing

    2017-06-01

    Full Text Available For targets with complex motion, such as ships fluctuating with oceanic waves and high maneuvering airplanes, azimuth echo signals can be modeled as multicomponent quadratic frequency modulation (QFM signals after migration compensation and phase adjustment. For the QFM signal model, the chirp rate (CR and the quadratic chirp rate (QCR are two important physical quantities, which need to be estimated. For multicomponent QFM signals, the cross terms create a challenge for detection, which needs to be addressed. In this paper, by employing a novel multi-scale parametric symmetric self-correlation function (PSSF and modified scaled Fourier transform (mSFT, an effective parameter estimation algorithm is proposed—referred to as the Two-Dimensional product modified Lv’s distribution (2D-PMLVD—for QFM signals. The 2D-PMLVD is simple and can be easily implemented by using fast Fourier transform (FFT and complex multiplication. These measures are analyzed in the paper, including the principle, the cross term, anti-noise performance, and computational complexity. Compared to the other three representative methods, the 2D-PMLVD can achieve better anti-noise performance. The 2D-PMLVD, which is free of searching and has no identifiability problems, is more suitable for multicomponent situations. Through several simulations and analyses, the effectiveness of the proposed estimation algorithm is verified.

  8. MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Prakash Radhakrishnan

    Full Text Available Transmembrane mucins, MUC4 and MUC16 are associated with tumor progression and metastatic potential in human pancreatic adenocarcinoma. We discovered that miR-200c interacts with specific sequences within the coding sequence of MUC4 and MUC16 mRNAs, and evaluated the regulatory nature of this association. Pancreatic cancer cell lines S2.028 and T3M-4 transfected with miR-200c showed a 4.18 and 8.50 fold down regulation of MUC4 mRNA, and 4.68 and 4.82 fold down regulation of MUC16 mRNA compared to mock-transfected cells, respectively. A significant reduction of glycoprotein expression was also observed. These results indicate that miR-200c overexpression regulates MUC4 and MUC16 mucins in pancreatic cancer cells by directly targeting the mRNA coding sequence of each, resulting in reduced levels of MUC4 and MUC16 mRNA and protein. These data suggest that, in addition to regulating proteins that modulate EMT, miR-200c influences expression of cell surface mucins in pancreatic cancer.

  9. Targeting glia with N-Acetylcysteine modulates brain glutamate and behaviours relevant to neurodevelopmental disorders in C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Alice Marie Sybille Durieux

    2015-12-01

    Full Text Available An imbalance between excitatory (E glutamate and inhibitory (I GABA transmission may underlie neurodevelopmental conditions such as Autism Spectrum Disorder (ASD and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC, which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in-vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviours relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span.

  10. Feasibility of omitting clinical target volume for limited-disease small cell lung cancer treated with chemotherapy and intensity-modulated radiotherapy

    International Nuclear Information System (INIS)

    Cai, Shuhua; Shi, Anhui; Yu, Rong; Zhu, Guangying

    2014-01-01

    To analyze the feasibility of omitting clinical target volume (CTV) for limited small cell lung cancer treated with chemotherapy and intensity modulated radiotherapy. 89 patients were treated from January 1, 2008 to August 31, 2011, 54 cases were irradiated with target volume without CTV, and 35 cases were irradiated with CTV. Both arms were irradiated post chemotherapy tumor extent and omitted elective nodal irradiation; dose prescription was 95% PTV56-63 Gy/28-35 F/5.6-7 weeks. In the arm without CTV and arm with CTV, the local relapse rates were 16.7% and 17.1% (p = 0.586) respectively. In the arm without CTV, of the 9 patients with local relapse, 6 recurred in-field, 2 recurred in margin, 1 recurred out of field. In the arm with CTV, of the 6 patients with local relapse, 4 recurred in-field, 1 recurred in margin, 1 recurred out of field. The distant metastases rates were 42.6% and 51.4% (p = 0.274) respectively. Grade 3-4 hematological toxicity and radiation esophagitis had no statistically significant, but grade 3-4 radiation pneumonia was observed in only 7.4% in the arm without CTV, compared 22.9% in the arm with CTV (p = 0.040). The median survival in the arm without CTV had not reached, compared with 38 months in the with CTV arm. The l- years, 2- years, 3- years survival rates of the arm without CTV and the arm with CTV were 81.0%, 66.2%, 61.5% and 88.6%, 61.7%, 56.6% (p = 0.517). The multivariate analysis indicated that the distant metastases (p = 0.000) and PCI factor (p = 0.004) were significantly related to overall survival. Target delineation omitting CTV for limited-disease small cell lung cancer received IMRT was feasible. The distant metastases and PCI factor were significantly related to overall survival

  11. A Study of volumetric modulated arc therapy for stereotactic body radiation therapy in case of multi-target liver cancer using flattening filter free beam

    International Nuclear Information System (INIS)

    Yeom, Mi Sook; Yoon, In Ha; Hong, Dong Gi; Back, Geum Mun

    2015-01-01

    Stereotactic body radiation therapy (SBRT) has proved its efficacy in several patient populations with primary and metastatic limited tumors. Because SBRT prescription is high dose level than Conventional radiation therapy. SBRT plan is necessary for effective Organ at risk (OAR) protection and sufficient Planning target volume (PTV) dose coverage. In particular, multi-target cases may result excessive doses to OAR and hot spot due to dose overlap. This study evaluate usefulness of Volumetric modulated arc therapy (VMAT) in dosimetric and technical considerations using Flattening filter free (FFF) beam. The treatment plans for five patients, being treated on TrueBeam STx(Varian™, USA) with VMAT using 10MV FFF beam and Standard conformal radiotherapy (CRT) using 15MV Flattening filter (FF) beam. PTV, liver, duodenum, bowel, spinal cord, esophagus, stomach dose were evaluated using the dose volume histogram(DVH). Conformity index(CI), homogeneity index(HI), Paddick's index(PCI) for the PTV was assessed. Total Monitor unit (MU) and beam on time was assessed. Average value of CI, HI and PCI for PTV was 1.381±0.028, 1.096±0.016, 0.944±0.473 in VMAT and 1.381± 0.042, 1.136±0.042, 1.534±0.465 in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT. VMAT for SBRT in multi-target liver cancer using FFF beam is effective treatment techniqe in dosimetric and technical considerations. VMAT decrease intra-fraction error due to treatment time shortening using high dose rate of FFF beam

  12. MiR-137 inhibited cell proliferation and migration of vascular smooth muscle cells via targeting IGFBP-5 and modulating the mTOR/STAT3 signaling.

    Directory of Open Access Journals (Sweden)

    Jin Pan

    Full Text Available Abnormal proliferation of vascular smooth muscle cells (VSMCs contributes to the development of cardiovascular diseases. Studies have shown the great impact of microRNAs (miRNAs on the cell proliferation of VSMCs. This study examined the effects of miR-137 on the cell proliferation and migration of VSMCs and also explored the underlying molecular mechanisms. The mRNA and protein expression levels were determined by qRT-PCR and western blot assays, respectively. The CCK-8 assay, wound healing assay and transwell migration assay were performed to measure cell proliferation and migration of VSMCs. The miR-137-targeted 3'untranslated region of insulin-like growth factor-binding protein-5 (IGFBP-5 was confirmed by luciferase reporter assay. Platelet-derived growth factor-bb (PDGF-bb treatment enhanced cell proliferation and suppressed the expression of miR-137 in VSMCs. The gain-of-function and loss-of-function assays showed that overexpression of miR-137 suppressed the cell proliferation and migration, and also inhibited the expression of matrix genes of VSMCs; down-regulation of miR-137 had the opposite effects on VSMCs. Bioinformatics analysis and luciferase report assay results showed that IGFBP-5 was a direct target of miR-137, and miR-137 overexpression suppressed the IGFBP-5 expression and down-regulation of miR-137 increased the IGFBP-5 expression in VSMCs. PDGF-bb treatment also increased the IGFBP-5 mRNA expression. In addition, enforced expression of IGFBP-5 reversed the inhibitory effects of miR-137 on cell proliferation and migration of VSMCs. More importantly, overexpression of miR-137 also suppressed the activity of mTOR/STAT3 signaling in VSMCs. Taken together, the results suggest that miR-137 may suppress cell proliferation and migration of VSMCs via targeting IGFBP-5 and modulating mTOR/STAT3 signaling pathway.

  13. miR-145-dependent targeting of junctional adhesion molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness.

    Science.gov (United States)

    Götte, M; Mohr, C; Koo, C-Y; Stock, C; Vaske, A-K; Viola, M; Ibrahim, S A; Peddibhotla, S; Teng, Y H-F; Low, J-Y; Ebnet, K; Kiesel, L; Yip, G W

    2010-12-16

    Micro RNAs are small non-coding RNAs, which regulate fundamental cellular and developmental processes at the transcriptional and translational level. In breast cancer, miR-145 expression is downregulated compared with healthy control tissue. As several predicted targets of miR-145 potentially regulate cell motility, we aimed at investigating a potential role for miR-145 in breast cancer cell motility and invasiveness. Assisted by Affymetrix array technology, we demonstrate that overexpression of miR-145 in MDA-MB-231, MCF-7, MDA-MB-468 and SK-BR-3 breast cancer cells and in Ishikawa endometrial carcinoma cells leads to a downregulation of the cell-cell adhesion protein JAM-A and of the actin bundling protein fascin. Moreover, podocalyxin and Serpin E1 mRNA levels were downregulated, and gamma-actin, transgelin and MYL9 were upregulated upon miR-145 overexpression. These miR-145-dependent expression changes drastically decreased cancer cell motility, as revealed by time-lapse video microscopy, scratch wound closure assays and matrigel invasion assays. Immunofluorescence microscopy demonstrated restructuring of the actin cytoskeleton and a change in cell morphology by miR-145 overexpression, resulting in a more cortical actin distribution, and reduced actin stress fiber and filopodia formation. Nuclear rotation was observed in 10% of the pre-miR-145 transfected MDA-MB-231 cells, accompanied by a reduction of perinuclear actin. Luciferase activation assays confirmed direct miR-145-dependent regulation of the 3'UTR of JAM-A, whereas siRNA-mediated knockdown of JAM-A expression resulted in decreased motility and invasiveness of MDA-MB-231 and MCF-7 breast cancer cells. Our data identify JAM-A and fascin as novel targets of miR-145, firmly establishing a role for miR-145 in modulating breast cancer cell motility. Our data provide a rationale for future miR-145-targeted approaches of antimetastatic cancer therapy.

  14. A Study of volumetric modulated arc therapy for stereotactic body radiation therapy in case of multi-target liver cancer using flattening filter free beam

    Energy Technology Data Exchange (ETDEWEB)

    Yeom, Mi Sook; Yoon, In Ha; Hong, Dong Gi; Back, Geum Mun [Dept. of Radiation Oncology, ASAN Medical Center, Seoul (Korea, Republic of)

    2015-06-15

    Stereotactic body radiation therapy (SBRT) has proved its efficacy in several patient populations with primary and metastatic limited tumors. Because SBRT prescription is high dose level than Conventional radiation therapy. SBRT plan is necessary for effective Organ at risk (OAR) protection and sufficient Planning target volume (PTV) dose coverage. In particular, multi-target cases may result excessive doses to OAR and hot spot due to dose overlap. This study evaluate usefulness of Volumetric modulated arc therapy (VMAT) in dosimetric and technical considerations using Flattening filter free (FFF) beam. The treatment plans for five patients, being treated on TrueBeam STx(Varian™, USA) with VMAT using 10MV FFF beam and Standard conformal radiotherapy (CRT) using 15MV Flattening filter (FF) beam. PTV, liver, duodenum, bowel, spinal cord, esophagus, stomach dose were evaluated using the dose volume histogram(DVH). Conformity index(CI), homogeneity index(HI), Paddick's index(PCI) for the PTV was assessed. Total Monitor unit (MU) and beam on time was assessed. Average value of CI, HI and PCI for PTV was 1.381±0.028, 1.096±0.016, 0.944±0.473 in VMAT and 1.381± 0.042, 1.136±0.042, 1.534±0.465 in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT respectively. OAR dose in CRT plans evaluated 1.8 times higher than VMAT. Total MU in VMAT evaluated 1.3 times increase than CRT. Average beam on time was 6.8 minute in VMAT and 21.3 minute in CRT. VMAT for SBRT in multi-target liver cancer using FFF beam is effective treatment techniqe in dosimetric and technical considerations. VMAT decrease intra-fraction error due to treatment time shortening using high dose rate of FFF beam.

  15. Large planning target volume in whole abdomen radiation therapy in ovarian cancers - a comparison between volumetric arc and fixed beam based intensity modulation in ovarian cancers: a comparison between volumetric arc and fixed beam based intensity modulation

    International Nuclear Information System (INIS)

    Krishnan, Jayapalan; Rao, Suresh; Hedge, Sanath; Shambhavi

    2013-01-01

    Aim of this study is to assess dosimetric characteristics of multiple iso-centre volumetric-modulated arc therapy for the treatment of a large PTV in whole abdomen and ovarian cancers and in comparison with IMRT. Two patients with Epithelial Ovarian Cancer (EOC) underwent CT-simulation in supine position with vacuum cushion and acquired CT-image with 3 mm slice thickness. IMRT and VMAT plans were generated with multiple isocenter using Eclipse Planning System (V10.0.39) for (6 MV photon) Varian UNIQUE Performance Linac equipped with a Millennium-120 MLC and optimised with Progressive Resolution optimizer (PRO3) for prescription 36 Gy to the whole abdomen (PTV W AR) and 45 Gy with daily fraction of 1.8 Gy to the pelvis and pelvic nodes (PTV P elvis) with Simultaneous Integrated Boost and calculated with AAA algorithm in 2.5 mm grid resolution. Mean, V 95% , V 90% , V 107% and uniformity number (Uniformity was defined as US-95%=D5%-D95%/D mean ) was calculated for Planning Target Volumes (PTVs). Organs at Risk (OAR's) were analysed statistically in terms of dose and volume. MU and delivery time were compared. Pre-treatment quality assurance was scored with Gamma Agreement Index (GAl) with 3% and 3 mm thresholds with EPID as well as corresponding Dynalog files were generated and analysed. Feasibility and deliverability of VMAT plans showed to be a solution for the treatment planning and delivery for a large PTV volume (PTV-WAR) treatments, surrounded by critical structures such as liver, spinal canal, and kidneys, offering good dosimetric features with significant logistic improvements compared to IMRT. VMAT combines the advantages of faster delivery and lower number of monitor units (MU). It would help to reduce potential risk of secondary malignancy. VMAT(RapidArc) showed to be a solution to WAR treatments offering good dosimetric features with significant logistic improvements compared to IMRT

  16. Simple and rapid mercury ion selective electrode based on 1-undecanethiol assembled Au substrate and its recognition mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xian-Qing; Liang, Hai-Qing [Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410114 (China); Cao, Zhong, E-mail: zhongcao2004@163.com [Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410114 (China); Xiao, Qing [Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410114 (China); Xiao, Zhong-Liang, E-mail: xiaozhongliang@163.com [Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410114 (China); State Key Laboratory of High Performance Complex Manufacturing, School of Mechanical and Electrical Engineering, Central South University, Changsha 410083 (China); Song, Liu-Bin [Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of Chemistry and Biological Engineering, Changsha University of Science and Technology, Changsha 410114 (China); Chen, Dan [Hunan Airbluer Environmental Protection Technology Co., Ltd., Changsha 410014 (China); Wang, Fu-Liang [State Key Laboratory of High Performance Complex Manufacturing, School of Mechanical and Electrical Engineering, Central South University, Changsha 410083 (China)

    2017-03-01

    A simple and rapid mercury ion selective electrode based on 1-undecanethiol (1-UDT) assembled Au substrate (Au/1-UDT) has been well constructed. 1-UDT was for the purpose of generating self-assembled monolayer on gold surface to recognize Hg{sup 2+} in aqueous solution, which had a working concentration range of 1.0 × 10{sup −} {sup 8}–1.0 × 10{sup −4} mol L{sup −1}, with a Nernst response slope of 28.83 ± 0.4 mV/-pC, a detection limit of 4.5 × 10{sup −9} mol L{sup −1}, and a good selectivity over the other tested cations. Also, the Au/1-UDT possessed good reproducibility, stability, and short response time. The recovery obtained for the determination of mercury ion in practical tremella samples was in the range of 99.8–103.4%. Combined electrochemical analysis and X-ray photoelectron spectroscopy (XPS) with quantum chemical computation, the probable recognition mechanism of the electrode for selective recognition of Hg{sup 2+} has been investigated. The covalent bond formed between mercury and sulfur is stronger than the one between gold and sulfur and thus prevents the adsorption of 1-UDT molecules on the gold surface. The quantum chemical computation with density functional theory further demonstrates that the strong interaction between the mercury atom and the sulfur atom on the gold surface leads to the gold sulfur bond ruptured and the gold mercury metallophilic interaction. - Highlights: • A simple and rapid mercury ion selective electrode has been well constructed. • The Au/1-UDT electrode for sensing Hg{sup 2+} has a sensitivity of 28.83 ± 0.4 mV/− pC. • The ISE method has a detection limit of Hg{sup 2+} down to 4.5 × 10{sup −9} mol L{sup −1}. • A mechanism with density functional theory for recognition of Hg{sup 2+} is developed. • The quantum chemical computation demonstrates Au-Hg metallophilic interaction.

  17. A sensitive determination of terbutaline in pharmaceuticals and urine samples using a composite electrode based on zirconium oxide nanoparticles

    International Nuclear Information System (INIS)

    Baytak, Aysegul Kutluay; Teker, Tugce; Duzmen, Sehriban; Aslanoglu, Mehmet

    2016-01-01

    An accurate and precise determination of terbutaline has been carried out using a glassy carbon electrode (GCE) modified with a composite of multi-walled carbon nanotubes (MWCNTs) and nanoparticles of zirconium oxide (ZrO_2NPs). Energy dispersive X-ray and scanning electron microscopic techniques were utilized for the characterization of the composite layer. Terbutaline exhibited a broad oxidation peak at 770 mV on a GCE. However, MWCNTs/GCE presented an electrocatalytic effect toward the oxidation of terbutaline with a better anodic peak at 660 mV. Furthermore, the electrochemical behavior of terbutaline has greatly been improved at a GCE modified with a composite of MWCNTs and nanoparticles of ZrO_2. The ZrO_2NPs/MWCNTs/GCE exhibited a sharp anodic wave at 645 mV with a large enhancement of the current response for terbutaline. Square wave voltammetry (SWV) was performed for the determination of terbutaline at ZrO_2NPs/MWCNTs/GCE. A linear plot was obtained for the current responses of terbutaline against concentrations in the range of 10–160 nM yielding a detection limit of 2.25 nM (based on 3S_b/m). Improved voltammetric behavior, long-time stability and good reproducibility were obtained for terbutaline at the proposed electrode. A mean recovery of 101.2% with an RSD% of 1.9 was obtained for the analysis of the drug formulation. The accurate and precise quantification of terbutaline makes the ZrO_2NPs/MWCNTs/GCE system of great interest for monitoring its therapeutic use. - Graphical abstract: A sensitive determination of terbutaline in pharmaceuticals and urine samples using a composite electrode based on zirconium oxide nanoparticles. Display Omitted - Highlights: • A composite electrode was prepared using nanoparticles of ZrO_2 and MWCNTs. • The ZrO_2NPs/MWCNTs/GCE has greatly improved the voltammetry of terbutaline • The proposed electrode enabled a detection limit of 2.25 nM. • The proposed electrode exhibited good reproducibility and long

  18. Boswellic acid suppresses growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model through modulation of multiple targets.

    Directory of Open Access Journals (Sweden)

    Byoungduck Park

    Full Text Available Pancreatic cancer (PaCa is one of the most lethal cancers, with an estimated 5-year survival of <5% even when patients are given the best treatment available. In addition, these treatments are often toxic and expensive, thus new agents which are safe, affordable and effective are urgently needed. We describe here the results of our study with acetyl-11-keto-β-boswellic acid (AKBA, an agent obtained from an Ayurvedic medicine, gum resin of Boswellia serrata. Whether AKBA has an activity against human PaCa, was examined in in vitro models and in an orthotopic nude mouse model of PaCa. We found that AKBA inhibited the proliferation of four different PaCa cell lines (AsPC-1, PANC-28, and MIA PaCa-2 with K-Ras and p53 mutations, and BxPC-3 with wild-type K-Ras and p53 mutation. These effects correlated with an inhibition of constitutively active NF-κB and suppression of NF-κB regulating gene expression. AKBA also induced apoptosis, and sensitized the cells to apoptotic effects of gemcitabine. In the orthotopic nude mouse model of PaCa, p.o. administration of AKBA alone (100 mg/kg significantly inhibited the tumor growth; this activity was enhanced by gemcitabine. In addition, AKBA inhibited the metastasis of the PaCa to spleen, liver, and lungs. This correlated with decreases in Ki-67, a biomarker of proliferation, and CD31, a biomarker of microvessel density, in the tumor tissue. AKBA produced significant decreases in the expression of NF-κB regulating genes in the tissues. Immunohistochemical analysis also showed AKBA downregulated the expression of COX-2, MMP-9, CXCR4, and VEGF in the tissues. Overall these results demonstrate that AKBA can suppress the growth and metastasis of human pancreatic tumors in an orthotopic nude mouse model that correlates with modulation of multiple targets.

  19. A predictive model to guide management of the overlap region between target volume and organs at risk in prostate cancer volumetric modulated arc therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mattes, Malcolm D.; Lee, Jennifer C.; Einaiem, Sara; Guirguis, Adel; Ikoro, N. C.; Ashamalla Hani [Dept. of Radiation Oncology, New York Methodist Hospital, Brooklyn (United States)

    2013-12-15

    The goal of this study is to determine whether the magnitude of overlap between planning target volume (PTV) and rectum (Rectum{sub overlap}) or PTV and bladder (Bladder{sub overlap}) in prostate cancer volumetric-modulated arc therapy (VMAT) is predictive of the dose-volume relationships achieved after optimization, and to identify predictive equations and cutoff values using these overlap volumes beyond which the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) dose-volume constraints are unlikely to be met. Fifty-seven patients with prostate cancer underwent VMAT planning using identical optimization conditions and normalization. The PTV (for the 50.4 Gy primary plan and 30.6 Gy boost plan) included 5 to 10 mm margins around the prostate and seminal vesicles. Pearson correlations, linear regression analyses, and receiver operating characteristic (ROC) curves were used to correlate the percentage overlap with dose-volume parameters. The percentage Rectum{sub overlap} and Bladder{sub overlap} correlated with sparing of that organ but minimally impacted other dose-volume parameters, predicted the primary plan rectum V{sub 45} and bladder V{sub 50} with R{sup 2} = 0.78 and R{sup 2} = 0.83, respectively, and predicted the boost plan rectum V{sub 30} and bladder V{sub 30} with R{sup 2} = 0.53 and R{sup 2} = 0.81, respectively. The optimal cutoff value of boost Rectumoverlap to predict rectum V75 >15% was 3.5% (sensitivity 100%, specificity 94%, p < 0.01), and the optimal cutoff value of boost Bladder{sub overlap} to predict bladder V{sub 80} >10% was 5.0% (sensitivity 83%, specificity 100%, p < 0.01). The degree of overlap between PTV and bladder or rectum can be used to accurately guide physicians on the use of interventions to limit the extent of the overlap region prior to optimization.

  20. A predictive model to guide management of the overlap region between target volume and organs at risk in prostate cancer volumetric modulated arc therapy

    International Nuclear Information System (INIS)

    Mattes, Malcolm D.; Lee, Jennifer C.; Einaiem, Sara; Guirguis, Adel; Ikoro, N. C.; Ashamalla Hani

    2013-01-01

    The goal of this study is to determine whether the magnitude of overlap between planning target volume (PTV) and rectum (Rectum overlap ) or PTV and bladder (Bladder overlap ) in prostate cancer volumetric-modulated arc therapy (VMAT) is predictive of the dose-volume relationships achieved after optimization, and to identify predictive equations and cutoff values using these overlap volumes beyond which the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) dose-volume constraints are unlikely to be met. Fifty-seven patients with prostate cancer underwent VMAT planning using identical optimization conditions and normalization. The PTV (for the 50.4 Gy primary plan and 30.6 Gy boost plan) included 5 to 10 mm margins around the prostate and seminal vesicles. Pearson correlations, linear regression analyses, and receiver operating characteristic (ROC) curves were used to correlate the percentage overlap with dose-volume parameters. The percentage Rectum overlap and Bladder overlap correlated with sparing of that organ but minimally impacted other dose-volume parameters, predicted the primary plan rectum V 45 and bladder V 50 with R 2 = 0.78 and R 2 = 0.83, respectively, and predicted the boost plan rectum V 30 and bladder V 30 with R 2 = 0.53 and R 2 = 0.81, respectively. The optimal cutoff value of boost Rectumoverlap to predict rectum V75 >15% was 3.5% (sensitivity 100%, specificity 94%, p overlap to predict bladder V 80 >10% was 5.0% (sensitivity 83%, specificity 100%, p < 0.01). The degree of overlap between PTV and bladder or rectum can be used to accurately guide physicians on the use of interventions to limit the extent of the overlap region prior to optimization.

  1. Modulation of mdm2 pre-mRNA splicing by 9-aminoacridine-PNA (peptide nucleic acid) conjugates targeting intron-exon junctions

    DEFF Research Database (Denmark)

    Shiraishi, Takehiko; Eysturskard, Jonhard; Nielsen, Peter E

    2010-01-01

    ABSTRACT: BACKGROUND: Modulation of pre-mRNA splicing by antisense molecules is a promising mechanism of action for gene therapeutic drugs. In this study, we have examined the potential of peptide nucleic acid (PNA) 9-aminoacridine conjugates to modulate the pre-mRNA splicing of the mdm2 human ca...

  2. Intensity modulated radiation therapy (IMRT: differences in target volumes and improvement in clinically relevant doses to small bowel in rectal carcinoma

    Directory of Open Access Journals (Sweden)

    Delclos Marc E

    2011-06-01

    Full Text Available Abstract Background A strong dose-volume relationship exists between the amount of small bowel receiving low- to intermediate-doses of radiation and the rates of acute, severe gastrointestinal toxicity, principally diarrhea. There is considerable interest in the application of highly conformal treatment approaches, such as intensity-modulated radiation therapy (IMRT, to reduce dose to adjacent organs-at-risk in the treatment of carcinoma of the rectum. Therefore, we performed a comprehensive dosimetric evaluation of IMRT compared to 3-dimensional conformal radiation therapy (3DCRT in standard, preoperative treatment for rectal cancer. Methods Using RTOG consensus anorectal contouring guidelines, treatment volumes were generated for ten patients treated preoperatively at our institution for rectal carcinoma, with IMRT plans compared to plans derived from classic anatomic landmarks, as well as 3DCRT plans treating the RTOG consensus volume. The patients were all T3, were node-negative (N = 1 or node-positive (N = 9, and were planned to a total dose of 45-Gy. Pairwise comparisons were made between IMRT and 3DCRT plans with respect to dose-volume histogram parameters. Results IMRT plans had superior PTV coverage, dose homogeneity, and conformality in treatment of the gross disease and at-risk nodal volume, in comparison to 3DCRT. Additionally, in comparison to the 3DCRT plans, IMRT achieved a concomitant reduction in doses to the bowel (small bowel mean dose: 18.6-Gy IMRT versus 25.2-Gy 3DCRT; p = 0.005, bladder (V40Gy: 56.8% IMRT versus 75.4% 3DCRT; p = 0.005, pelvic bones (V40Gy: 47.0% IMRT versus 56.9% 3DCRT; p = 0.005, and femoral heads (V40Gy: 3.4% IMRT versus 9.1% 3DCRT; p = 0.005, with an improvement in absolute volumes of small bowel receiving dose levels known to induce clinically-relevant acute toxicity (small bowel V15Gy: 138-cc IMRT versus 157-cc 3DCRT; p = 0.005. We found that the IMRT treatment volumes were typically larger than that

  3. Selective estrogen receptor modulators and betulinic acid act synergistically to target ERα and SP1 transcription factor dependent Pygopus expression in breast cancer.

    Science.gov (United States)

    Tzenov, Youlian R; Andrews, Phillip; Voisey, Kim; Gai, Luis; Carter, Beverley; Whelan, Kathryn; Popadiuk, Catherine; Kao, Kenneth R

    2016-06-01

    Estrogen and progesterone hormone receptor (ER and PR) expression in invasive breast cancer predicts response to hormone disruptive therapy. Pygopus2 (hPYGO2) encodes a chromatin remodelling protein important for breast cancer growth and cell cycle progression. The aims of this study were to determine the mechanism of expression of hPYGO2 in breast cancer and to examine how this expression is affected therapeutically. hPYGO2 and ER protein expression was examined in a breast tumour microarray by immunohistochemistry. hPYGO2 RNA and protein expression was examined in ER+ and ER- breast cancer cell lines in the presence of selective estrogen hormone receptor modulator drugs and the specificity protein-1 (SP1) inhibitor, betulinic acid (BA). The effects of these drugs on the ability for ER and SP1 to bind the hPYGO2 promoter and affect cell cycle progression were studied using chromatin immunoprecipitation assays. hPYGO2 was expressed in seven of eight lines and in nuclei of 98% of 65 breast tumours, including 3 Ductal carcinoma in situ and 62 invasive specimens representing ER-negative (22%) and ER-positive (78%) cases. Treatment with either 4-Hydroxytamoxifen (OHT) or fulvestrant reduced hPYGO2 mRNA 10-fold and protein 5-10-fold within 4 h. Promoter analysis indicated an ER/SP1 binding site at nt -225 to -531 of hPYGO2. SP1 RNA interference and BA reduced hPYGO2 protein and RNA expression by fivefold in both ER- and ER+ cells. Further attenuation was achieved by combining BA and 4-OHT resulting in eightfold reduction in cell growth. Our findings reveal a mechanistic link between hormone signalling and the growth transcriptional programme. The activation of its expression by ERα and/or SP1 suggests hPYGO2 as a theranostic target for hormone therapy responsive and refractory breast cancer. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  4. Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

    Science.gov (United States)

    D'Souza, Deepak Cyril; Fridberg, Daniel J; Skosnik, Patrick D; Williams, Ashley; Roach, Brian; Singh, Nagendra; Carbuto, Michelle; Elander, Jacqueline; Schnakenberg, Ashley; Pittman, Brian; Sewell, R Andrew; Ranganathan, Mohini; Mathalon, Daniel

    2012-01-01

    Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball' P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high' in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact

  5. X-ray fluorescence in Member States: Austria and Sri Lanka. A new attachment module for secondary target excitation with sample changer and vacuum chamber

    International Nuclear Information System (INIS)

    Wobrauschek, P.; Smolek, S.; Streli, C.; Waduge, V.A.; Seneviratne, S.

    2009-01-01

    A new secondary target attachment vacuum chamber was developed, designed and constructed at the Atomic Institute of Vienna Technical University X ray Laboratory and installed at the Atomic Energy Authorities, Colombo, Sri Lanka. The prerequisites were that the new system had to fit physically next to the Wobistrax TXRF spectrometer and to use the same existing X ray tube and an existing uplooking LN2 cooled Si(Li) detector. This new spectrometer replaces a simple secondary target system previously installed. The new system offers a 10 position sample changer integrated in a vacuum chamber. The secondary targets are exchangeable, and Mo, Zr, Ti, Al, KBr and Teflon as Barkla polarizer are available. The system is designed for the emission-transmission method for quantification but can also be used for air filter samples where the thin film model for the quantification is applicable

  6. Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model

    DEFF Research Database (Denmark)

    Tentillier, Noemie; Etzerodt, Anders; Olesen, Mads N

    2016-01-01

    intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia...

  7. Tissue- and stage-specific Wnt target gene expression is controlled subsequent to beta-catenin recruitment to cis-regulatory modules

    NARCIS (Netherlands)

    Nakamura, Y.; de Paiva Alves, E.; Veenstra, G.J.C.; Hoppler, S.

    2016-01-01

    Key signalling pathways, such as canonical Wnt/beta-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear beta-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling,

  8. Titanium (III) cation selective electrode based on synthesized tris(2pyridyl) methylamine ionophore and its application in water samples

    Science.gov (United States)

    Rezayi, Majid; Karazhian, Reza; Abdollahi, Yadollah; Narimani, Leila; Sany, Seyedeh Belin Tavakoly; Ahmadzadeh, Saeid; Alias, Yatimah

    2014-04-01

    The introduction of low detection limit ion selective electrodes (ISEs) may well pave the way for the determination of trace targets of cationic compounds. This research focuses on the detection of titanium (III) cation using a new PVC-membrane sensor based on synthesized tris(2pyridyl) methylamine (tpm) ionophore. The application and validation of the proposed sensor was done using potentiometric titration, inductively coupled plasma atomic emission spectrometry (ICP-AES), and atomic absorption spectrometry (AAS). The membrane sensor exhibited a Nernstian response to the titanium (III) cation over a concentration range of 1.0 × 10-6-1.0 × 10-2 M and pH range from 1-2.5. The Nernstian slope, the lower of detection (LOD), and the response time (t95%) of the proposed sensor were 29.17 +/- 0.24 mV/dec, 7.9 × 10-7 M, and 20 s, respectively. The direct determination of 4-39 μg/ml of titanium (III) standard solution showed an average recovery of 94.60 and a mean relative standard deviation of 1.8 at 100.0 μg/ml. Finally, the utilization of the electrodes as end-point indicators for potentiometric titration with EDTA solutions for titanium (III) sensor was successfully carried out.

  9. MiR-23a-5p modulates mycobacterial survival and autophagy during mycobacterium tuberculosis infection through TLR2/MyD88/NF-κB pathway by targeting TLR2.

    Science.gov (United States)

    Gu, Xing; Gao, Yan; Mu, De-Guang; Fu, En-Qing

    2017-05-15

    Autophagy plays a pivotal role in activating the antimicrobial host defense against Mycobacterium tuberculosis (M.tb.). The emerging roles of microRNAs (miRNAs) in regulating immune responses have attracted increasing attention in recent years. Appreciating the potential of host-directed therapies designed to control autophagy during mycobacterial infection, we focused on the influence of miR-23a-5p on the activation of macrophage autophagy during M.tb. infection in bone marrow-derived macrophages (BMDMs) and murine RAW264.7 cells. Here, we demonstrated that M.tb.-infection of macrophages lead to markedly enhanced expression of miR-23a-5p in a time- and dose-dependent manner. Furthermore, forced expression of miR-23a-5p accelerated the survival rate of intracellular mycobacteria, while transfection with miR-23a-5p inhibitors attenuated mycobacterial survival. More importantly, overexpression of miR-23a-5p dramatically prevented M.tb.-induced activation of autophagy in macrophages, whereas inhibitors of miR-23a-5p remarkably accelerated M.tb.-induced autophagy. Mechanistically, miR-23a-5p is able to modulate TLR2/MyD88/NF-κB signaling activity by targeting TLR2 in RAW264.7 cells in response to M.tb.-infection. Collectively, these findings demonstrated that miR-23a-5p modulated the innate host defense by promoting mycobacteria survival and inhibiting the activation of autophagy against M.tb. through TLR2/MyD88/NF-κB pathway by targeting TLR2, which may provide a promising therapeutic target for tuberculosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

    OpenAIRE

    Schreiner, Jens; Thommen, Daniela S.; Herzig, Petra; Bacac, Marina; Klein, Christian; Roller, Andreas; Belousov, Anton; Levitsky, Victor; Savic, Spasenija; Moersig, Wolfgang; Uhlenbrock, Franziska; Heinzelmann-Schwarz, Viola A.; Umana, Pablo; Pisa, Pavel; Lardinois, Didier

    2015-01-01

    T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting fola...

  11. Vitamin D Impacts the Expression of Runx2 Target Genes and Modulates Inflammation, Oxidative Stress and Membrane Vesicle Biogenesis Gene Networks in 143B Osteosarcoma Cells

    Directory of Open Access Journals (Sweden)

    Rama Garimella

    2017-03-01

    Full Text Available Osteosarcoma (OS is an aggressive malignancy of bone affecting children, adolescents and young adults. Understanding vitamin D metabolism and vitamin D regulated genes in OS is an important aspect of vitamin D/cancer paradigm, and in evaluating vitamin D as adjuvant therapy for human OS. Vitamin D treatment of 143B OS cells induced significant and novel changes in the expression of genes that regulate: (a inflammation and immunity; (b formation of reactive oxygen species, metabolism of cyclic nucleotides, sterols, vitamins and mineral (calcium, quantity of gap junctions and skeletogenesis; (c bone mineral density; and (d cell viability of skeletal cells, aggregation of bone cancer cells and exocytosis of secretory vesicles. Ingenuity pathway analysis revealed significant reduction in Runx2 target genes such as fibroblast growth factor -1, -12 (FGF1 and FGF12, bone morphogenetic factor-1 (BMP1, SWI/SNF related, matrix associated actin dependent regulator of chromatin subfamily a, member 4 (SMARCA4, Matrix extracellular phosphoglycoprotein (MEPE, Integrin, β4 (ITGBP4, Matrix Metalloproteinase -1, -28 (MMP1 and MMP28, and signal transducer and activator of transcription-4 (STAT4 in vitamin D treated 143B OS cells. These genes interact with the inflammation, oxidative stress and membrane vesicle biogenesis gene networks. Vitamin D not only inhibited the expression of Runx2 target genes MMP1, MMP28 and kallikrein related peptidase-7 (KLK7, but also migration and invasion of 143B OS cells. Vitamin D regulated Runx2 target genes or their products represent potential therapeutic targets and laboratory biomarkers for applications in translational oncology.

  12. Vitamin D Impacts the Expression of Runx2 Target Genes and Modulates Inflammation, Oxidative Stress and Membrane Vesicle Biogenesis Gene Networks in 143B Osteosarcoma Cells

    Science.gov (United States)

    Garimella, Rama; Tadikonda, Priyanka; Tawfik, Ossama; Gunewardena, Sumedha; Rowe, Peter; Van Veldhuizen, Peter

    2017-01-01

    Osteosarcoma (OS) is an aggressive malignancy of bone affecting children, adolescents and young adults. Understanding vitamin D metabolism and vitamin D regulated genes in OS is an important aspect of vitamin D/cancer paradigm, and in evaluating vitamin D as adjuvant therapy for human OS. Vitamin D treatment of 143B OS cells induced significant and novel changes in the expression of genes that regulate: (a) inflammation and immunity; (b) formation of reactive oxygen species, metabolism of cyclic nucleotides, sterols, vitamins and mineral (calcium), quantity of gap junctions and skeletogenesis; (c) bone mineral density; and (d) cell viability of skeletal cells, aggregation of bone cancer cells and exocytosis of secretory vesicles. Ingenuity pathway analysis revealed significant reduction in Runx2 target genes such as fibroblast growth factor -1, -12 (FGF1 and FGF12), bone morphogenetic factor-1 (BMP1), SWI/SNF related, matrix associated actin dependent regulator of chromatin subfamily a, member 4 (SMARCA4), Matrix extracellular phosphoglycoprotein (MEPE), Integrin, β4 (ITGBP4), Matrix Metalloproteinase -1, -28 (MMP1 and MMP28), and signal transducer and activator of transcription-4 (STAT4) in vitamin D treated 143B OS cells. These genes interact with the inflammation, oxidative stress and membrane vesicle biogenesis gene networks. Vitamin D not only inhibited the expression of Runx2 target genes MMP1, MMP28 and kallikrein related peptidase-7 (KLK7), but also migration and invasion of 143B OS cells. Vitamin D regulated Runx2 target genes or their products represent potential therapeutic targets and laboratory biomarkers for applications in translational oncology. PMID:28300755

  13. Genome-wide identification of microRNA targets in human ES cells reveals a role for miR-302 in modulating BMP response

    Science.gov (United States)

    Lipchina, Inna; Elkabetz, Yechiel; Hafner, Markus; Sheridan, Robert; Mihailovic, Aleksandra; Tuschl, Thomas; Sander, Chris; Studer, Lorenz; Betel, Doron

    2011-01-01

    MicroRNAs are important regulators in many cellular processes, including stem cell self-renewal. Recent studies demonstrated their function as pluripotency factors with the capacity for somatic cell reprogramming. However, their role in human embryonic stem (ES) cells (hESCs) remains poorly understood, partially due to the lack of genome-wide strategies to identify their targets. Here, we performed comprehensive microRNA profiling in hESCs and in purified neural and mesenchymal derivatives. Using a combination of AGO cross-linking and microRNA perturbation experiments, together with computational prediction, we identified the targets of the miR-302/367 cluster, the most abundant microRNAs in hESCs. Functional studies identified novel roles of miR-302/367 in maintaining pluripotency and regulating hESC differentiation. We show that in addition to its role in TGF-β signaling, miR-302/367 promotes bone morphogenetic protein (BMP) signaling by targeting BMP inhibitors TOB2, DAZAP2, and SLAIN1. This study broadens our understanding of microRNA function in hESCs and is a valuable resource for future studies in this area. PMID:22012620

  14. The planning target volume margins detected by cone-beam CT in head and neck cancer patients treated by image-guided intensity modulated radiotherapy

    International Nuclear Information System (INIS)

    Liu Jun; Chen Hong; Zhang Guoqiao; Chen Fei; Zhang Li

    2011-01-01

    Objective: To determine the planning target volume margins of head and neck cancers treated by image guided radiotherapy (IGRT). Methods: 464 sets cone beam computed tomography (CBCT) images before setup correction and 126 sets CBCT images after correction were obtained from 51 head and neck cancer patients treated by IGRT in our department. The systematic and random errors were evaluated by either online or offline correction through registering the CBCT images to the planning CT. The data was divided into 3 groups according to the online correction times. Results: The isocenter shift were 0.37 mm ± 2.37 mm, -0.43 mm ± 2.30 mm and 0.47 mm ± 2.65 mm in right-left (RL), anterior-posterior (AP) and superior-inferior (SI) directions respectively before correction, and it reduced to 0.08 mm ± 0.68 mm, -0.03 mm ± 0.74 mm and 0.03 mm ± 0.80 mm when evaluated by 126 sets corrected CBCT images. The planning target volume (PTV) margin from clinical target volume (CTV) before correction were: 6.41 mm, 6.15 mm and 7.10 mm based on two parameter model, and it reduced to 1.78 mm, 1.80 mm and 1.97 mm after correction. The PTV margins were 3.8 mm, 3.8 mm, 4.0 mm; 4.0 mm, 4.0 mm, 5.0 mm and 5.4 mm, 5.2 mm, 6.1 mm in RL, AP and SI respectively when online-correction times were more than 15 times, 11-15 times, 5-10 times. Conclusions: CBCT-based on online correction reduce the PTV margin for head and neck cancers treated by IGRT and ensure more precise dose delivery and less normal tissue complications. (authors)

  15. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

    International Nuclear Information System (INIS)

    Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

    2013-01-01

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring

  16. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area

    Energy Technology Data Exchange (ETDEWEB)

    Girolami, Flavia [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Spalenza, Veronica [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Carletti, Monica [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Sacchi, Paola [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Rasero, Roberto [Department of Animal Production, Epidemiology and Ecology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy); Nebbia, Carlo [Department of Animal Pathology, University of Turin, Via Leonardo da Vinci 44, 10095 Grugliasco (Italy)

    2013-04-15

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. - Highlights: ► The expression of AHR-target genes in blood bovine lymphocytes was evaluated. ► The lymphocyte CYP1B1 expression appears to be related to bulk milk TEQ values. ► Blood lymphocytes from dairy cows might represent a matrix for dioxin biomonitoring.

  17. Modulation of post-stroke degenerative and regenerative processes and subacute protection by site-targeted inhibition of the alternative pathway of complement.

    Science.gov (United States)

    Alawieh, Ali; Elvington, Andrew; Zhu, Hong; Yu, Jin; Kindy, Mark S; Atkinson, Carl; Tomlinson, Stephen

    2015-12-30

    Complement promotes neuroinflammation and injury in models of stroke. However, complement is also being increasingly implicated in repair and regeneration after central nervous system (CNS) injury, and some complement deficiencies have been shown to provide acute, but not subacute, protection after murine stroke. Here, we investigate the dual role of complement in injury and repair after cerebral ischemia and reperfusion. We used complement-deficient mice and different complement inhibitors in a model of transient middle cerebral artery occlusion to investigate complement-dependent cellular and molecular changes that occur through the subacute phase after stroke. C3 deficiency and site-targeted complement inhibition with either CR2-Crry (inhibits all pathways) or CR2-fH (inhibits alternative pathway) significantly reduced infarct size, reduced apoptotic cell death, and improved neurological deficit score in the acute phase after stroke. However, only in CR2-fH-treated mice was there sustained protection with no evolution of injury in the subacute phase. Whereas both inhibitors significantly reduced microglia/macrophage activation and astrogliosis in the subacute phase, only CR2-fH improved neurological deficit and locomotor function, maintained neurogenesis markers, enhanced neuronal migration, and increased VEGF expression. These findings in CR2-fH-treated mice correlated with improved performance in spatial learning and passive avoidance tasks. The complement anaphylatoxins have been implicated in repair and regenerative mechanisms after CNS injury, and in this context CR2-fH significantly reduced, but did not eliminate the generation of C5a within the brain, unlike CR2-Crry that completely blocked C5a generation. Gene expression profiling revealed that CR2-fH treatment downregulated genes associated with apoptosis, TGFβ signaling, and neutrophil activation, and decreased neutrophil infiltration was confirmed by immunohistochemistry. CR2-fH upregulated genes for

  18. Interactions between Metal-binding Domains Modulate Intracellular Targeting of Cu(I)-ATPase ATP7B, as Revealed by Nanobody Binding*

    Science.gov (United States)

    Huang, Yiping; Nokhrin, Sergiy; Hassanzadeh-Ghassabeh, Gholamreza; Yu, Corey H.; Yang, Haojun; Barry, Amanda N.; Tonelli, Marco; Markley, John L.; Muyldermans, Serge; Dmitriev, Oleg Y.; Lutsenko, Svetlana

    2014-01-01

    The biologically and clinically important membrane transporters are challenging proteins to study because of their low level of expression, multidomain structure, and complex molecular dynamics that underlies their activity. ATP7B is a copper transporter that traffics between the intracellular compartments in response to copper elevation. The N-terminal domain of ATP7B (N-ATP7B) is involved in binding copper, but the role of this domain in trafficking is controversial. To clarify the role of N-ATP7B, we generated nanobodies that interact with ATP7B in vitro and in cells. In solution NMR studies, nanobodies revealed the spatial organization of N-ATP7B by detecting transient functionally relevant interactions between metal-binding domains 1–3. Modulation of these interactions by nanobodies in cells enhanced relocalization of the endogenous ATP7B toward the plasma membrane linking molecular and cellular dynamics of the transporter. Stimulation of ATP7B trafficking by nanobodies in the absence of elevated copper provides direct evidence for the important role of N-ATP7B structural dynamics in regulation of ATP7B localization in a cell. PMID:25253690

  19. TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis.

    Science.gov (United States)

    Rojas-Rivera, D; Armisén, R; Colombo, A; Martínez, G; Eguiguren, A L; Díaz, A; Kiviluoto, S; Rodríguez, D; Patron, M; Rizzuto, R; Bultynck, G; Concha, M L; Sierralta, J; Stutzin, A; Hetz, C

    2012-06-01

    Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX-inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane.

  20. Membrane cholesterol effect on the 5-HT2A receptor: Insights into the lipid-induced modulation of an antipsychotic drug target.

    Science.gov (United States)

    Ramírez-Anguita, Juan Manuel; Rodríguez-Espigares, Ismael; Guixà-González, Ramon; Bruno, Agostino; Torrens-Fontanals, Mariona; Varela-Rial, Alejandro; Selent, Jana

    2018-01-01

    The serotonin 5-hydroxytryptamine 2A (5-HT 2A ) receptor is a G-protein-coupled receptor (GPCR) relevant for the treatment of CNS disorders. In this regard, neuronal membrane composition in the brain plays a crucial role in the modulation of the receptor functioning. Since cholesterol is an essential component of neuronal membranes, we have studied its effect on the 5-HT 2A receptor dynamics through all-atom MD simulations. We find that the presence of cholesterol in the membrane increases receptor conformational variability in most receptor segments. Importantly, detailed structural analysis indicates that conformational variability goes along with the destabilization of hydrogen bonding networks not only within the receptor but also between receptor and lipids. In addition to increased conformational variability, we also find receptor segments with reduced variability. Our analysis suggests that this increased stabilization is the result of stabilizing effects of tightly bound cholesterol molecules to the receptor surface. Our finding contributes to a better understanding of membrane-induced alterations of receptor dynamics and points to cholesterol-induced stabilizing and destabilizing effects on the conformational variability of GPCRs. © 2017 International Union of Biochemistry and Molecular Biology, Inc.

  1. ICRU reference dose in an era of intensity-modulated radiation therapy clinical trials: Correlation with planning target volume mean dose and suitability for intensity-modulated radiation therapy dose prescription

    International Nuclear Information System (INIS)

    Yaparpalvi, Ravindra; Hong, Linda; Mah, Dennis; Shen Jin; Mutyala, Subhakar; Spierer, Marnee; Garg, Madhur; Guha, Chandan; Kalnicki, Shalom

    2008-01-01

    in 3D CRT distributions. Point doses in IMRT are influenced by the degree of intensity modulation as well as calculation grid size utilized. Although the ICRU reference point type prescriptions conceptually may be extended for IMRT dose prescriptions and used as a representative of tumor dose, new universally acceptable dose prescription and specification standards for IMRT based on RTOG IMRT prescription model incorporating dose-volume specification would likely lead to greater consistency among treatment centers

  2. Expression of inhibitory receptors on intratumoral T cells modulates the activity of a T cell-bispecific antibody targeting folate receptor

    Science.gov (United States)

    Schreiner, Jens; Thommen, Daniela S.; Herzig, Petra; Bacac, Marina; Klein, Christian; Roller, Andreas; Belousov, Anton; Levitsky, Victor; Savic, Spasenija; Moersig, Wolfgang; Uhlenbrock, Franziska; Heinzelmann-Schwarz, Viola A.; Umana, Pablo; Pisa, Pavel; von Bergwelt-Baildon, M.; Lardinois, Didier; Müller, Philipp; Karanikas, Vaios; Zippelius, Alfred

    2016-01-01

    ABSTRACT T-cell bispecific antibodies (TCBs) are a novel therapeutic tool designed to selectively recruit T-cells to tumor cells and simultaneously activate them. However, it is currently unknown whether the dysfunctional state of T-cells, embedded into the tumor microenvironment, imprints on the therapeutic activity of TCBs. We performed a comprehensive analysis of activation and effector functions of tumor-infiltrating T-cells (TILs) in different tumor types, upon stimulation by a TCB targeting folate receptor 1 and CD3 (FolR1-TCB). We observed a considerable heterogeneity in T-cell activation, cytokine production and tumor cell killing upon exposure to FolR1-TCB among different FolR1-expressing tumors. Of note, tumors presenting with a high frequency of PD-1hi TILs displayed significantly impaired tumor cell killing and T-cell function. Further characterization of additional T-cell inhibitory receptors revealed that PD-1hi TILs defined a T-cell subset with particularly high levels of multiple inhibitory receptors compared with PD-1int and PD-1neg T-cells. PD-1 blockade could restore cytokine secretion but not cytotoxicity of TILs in a subset of patients with scarce PD-1hi expressing cells; in contrast, patients with abundance of PD-1hi expressing T-cells did not benefit from PD-1 blockade. Our data highlight that FolR1-TCB is a promising novel immunotherapeutic treatment option which is capable of activating intratumoral T-cells in different carcinomas. However, its therapeutic efficacy may be substantially hampered by a pre-existing dysfunctional state of T-cells, reflected by abundance of intratumoral PD-1hi T-cells. These findings present a rationale for combinatorial approaches of TCBs with other therapeutic strategies targeting T-cell dysfunction. PMID:27057429

  3. MiR-142 modulates human pancreatic cancer proliferation and invasion by targeting hypoxia-inducible factor 1 (HIF-1α in the tumor microenvironments

    Directory of Open Access Journals (Sweden)

    Yebin Lu

    2017-02-01

    Full Text Available MicroRNAs regulate most protein-coding genes, including genes important in cancer and other diseases. In this study, we demonstrated that the expression of miR-142 could be significantly suppressed in pancreatic cancer specimens and cell lines compared to their adjacent tissues and normal pancreatic cells. Growth and invasion of PANC-1 and SW1990 cells were attenuated by overexpression of miR-142 in vitro. With the help of bioinformatics analysis, hypoxia-inducible factor 1 (HIF-1α was identified to be a direct target of miR-142, and a luciferase reporter experiment confirmed this discovery. Overexpression of miR-142 decreases protein expression of HIF-1α. In the hypoxic microenvironment, HIF-1α was up-regulated while miR-142 was down-regulated. The invaded cells significantly increased in the hypoxic microenvironment compared to the normoxic microenvironment. The hypoxia treatment induced cells’ proliferation, and invasion could be inhibited by miR-142 overexpression or HIF-1α inhibition. Moreover, expression of epithelial-mesenchymal transition (EMT markers, Vimentin, VEGF-C and E-cad, was altered under hypoxia conditions and regulated by miR-142/HIF-1α. Above all, these findings provided insights on the functional mechanism of miR-142, suggesting that the miR-142/HIF-1α axis may interfere with the proliferative and invasive properties of pancreatic cancer cells, and indicated that miR-142 could be a potential therapeutic target for pancreatic cancer.

  4. Modulation of aryl hydrocarbon receptor target genes in circulating lymphocytes from dairy cows bred in a dioxin-like PCB contaminated area.

    Science.gov (United States)

    Girolami, Flavia; Spalenza, Veronica; Carletti, Monica; Sacchi, Paola; Rasero, Roberto; Nebbia, Carlo

    2013-04-15

    Animal productions (i.e. fish, eggs, milk and dairy products) represent the major source of exposure to dioxins, furans, and dioxin-like (DL) polychlorobiphenyls for humans. The negative effects of these highly toxic and persistent pollutants are mediated by the activation of the aryl hydrocarbon receptor (AHR) that elicits the transcriptional induction of several genes, including those involved in xenobiotic metabolism. Previously we demonstrated the presence and functioning of the AHR signaling pathway in primary cultures of bovine blood lymphocytes. The aim of the present study was to investigate by real time PCR the expression and the inducibility of selected target genes (i.e. AHR, AHR nuclear translocator (ARNT), AHR repressor, CYP1A1 and CYP1B1) in uncultured cells from dairy cows naturally exposed to DL-compounds. The study was carried out on two groups of animals bred in a highly polluted area and characterized by a different degree of contamination, as assessed by bulk milk TEQ values, and a control group reared in an industry free area. Bovine lymphocytes expressed only AHR, ARNT and CYP1B1 genes to a detectable level; moreover, only CYP1B1 expression appeared to be correlated to TEQ values, being higher in the most contaminated group, and decreasing along with animal decontamination. Finally, lymphocytes from exposed cows displayed a lower inducibility of both CYP1A1 and CYP1B1 after the in vitro treatment with a specific AHR ligand. In conclusion, our results indicate that DL-compound contaminated cows may display significant changes in AHR-target gene expression of circulating lymphocytes. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR).

    Science.gov (United States)

    Xiong, Yaoyao; Wang, Long; Li, Yuan; Chen, Minfeng; He, Wei; Qi, Lin

    2017-01-01

    Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA's target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells' proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3'UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation. © 2017 The Author(s). Published by S. Karger AG, Basel.

  6. The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR

    Directory of Open Access Journals (Sweden)

    Yaoyao Xiong

    2017-08-01

    Full Text Available Backgrounds/Aims: Long non-coding RNA (lncRNA X-inactive specific transcript (XIST is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA’s target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. Methods: XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. Results: XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells’ proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3’UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. Conclusion: These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation.

  7. Differentiation and injury-repair signals modulate the interaction of E2F and pRB proteins with novel target genes in keratinocytes.

    Science.gov (United States)

    Chang, Wing Y; Andrews, Joseph; Carter, David E; Dagnino, Lina

    2006-08-01

    E2F transcription factors are central to epidermal morphogenesis and regeneration after injury. The precise nature of E2F target genes involved in epidermal formation and repair has yet to be determined. Identification of these genes is essential to understand how E2F proteins regulate fundamental aspects of epidermal homeostasis and transformation. We have conducted a genome-wide screen using CpG island microarray analysis to identify novel promoters bound by E2F3 and E2F5 in human keratinocytes. We further characterized several of these genes, and determined that multiple E2F and retinoblastoma (pRb) family proteins associate with them in exponentially proliferating cells. We also assessed the effect on E2F and pRb binding to those genes in response to differentiation induced by bone morphogenetic protein-6 (BMP-6), or to activation of repair mechanisms induced by transforming growth factor-beta (TGF-beta). These studies demonstrate promoter- and cytokine-specific changes in binding profiles of E2F and/or pRb family proteins. For example, E2F1, 3, 4 and p107 were recruited to the N-myc promoter in cells treated with BMP-6, whereas E2F1, 3, 4, 5, p107 and p130 were bound to this promoter in the presence of TGF-beta. Functionally, these different interactions resulted in transcriptional repression by BMP-6 and TGF-beta of the N-myc gene, via mechanisms that involved E2F binding to the promoter and association with pRb-family proteins. Thus, multiple combinations of E2F and pRb family proteins may associate with and transcriptionally regulate a given target promoter in response to differentiation and injury-repair stimuli in epidermal keratinocytes.

  8. A cost-effective nanoporous ultrathin film electrode based on nanoporous gold/IrO2 composite for proton exchange membrane water electrolysis

    Science.gov (United States)

    Zeng, Yachao; Guo, Xiaoqian; Shao, Zhigang; Yu, Hongmei; Song, Wei; Wang, Zhiqiang; Zhang, Hongjie; Yi, Baolian

    2017-02-01

    A cost-effective nanoporous ultrathin film (NPUF) electrode based on nanoporous gold (NPG)/IrO2 composite has been constructed for proton exchange membrane (PEM) water electrolysis. The electrode was fabricated by integrating IrO2 nanoparticles into NPG through a facile dealloying and thermal decomposition method. The NPUF electrode is featured in its 3D interconnected nanoporosity and ultrathin thickness. The nanoporous ultrathin architecture is binder-free and beneficial for improving electrochemical active surface area, enhancing mass transport and facilitating releasing of oxygen produced during water electrolysis. Serving as anode, a single cell performance of 1.728 V (@ 2 A cm-2) has been achieved by NPUF electrode with a loading of IrO2 and Au at 86.43 and 100.0 μg cm-2 respectively, the electrolysis voltage is 58 mV lower than that of conventional electrode with an Ir loading an order of magnitude higher. The electrolysis voltage kept relatively constant up to 300 h (@250 mA cm-2) during the course of durability test, manifesting that NPUF electrode is promising for gas evolution.

  9. Preparation of PbO nanoparticles by microwave irradiation and their application to Pb(II)-selective electrode based on cellulose acetate

    International Nuclear Information System (INIS)

    Li Shengying; Yang Wu; Chen Miao; Gao Jinzhang; Kang Jingwan; Youli, Q.

    2005-01-01

    Nanosized lead oxide particles were prepared by thermal decomposition of lead hydroxycarbonate synthesized under microwave irradiation. Urea and lead nitrate were used as the starting materials. Microstructure and morphology of the products were investigated by means of XRD, AFM, TEM, and IR absorption spectra. The results indicated that well crystallized, finely dispersed and spherical α-PbO nanoparticles with a size of ca. 30 nm were obtained. Meanwhile, an orthogonal phase β-PbO with a size of ca. 38 nm was also obtained when the calcinations temperature was up to 600 deg. C. In addition, a Pb(II)-selective electrode based on cellulose acetate was prepared using nanosized α-PbO powders synthesized. The electrode exhibited a Nernstian slope of 29±1 mV per decade in a linear range of 2.5x10 -5 mol L -1 to 1.0x10 -1 mol L -1 for Pb 2+ ion. The detection limit of this electrode is down to 8.0x10 -6 mol L -1 . This sensor has a short response time of about 10 s and could be used in a pH range of 2.0-8.0. High selectivity was obtained over a wide variety of metal ions

  10. An all-solid-state screen-printed carbon paste reference electrode based on poly(3,4-ethylenedioxythiophene) as solid contact transducer

    International Nuclear Information System (INIS)

    Xu, Hui; Pan, Yiwen; Chen, Ying; Ye, Ying; Wang, You; Li, Guang

    2012-01-01

    The paper presents the design of an all-solid-state portable reference electrode based on a screen-printed carbon paste electrode suitable for rapid human serum testing. The electrode was covered by electropolymerized poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly(styrenesulfonate) (PSS) as an internal solid contact layer and polyvinyl chloride (PVC) membrane containing lipophilic anion and cation additives. The electrochemical properties of PEDOT(PSS) and PEDOT(PSS)/PVC film on a carbon paste electrode were studied by electrochemical impedance spectroscopy and cyclic voltammetry methods. The reference electrode exhibited good potential stability (for H + , Na + , K + , Ca 2+ , Cl − and CO 2− 3 /HCO − 3 ), good reproducibility and long-term stability. The structure is applied as reference electrodes in human serum pH analysis with pH ion selective planar electrodes, forming a serum pH sensor. The response time of such a pH sensor was 15 s and the sensitivity was −52.2 ± 1.0 mV per decade. Other properties, such as repeatability, reproducibility and stability, were also evaluated. Clinical trials were carried out and compared with the results obtained from the routine hospital electrolyte analyzer, which demonstrated that their analytical performance was closely matched. (paper)

  11. A polymeric membrane ion selective electrode based on organic-inorganic composite ion exchanger for the determination of thorium(IV)

    International Nuclear Information System (INIS)

    Chandra, Sulekh; Agarwal, Himanshu; Chandan Kumar, Singh; Sindhu, Susheel Kumar; Pankaj Kumar

    2005-01-01

    A poly(vinyl chloride) membrane electrode based on organic- inorganic composite ion exchanger, tin(IV) tungstoselenate-pyridine, has been prepared and tested for the selective determination of thorium(IV) ions. The PVC membrane electrode comprising 16% composite ion exchanger as the electroactive phase, 50% o-dioctyl phthalate as plasticizer, 4% tetraphenyl borate as anionic excluder and 30% poly(vinylchloride) displays a linear response to thorium(IV) ions over a wide concentration range of 1.0 x 10 -1 -8.0 x 10 -6 M with a Nernstain slope of 14.2 mV/ decade. The electrode shows a very short response time (∼15 s) and may be used in the pH range 2.5-9.0. The selectivity coefficient for alkali, alkaline earth and transition is smaller than 4.0 x 10 -4 . The sensor has been successfully used as an indicator electrode in the potentiometric titration of Th 4+ with EDTA as well as also for the determination of Th 4+ in the binary mixtures. (author)

  12. A new cerium (III) ion selective electrode based on 2,9-dihydroxy-1,10-diphenoxy-4,7-dithia decane, a novel synthetic ligand

    Energy Technology Data Exchange (ETDEWEB)

    Rounaghi, Gholamhossein, E-mail: ghrounagh@yahoo.com [Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad (Iran, Islamic Republic of); Zadeh Kakhki, Roya Mohammad; Sadeghian, Hamid [Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad (Iran, Islamic Republic of)

    2011-11-30

    Highlights: > An ISE based on a new ionophore is used successfully to determine cerium (III) cation over the concentration range 1.0 x 10{sup -1}-2.1 x 10{sup -9} mol l{sup -1}. > It has a fast response time of 10 s. > It has comparatively good selectivities with respect to metal cations. > It can be used in a pH range of 5.0-8.0. > It also was used as an indicator electrode in potentiometric determination of F{sup -} ion in some real sample preparations. - Abstract: In the present study, a novel electrode based on 2,9-dihydroxy-1,10-diphenoxy-4,7-dithiadecane (DHDPDTD) that is selective to cerium (III) cations was evaluated electrochemically, and a Nerenstian slope (19.3 {+-} 1 mV decade{sup -1}) over a concentration range of 1.0 x 10{sup -8}-1.0 x 10{sup -1} M and a detection limit of 2.1 x 10{sup -9} M were observed. The proposed electrochemical sensor displayed a rapid response time of 10 s, improved selectivity towards Ce (III) cations in the presence of alkali, alkaline earth, transition and heavy metal cations, and could be used in a pH range of 5.0-8.0. Additionally, the proposed sensor was used as an indicator in the potentiometric titration of fluoride and the determination of F{sup -} ions in real samples.

  13. Construction of Eu3+ Ion-Selective Electrode Based on 1,2-Diaminopropane-N,N,N',N'-tetraacetic acid

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Abedi

    2011-01-01

    Full Text Available A new Eu3+ PVC membrane electrode based on 1,2-diaminopropane-N, N,N',N'-tetraacetic acid (DAPTA as a suitable ionophore has been prepared and studied. The electrode shows a good selectivity for Eu(III ion with respect to most common cations including alkali, alkaline earth, transition and heavy metal ions. This electrode has a wide linear dynamic range from 1.0×10-6 to 1.0×10-2 M with a Nernstian slope of 19.7±0.5 mV per decade and a low detection limit of 7.2×10-7 M in the pH range of 2.5–9.1, while the response time was rapid (<10 s. The practical utility of the electrodes has been demonstratedby their use as indicator electrodes in the potentiometric titration of Eu3+ ions with EDTA and for the determination of Eu3+ in some water sample solutions.

  14. New pediatric vision screener employing polarization-modulated, retinal-birefringence-scanning-based strabismus detection and bull's eye focus detection with an improved target system: opto-mechanical design and operation

    Science.gov (United States)

    Irsch, Kristina; Gramatikov, Boris I.; Wu, Yi-Kai; Guyton, David L.

    2014-06-01

    Amblyopia ("lazy eye") is a major public health problem, caused by misalignment of the eyes (strabismus) or defocus. If detected early in childhood, there is an excellent response to therapy, yet most children are detected too late to be treated effectively. Commercially available vision screening devices that test for amblyopia's primary causes can detect strabismus only indirectly and inaccurately via assessment of the positions of external light reflections from the cornea, but they cannot detect the anatomical feature of the eyes where fixation actually occurs (the fovea). Our laboratory has been developing technology to detect true foveal fixation, by exploiting the birefringence of the uniquely arranged Henle fibers delineating the fovea using retinal birefringence scanning (RBS), and we recently described a polarization-modulated approach to RBS that enables entirely direct and reliable detection of true foveal fixation, with greatly enhanced signal-to-noise ratio and essentially independent of corneal birefringence (a confounding variable with all polarization-sensitive ophthalmic technology). Here, we describe the design and operation of a new pediatric vision screener that employs polarization-modulated, RBS-based strabismus detection and bull's eye focus detection with an improved target system, and demonstrate the feasibility of this new approach.

  15. New pediatric vision screener employing polarization-modulated, retinal-birefringence-scanning-based strabismus detection and bull's eye focus detection with an improved target system: opto-mechanical design and operation.

    Science.gov (United States)

    Irsch, Kristina; Gramatikov, Boris I; Wu, Yi-Kai; Guyton, David L

    2014-06-01

    Amblyopia ("lazy eye") is a major public health problem, caused by misalignment of the eyes (strabismus) or defocus. If detected early in childhood, there is an excellent response to therapy, yet most children are detected too late to be treated effectively. Commercially available vision screening devices that test for amblyopia's primary causes can detect strabismus only indirectly and inaccurately via assessment of the positions of external light reflections from the cornea, but they cannot detect the anatomical feature of the eyes where fixation actually occurs (the fovea). Our laboratory has been developing technology to detect true foveal fixation, by exploiting the birefringence of the uniquely arranged Henle fibers delineating the fovea using retinal birefringence scanning (RBS), and we recently described a polarization-modulated approach to RBS that enables entirely direct and reliable detection of true foveal fixation, with greatly enhanced signal-to-noise ratio and essentially independent of corneal birefringence (a confounding variable with all polarization-sensitive ophthalmic technology). Here, we describe the design and operation of a new pediatric vision screener that employs polarization-modulated, RBS-based strabismus detection and bull's eye focus detection with an improved target system, and demonstrate the feasibility of this new approach.

  16. Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Pool-Zobel, Beatrice [Department of Nutritional Toxicology, Institute for Nutrition, Friedrich Schiller University Jena, 07743 Jena (Germany)]. E-mail: b8pobe@uni-jena.de; Veeriah, Selvaraju [Department of Nutritional Toxicology, Institute for Nutrition, Friedrich Schiller University Jena, 07743 Jena (Germany); Boehmer, Frank-D. [Institute of Molecular Cell Biology, University Hospital, Friedrich Schiller University Jena, 07743 Jena (Germany)

    2005-12-11

    There is evidence that consumption of certain dietary ingredients may favourably modulate biotransformation of carcinogens. Associated with this is the hypothesis that the risk for developing colorectal cancer could be reduced, since its incidence is related to diet. Two main groups of biotransformation enzymes metabolize carcinogens, namely Phase I enzymes, which convert hydrophobic compounds to more water-soluble moieties, and Phase II enzymes (e.g. glutathione S-transferases [GST]), which primarily catalyze conjugation reactions. The conjugation of electrophilic Phase I intermediates with glutathione, for instance, frequently results in detoxification. Several possible colon carcinogens may serve as substrates for GST isoenzymes that can have marked substrate specificity. The conjugated products could be less toxic/genotoxic if GSTs are induced, thereby reducing exposure. Thus, numerous studies have shown that the induction of GSTs by antioxidants enables experimental animals to tolerate exposure to carcinogens. One important mechanism of GST induction involves an antioxidant-responsive response element (ARE) and the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is bound to the Kelch-like ECH associated protein 1 (Keap1) in the cytoplasm. Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE. GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods, which may act via different mechanisms, e.g. by increasing histone acetylation. GSTs are expressed with high inter-individual variability in human colonocytes, which points to large differences in cellular susceptibility to xenobiotics. Enhancing expression of GSTs in human colon tissue could therefore contribute to reducing cancer risks. However, it has not been demonstrated in humans that this mechanism is associated with cancer prevention. In the

  17. Modulation of xenobiotic metabolising enzymes by anticarcinogens-focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis

    International Nuclear Information System (INIS)

    Pool-Zobel, Beatrice; Veeriah, Selvaraju; Boehmer, Frank-D.

    2005-01-01

    There is evidence that consumption of certain dietary ingredients may favourably modulate biotransformation of carcinogens. Associated with this is the hypothesis that the risk for developing colorectal cancer could be reduced, since its incidence is related to diet. Two main groups of biotransformation enzymes metabolize carcinogens, namely Phase I enzymes, which convert hydrophobic compounds to more water-soluble moieties, and Phase II enzymes (e.g. glutathione S-transferases [GST]), which primarily catalyze conjugation reactions. The conjugation of electrophilic Phase I intermediates with glutathione, for instance, frequently results in detoxification. Several possible colon carcinogens may serve as substrates for GST isoenzymes that can have marked substrate specificity. The conjugated products could be less toxic/genotoxic if GSTs are induced, thereby reducing exposure. Thus, numerous studies have shown that the induction of GSTs by antioxidants enables experimental animals to tolerate exposure to carcinogens. One important mechanism of GST induction involves an antioxidant-responsive response element (ARE) and the transcription factor nuclear factor E2-related factor 2 (Nrf2), which is bound to the Kelch-like ECH associated protein 1 (Keap1) in the cytoplasm. Antioxidants may disrupt the Keap-Nrf2 complex, allowing Nrf2 to translocate to the nucleus and mediate expression of Phase II genes via interaction with the ARE. GSTs are also induced by butyrate, a product of gut flora-derived fermentation of plant foods, which may act via different mechanisms, e.g. by increasing histone acetylation. GSTs are expressed with high inter-individual variability in human colonocytes, which points to large differences in cellular susceptibility to xenobiotics. Enhancing expression of GSTs in human colon tissue could therefore contribute to reducing cancer risks. However, it has not been demonstrated in humans that this mechanism is associated with cancer prevention. In the

  18. The lncRNA PDIA3P Interacts with miR-185-5p to Modulate Oral Squamous Cell Carcinoma Progression by Targeting Cyclin D2

    Directory of Open Access Journals (Sweden)

    Cheng-Cao Sun

    2017-12-01

    Full Text Available Long noncoding RNAs (lncRNAs are emerging as important regulators during tumorigenesis by serving as competing endogenous RNAs (ceRNAs. In this study, the qRT-PCR results indicated that the lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P was overexpressed in oral squamous cell carcinoma (OSCC and decreased the survival rate of OSCC patients. CCK-8 and clonal colony formation assays were used to detect the effects of PDIA3P on proliferation. Results revealed that silencing PDIA3P by small interfering RNA (siRNA inhibited OSCC cell proliferation and repressed tumor growth and reduced the expression of proliferation antigen Ki-67 in vivo. Furthermore, the interaction between PDIA3P and miRNAs was then analyzed by qRT-PCR and luciferase reporter gene assay. We found that PDIA3P negatively regulated miR-185-5p in OSCC cells. Simultaneously, we found that silencing PDIA3P by siRNA suppressed proliferation via miR-185-5p in OSCC cells. Moreover, silencing PDIA3P by siRNA inhibited CCND2 protein (no influence on mRNA levels expression via miR-185-5p in OSCC cells, and CCND2 facilitated cell proliferation of SCC4 and SCC15 cells induced by sh-PDIA3P#1. Therefore, our study demonstrated that PDIA3P may be a therapeutic target for the treatment of OSCC.

  19. Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia

    Science.gov (United States)

    Vicente, Carmen; Schwab, Claire; Broux, Michaël; Geerdens, Ellen; Degryse, Sandrine; Demeyer, Sofie; Lahortiga, Idoya; Elliott, Alannah; Chilton, Lucy; La Starza, Roberta; Mecucci, Cristina; Vandenberghe, Peter; Goulden, Nicholas; Vora, Ajay; Moorman, Anthony V.; Soulier, Jean; Harrison, Christine J.; Clappier, Emmanuelle; Cools, Jan

    2015-01-01

    T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia. PMID:26206799

  20. Anorexigenic and Orexigenic Hormone Modulation of Mammalian Target of Rapamycin Complex 1 Activity and the Regulation of Hypothalamic Agouti-Related Protein mRNA Expression

    Directory of Open Access Journals (Sweden)

    Kenneth R. Watterson

    2012-03-01

    Full Text Available Activation of mammalian target of rapamycin 1 (mTORC1 by nutrients, insulin and leptin leads to appetite suppression (anorexia. Contrastingly, increased AMP-activated protein kinase (AMPK activity by ghrelin promotes appetite (orexia. However, the interplay between these mechanisms remains poorly defined. The relationship between the anorexigenic hormones, insulin and leptin, and the orexigenic hormone, ghrelin, on mTORC1 signalling was examined using S6 kinase phosphorylation as a marker for changes in mTORC1 activity in mouse hypothalamic GT1-7 cells. Additionally, the contribution of AMPK and mTORC1 signalling in relation to insulin-, leptin- and ghrelin-driven alterations to mouse hypothalamic agouti-related protein (AgRP mRNA levels was examined. Insulin and leptin increase mTORC1 activity in a phosphoinositide-3-kinase (PI3K- and protein kinase B (PKB-dependent manner, compared to vehicle controls, whereas increasing AMPK activity inhibits mTORC1 activity and blocks the actions of the anorexigenic hormones. Ghrelin mediates an AMPK-dependent decrease in mTORC1 activity and increases hypothalamic AgRP mRNA levels, the latter effect being prevented by insulin in an mTORC1-dependent manner. In conclusion, mTORC1 acts as an integration node in hypothalamic neurons for hormone-derived PI3K and AMPK signalling and mediates at least part of the assimilated output of anorexigenic and orexigenic hormone actions in the hypothalamus.

  1. MiR-34a/miR-93 target c-Ski to modulate the proliferaton of rat cardiac fibroblasts and extracellular matrix deposition in vivo and in vitro.

    Science.gov (United States)

    Zhang, Chengliang; Zhang, Yanfeng; Zhu, Hong; Hu, Jiajia; Xie, Zhongshang

    2018-06-01

    Cardiac fibrosis is associated with diverse heart diseases. In response to different pathological irritants, cardiac fibroblasts may be induced to proliferate and differentiate into cardiac myofibroblasts, thus contributing to cardiac fibrosis. TGF-β signaling is implicated in the development of heart failure through the induction of cardiac fibrosis. C-Ski, an inhibitory regulator of TGF-β signaling, has been reported to suppress TGF-β1-induced human cardiac fibroblasts' proliferation and ECM protein increase; however, the underlying molecular mechanism needs further investigation. In the present study, we demonstrated that c-Ski could ameliorate isoproterenol (ISO)-induced rat myocardial fibrosis model and TGF-β1-induced primary rat cardiac fibroblasts' proliferation, as well as extracellular matrix (ECM) deposition. The protein level of c-Ski was dramatically decreased in cardiac fibrosis and TGF-β1-stimulated primary rat cardiac fibroblasts. In recent decades, a family of small non-coding RNA, namely miRNAs, has been reported to regulate gene expression by interacting with diverse mRNAs and inducing either translational suppression or mRNA degradation. Herein, we selected miR-34a and miR-93 as candidate miRNAs that might target to regulate c-Ski expression. After confirming that miR-34a/miR-93 targeted c-Ski to inhibit its expression, we also revealed that miR-34a/miR-93 affected TGF-β1-induced fibroblasts' proliferation and ECM deposition through c-Ski. Taken together, we demonstrated a miR-34a/miR-93-c-Ski axis which modulates TGF-β1- and ISO-induced cardiac fibrosis in vitro and in vivo; targeting the inhibitory factors of c-Ski to rescue its expression may be a promising strategy for the treatment of cardiac fibrosis. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Selective determination of four arsenic species in rice and water samples by modified graphite electrode-based electrolytic hydride generation coupled with atomic fluorescence spectrometry.

    Science.gov (United States)

    Yang, Xin-An; Lu, Xiao-Ping; Liu, Lin; Chi, Miao-Bin; Hu, Hui-Hui; Zhang, Wang-Bing

    2016-10-01

    This work describes a novel non-chromatographic approach for the accurate and selective determining As species by modified graphite electrode-based electrolytic hydride generation (EHG) for sample introduction coupled with atomic fluorescence spectrometry (AFS) detection. Two kinds of sulfydryl-containing modifiers, l-cysteine (Cys) and glutathione (GSH), are used to modify cathode. The EHG performance of As has been changed greatly at the modified cathode, which has never been reported. Arsenite [As(III)] on the GSH modified graphite electrode (GSH/GE)-based EHG can be selectively and quantitatively converted to AsH3 at applied current of 0.4A. As(III) and arsenate [As(V)] on the Cys modified graphite electrode (Cys/GE) EHG can be selectively and efficiently converted to arsine at applied current of 0.6A, whereas monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) do not form any or only less volatile hydrides under this condition. By changing the analytical conditions, we also have achieved the analysis of total As (tAs) and DMA. Under the optimal condition, the detection limits (3s) of As(III), iAs and tAs in aqueous solutions are 0.25μgL(-1), 0.22μgL(-1) and 0.10μgL(-1), respectively. The accuracy of the method is verified through the analysis of standard reference materials (SRM 1568a). Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Fabrication of new carbon paste electrodes based on gold nano-particles self-assembled to mercapto compounds as suitable ionophores for potentiometric determination of copper ions

    Directory of Open Access Journals (Sweden)

    Rasoul Pourtaghavi Talemi

    2013-12-01

    Full Text Available In the present study, we investigate the potentiometric behavior of Cu2+ carbon paste electrodes based on two mercapto compounds 2-ethylmino-5-mercapto-1,3,4-thiadiazole (EAMT and 2-acetylamino-5-mercapto-1,3,4-thiadiazole (AAMT self-assembled on gold nano-paricle (GNP as ionophore. Then, the obtained results from the modified electrodes are compared. The self-assembled ionophores exhibit a high selectivity for copper ion (Cu2+, in which the sulfur and nitrogen atoms in their structure play a significant role as the effective coordination donor site for the copper ion. Among these electrodes, the best performance was obtained with the sensor with a EAMT/graphite powder/paraffin oil weight ratio of 4.0/68/28 with 200 µL of GNP which exhibits the working concentration range of 1.6×10−9 to 6.3×10−2 M and a nernstian slope of 28.9±0.4 mVdecade−1 of copper(II activity. The detection limit of electrode was 2.9(±0.2×10−10M and potential response was pH ; in other words, it was independent across the range of 2.8–6.3. The proposed electrode presented very good selectivity and sensitivity towards the Cu2+ ions over a wide variety of cations including alkali, alkaline earth, transition and heavy metal ions. Moreover, the proposed electrode was successfully applied as an indicator electrode in the potentiometric titration of Cu(II ions with EDTA and also the potentiometric determination of copper ions in spiked water samples.

  4. Spectro-temporal modulation masking patterns reveal frequency selectivity.

    Science.gov (United States)

    Oetjen, Arne; Verhey, Jesko L

    2015-02-01

    The present study investigated the possibility that the human auditory system demonstrates frequency selectivity to spectro-temporal amplitude modulations. Threshold modulation depth for detecting sinusoidal spectro-temporal modulations was measured using a generalized masked threshold pattern paradigm with narrowband masker modulations. Four target spectro-temporal modulations were examined, differing in their temporal and spectral modulation frequencies: a temporal modulation of -8, 8, or 16 Hz combined with a spectral modulation of 1 cycle/octave and a temporal modulation of 4 Hz combined with a spectral modulation of 0.5 cycles/octave. The temporal center frequencies of the masker modulation ranged from 0.25 to 4 times the target temporal modulation. The spectral masker-modulation center-frequencies were 0, 0.5, 1, 1.5, and 2 times the target spectral modulation. For all target modulations, the pattern of average thresholds for the eight normal-hearing listeners was consistent with the hypothesis of a spectro-temporal modulation filter. Such a pattern of modulation-frequency sensitivity was predicted on the basis of psychoacoustical data for purely temporal amplitude modulations and purely spectral amplitude modulations. An analysis of separability indicates that, for the present data set, selectivity in the spectro-temporal modulation domain can be described by a combination of a purely spectral and a purely temporal modulation filter function.

  5. An ex vivo evaluation of the efficacy of andrographolide in modulating differential expression of transcription factors and target genes in periodontal cells and its potential role in treating periodontal diseases.

    Science.gov (United States)

    Ambili R; Janam, Prasanthila; Saneesh Babu, P S; Prasad, Manu; Vinod, D; Anil Kumar, P R; Kumary, T V; Asha Nair, S; Radhakrishna Pillai, M

    2017-01-20

    Andrographolide is a herbal extract traditionally used in South Asian countries for treating inflammatory diseases. To evaluate the efficacy of andrographolide in management of periodontal disease which is a highly prevalent oral disease. Periodontal ligament fibroblasts (PDLF) were cultured from healthy and diseased periodontium using explant culture methods. The safe dose of AG was determined using MTT assay. LPS (lipopolysaccharide) of the most important periodontopathogen, P gingivalis was used to activate NF-κB and STAT3 in PDLF. The efficacy of AG in inhibiting NF-κB and STAT3 was analyzed using immunofluorescence. Down regulation of expression of target genes of these transcription factors related to inflammation and bone resorption were analyzed using real time PCR. AG up to the concentration of 25μM was found to be safe as determined by MTT assay. Statistically significant activation of NF-κB and STAT3 in cultured PDLF was observed in diseased group compared to healthy controls before and after LPS challenge. 5μM AG pretreatment significantly inhibited activation of NF-κB and STAT3 and down regulated expression of inflammatory and bone resorptive genes in cultured PDLF. The findings of the present study propose the adjunctive use of a novel herbal drug andrographolide as a promising host modulation agent for periodontal therapy by inhibiting NF-κB and STAT3 activation and inhibition of inflammation and bone resorption related genes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Verification system development a dosimetric tridimensional using Solution Fricke gel in the application for verification of radiation therapy in arc modulated volumetric (VMAT) in treatment with target moving for breathing

    International Nuclear Information System (INIS)

    Sakuraba, Roberto Kenji

    2015-01-01

    Volumetric Modulated Arc Therapy (VMAT) is one of the methods most commonly used in teletherapy to treat cancer. The various technological advances and the evolution of treatment techniques made the VMAT as one of the state of the art methods for the treatment of some cancers. Part of this improvement is credited to improvements in accuracy and prescription dose absorbed recommended to the patient over the years. This advance allows currently is possible to perform dosimetric calculations by means of the computerized planning system, considering the heterogeneity of patients, such as tissues and organs with different water compositions medium (reference radiation), and individual patient contour the movement of tumors breathing. Such advances require quality control of these tools, in order to ensure that the entire treatment process is satisfactory and accurate. Up to now, the community lacks an experimental system capable of evaluating, considering the uncertainty levels if the computerized planning systems are able to consider the movement of targets in the treatments with VMAT. In this paper, will be presented the results obtained with the phantom Fricke Xylenol Gel, capable of measuring the differences introduced by movement using the Magnetic Resonance Image - MRI and compared qualitatively and quantitatively. The main stages of the phantom development, their experimental results, conclusions and comparisons with other systems are discussed. (author)

  7. Use beam steering dipoles to minimize aberrations associated with off-centered transit through the induction bunching module. Design an improved NDCX-I drift compression section to make best use of the new bunching module to optimize planned initial NDCX-I target experiments

    International Nuclear Information System (INIS)

    HIFS-VNL; Seidl, Peter; Seidl, P.; Barnard, J.; Bieniosek, F.; Coleman, J.; Grote, D.; Leitner, M.; Gilson, E.; Logan, B.G.; Lund, S.; Lidia, S.; Ni, P.; Ogata, D.; Roy, P.; Waldron, W.; Welch, D.; Wooton, C.

    2008-01-01

    This milestone has been met by: (1) calculating steering solutions and implementing them in the experiment using the three pairs of crossed magnetic dipoles installed in between the matching solenoids, S1-S4. We have demonstrated the ability to center the beam position and angle to < 1 mm and < 1 mrad upstream of the induction bunching module (IBM) gap, compared to uncorrected beam offsets of several millimeters and milli-radians. (2) Based on LSP and analytic study, the new IBM, which has twice the volt-seconds of our first IBM, should be accompanied by a longer drift compression section in order to achieve a predicted doubling of the energy deposition on future warm-dense matter targets. This will be accomplished by constructing a longer ferro-electric plasma source. (3) Because the bunched current is a function of the longitudinal phase space and emittance of the beam entering the IBM we have characterized the longitudinal phase space with a high-resolution energy analyzer

  8. CERN: Fixed target targets

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1993-03-15

    Full text: While the immediate priority of CERN's research programme is to exploit to the full the world's largest accelerator, the LEP electron-positron collider and its concomitant LEP200 energy upgrade (January, page 1), CERN is also mindful of its long tradition of diversified research. Away from LEP and preparations for the LHC proton-proton collider to be built above LEP in the same 27-kilometre tunnel, CERN is also preparing for a new generation of heavy ion experiments using a new source, providing heavier ions (April 1992, page 8), with first physics expected next year. CERN's smallest accelerator, the LEAR Low Energy Antiproton Ring continues to cover a wide range of research topics, and saw a record number of hours of operation in 1992. The new ISOLDE on-line isotope separator was inaugurated last year (July, page 5) and physics is already underway. The remaining effort concentrates around fixed target experiments at the SPS synchrotron, which formed the main thrust of CERN's research during the late 1970s. With the SPS and LEAR now approaching middle age, their research future was extensively studied last year. Broadly, a vigorous SPS programme looks assured until at least the end of 1995. Decisions for the longer term future of the West Experimental Area of the SPS will have to take into account the heavy demand for test beams from work towards experiments at big colliders, both at CERN and elsewhere. The North Experimental Area is the scene of larger experiments with longer lead times. Several more years of LEAR exploitation are already in the pipeline, but for the longer term, the ambitious Superlear project for a superconducting ring (January 1992, page 7) did not catch on. Neutrino physics has a long tradition at CERN, and this continues with the preparations for two major projects, the Chorus and Nomad experiments (November 1991, page 7), to start next year in the West Area. Delicate neutrino oscillation effects could become visible for the first

  9. Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers.

    Science.gov (United States)

    Kim, Dong-Hyeon; Kim, Hyunsook; Jeong, Dana; Kang, Il-Byeong; Chon, Jung-Whan; Kim, Hong-Seok; Song, Kwang-Young; Seo, Kun-Ho

    2017-06-01

    Kefir is a probiotic beverage containing over 50 species of lactic acid bacteria and yeast. In this study, the anti-obesity and anti-non-alcoholic fatty liver disease (NAFLD) effects of kefir were comprehensively addressed along with targeted and untargeted community analysis of the fecal microbiota in a high-fat diet (HFD)-induced obese mouse model. HFD-fed C57BL/6 mice were orally administrated either kefir or milk (control) once a day for 12 weeks, and body and organ weight, fecal microbiota and mycobiota, histopathology, blood cholesterol and cytokines and gene expressions were analyzed. Compared to the control, mice in the kefir group exhibited a significantly lower body weight (34.18 g vs. 40.24 g; p=0.00004) and histopathological liver lesion score (1.13 vs. 3.25; p=0.002). Remarkably, the kefir-fed mice also harbored more Lactobacillus/Lactococcus (7.01 vs. 6.32 log CFU/g), total yeast (6.07 vs. 5.01 log CFU/g) and Candida (5.56 vs. 3.88 log CFU/g). Kefir administration also up-regulated genes related to fatty acid oxidation, PPARα and AOX, in both the liver and adipose tissue (PPARα, 2.95- and 2.15-fold; AOX, 1.89- and 1.9-fold, respectively). The plasma concentration of IL-6, a proinflammatory marker, was significantly reduced following kefir consumption (50.39 pg/ml vs. 111.78 pg/ml; p=0.03). Strikingly, the populations of Lactobacillus/Lactococcus, total yeast and Candida were strongly correlated with PPARα gene expression in adipose and hepatic tissue (r=0.599, 0.580 and 0.562, respectively). These data suggest that kefir consumption modulates gut microbiota and mycobiota in HFD-fed mice, which prevents obesity and NAFLD via promoting fatty acid oxidation. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Persistently better treatment planning results of intensity-modulated (IMRT) over conformal radiotherapy (3D-CRT) in prostate cancer patients with significant variation of clinical target volume and/or organs-at-risk

    International Nuclear Information System (INIS)

    Fenoglietto, Pascal; Laliberte, Benoit; Allaw, Ali; Ailleres, Norbert; Idri, Katia; Hay, Meng Huor; Moscardo, Carmen Llacer; Gourgou, Sophie; Dubois, Jean-Bernard; Azria, David

    2008-01-01

    Purpose: To compare the dose coverage of planning and clinical target volume (PTV, CTV), and organs-at-risk (OAR) between intensity-modulated (3D-IMRT) and conventional conformal radiotherapy (3D-CRT) before and after internal organ variation in prostate cancer. Methods and materials: We selected 10 patients with clinically significant interfraction volume changes. Patients were treated with 3D-IMRT to 80 Gy (minimum PTV dose of 76 Gy, excluding rectum). Fictitious, equivalent 3D-CRT plans (80 Gy at isocenter, with 95% isodose (76 Gy) coverage of PTV, with rectal blocking above 76 Gy) were generated using the same planning CT data set ('CT planning'). The plans were then also applied to a verification CT scan ('CT verify') obtained at a different moment. PTV, CTV, and OAR dose coverage were compared using non-parametric tests statistics for V95, V90 (% of the volume receiving ≥95 or 90% of the dose) and D50 (dose to 50% of the volume). Results: Mean V95 of the PTV for 'CT planning' was 94.3% (range, 88-99) vs 89.1% (range, 84-94.5) for 3D-IMRT and 3D-CRT (p = 0.005), respectively. Mean V95 of the CTV for 'CT verify' was 97% for both 3D-IMRT and 3D-CRT. Mean D50 of the rectum for 'CT planning' was 26.8 Gy (range, 22-35) vs 43.5 Gy (range, 33.5-50.5) for 3D-IMRT and 3D-CRT (p = 0.0002), respectively. For 'CT verify', this D50 was 31.1 Gy (range, 16.5-44) vs 44.2 Gy (range, 34-55) for 3D-IMRT and 3D-CRT (p = 0.006), respectively. V95 of the rectum was 0% for both plans for 'CT planning', and 2.3% (3D-IMRT) vs 2.1% (3D-CRT) for 'CT verify' (p = non-sig.). Conclusion: Dose coverage of the PTV and OAR was better with 3D-IMRT for each patient and remained so after internal volume changes

  11. Irreducible Specht modules are signed Young modules

    OpenAIRE

    Hemmer, David J.

    2005-01-01

    Recently Donkin defined signed Young modules as a simultaneous generalization of Young and twisted Young modules for the symmetric group. We show that in odd characteristic, if a Specht module $S^\\lambda$ is irreducible, then $S^\\lambda$ is a signed Young module. Thus the set of irreducible Specht modules coincides with the set of irreducible signed Young modules. This provides evidence for our conjecture that the signed Young modules are precisely the class of indecomposable self-dual module...

  12. CERN: Fixed target targets

    International Nuclear Information System (INIS)

    Anon.

    1993-01-01

    Full text: While the immediate priority of CERN's research programme is to exploit to the full the world's largest accelerator, the LEP electron-positron collider and its concomitant LEP200 energy upgrade (January, page 1), CERN is also mindful of its long tradition of diversified research. Away from LEP and preparations for the LHC proton-proton collider to be built above LEP in the same 27-kilometre tunnel, CERN is also preparing for a new generation of heavy ion experiments using a new source, providing heavier ions (April 1992, page 8), with first physics expected next year. CERN's smallest accelerator, the LEAR Low Energy Antiproton Ring continues to cover a wide range of research topics, and saw a record number of hours of operation in 1992. The new ISOLDE on-line isotope separator was inaugurated last year (July, page 5) and physics is already underway. The remaining effort concentrates around fixed target experiments at the SPS synchrotron, which formed the main thrust of CERN's research during the late 1970s. With the SPS and LEAR now approaching middle age, their research future was extensively studied last year. Broadly, a vigorous SPS programme looks assured until at least the end of 1995. Decisions for the longer term future of the West Experimental Area of the SPS will have to take into account the heavy demand for test beams from work towards experiments at big colliders, both at CERN and elsewhere. The North Experimental Area is the scene of larger experiments with longer lead times. Several more years of LEAR exploitation are already in the pipeline, but for the longer term, the ambitious Superlear project for a superconducting ring (January 1992, page 7) did not catch on. Neutrino physics has a long tradition at CERN, and this continues with the preparations for two major projects, the Chorus and Nomad experiments (November 1991, page 7), to start next year in the West Area. Delicate neutrino oscillation effects could become

  13. Evaluation of local electric fields generated by transcranial direct current stimulation with an extracephalic reference electrode based on realistic 3D body modeling

    Science.gov (United States)

    Im, Chang-Hwan; Park, Ji-Hye; Shim, Miseon; Chang, Won Hyuk; Kim, Yun-Hee

    2012-04-01

    In this study, local electric field distributions generated by transcranial direct current stimulation (tDCS) with an extracephalic reference electrode were evaluated to address extracephalic tDCS safety issues. To this aim, we generated a numerical model of an adult male human upper body and applied the 3D finite element method to electric current conduction analysis. In our simulations, the active electrode was placed over the left primary motor cortex (M1) and the reference electrode was placed at six different locations: over the right temporal lobe, on the right supraorbital region, on the right deltoid, on the left deltoid, under the chin, and on the right buccinator muscle. The maximum current density and electric field intensity values in the brainstem generated by the extracephalic reference electrodes were comparable to, or even less than, those generated by the cephalic reference electrodes. These results suggest that extracephalic reference electrodes do not lead to unwanted modulation of the brainstem cardio-respiratory and autonomic centers, as indicated by recent experimental studies. The volume energy density was concentrated at the neck area by the use of deltoid reference electrodes, but was still smaller than that around the active electrode locations. In addition, the distributions of elicited cortical electric fields demonstrated that the use of extracephalic reference electrodes might allow for the robust prediction of cortical modulations with little dependence on the reference electrode locations.

  14. Development of a methodology for defining whole-building energy design targets for commercial buildings: Phase 2, Development Concept Stage Report

    Energy Technology Data Exchange (ETDEWEB)

    McKay, H.N. (Illuminating Engineering Society of North America, New York, NY (USA)); Deringer, J.J. (American Inst. of Architects, Washington, DC (USA)); Jones, J.W. (American Society of Heating, Refrigerating and Air-Conditioning Engineers, Inc., Atlanta, GA (USA)); Hall, J.D. (Deringer Group, Riva, MD (USA))

    1990-09-01

    This report documents eight tasks performed as part of the Whole-Building Energy Design Targets project, in which detailed conceptual approaches were produced for each element of the proposed Targets model. The eight task reports together describe the important modules proposed for inclusion in the Targets model: input module, energy module, characteristic development moduel, building cost module, analysis control module, energy cost module, search routines module, and economic analysis module. 16 refs., 16 figs., 5 tabs.

  15. Target laboratory

    International Nuclear Information System (INIS)

    Ephraim, D.C.; Pednekar, A.R.

    1993-01-01

    A target laboratory to make stripper foils for the accelerator and various targets for use in the experiments is set up in the pelletron accelerator facility. The facilities available in the laboratory are: (1) D.C. glow discharge setup, (2) carbon arc set up, and (3) vacuum evaporation set up (resistance heating), electron beam source, rolling mill - all for target preparation. They are described. Centrifugal deposition technique is used for target preparation. (author). 3 figs

  16. Ice targets

    International Nuclear Information System (INIS)

    Pacheco, C.; Stark, C.; Tanaka, N.; Hodgkins, D.; Barnhart, J.; Kosty, J.

    1979-12-01

    This report presents a description of ice targets that were constructed for research work at the High Resolution Spectrometer (HRS) and at the Energetic Pion Channel and Spectrometer (EPICS). Reasons for using these ice targets and the instructions for their construction are given. Results of research using ice targets will be published at a later date

  17. Post-targeting strategy for ready-to-use targeted nanodelivery post cargo loading.

    Science.gov (United States)

    Zhu, J Y; Hu, J J; Zhang, M K; Yu, W Y; Zheng, D W; Wang, X Q; Feng, J; Zhang, X Z

    2017-12-14

    Based on boronate formation, this study reports a post-targeting methodology capable of readily installing versatile targeting modules onto a cargo-loaded nanoplatform in aqueous mediums. This permits the targeted nanodelivery of broad-spectrum therapeutics (drug/gene) in a ready-to-use manner while overcoming the PEGylation-dilemma that frequently occurs in conventional targeting approaches.

  18. Signed Young Modules and Simple Specht Modules

    OpenAIRE

    Danz, Susanne; Lim, Kay Jin

    2015-01-01

    By a result of Hemmer, every simple Specht module of a finite symmetric group over a field of odd characteristic is a signed Young module. While Specht modules are parametrized by partitions, indecomposable signed Young modules are parametrized by certain pairs of partitions. The main result of this article establishes the signed Young module labels of simple Specht modules. Along the way we prove a number of results concerning indecomposable signed Young modules that are of independent inter...

  19. Memory Modulation

    NARCIS (Netherlands)

    Roozendaal, Benno; McGaugh, James L.

    2011-01-01

    Our memories are not all created equally strong: Some experiences are well remembered while others are remembered poorly, if at all. Research on memory modulation investigates the neurobiological processes and systems that contribute to such differences in the strength of our memories. Extensive

  20. Module descriptor

    DEFF Research Database (Denmark)

    Vincenti, Gordon; Klausen, Bodil; Kjær Jensen, Jesper

    2016-01-01

    The Module Descriptor including a Teacher’s Guide explains and describes how to work innovatively and co-creatively with wicked problems and young people. The descriptor shows how interested educators and lecturers in Europe can copy the lessons of the Erasmus+ project HIP when teaching their own...

  1. Glucocorticoid receptor modulators.

    Science.gov (United States)

    Meijer, Onno C; Koorneef, Lisa L; Kroon, Jan

    2018-06-01

    The glucocorticoid hormone cortisol acts throughout the body to support circadian processes and adaptation to stress. The glucocorticoid receptor is the target of cortisol and of synthetic glucocorticoids, which are used widely in the clinic. Both agonism and antagonism of the glucocorticoid receptor may be beneficial in disease, but given the wide expression of the receptor and involvement in various processes, beneficial effects are often accompanied by unwanted side effects. Selective glucocorticoid receptor modulators are ligands that induce a receptor conformation that allows activation of only a subset of downstream signaling pathways. Such molecules thereby combine agonistic and antagonistic properties. Here we discuss the mechanisms underlying selective receptor modulation and their promise in treating diseases in several organ systems where cortisol signaling plays a role. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. Auditory sensitivity to spectral modulation phase reversal as a function of modulation depth.

    Science.gov (United States)

    Buss, Emily; Grose, John

    2018-01-01

    The present study evaluated auditory sensitivity to spectral modulation by determining the modulation depth required to detect modulation phase reversal. This approach may be preferable to spectral modulation detection with a spectrally flat standard, since listeners appear unable to perform the task based on the detection of temporal modulation. While phase reversal thresholds are often evaluated by holding modulation depth constant and adjusting modulation rate, holding rate constant and adjusting modulation depth supports rate-specific assessment of modulation processing. Stimuli were pink noise samples, filtered into seven octave-wide bands (0.125-8 kHz) and spectrally modulated in dB. Experiment 1 measured performance as a function of modulation depth to determine appropriate units for adaptive threshold estimation. Experiment 2 compared thresholds in dB for modulation detection with a flat standard and modulation phase reversal; results supported the idea that temporal cues were available at high rates for the former but not the latter. Experiment 3 evaluated spectral modulation phase reversal thresholds for modulation that was restricted to either one or two neighboring bands. Flanking bands of unmodulated noise had a larger detrimental effect on one-band than two-band targets. Thresholds for high-rate modulation improved with increasing carrier frequency up to 2 kHz, whereas low-rate modulation appeared more consistent across frequency, particularly in the two-band condition. Experiment 4 measured spectral weights for spectral modulation phase reversal detection and found higher weights for bands in the spectral center of the stimulus than for the lowest (0.125 kHz) or highest (8 kHz) band. Experiment 5 compared performance for highly practiced and relatively naïve listeners, and found weak evidence of a larger practice effect at high than low spectral modulation rates. These results provide preliminary data for a task that may provide a better estimate of

  3. BK channel modulators: a comprehensive overview

    DEFF Research Database (Denmark)

    Nardi, Antonio; Olesen, Søren-Peter

    2008-01-01

    channels as a potentially attractive target, the design and synthesis of potent and selective BK modulators continue based on novel chemical ideas. A comprehensive overview of BK channel modulators is therefore timely and important to the current medicinal chemist for review, summary, and classification...

  4. Postdictive modulation of visual orientation.

    Directory of Open Access Journals (Sweden)

    Takahiro Kawabe

    Full Text Available The present study investigated how visual orientation is modulated by subsequent orientation inputs. Observers were presented a near-vertical Gabor patch as a target, followed by a left- or right-tilted second Gabor patch as a distracter in the spatial vicinity of the target. The task of the observers was to judge whether the target was right- or left-tilted (Experiment 1 or whether the target was vertical or not (Supplementary experiment. The judgment was biased toward the orientation of the distracter (the postdictive modulation of visual orientation. The judgment bias peaked when the target and distracter were temporally separated by 100 ms, indicating a specific temporal mechanism for this phenomenon. However, when the visibility of the distracter was reduced via backward masking, the judgment bias disappeared. On the other hand, the low-visibility distracter could still cause a simultaneous orientation contrast, indicating that the distracter orientation is still processed in the visual system (Experiment 2. Our results suggest that the postdictive modulation of visual orientation stems from spatiotemporal integration of visual orientation on the basis of a slow feature matching process.

  5. Postdictive modulation of visual orientation.

    Science.gov (United States)

    Kawabe, Takahiro

    2012-01-01

    The present study investigated how visual orientation is modulated by subsequent orientation inputs. Observers were presented a near-vertical Gabor patch as a target, followed by a left- or right-tilted second Gabor patch as a distracter in the spatial vicinity of the target. The task of the observers was to judge whether the target was right- or left-tilted (Experiment 1) or whether the target was vertical or not (Supplementary experiment). The judgment was biased toward the orientation of the distracter (the postdictive modulation of visual orientation). The judgment bias peaked when the target and distracter were temporally separated by 100 ms, indicating a specific temporal mechanism for this phenomenon. However, when the visibility of the distracter was reduced via backward masking, the judgment bias disappeared. On the other hand, the low-visibility distracter could still cause a simultaneous orientation contrast, indicating that the distracter orientation is still processed in the visual system (Experiment 2). Our results suggest that the postdictive modulation of visual orientation stems from spatiotemporal integration of visual orientation on the basis of a slow feature matching process.

  6. Antiproton Target

    CERN Multimedia

    1980-01-01

    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  7. Modulation of gene expression made easy

    DEFF Research Database (Denmark)

    Solem, Christian; Jensen, Peter Ruhdal

    2002-01-01

    A new approach for modulating gene expression, based on randomization of promoter (spacer) sequences, was developed. The method was applied to chromosomal genes in Lactococcus lactis and shown to generate libraries of clones with broad ranges of expression levels of target genes. In one example...... that the method can be applied to modulating the expression of native genes on the chromosome. We constructed a series of strains in which the expression of the las operon, containing the genes pfk, pyk, and ldh, was modulated by integrating a truncated copy of the pfk gene. Importantly, the modulation affected...

  8. Scannerless laser range imaging using loss modulation

    Energy Technology Data Exchange (ETDEWEB)

    Sandusky, John V [Albuquerque, NM

    2011-08-09

    A scannerless 3-D imaging apparatus is disclosed which utilizes an amplitude modulated cw light source to illuminate a field of view containing a target of interest. Backscattered light from the target is passed through one or more loss modulators which are modulated at the same frequency as the light source, but with a phase delay .delta. which can be fixed or variable. The backscattered light is demodulated by the loss modulator and detected with a CCD, CMOS or focal plane array (FPA) detector to construct a 3-D image of the target. The scannerless 3-D imaging apparatus, which can operate in the eye-safe wavelength region 1.4-1.7 .mu.m and which can be constructed as a flash LADAR, has applications for vehicle collision avoidance, autonomous rendezvous and docking, robotic vision, industrial inspection and measurement, 3-D cameras, and facial recognition.

  9. MEMORY MODULATION

    Science.gov (United States)

    Roozendaal, Benno; McGaugh, James L.

    2011-01-01

    Our memories are not all created equally strong: Some experiences are well remembered while others are remembered poorly, if at all. Research on memory modulation investigates the neurobiological processes and systems that contribute to such differences in the strength of our memories. Extensive evidence from both animal and human research indicates that emotionally significant experiences activate hormonal and brain systems that regulate the consolidation of newly acquired memories. These effects are integrated through noradrenergic activation of the basolateral amygdala which regulates memory consolidation via interactions with many other brain regions involved in consolidating memories of recent experiences. Modulatory systems not only influence neurobiological processes underlying the consolidation of new information, but also affect other mnemonic processes, including memory extinction, memory recall and working memory. In contrast to their enhancing effects on consolidation, adrenal stress hormones impair memory retrieval and working memory. Such effects, as with memory consolidation, require noradrenergic activation of the basolateral amygdala and interactions with other brain regions. PMID:22122145

  10. Targets of curcumin

    Science.gov (United States)

    Zhou, Hongyu; Beevers, Christopher S.; Huang, Shile

    2010-01-01

    Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-κB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here. PMID:20955148

  11. The targets of curcumin.

    Science.gov (United States)

    Zhou, Hongyu; Beevers, Christopher S; Huang, Shile

    2011-03-01

    Curcumin (diferuloylmethane), an orange-yellow component of turmeric or curry powder, is a polyphenol natural product isolated from the rhizome of the plant Curcuma longa. For centuries, curcumin has been used in some medicinal preparation or used as a food-coloring agent. In recent years, extensive in vitro and in vivo studies suggested curcumin has anticancer, antiviral, antiarthritic, anti-amyloid, antioxidant, and anti-inflammatory properties. The underlying mechanisms of these effects are diverse and appear to involve the regulation of various molecular targets, including transcription factors (such as nuclear factor-kB), growth factors (such as vascular endothelial cell growth factor), inflammatory cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6), protein kinases (such as mammalian target of rapamycin, mitogen-activated protein kinases, and Akt) and other enzymes (such as cyclooxygenase 2 and 5 lipoxygenase). Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, curcumin has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer's disease, and other inflammatory illnesses. This review summarizes various in vitro and in vivo pharmacological aspects of curcumin as well as the underlying action mechanisms. The recently identified molecular targets and signaling pathways modulated by curcumin are also discussed here.

  12. Targeted Learning

    CERN Document Server

    van der Laan, Mark J

    2011-01-01

    The statistics profession is at a unique point in history. The need for valid statistical tools is greater than ever; data sets are massive, often measuring hundreds of thousands of measurements for a single subject. The field is ready to move towards clear objective benchmarks under which tools can be evaluated. Targeted learning allows (1) the full generalization and utilization of cross-validation as an estimator selection tool so that the subjective choices made by humans are now made by the machine, and (2) targeting the fitting of the probability distribution of the data toward the targe

  13. Target preparation

    International Nuclear Information System (INIS)

    Hinn, G.M.

    1984-01-01

    A few of the more interesting of the 210 targets prepared in the Laboratory last year are listed. In addition the author continues to use powdered silver mixed with /sup 9,10/BeO to produce sources for accelerator radio dating of Alaskan and South Polar snow. Currently, he is trying to increase production by multiple sample processing. Also the author routinely makes 3 μg/cm 2 cracked slacked carbon stripper foils and is continuing research with some degree of success in making enriched 28 Si targets starting with the oxide

  14. Characteristics of spectro-temporal modulation frequency selectivity in humans.

    Science.gov (United States)

    Oetjen, Arne; Verhey, Jesko L

    2017-03-01

    There is increasing evidence that the auditory system shows frequency selectivity for spectro-temporal modulations. A recent study of the authors has shown spectro-temporal modulation masking patterns that were in agreement with the hypothesis of spectro-temporal modulation filters in the human auditory system [Oetjen and Verhey (2015). J. Acoust. Soc. Am. 137(2), 714-723]. In the present study, that experimental data and additional data were used to model this spectro-temporal frequency selectivity. The additional data were collected to investigate to what extent the spectro-temporal modulation-frequency selectivity results from a combination of a purely temporal amplitude-modulation filter and a purely spectral amplitude-modulation filter. In contrast to the previous study, thresholds were measured for masker and target modulations with opposite directions, i.e., an upward pointing target modulation and a downward pointing masker modulation. The comparison of this data set with previous corresponding data with the same direction from target and masker modulations indicate that a specific spectro-temporal modulation filter is required to simulate all aspects of spectro-temporal modulation frequency selectivity. A model using a modified Gabor filter with a purely temporal and a purely spectral filter predicts the spectro-temporal modulation masking data.

  15. Fabrication of a new samarium(III) ion-selective electrode based on 3-{l_brace}[2-oxo-1(2h)-acenaphthylenyliden]amino{r_brace}-2-thioxo -1,3-thiazolidin-4-one

    Energy Technology Data Exchange (ETDEWEB)

    Zamani, Hassan Ali [Islamic Azad University, Quchan (Iran, islamic Republic of). Quchan Branch. Dept. of Chemistry]. E-mail: haszamani@yahoo.com; Ganjali, Mohammad Reza [Tehran University of Medical Sciences, Tehran (Iran, Islamic Republic of). Endocrine and Metabolism Research Center; Adib, Mehdi [University of Tehran, Tehran (Iran, Islamic Republic of). Faculty of Chemistry. Center of Excellence in Electrochemistry

    2007-07-01

    This paper introduces the development of an original PVC membrane electrode, based on 3-{l_brace}[2-oxo-1(2H)-acenaphthylenyliden]amino{r_brace}-2-thioxo-1,3-thiazolidin-4-one (ATTO) which has revealed to be a suitable carrier for Sm{sup 3+} ions. The resulting data illustrated that the electrode shows a Nernstian slope of 19.3 {+-} 0.6 mV per decade for Sm{sup 3+} ions over a broad working concentration range of 1.0 X 10{sup -6} to 1.0 X 10{sup -1} mol L{sup -1}. The lower detection limit was found to be equal to (5.5{+-} 0.3) X 10{sup -7} mol L{sup -}'1 in the pH range of 3.5-7.5, and the response time was very short ({approx}10 s). The potentiometric sensor displayed good selectivities for a number of cations such as alkali, alkaline earth, transition and heavy metal ions. (author)

  16. The specificity of Av3 sea anemone toxin for arthropods is determined at linker DI/SS2-S6 in the pore module of target sodium channels.

    Science.gov (United States)

    Gur Barzilai, Maya; Kahn, Roy; Regev, Noa; Gordon, Dalia; Moran, Yehu; Gurevitz, Michael

    2014-10-15

    Av3 is a peptide neurotoxin from the sea anemone Anemonia viridis that shows specificity for arthropod voltage-gated sodium channels (Navs). Interestingly, Av3 competes with a scorpion α-toxin on binding to insect Navs and similarly inhibits the inactivation process, and thus has been classified as 'receptor site-3 toxin', although the two peptides are structurally unrelated. This raises questions as to commonalities and differences in the way both toxins interact with Navs. Recently, site-3 was partly resolved for scorpion α-toxins highlighting S1-S2 and S3-S4 external linkers at the DIV voltage-sensor module and the juxtaposed external linkers at the DI pore module. To uncover channel determinants involved in Av3 specificity for arthropods, the toxin was examined on channel chimaeras constructed with the external linkers of the mammalian brain Nav1.2a, which is insensitive to Av3, in the background of the Drosophila DmNav1. This approach highlighted the role of linker DI/SS2-S6, adjacent to the channel pore, in determining Av3 specificity. Point mutagenesis at DI/SS2-S6 accompanied by functional assays highlighted Trp404 and His405 as a putative point of Av3 interaction with DmNav1. His405 conservation in arthropod Navs compared with tyrosine in vertebrate Navs may represent an ancient substitution that explains the contemporary selectivity of Av3. Trp404 and His405 localization near the membrane surface and the hydrophobic bioactive surface of Av3 suggest that the toxin possibly binds at a cleft by DI/S6. A partial overlap in receptor site-3 of both toxins nearby DI/S6 may explain their binding competition capabilities.

  17. Effects of amplitude modulation on perception of wind turbine noise

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Ki Seop; Lee, Soo Gab; Gwak, Doo Young [Dept. of Mechanical and Aerospace Engineering, Seoul National University, Seoul (Korea, Republic of); Seong, Yeol Wan [Ammunition Engineering Team, Defense Agency for Technology and Quality, Daejeon (Korea, Republic of); Lee, Seung Hoon [Aerodynamics Research Team, Korea Aerospace Research Institute, Daejeon (Korea, Republic of); Hong, Ji Young [Transportation Environmental Research Team, Green Transport and Logistics Institute, Korea Railroad Research Institute, Uiwang (Korea, Republic of)

    2016-10-15

    Wind turbine noise is considered to be easily detectable and highly annoying at relatively lower sound levels than other noise sources. Many previous studies attributed this characteristic to amplitude modulation. However, it is unclear whether amplitude modulation is the main cause of these properties of wind turbine noise. Therefore, the aim of the current study is to identify the relationship between amplitude modulation and these two properties of wind turbine noise. For this investigation, two experiments were conducted. In the first experiment, 12 participants determined the detection thresholds of six target sounds in the presence of background noise. In the second experiment, 12 participants matched the loudness of modified sounds without amplitude modulation to that of target sounds with amplitude modulation. The results showed that the detection threshold was lowered as the modulation depth increased; additionally, sounds with amplitude modulation had higher subjective loudness than those without amplitude modulation.

  18. Effects of amplitude modulation on perception of wind turbine noise

    International Nuclear Information System (INIS)

    Yoon, Ki Seop; Lee, Soo Gab; Gwak, Doo Young; Seong, Yeol Wan; Lee, Seung Hoon; Hong, Ji Young

    2016-01-01

    Wind turbine noise is considered to be easily detectable and highly annoying at relatively lower sound levels than other noise sources. Many previous studies attributed this characteristic to amplitude modulation. However, it is unclear whether amplitude modulation is the main cause of these properties of wind turbine noise. Therefore, the aim of the current study is to identify the relationship between amplitude modulation and these two properties of wind turbine noise. For this investigation, two experiments were conducted. In the first experiment, 12 participants determined the detection thresholds of six target sounds in the presence of background noise. In the second experiment, 12 participants matched the loudness of modified sounds without amplitude modulation to that of target sounds with amplitude modulation. The results showed that the detection threshold was lowered as the modulation depth increased; additionally, sounds with amplitude modulation had higher subjective loudness than those without amplitude modulation

  19. Unity connecting module in SSPF

    Science.gov (United States)

    1998-01-01

    In the Space Station Processing Facility, the Unity connecting module, part of the International Space Station, is shown with Pressurized Mating Adapters 1 (left) and 2 (right) attached. Unity is scheduled to undergo testing of the common berthing mechanism to which other space station elements will dock. Unity is the primary payload on mission STS-88, targeted to launch Dec. 3, 1998. Other testing includes the Pad Demonstration Test to verify the compatibility of the module with the Space Shuttle as well as the ability of the astronauts to send and receive commands to Unity from the flight deck of the orbiter. Unity is expected to be ready for installation into the payload canister on Oct. 25, and transported to Launch Pad 39-A on Oct. 27. The Unity will be mated to the Russian-built Zarya control module which should already be in orbit at that time.

  20. Fast Convolution Module (Fast Convolution Module)

    National Research Council Canada - National Science Library

    Bierens, L

    1997-01-01

    This report describes the design and realisation of a real-time range azimuth compression module, the so-called 'Fast Convolution Module', based on the fast convolution algorithm developed at TNO-FEL...

  1. Intensity-modulated radiation therapy.

    Science.gov (United States)

    Goffman, Thomas E; Glatstein, Eli

    2002-07-01

    Intensity-modulated radiation therapy (IMRT) is an increasingly popular technical means of tightly focusing the radiation dose around a cancer. As with stereotactic radiotherapy, IMRT uses multiple fields and angles to converge on the target. The potential for total dose escalation and for escalation of daily fraction size to the gross cancer is exciting. The excitement, however, has greatly overshadowed a range of radiobiological and clinical concerns.

  2. Module theory, extending modules and generalizations

    CERN Document Server

    Tercan, Adnan

    2016-01-01

    The main focus of this monograph is to offer a comprehensive presentation of known and new results on various generalizations of CS-modules and CS-rings. Extending (or CS) modules are generalizations of injective (and also semisimple or uniform) modules. While the theory of CS-modules is well documented in monographs and textbooks, results on generalized forms of the CS property as well as dual notions are far less present in the literature. With their work the authors provide a solid background to module theory, accessible to anyone familiar with basic abstract algebra. The focus of the book is on direct sums of CS-modules and classes of modules related to CS-modules, such as relative (injective) ejective modules, (quasi) continuous modules, and lifting modules. In particular, matrix CS-rings are studied and clear proofs of fundamental decomposition results on CS-modules over commutative domains are given, thus complementing existing monographs in this area. Open problems round out the work and establish the...

  3. Targeting insulin resistance in type 2 diabetes via immune modulation of cord blood-derived multipotent stem cells (CB-SCs) in stem cell educator therapy: phase I/II clinical trial.

    Science.gov (United States)

    Zhao, Yong; Jiang, Zhaoshun; Zhao, Tingbao; Ye, Mingliang; Hu, Chengjin; Zhou, Huimin; Yin, Zhaohui; Chen, Yana; Zhang, Ye; Wang, Shanfeng; Shen, Jie; Thaker, Hatim; Jain, Summit; Li, Yunxiang; Diao, Yalin; Chen, Yingjian; Sun, Xiaoming; Fisk, Mary Beth; Li, Heng

    2013-07-09

    The prevalence of type 2 diabetes (T2D) is increasing worldwide and creating a significant burden on health systems, highlighting the need for the development of innovative therapeutic approaches to overcome immune dysfunction, which is likely a key factor in the development of insulin resistance in T2D. It suggests that immune modulation may be a useful tool in treating the disease. In an open-label, phase 1/phase 2 study, patients (N=36) with long-standing T2D were divided into three groups (Group A, oral medications, n=18; Group B, oral medications+insulin injections, n=11; Group C having impaired β-cell function with oral medications+insulin injections, n=7). All patients received one treatment with the Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, briefly co-cultures them with adherent cord blood-derived multipotent stem cells (CB-SCs), and returns the educated autologous cells to the patient's circulation. Clinical findings indicate that T2D patients achieve improved metabolic control and reduced inflammation markers after receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C) in Group A and B was significantly reduced from 8.61%±1.12 at baseline to 7.25%±0.58 at 12 weeks (P=2.62E-06), and 7.33%±1.02 at one year post-treatment (P=0.0002). Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that insulin sensitivity was improved post-treatment. Notably, the islet beta-cell function in Group C subjects was markedly recovered, as demonstrated by the restoration of C-peptide levels. Mechanistic studies revealed that Stem Cell Educator therapy reverses immune dysfunctions through immune modulation on monocytes and balancing Th1/Th2/Th3 cytokine production. Clinical data from the current phase 1/phase 2 study demonstrate that Stem Cell Educator therapy is a safe approach that produces lasting improvement in

  4. Reference Electrodes Based on Solid Amalgams

    Czech Academy of Sciences Publication Activity Database

    Josypčuk, Bohdan; Novotný, Ladislav

    2004-01-01

    Roč. 16, č. 3 (2004), s. 238-241 ISSN 1040-0397 Grant - others:GIT(AR) 101/02/U111/CZ Institutional research plan: CEZ:AV0Z4040901 Keywords : solid amalgam * reference electrode * voltammetry Subject RIV: CG - Electrochemistry Impact factor: 2.038, year: 2004

  5. Aperture modulated arc therapy

    International Nuclear Information System (INIS)

    Crooks, S M; Wu, Xiaodong; Takita, C; Watzich, M; Xing Lei

    2003-01-01

    We show that it is possible to translate an intensity modulated radiation therapy (IMRT) treatment plan and deliver it as a single arc. This technique is referred to in this paper as aperture modulation arc therapy (AMAT). During this arc, the MLC leaves do not conform to the projection of the target PTV and the machine output of the accelerator has a constant value. Dose was calculated using the CORVUS 4.0 IMRT system, which uses a pencil beam dose algorithm, and treatments were delivered using a Varian 2100C/D Clinac. Results are presented for a head and neck and a prostate case, showing the equivalence of the IMRT and the translated AMAT delivery. For a prostate AMAT delivery, coronal plane film dose for the IMRT and AMAT deliveries agreed within 7.19 ± 6.62%. For a meningioma the coronal plane dose distributions were similar to a value of 4.6 ± 6.62%. Dose to the isocentre was measured as being within 2% of the planned value in both cases

  6. A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways.

    Science.gov (United States)

    Jiang, Kai; Chi, Ting; Li, Tao; Zheng, Guirong; Fan, Lulu; Liu, Yajun; Chen, Xiufen; Chen, Sijia; Jia, Lee; Shao, Jingwei

    2017-07-13

    Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.

  7. Simultaneous trace-levels determination of Hg(II) and Pb(II) ions in various samples using a modified carbon paste electrode based on multi-walled carbon nanotubes and a new synthesized Schiff base

    International Nuclear Information System (INIS)

    Afkhami, Abbas; Bagheri, Hasan; Khoshsafar, Hosein; Saber-Tehrani, Mohammad; Tabatabaee, Masoumeh; Shirzadmehr, Ali

    2012-01-01

    Highlights: ► A new chemically modified carbon paste electrode was constructed and used. ► A new Schiff base and multi-walled carbon nanotube was used as a modifier. ► The electrochemical properties of the modified electrode were studied. ► The electrode was used to the simultaneous determination of Pb 2+ and Hg 2+ . - Abstract: A modified carbon paste electrode based on multi-walled carbon nanotubes (MWCNTs) and 3-(4-methoxybenzylideneamino)-2-thioxothiazolodin-4-one as a new synthesized Schiff base was constructed for the simultaneous determination of trace amounts of Hg(II) and Pb(II) by square wave anodic stripping voltammetry. The modified electrode showed an excellent selectivity and stability for Hg(II) and Pb(II) determinations and for accelerated electron transfer between the electrode and the analytes. The electrochemical properties and applications of the modified electrode were studied. Operational parameters such as pH, deposition potential and deposition time were optimized for the purpose of determination of traces of metal ions at pH 3.0. Under optimal conditions the limits of detection, based on three times the background noise, were 9.0 × 10 −4 and 6.0 × 10 −4 μmol L −1 for Hg(II) and Pb(II) with a 90 s preconcentration, respectively. In addition, the modified electrode displayed a good reproducibility and selectivity, making it suitable for the simultaneous determination of Hg(II) and Pb(II) in real samples such as sea water, waste water, tobacco, marine and human teeth samples.

  8. Controlling data transfers from an origin compute node to a target compute node

    Science.gov (United States)

    Archer, Charles J [Rochester, MN; Blocksome, Michael A [Rochester, MN; Ratterman, Joseph D [Rochester, MN; Smith, Brian E [Rochester, MN

    2011-06-21

    Methods, apparatus, and products are disclosed for controlling data transfers from an origin compute node to a target compute node that include: receiving, by an application messaging module on the target compute node, an indication of a data transfer from an origin compute node to the target compute node; and administering, by the application messaging module on the target compute node, the data transfer using one or more messaging primitives of a system messaging module in dependence upon the indication.

  9. Variation in radiotherapy target volume definition, dose to organs at risk and clinical target volumes using anatomic (computed tomography) versus combined anatomic and molecular imaging (positron emission tomography/computed tomography): intensity-modulated radiotherapy delivered using a tomotherapy Hi Art machine: final results of the VortigERN study.

    Science.gov (United States)

    Chatterjee, S; Frew, J; Mott, J; McCallum, H; Stevenson, P; Maxwell, R; Wilsdon, J; Kelly, C G

    2012-12-01

    Contrast-enhanced computed tomography (CECT) is the current standard for delineating tumours of the head and neck for radiotherapy. Although metabolic imaging with positron emission tomography (PET) has been used in recent years, the studies were non-confirmatory in establishing its routine role in radiotherapy planning in the modern era. This study explored the difference in gross tumour volume and clinical target volume definitions for the primary and nodal volumes when FDG PET/CT was used as compared with CECT in oropharyngeal cancer cases. Twenty patients with oropharyngeal cancers had a PET/CT scan in the treatment position after consent. Target volumes were defined on CECT scans by a consultant clinical oncologist who was blind to the PET scans. After obtaining inputs from a radiologist, another set of target volumes were outlined on the PET/CT data set. The gross and clinical target volumes as defined on the two data sets were then analysed. The hypothesis of more accurate target delineation, preventing geographical miss and comparative overlap volumes between CECT and PET/CT, was explored. The study also analysed the volumes of intersection and analysed whether there was any TNM stage migration when PET/CT was used as compared with CECT for planning. In 17 of 20 patients, the TNM stage was not altered when adding FDG PET information to CT. PET information prevented geographical miss in two patients and identified distant metastases in one case. PET/CT gross tumour volumes were smaller than CECT volumes (mean ± standard deviation: 25.16 cm(3) ± 35.8 versus 36.56 cm(3) ± 44.14; P standard deviation: CECT versus PET/CT 32.48 cm(3) ± 36.63 versus 32.21 cm(3) ± 37.09; P > 0.86) were not statistically different. Similarity and discordance coefficients were calculated and are reported. PET/CT as compared with CECT could provide more clinically relevant information and prevent geographical miss when used for radiotherapy planning for advanced oropharyngeal

  10. Reduced multiplication modules

    Indian Academy of Sciences (India)

    if M is a von Neumann regular module (VNM); i.e., every principal submodule of M is a summand submodule. Also if M is an injective R-module, then M is a VNM. Keywords. Multiplication module; reduced module; minimal prime submodule;. Zariski topology; extremally disconnected. 1. Introduction. In this paper all rings are ...

  11. Amplitude and phase modulation with waveguide optics

    International Nuclear Information System (INIS)

    Burkhart, S.C.; Wilcox, R.B.; Browning, D.; Penko, F.A.

    1996-01-01

    We have developed amplitude and phase modulation systems for glass lasers using integrated electro-optic modulators and solid state high-speed electronics. The present and future generation of lasers for Inertial Confinement Fusion require laser beams with complex temporal and phase shaping to compensate for laser gain saturation, mitigate parametric processes such as transverse stimulated Brillouin scattering in optics, and to provide specialized drive to the fusion targets. These functions can be performed using bulk optoelectronic modulators, however using high-speed electronics to drive low voltage integrated optical modulators has many practical advantages. In particular, we utilize microwave GaAs transistors to perform precision, 250 ps resolution temporal shaping. Optical bandwidth is generated using a microwave oscillator at 3 GHz amplified by a solid state amplifier. This drives an integrated electrooptic modulator to achieve laser bandwidths exceeding 30 GHz

  12. Modulational effects in accelerators

    International Nuclear Information System (INIS)

    Satogata, T.

    1997-01-01

    We discuss effects of field modulations in accelerators, specifically those that can be used for operational beam diagnostics and beam halo control. In transverse beam dynamics, combined effects of nonlinear resonances and tune modulations influence diffusion rates with applied tune modulation has been demonstrated. In the longitudinal domain, applied RF phase and voltage modulations provide mechanisms for parasitic halo transport, useful in slow crystal extraction. Experimental experiences with transverse tune and RF modulations are also discussed

  13. APT target-blanket fabrication development

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, D.L.

    1997-06-13

    Concepts for producing tritium in an accelerator were translated into hardware for engineering studies of tritium generation, heat transfer, and effects of proton-neutron flux on materials. Small-scale target- blanket assemblies were fabricated and material samples prepared for these performance tests. Blanket assemblies utilize composite aluminum-lead modules, the two primary materials of the blanket. Several approaches are being investigated to produce large-scale assemblies, developing fabrication and assembly methods for their commercial manufacture. Small-scale target-blanket assemblies, designed and fabricated at the Savannah River Site, were place in Los Alamos Neutron Science Center (LANSCE) for irradiation. They were subjected to neutron flux for nine months during 1996-97. Coincident with this test was the development of production methods for large- scale modules. Increasing module size presented challenges that required new methods to be developed for fabrication and assembly. After development, these methods were demonstrated by fabricating and assembling two production-scale modules.

  14. Intensity Modulated Radiotherapy Improves Target Coverage and Parotid Gland Sparing When Delivering Total Mucosal Irradiation in Patients With Squamous Cell Carcinoma of Head and Neck of Unknown Primary Site

    International Nuclear Information System (INIS)

    Bhide, Shreerang; Clark, Catherine; Harrington, Kevin; Nutting, Christopher M.

    2007-01-01

    Head and neck squamous cell carcinoma with occult primary site represents a controversial clinical problem. Conventional total mucosal irradiation (TMI) maximizes local control, but at the expense of xerostomia. IMRT has been shown to spare salivary tissue in head and cancer patients. This study has been performed to investigate the potential of IMRT to perform nodal and TMI and also allow parotid gland sparing in this patient group. Conventional radiotherapy (CRT) and IMRT plans were produced for six patients to treat the ipsilateral (involved) post-operative neck (PTV1) and the un-operated contralateral neck and mucosal axis (PTV2). Plans were produced with and without the inclusion of nasopharynx in the PTV2. The potential to improve target coverage and spare the parotid glands was investigated for the IMRT plans. There was no significant difference in the mean doses to the PTV1 using CRT and IMRT (59.7 and 60.0 respectively, p = 0.5). The maximum doses to PTV1 and PTV2 were lower for the IMRT technique as compared to CRT (P = 0.008 and P < 0.0001), respectively, and the minimum doses to PTV1 and PTV2 were significantly higher for IMRT as compared to CRT (P = 0.001 and P = 0.001), respectively, illustrating better dose homogeneity with IMRT. The mean dose to the parotid gland contralateral to PTV1 was significantly lower for IMRT (23.21 ± 0.7) as compared to CRT (50.5 ± 5.8) (P < 0.0001). There was a significant difference in parotid dose between plans with and without the inclusion of the nasopharynx. IMRT offers improved dose homogeneity in PTV1 and PTV2 and allows for parotid sparing

  15. Attention modulates visual size adaptation.

    Science.gov (United States)

    Kreutzer, Sylvia; Fink, Gereon R; Weidner, Ralph

    2015-01-01

    The current study determined in healthy subjects (n = 16) whether size adaptation occurs at early, i.e., preattentive, levels of processing or whether higher cognitive processes such as attention can modulate the illusion. To investigate this issue, bottom-up stimulation was kept constant across conditions by using a single adaptation display containing both small and large adapter stimuli. Subjects' attention was directed to either the large or small adapter stimulus by means of a luminance detection task. When attention was directed toward the small as compared to the large adapter, the perceived size of the subsequent target was significantly increased. Data suggest that different size adaptation effects can be induced by one and the same stimulus depending on the current allocation of attention. This indicates that size adaptation is subject to attentional modulation. These findings are in line with previous research showing that transient as well as sustained attention modulates visual features, such as contrast sensitivity and spatial frequency, and influences adaptation in other contexts, such as motion adaptation (Alais & Blake, 1999; Lankheet & Verstraten, 1995). Based on a recently suggested model (Pooresmaeili, Arrighi, Biagi, & Morrone, 2013), according to which perceptual adaptation is based on local excitation and inhibition in V1, we conclude that guiding attention can boost these local processes in one or the other direction by increasing the weight of the attended adapter. In sum, perceptual adaptation, although reflected in changes of neural activity at early levels (as shown in the aforementioned study), is nevertheless subject to higher-order modulation.

  16. Fixed target beams

    CERN Document Server

    Kain, V; Cettour-Cave, S; Cornelis, K; Fraser, M A; Gatignon, L; Goddard, B; Velotti, F

    2017-01-01

    The CERN SPS (Super Proton Synchrotron) serves asLHC injector and provides beam for the North Area fixedtarget experiments. At low energy, the vertical acceptancebecomes critical with high intensity large emittance fixed tar-get beams. Optimizing the vertical available aperture is a keyingredient to optimize transmission and reduce activationaround the ring. During the 2016 run a tool was developed toprovide an automated local aperture scan around the entirering.The flux of particles slow extracted with the1/3inte-ger resonance from the Super Proton Synchrotron at CERNshould ideally be constant over the length of the extractionplateau, for optimum use of the beam by the fixed target ex-periments in the North Area. The extracted intensity is con-trolled in feed-forward correction of the horizontal tune viathe main SPS quadrupoles. The Mains power supply noiseat 50 Hz and harmonics is also corrected in feed-forwardby small amplitude tune modulation at the respective fre-quencies with a dedicated additional quad...

  17. Radioligand Recognition of Insecticide Targets.

    Science.gov (United States)

    Casida, John E

    2018-04-04

    Insecticide radioligands allow the direct recognition and analysis of the targets and mechanisms of toxic action critical to effective and safe pest control. These radioligands are either the insecticides themselves or analogs that bind at the same or coupled sites. Preferred radioligands and their targets, often in both insects and mammals, are trioxabicyclooctanes for the γ-aminobutyric acid (GABA) receptor, avermectin for the glutamate receptor, imidacloprid for the nicotinic receptor, ryanodine and chlorantraniliprole for the ryanodine receptor, and rotenone or pyridaben for NADH + ubiquinone oxidoreductase. Pyrethroids and other Na + channel modulator insecticides are generally poor radioligands due to lipophilicity and high nonspecific binding. For target site validation, the structure-activity relationships competing with the radioligand in the binding assays should be the same as that for insecticidal activity or toxicity except for rapidly detoxified or proinsecticide analogs. Once the radioligand assay is validated for relevance, it will often help define target site modifications on selection of resistant pest strains, selectivity between insects and mammals, and interaction with antidotes and other chemicals at modulator sites. Binding assays also serve for receptor isolation and photoaffinity labeling to characterize the interactions involved.

  18. Electroabsorption optical modulator

    Energy Technology Data Exchange (ETDEWEB)

    Skogen, Erik J.

    2017-11-21

    An electroabsorption modulator incorporates waveguiding regions along the length of the modulator that include quantum wells where at least two of the regions have quantum wells with different bandgaps. In one embodiment of the invention, the regions are arranged such that the quantum wells have bandgaps with decreasing bandgap energy along the length of the modulator from the modulator's input to its output. The bandgap energy of the quantum wells may be decreased in discrete steps or continuously. Advantageously, such an arrangement better distributes the optical absorption as well as the carrier density along the length of the modulator. Further advantageously, the modulator may handle increased optical power as compared with prior art modulators of similar dimensions, which allows for improved link gain when the optical modulator is used in an analog optical communication link.

  19. CDC 7600 module slice

    CERN Multimedia

    Each module contained 8 circuit cards for a total of about 300-500 uncovered transistors packaged with face plates so the Freon plates wouldn't touch the circuits. (cooling plates that surrounded each module).

  20. Exploration Augmentation Module Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The Exploration Augmentation Module (EAM) project goal is to design and deliver a flight module that is to be deployed to Earth-Lunar Distant Retrograde Orbit (DRO)....

  1. CDC 6600 Cordwood Module

    CERN Multimedia

    1964-01-01

    The CDC 6600 cordwood module containing 64 silicon transistors. The module was mounted between two plates that were cooled conductive by a refrigeration unit via the front panel. The construction of this module uses the cord method, so called because the resistors seem to be stacked like cord between the two circuit boards in order to obtain a high density. The 6600 model contained nearly 6,000 such modules.

  2. Modulating lignin in plants

    Science.gov (United States)

    Apuya, Nestor; Bobzin, Steven Craig; Okamuro, Jack; Zhang, Ke

    2013-01-29

    Materials and methods for modulating (e.g., increasing or decreasing) lignin content in plants are disclosed. For example, nucleic acids encoding lignin-modulating polypeptides are disclosed as well as methods for using such nucleic acids to generate transgenic plants having a modulated lignin content.

  3. An investigation into modulators

    International Nuclear Information System (INIS)

    Heine, E.

    1988-01-01

    In the framework of the MEA-update it is important to establish which modulators are necessary. In this report it is lookedif the existing modulators can be maintained or new modulators have to be made. Besides technical aspects also material expenses and necessary manpower play a role. 12 figs.; 6 tabs

  4. Weakly Coretractable Modules

    Science.gov (United States)

    Hadi, Inaam M. A.; Al-aeashi, Shukur N.

    2018-05-01

    If R is a ring with identity and M is a unitary right R-module. Here we introduce the class of weakly coretractable module. Some basic properties are investigated and some relationships between these modules and other related one are introduced.

  5. Getting started with Magento module development

    CERN Document Server

    Ajzele, Branko

    2013-01-01

    This project-based tutorial gives you a strong foundation and guides you through practical, real-world examples.This book contains valuable insights for both newbies and already established Magento developers. This book is targeted at new and intermediate PHP developers starting afresh with Magento module development.

  6. Amplitude modulation detection with concurrent frequency modulation.

    Science.gov (United States)

    Nagaraj, Naveen K

    2016-09-01

    Human speech consists of concomitant temporal modulations in amplitude and frequency that are crucial for speech perception. In this study, amplitude modulation (AM) detection thresholds were measured for 550 and 5000 Hz carriers with and without concurrent frequency modulation (FM), at AM rates crucial for speech perception. Results indicate that adding 40 Hz FM interferes with AM detection, more so for 5000 Hz carrier and for frequency deviations exceeding the critical bandwidth of the carrier frequency. These findings suggest that future cochlear implant processors, encoding speech fine-structures may consider limiting the FM to narrow bandwidth and to low frequencies.

  7. Adaptive Modulation for a Downlink Multicast Channel in OFDMA Systems

    DEFF Research Database (Denmark)

    Wang, Haibo; Schwefel, Hans-Peter; Toftegaard, Thomas Skjødeberg

    2007-01-01

    In this paper we focus on adaptive modulation strategies for multicast service in orthogonal frequency division multiple access systems. A reward function has been defined as the optimization target, which includes both the average user throughput and bit error rate. We also developed an adaptive...... modulation strategy, namely local best reward strategy, to maximize this reward function. The performance of different modulation strategies are compared in different SNR distribution scenarios, and the optimum strategy in each scenario is suggested....

  8. Properties of Protein Drug Target Classes

    Science.gov (United States)

    Bull, Simon C.; Doig, Andrew J.

    2015-01-01

    Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein’s sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein’s sequence (e.g. secondary structure). Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins’ hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme. PMID

  9. The time course of attention modulation elicited by spatial uncertainty.

    Science.gov (United States)

    Huang, Dan; Liang, Huilou; Xue, Linyan; Wang, Meijian; Hu, Qiyi; Chen, Yao

    2017-09-01

    Uncertainty regarding the target location is an influential factor for spatial attention. Modulation in spatial uncertainty can lead to adjustments in attention scope and variations in attention effects. Hence, investigating spatial uncertainty modulation is important for understanding the underlying mechanism of spatial attention. However, the temporal dynamics of this modulation remains unclear. To evaluate the time course of spatial uncertainty modulation, we adopted a Posner-like attention orienting paradigm with central or peripheral cues. Different numbers of cues were used to indicate the potential locations of the target and thereby manipulate the spatial uncertainty level. The time interval between the onsets of the cue and the target (stimulus onset asynchrony, SOA) varied from 50 to 2000ms. We found that under central cueing, the effect of spatial uncertainty modulation could be detected from 200 to 2000ms after the presence of the cues. Under peripheral cueing, the effect of spatial uncertainty modulation was observed from 50 to 2000ms after cueing. Our results demonstrate that spatial uncertainty modulation produces robust and sustained effects on target detection speed. The time course of this modulation is influenced by the cueing method, which suggests that discrepant processing procedures are involved under different cueing conditions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Gas puff modulation experiments in Tore Supra

    International Nuclear Information System (INIS)

    Haas, J.C.M. de; Devynck, P.; Dudok de Wit, T.; Garbet, X.; Gil, C.; Harris, G.; Laviron, C.; Martin, G.

    1993-01-01

    Experiments with a modulation of the gas puff have been done in Tore Supra with the aim to investigate the transport of particles and heat. The target plasma is ohmically heated, sawtoothing with frequencies between 12 and 20 Hz, deuterium for both the plasma and the injection, and with various densities, rising in a series of shots. Both the diffusion coefficient and the pinch velocity for the particle transport were determined using an harmonic modulation. The method gives reasonable results, even for small perturbations, and the obtained values are able to reproduce the stationary values. The heat flow carried by electrons also shows a modulation. The part of the modulation which is not caused by the density can in principle be used to discriminate diffusive and convective terms in the heat flux. An ion temperature profile calculated with empirically determined value of heat diffusivity reproduces the slow evolution of the total kinetic energy. 6 figs., 7 refs

  11. Divisible ℤ-modules

    Directory of Open Access Journals (Sweden)

    Futa Yuichi

    2016-03-01

    Full Text Available In this article, we formalize the definition of divisible ℤ-module and its properties in the Mizar system [3]. We formally prove that any non-trivial divisible ℤ-modules are not finitely-generated.We introduce a divisible ℤ-module, equivalent to a vector space of a torsion-free ℤ-module with a coefficient ring ℚ. ℤ-modules are important for lattice problems, LLL (Lenstra, Lenstra and Lovász base reduction algorithm [15], cryptographic systems with lattices [16] and coding theory [8].

  12. Status of Cea spallation modules for ads

    International Nuclear Information System (INIS)

    Enderle, R.; Poitevin, Y.; Deffain, J.P.; Bergeron, J.

    2001-01-01

    In the framework of CEA studies on ADS dedicated to waste transmutation, a liquid metal reference concept and an alternative solid target have been evaluated to produce neutrons inside the spallation module. This work examines the design (neutronic, thermohydraulic and mechanical aspects) and the performances of both options. It is shown that a liquid Pb-Bi target offers more possibilities regarding to high protons current densities (possible industrial extrapolation) but that a solid target made with tungsten particles offers also interesting ability to create a neutrons flux appropriated (strong spectrum and flat axial distribution) to an sub-critical core dedicated to incineration. (author)

  13. Mediator kinase module and human tumorigenesis.

    Science.gov (United States)

    Clark, Alison D; Oldenbroek, Marieke; Boyer, Thomas G

    2015-01-01

    Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit "kinase" module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways.

  14. Survivin, a target to modulate the radiosensitivity of Ewing's sarcoma

    International Nuclear Information System (INIS)

    Greve, B.; Sheikh-Mounessi, F.; Ernst, I.; Eich, H.T.; Kemper, B.; Goette, M.

    2012-01-01

    Background and purpose: Radiotherapy constitutes an essential element in the multimodal therapy of Ewing's sarcoma. Compared to other sarcomas, Ewing tumors normally show a good response to radiotherapy. However, there are consistently tumors with a radioresistant phenotype, and the underlying mechanisms are not known in detail. Here we investigated the association between survivin protein expression and the radiosensitivity of Ewing's sarcoma in vitro. Material and methods: An siRNA-based knockdown approach was used to investigate the influence of survivin expression on cell proliferation, double-strand break (DSB) induction and repair, apoptosis and colony-forming ability in four Ewing's sarcoma cell lines with and without irradiation. Results: Survivin protein and mRNA were upregulated in all cell lines tested in a dose-dependent manner. As a result of survivin knockdown, STA-ET-1 cells showed reduced cell proliferation, an increased number of radiation-induced DSBs, and reduced repair. Apoptosis was increased by knockdown alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin knockdown in combination with irradiation. Conclusion: Survivin is a radiation-inducible protein in Ewing's sarcoma and its down-regulation sensitizes cells toward irradiation. Survivin knockdown in combination with radiation inhibits cell proliferation, repair, and colony formation significantly and increases apoptosis more than each single treatment alone. This might open new perspectives in the radiation treatment of Ewing's sarcoma. (orig.)

  15. Targeting Prostate Cancer with Bifunctional Modulators of the Androgen Receptor

    Science.gov (United States)

    2015-06-01

    Wittmann, B.; Dwyer, M.; Cui, H.; Dye, D.; McDonnell, D.; Norris , J. Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists...Wittmann, B.; Dwyer, M.; Cui, H.; Dye, D.; McDonnell, D.; Norris , J. Inhibition of prostate cancer cell growth by second-site androgen receptor...important clin- ical problem in diseases such as asthma (51, 52), ne- phrotic syndrome (53), and malignancies such as acute lymphoblastic leukemia (54

  16. Oct4 targets regulatory nodes to modulate stem cell function.

    Directory of Open Access Journals (Sweden)

    Pearl A Campbell

    2007-06-01

    Full Text Available Stem cells are characterized by two defining features, the ability to self-renew and to differentiate into highly specialized cell types. The POU homeodomain transcription factor Oct4 (Pou5f1 is an essential mediator of the embryonic stem cell state and has been implicated in lineage specific differentiation, adult stem cell identity, and cancer. Recent description of the regulatory networks which maintain 'ES' have highlighted a dual role for Oct4 in the transcriptional activation of genes required to maintain self-renewal and pluripotency while concomitantly repressing genes which facilitate lineage specific differentiation. However, the molecular mechanism by which Oct4 mediates differential activation or repression at these loci to either maintain stem cell identity or facilitate the emergence of alternate transcriptional programs required for the realization of lineage remains to be elucidated. To further investigate Oct4 function, we employed gene expression profiling together with a robust statistical analysis to identify genes highly correlated to Oct4. Gene Ontology analysis to categorize overrepresented genes has led to the identification of themes which may prove essential to stem cell identity, including chromatin structure, nuclear architecture, cell cycle control, DNA repair, and apoptosis. Our experiments have identified previously unappreciated roles for Oct4 for firstly, regulating chromatin structure in a state consistent with self-renewal and pluripotency, and secondly, facilitating the expression of genes that keeps the cell poised to respond to cues that lead to differentiation. Together, these data define the mechanism by which Oct4 orchestrates cellular regulatory pathways to enforce the stem cell state and provides important insight into stem cell function and cancer.

  17. Survivin, a target to modulate the radiosensitivity of Ewing's sarcoma.

    Science.gov (United States)

    Greve, B; Sheikh-Mounessi, F; Kemper, B; Ernst, I; Götte, M; Eich, H T

    2012-11-01

    Radiotherapy constitutes an essential element in the multimodal therapy of Ewing's sarcoma. Compared to other sarcomas, Ewing tumors normally show a good response to radiotherapy. However, there are consistently tumors with a radioresistant phenotype, and the underlying mechanisms are not known in detail. Here we investigated the association between survivin protein expression and the radiosensitivity of Ewing's sarcoma in vitro. An siRNA-based knockdown approach was used to investigate the influence of survivin expression on cell proliferation, double-strand break (DSB) induction and repair, apoptosis and colony-forming ability in four Ewing's sarcoma cell lines with and without irradiation. Survivin protein and mRNA were upregulated in all cell lines tested in a dose-dependent manner. As a result of survivin knockdown, STA-ET-1 cells showed reduced cell proliferation, an increased number of radiation-induced DSBs, and reduced repair. Apoptosis was increased by knockdown alone and increased further in combination with irradiation. Colony formation was significantly reduced by survivin knockdown in combination with irradiation. Survivin is a radiation-inducible protein in Ewing's sarcoma and its down-regulation sensitizes cells toward irradiation. Survivin knockdown in combination with radiation inhibits cell proliferation, repair, and colony formation significantly and increases apoptosis more than each single treatment alone. This might open new perspectives in the radiation treatment of Ewing's sarcoma.

  18. System and Method for Generating a Frequency Modulated Linear Laser Waveform

    Science.gov (United States)

    Pierrottet, Diego F. (Inventor); Petway, Larry B. (Inventor); Amzajerdian, Farzin (Inventor); Barnes, Bruce W. (Inventor); Lockard, George E. (Inventor); Hines, Glenn D. (Inventor)

    2017-01-01

    A system for generating a frequency modulated linear laser waveform includes a single frequency laser generator to produce a laser output signal. An electro-optical modulator modulates the frequency of the laser output signal to define a linear triangular waveform. An optical circulator passes the linear triangular waveform to a band-pass optical filter to filter out harmonic frequencies created in the waveform during modulation of the laser output signal, to define a pure filtered modulated waveform having a very narrow bandwidth. The optical circulator receives the pure filtered modulated laser waveform and transmits the modulated laser waveform to a target.

  19. Characterization of polarization-independent phase modulation method for practical plug and play quantum cryptography

    International Nuclear Information System (INIS)

    Kwon, Osung; Lee, Min-Soo; Woo, Min Ki; Park, Byung Kwon; Kim, Il Young; Kim, Yong-Su; Han, Sang-Wook; Moon, Sung

    2015-01-01

    We characterized a polarization-independent phase modulation method, called double phase modulation, for a practical plug and play quantum key distribution (QKD) system. Following investigation of theoretical backgrounds, we applied the method to the practical QKD system and characterized the performance through comparing single phase modulation (SPM) and double phase modulation. Consequently, we obtained repeatable and accurate phase modulation confirmed by high visibility single photon interference even for input signals with arbitrary polarization. Further, the results show that only 80% of the bias voltage required in the case of single phase modulation is needed to obtain the target amount of phase modulation. (paper)

  20. Cerebral cortex modulation of pain

    Institute of Scientific and Technical Information of China (English)

    Yu-feng XIE; Fu-quan HUO; Jing-shi TANG

    2009-01-01

    Pain is a complex experience encompassing sensory-discriminative, affective-motivational and cognitiv e-emotional com-ponents mediated by different mechanisms. Contrary to the traditional view that the cerebral cortex is not involved in pain perception, an extensive cortical network associated with pain processing has been revealed using multiple methods over the past decades. This network consistently includes, at least, the anterior cingulate cortex, the agranular insular cortex, the primary (SⅠ) and secondary somatosensory (SⅡ) cortices, the ventrolateral orbital cortex and the motor cortex. These corti-cal structures constitute the medial and lateral pain systems, the nucleus submedius-ventrolateral orbital cortex-periaque-ductal gray system and motor cortex system, respectively. Multiple neurotransmitters, including opioid, glutamate, GABA and dopamine, are involved in the modulation of pain by these cortical structures. In addition, glial cells may also be in-volved in cortical modulation of pain and serve as one target for pain management research. This review discusses recent studies of pain modulation by these cerebral cortical structures in animals and human.

  1. Classes of modules

    CERN Document Server

    Dauns, John

    2006-01-01

    Because traditional ring theory places restrictive hypotheses on all submodules of a module, its results apply only to small classes of already well understood examples. Often, modules with infinite Goldie dimension have finite-type dimension, making them amenable to use with type dimension, but not Goldie dimension. By working with natural classes and type submodules (TS), Classes of Modules develops the foundations and tools for the next generation of ring and module theory. It shows how to achieve positive results by placing restrictive hypotheses on a small subset of the complement submodules, Furthermore, it explains the existence of various direct sum decompositions merely as special cases of type direct sum decompositions. Carefully developing the foundations of the subject, the authors begin by providing background on the terminology and introducing the different module classes. The modules classes consist of torsion, torsion-free, s[M], natural, and prenatural. They expand the discussion by exploring...

  2. Heavy-ion targets

    International Nuclear Information System (INIS)

    Adair, H.L.; Kobisk, E.H.

    1985-01-01

    This chapter examines the characteristics of targets required in heavy-ion accelerator physics experiments. The effects of target parameters on heavy-ion experimental results are reviewed. The target fabrication and characterization techniques used to minimize experimental problems during heavy-ion bombardment are described. Topics considered include target thickness and uniformity, target lifetime, target purity, substrate materials, Doppler shift effects, metal preparations, and target preparation methods

  3. Pengembangan Modul Bimbingan dan Konseling untuk Pencegahan Bullying di Sekolah

    Directory of Open Access Journals (Sweden)

    Hengki Yandri

    2013-03-01

    Full Text Available This research aims to formulate guidance and counseling module to prevent bullying at school and to describe the level of applicability used by counselor. The method used was ADDIE model development. The subjects of the research consisted of guidance and counseling expert and the intended target of the module (counselor, chosen through purposive sampling. The instruments used were questionnaire and focus group discussion (FGD. The data were analyzed descriptively. The results showed that prototype modules developed to prevent bullying at school is applicable used by the counselor and those modules can be utilized by counselor to prevent bullying at school.

  4. Direct drive acceleration of planar liquid deuterium targets

    International Nuclear Information System (INIS)

    Sethian, J.D.; Bodner, S.E.; Colombant, D.G.; Dahlburg, J.P.; Obenschain, S.P.; Pawley, C.J.; Serlin, V.; Gardner, J.H.; Aglitskiy, Y.; Chan, Y.; Deniz, A.V.; Lehecka, T.; Klapisch, M.

    1999-01-01

    The Nike laser (∼2 - 3 kJ, ∼10 14 W/cm 2 ) has been used to ablatively accelerate planar liquid deuterium targets. These experiments are designed to test some aspects of a high gain direct drive target design. The target consists of a low-density foam that is filled with liquid deuterium and covered with a thin polyimide membrane. The measured target trajectory agrees well with one-dimensional (1D) simulations. The growth of the areal mass modulations were measured with a new, 1.26 keV x-ray backlighter. The modulations appear later and grow to a smaller amplitude when the foot of the laser pulse is made spatially smoother. A thin layer of gold on the front of the target reduces the modulations. The results are compared with 2D modeling

  5. FASTBUS Snoop Diagnostic Module

    International Nuclear Information System (INIS)

    Walz, H.V.; Downing, R.

    1980-11-01

    Development of the FASTBUS Snoop Module, undertaken as part of the prototype program for the new interlaboratory data bus standard, is described. The Snoop Module resides on a FASTBUS crate segment and provides diagnostic monitoring and testing capability. Communication with a remote host computer is handled independent of FASTBUS through a serial link. The module consists of a high-speed ECL front-end to monitor and single-step FASTBUS cycles, a master-slave interface, and a control microprocessor with serial communication ports. Design details and performance specifications of the prototype module are reported. 9 figures, 1 table

  6. Bracket for photovoltaic modules

    Science.gov (United States)

    Ciasulli, John; Jones, Jason

    2014-06-24

    Brackets for photovoltaic ("PV") modules are described. In one embodiment, a saddle bracket has a mounting surface to support one or more PV modules over a tube, a gusset coupled to the mounting surface, and a mounting feature coupled to the gusset to couple to the tube. The gusset can have a first leg and a second leg extending at an angle relative to the mounting surface. Saddle brackets can be coupled to a torque tube at predetermined locations. PV modules can be coupled to the saddle brackets. The mounting feature can be coupled to the first gusset and configured to stand the one or more PV modules off the tube.

  7. Crossed modules of racks

    OpenAIRE

    Crans, Alissa S.; Wagemann, Friedrich

    2014-01-01

    We generalize the notion of a crossed module of groups to that of a crossed module of racks. We investigate the relation to categorified racks, namely strict 2-racks, and trunk-like objects in the category of racks, generalizing the relation between crossed modules of groups and strict 2-groups. Then we explore topological applications. We show that by applying the rack-space functor, a crossed module of racks gives rise to a covering. Our main result shows how the fundamental racks associate...

  8. Model theory and modules

    CERN Document Server

    Prest, M

    1988-01-01

    In recent years the interplay between model theory and other branches of mathematics has led to many deep and intriguing results. In this, the first book on the topic, the theme is the interplay between model theory and the theory of modules. The book is intended to be a self-contained introduction to the subject and introduces the requisite model theory and module theory as it is needed. Dr Prest develops the basic ideas concerning what can be said about modules using the information which may be expressed in a first-order language. Later chapters discuss stability-theoretic aspects of module

  9. Delphi Accounts Receivable Module -

    Data.gov (United States)

    Department of Transportation — Delphi accounts receivable module contains the following data elements, but are not limited to customer information, cash receipts, line of accounting details, bill...

  10. Design of small-molecule epigenetic modulators

    Science.gov (United States)

    Pachaiyappan, Boobalan

    2013-01-01

    The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be catagorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. PMID:24300735

  11. Growth Modulation in Achondroplasia.

    Science.gov (United States)

    McClure, Philip K; Kilinc, Eray; Birch, John G

    2017-09-01

    Achondroplasia is the most common skeletal dysplasia with a rate of nearly 1/10,000. The development of lower extremity deformity is well documented, and various modes of correction have been reported. There are no reports on the use of growth modulation to correct angular deformity in achondroplasia. Medical Records from 1985 to 2015 were reviewed for the diagnosis of achondroplasia and growth modulation procedures. Patients who had been treated for angular deformity of the legs by growth modulation were identified. A detailed analysis of their medical record and preoperative and final lower extremity radiographs was completed. Four patients underwent growth modulation procedures, all to correct existing varus deformity of the legs. Three of the 4 patients underwent bilateral distal femoral and proximal tibial growth modulation. The remaining patient underwent tibial correction only. Two of the 4 patients had a combined proximal fibular epiphysiodesis. All limbs had some improvement of alignment; however, 1 patient went on to bilateral osteotomies. Only 1 limb corrected to a neutral axis with growth modulation alone at last follow-up, initial implantation was done before 5 years of age. Growth modulation is an effective means for deformity correction in the setting of achondroplasia. However implantation may need to be done earlier than would be typical for patients without achondroplasia. Osteotomy may still be required after growth modulation for incomplete correction.

  12. Defect detection module

    International Nuclear Information System (INIS)

    Ernwein, R.; Westermann, G.

    1986-01-01

    The ''defect detector'' module is aimed at exceptional event or state recording. Foreseen for voltage presence monitoring on high supply voltage module of drift chambers, its characteristics can also show up the vanishing of supply voltage and take in account transitory fast signals [fr

  13. The Strip Module

    DEFF Research Database (Denmark)

    Pedersen, Tommy

    1996-01-01

    When the behaviour of a ship in waves is to be predicted it is convenient to have a tool which includes different approaches to the problem.The aim of this project is to develop such a tool named the strip theory module. The strip theory module will consist of submodules dependent on the I...

  14. The FPAX fastbus module

    International Nuclear Information System (INIS)

    Barlag, S.; Bouquet, B.; Lavigne, B.; Rypko, J.

    1989-07-01

    The FPAX is a Fastbus module with 4 independent, 2 slave and 2 master, ports on two segments. It operates as a normal master on either segment or as a Block-Mover on both. The processor board is based on a 68020 microprocessor. A local/network switch allows operation as a host or as a normal module on the Fastbus network

  15. Photovoltaic module and laminate

    Science.gov (United States)

    Bunea, Gabriela E.; Kim, Sung Dug; Kavulak, David F.J.

    2018-04-10

    A photovoltaic module is disclosed. The photovoltaic module has a first side directed toward the sun during normal operation and a second, lower side. The photovoltaic module comprises a perimeter frame and a photovoltaic laminate at least partially enclosed by and supported by the perimeter frame. The photovoltaic laminate comprises a transparent cover layer positioned toward the first side of the photovoltaic module, an upper encapsulant layer beneath and adhering to the cover layer, a plurality of photovoltaic solar cells beneath the upper encapsulant layer, the photovoltaic solar cells electrically interconnected, a lower encapsulant layer beneath the plurality of photovoltaic solar cells, the upper and lower encapsulant layers enclosing the plurality of photovoltaic solar cells, and a homogenous rear environmental protection layer, the rear environmental protection layer adhering to the lower encapsulant layer, the rear environmental protection layer exposed to the ambient environment on the second side of the photovoltaic module.

  16. Solar energy modulator

    Science.gov (United States)

    Hale, R. R. (Inventor); Mcdougal, A. R.

    1984-01-01

    A module is described with a receiver having a solar energy acceptance opening and supported by a mounting ring along the optic axis of a parabolic mirror in coaxial alignment for receiving solar energy from the mirror, and a solar flux modulator plate for varying the quantity of solar energy flux received by the acceptance opening of the module. The modulator plate is characterized by an annular, plate-like body, the internal diameter of which is equal to or slightly greater than the diameter of the solar energy acceptance opening of the receiver. Slave cylinders are connected to the modulator plate for supporting the plate for axial displacement along the axis of the mirror, therby shading the opening with respect to solar energy flux reflected from the surface of the mirror to the solar energy acceptance opening.

  17. Smart lighting using a liquid crystal modulator

    Science.gov (United States)

    Baril, Alexandre; Thibault, Simon; Galstian, Tigran

    2017-08-01

    Now that LEDs have massively invaded the illumination market, a clear trend has emerged for more efficient and targeted lighting. The project described here is at the leading edge of the trend and aims at developing an evaluation board to test smart lighting applications. This is made possible thanks to a new liquid crystal light modulator recently developed for broadening LED light beams. The modulator is controlled by electrical signals and is characterized by a linear working zone. This feature allows the implementation of a closed loop control with a sensor feedback. This project shows that the use of computer vision is a promising opportunity for cheap closed loop control. The developed evaluation board integrates the liquid crystal modulator, a webcam, a LED light source and all the required electronics to implement a closed loop control with a computer vision algorithm.

  18. Universal Reconfigurable Translator Module (URTM) Final Report

    Science.gov (United States)

    Leventhal, Edward; Machan, Roman; Jones, Rob

    2009-01-01

    This report describes the Universal Reconfigurable Translation Module, or URTM. The URTM was developed by Sigma Space Corporation for NASA in order to translate specific serial protocols, both logically and physically. At present, the prototype configuration has targeted MIL-STD-1553B (RT and BC), IEEE 1394b (Firewire), and ECSS-E-50-12A (SpaceWire). The objectives of this program were to study the feasibility of a configurable URTM to translate serial link data as might be used in a space-flight mission and to design, develop, document, and deliver an engineering prototype model of the URTM with a path to spaceflight. By simply connecting two of the three Physical Interface Modules (PIM) on either end of the RPTM (Reconfigurable Protocol Translator Module), the URTM then self configures via a library of interface translation functions, thereby allowing the two data links to communicate seamlessly.

  19. Attractive faces temporally modulate visual attention

    Science.gov (United States)

    Nakamura, Koyo; Kawabata, Hideaki

    2014-01-01

    Facial attractiveness is an important biological and social signal on social interaction. Recent research has demonstrated that an attractive face captures greater spatial attention than an unattractive face does. Little is known, however, about the temporal characteristics of visual attention for facial attractiveness. In this study, we investigated the temporal modulation of visual attention induced by facial attractiveness by using a rapid serial visual presentation. Fourteen male faces and two female faces were successively presented for 160 ms, respectively, and participants were asked to identify two female faces embedded among a series of multiple male distractor faces. Identification of a second female target (T2) was impaired when a first target (T1) was attractive compared to neutral or unattractive faces, at 320 ms stimulus onset asynchrony (SOA); identification was improved when T1 was attractive compared to unattractive faces at 640 ms SOA. These findings suggest that the spontaneous appraisal of facial attractiveness modulates temporal attention. PMID:24994994

  20. Attractive faces temporally modulate visual attention

    Directory of Open Access Journals (Sweden)

    Koyo eNakamura

    2014-06-01

    Full Text Available Facial attractiveness is an important biological and social signal on social interaction. Recent research has demonstrated that an attractive face captures greater spatial attention than an unattractive face does. Little is known, however, about the temporal characteristics of visual attention for facial attractiveness. In this study, we investigated the temporal modulation of visual attention induced by facial attractiveness by using a rapid serial visual presentation (RSVP. Fourteen male faces and two female faces were successively presented for 160 ms respectively, and participants were asked to identify two female faces embedded among a series of multiple male distractor faces. Identification of a second female target (T2 was impaired when a first target (T1 was attractive compared to neutral or unattractive faces, at 320 ms SOA; identification was improved when T1 was attractive compared to unattractive faces at 640 ms SOA. These findings suggest that the spontaneous appraisal of facial attractiveness modulates temporal attention.

  1. Drug-Target Kinetics in Drug Discovery.

    Science.gov (United States)

    Tonge, Peter J

    2018-01-17

    The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

  2. Photovoltaic module and interlocked stack of photovoltaic modules

    Science.gov (United States)

    Wares, Brian S.

    2014-09-02

    One embodiment relates to an arrangement of photovoltaic modules configured for transportation. The arrangement includes a plurality of photovoltaic modules, each photovoltaic module including a frame. A plurality of individual male alignment features and a plurality of individual female alignment features are included on each frame. Adjacent photovoltaic modules are interlocked by multiple individual male alignment features on a first module of the adjacent photovoltaic modules fitting into and being surrounded by corresponding individual female alignment features on a second module of the adjacent photovoltaic modules. Other embodiments, features and aspects are also disclosed.

  3. The ANTARES optical module

    Energy Technology Data Exchange (ETDEWEB)

    Amram, P.; Anghinolfi, M.; Anvar, S.; Ardellier-Desages, F.E.; Aslanides, E.; Aubert, J.-J.; Azoulay, R.; Bailey, D.; Basa, S.; Battaglieri, M.; Bellotti, R.; Benhammou, Y.; Bernard, F.; Berthier, R.; Bertin, V.; Billault, M.; Blaes, R.; Bland, R.W.; Blondeau, F.; Botton, N. de; Boulesteix, J.; Brooks, C.B.; Brunner, J.; Cafagna, F.; Calzas, A.; Capone, A.; Caponetto, L.; Carloganu, C.; Carmona, E.; Carr, J.; Carton, P.-H.; Cartwright, S.L.; Cassol, F.; Cecchini, S.; Ciacio, F.; Circella, M.; Compere, C.; Cooper, S.; Coyle, P.; Croquette, J.; Cuneo, S.; Danilov, M.; Dantzig, R. van; De Marzo, C.; DeVita, R.; Deck, P.; Destelle, J.-J.; Dispau, G.; Drougou, J.F.; Druillole, F.; Engelen, J.; Feinstein, F.; Festy, D.; Fopma, J.; Gallone, J.-M.; Giacomelli, G.; Goret, P.; Gosset, L.; Gournay, J.-F.; Heijboer, A.; Hernandez-Rey, J.J.; Herrouin, G.; Hubbard, J.R.; Jaquet, M.; Jong, M. de; Karolak, M.; Kooijman, P.; Kouchner, A.; Kudryavtsev, V.A.; Lachartre, D.; Lafoux, H. E-mail: lafoux@cea.fr; Lamare, P.; Languillat, J.-C.; Laubier, L.; Laugier, J.-P.; Le Guen, Y.; Le Provost, H.; Le Van Suu, A.; Lemoine, L.; Lo Nigro, L.; Lo Presti, D.; Loucatos, S.; Louis, F.; Lyashuk, V.; Magnier, P.; Marcelin, M.; Margiotta, A.; Massol, A.; Masullo, R.; Mazeas, F.; Mazeau, B.; Mazure, A.; McMillan, J.E.; Michel, J.L.; Migneco, E.; Millot, C.; Mols, P.; Montanet, F.; Montaruli, T.; Morel, J.P.; Moscoso, L.; Musumeci, M.; Navas, S.; Nezri, E.; Nooren, G.J.; Oberski, J.; Olivetto, C.; Oppelt-Pohl, A.; Palanque-Delabrouille, N.; Papaleo, R.; Payre, P.; Perrin, P.; Petruccetti, M.; Petta, C.; Piattelli, P.; Poinsignon, J.; Potheau, R.; Queinec, Y.; Racca, C.; Raia, G.; Randazzo, N.; Rethore, F.; Riccobene, G.; Ricol, J.-S.; Ripani, M.; Roca-Blay, V.; Rolin, J.F.; Rostovstev, A.; Russo, G.V.; Sacquin, Y.; Salusti, E.; Schuller, J.-P.; Schuster, W.; Soirat, J.-P.; Souvorova, O.; Spooner, N.J.C.; Spurio, M.; Stolarczyk, T.; Stubert, D.; Taiuti, M.; Tao, C.; Tayalati, Y.; Thompson, L.F.

    2002-05-21

    The ANTARES collaboration is building a deep sea neutrino telescope in the Mediterranean Sea. This detector will cover a sensitive area of typically 0.1 km{sup 2} and will be equipped with about 1000 optical modules. Each of these optical modules consists of a large area photomultiplier and its associated electronics housed in a pressure resistant glass sphere. The design of the ANTARES optical module, which is a key element of the detector, has been finalized following extensive R and D studies and is reviewed here in detail.

  4. The ANTARES optical module

    International Nuclear Information System (INIS)

    Amram, P.; Anghinolfi, M.; Anvar, S.; Ardellier-Desages, F.E.; Aslanides, E.; Aubert, J.-J.; Azoulay, R.; Bailey, D.; Basa, S.; Battaglieri, M.; Bellotti, R.; Benhammou, Y.; Bernard, F.; Berthier, R.; Bertin, V.; Billault, M.; Blaes, R.; Bland, R.W.; Blondeau, F.; Botton, N. de; Boulesteix, J.; Brooks, C.B.; Brunner, J.; Cafagna, F.; Calzas, A.; Capone, A.; Caponetto, L.; Carloganu, C.; Carmona, E.; Carr, J.; Carton, P.-H.; Cartwright, S.L.; Cassol, F.; Cecchini, S.; Ciacio, F.; Circella, M.; Compere, C.; Cooper, S.; Coyle, P.; Croquette, J.; Cuneo, S.; Danilov, M.; Dantzig, R. van; De Marzo, C.; DeVita, R.; Deck, P.; Destelle, J.-J.; Dispau, G.; Drougou, J.F.; Druillole, F.; Engelen, J.; Feinstein, F.; Festy, D.; Fopma, J.; Gallone, J.-M.; Giacomelli, G.; Goret, P.; Gosset, L.; Gournay, J.-F.; Heijboer, A.; Hernandez-Rey, J.J.; Herrouin, G.; Hubbard, J.R.; Jaquet, M.; Jong, M. de; Karolak, M.; Kooijman, P.; Kouchner, A.; Kudryavtsev, V.A.; Lachartre, D.; Lafoux, H.; Lamare, P.; Languillat, J.-C.; Laubier, L.; Laugier, J.-P.; Le Guen, Y.; Le Provost, H.; Le Van Suu, A.; Lemoine, L.; Lo Nigro, L.; Lo Presti, D.; Loucatos, S.; Louis, F.; Lyashuk, V.; Magnier, P.; Marcelin, M.; Margiotta, A.; Massol, A.; Masullo, R.; Mazeas, F.; Mazeau, B.; Mazure, A.; McMillan, J.E.; Michel, J.L.; Migneco, E.; Millot, C.; Mols, P.; Montanet, F.; Montaruli, T.; Morel, J.P.; Moscoso, L.; Musumeci, M.; Navas, S.; Nezri, E.; Nooren, G.J.; Oberski, J.; Olivetto, C.; Oppelt-Pohl, A.; Palanque-Delabrouille, N.; Papaleo, R.; Payre, P.; Perrin, P.; Petruccetti, M.; Petta, C.; Piattelli, P.; Poinsignon, J.; Potheau, R.; Queinec, Y.; Racca, C.; Raia, G.; Randazzo, N.; Rethore, F.; Riccobene, G.; Ricol, J.-S.; Ripani, M.; Roca-Blay, V.; Rolin, J.F.; Rostovstev, A.; Russo, G.V.; Sacquin, Y.; Salusti, E.; Schuller, J.-P.; Schuster, W.; Soirat, J.-P.; Souvorova, O.; Spooner, N.J.C.; Spurio, M.; Stolarczyk, T.; Stubert, D.; Taiuti, M.; Tao, C.; Tayalati, Y.; Thompson, L.F.; Tilav, S.; Triay, R.; Valente, V.; Varlamov, I.; Vaudaine, G.; Vernin, P.; Witt Huberts, P. de; Wolf, E. de; Zakharov, V.; Zavatarelli, S.; D Zornoza, J. de; Zuniga, J.

    2002-01-01

    The ANTARES collaboration is building a deep sea neutrino telescope in the Mediterranean Sea. This detector will cover a sensitive area of typically 0.1 km 2 and will be equipped with about 1000 optical modules. Each of these optical modules consists of a large area photomultiplier and its associated electronics housed in a pressure resistant glass sphere. The design of the ANTARES optical module, which is a key element of the detector, has been finalized following extensive R and D studies and is reviewed here in detail

  5. The ANTARES Optical Module

    CERN Document Server

    Amram, P; Anvar, S; Ardellier-Desages, F E; Aslanides, Elie; Aubert, Jean-Jacques; Azoulay, R; Bailey, D; Basa, S; Battaglieri, M; Bellotti, R; Benhammou, Ya; Bernard, F; Berthier, R; Bertin, V; Billault, M; Blaes, R; Bland, R W; Blondeau, F; De Botton, N R; Boulesteix, J; Brooks, B; Brunner, J; Cafagna, F; Calzas, A; Capone, A; Caponetto, L; Cârloganu, C; Carmona, E; Carr, J; Carton, P H; Cartwright, S L; Cassol, F; Cecchini, S; Ciacio, F; Circella, M; Compere, C; Cooper, S; Coyle, P; Croquette, J; Cuneo, S; Danilov, M; Van Dantzig, R; De Marzo, C; De Vita, R; Deck, P; Destelle, J J; Dispau, G; Drougou, J F; Druillole, F; Engelen, J; Feinstein, F; Festy, D; Fopma, J; Gallone, J M; Giacomelli, G; Goret, P; Gosset, L G; Gournay, J F; Heijboer, A; Hernández-Rey, J J; Herrouin, G; Hubbard, John R; Jacquet, M; De Jong, M; Karolak, M; Kooijman, P M; Kouchner, A; Kudryavtsev, V A; Lachartre, D; Lafoux, H; Lamare, P; Languillat, J C; Laubier, L; Laugier, J P; Le Guen, Y; Le Provost, H; Le Van-Suu, A; Lemoine, L; Lo Nigro, L; Lo Presti, D; Loucatos, Sotirios S; Louis, F; Lyashuk, V I; Magnier, P; Marcelin, M; Margiotta, A; Massol, A; Masullo, R; Mazéas, F; Mazeau, B; Mazure, A; McMillan, J E; Michel, J L; Migneco, E; Millot, C; Mols, P; Montanet, François; Montaruli, T; Morel, J P; Moscoso, L; Navas, S; Nezri, E; Nooren, G J L; Oberski, J; Olivetto, C; Oppelt-pohl, A; Palanque-Delabrouille, Nathalie; Payre, P; Perrin, P; Petruccetti, M; Petta, P; Piattelli, P; Poinsignon, J; Popa, V; Potheau, R; Queinec, Y; Racca, C; Raia, G; Randazzo, N; Rethore, F; Riccobene, G; Ricol, J S; Ripani, M; Roca-Blay, V; Rolin, J F; Rostovtsev, A A; Russo, G V; Sacquin, Yu; Salusti, E; Schuller, J P; Schuster, W; Soirat, J P; Suvorova, O; Spooner, N J C; Spurio, M; Stolarczyk, T; Stubert, D; Taiuti, M; Tao, Charling; Tayalati, Y; Thompson, L F; Tilav, S; Triay, R; Valente, V; Varlamov, I; Vaudaine, G; Vernin, P; De Witt-Huberts, P K A; De Wolf, E; Zakharov, V; Zavatarelli, S; De Dios-Zornoza-Gomez, Juan; Zúñiga, J

    2002-01-01

    The ANTARES collaboration is building a deep sea neutrino telescope in the Mediterranean Sea. This detector will cover a sensitive area of typically 0.1 km-squared and will be equipped with about 1000 optical modules. Each of these optical modules consists of a large area photomultiplier and its associated electronics housed in a pressure resistant glass sphere. The design of the ANTARES optical module, which is a key element of the detector, has been finalized following extensive R & D studies and is reviewed here in detail.

  6. SSD with generalized phase modulation

    International Nuclear Information System (INIS)

    Rothenberg, J.

    1996-01-01

    Smoothing by spectral dispersion (SSD) with standard frequency modulation (FM), although simple to implement, has the disadvantage that low spatial frequencies present in the spectrum of the target illumination are not smoothed as effectively as with a more general smoothing method (eg, induced spatial incoherence method). The reduced smoothing performance of standard FM-SSD can result in spectral power of the speckle noise at these low spatial frequencies as much as one order of magnitude larger than that achieved with a more general method. In fact, at small integration times FM-SSD has no smoothing effect at all for a broad band of low spatial frequencies. This effect may have important implications for both direct and indirect drive ICF

  7. Pharmacological modulation of arterial stiffness.

    LENUS (Irish Health Repository)

    Boutouyrie, Pierre

    2011-09-10

    Arterial stiffness has emerged as an important marker of cardiovascular risk in various populations and reflects the cumulative effect of cardiovascular risk factors on large arteries, which in turn is modulated by genetic background. Arterial stiffness is determined by the composition of the arterial wall and the arrangement of these components, and can be studied in humans non-invasively. Age and distending pressure are two major factors influencing large artery stiffness. Change in arterial stiffness with drugs is an important endpoint in clinical trials, although evidence for arterial stiffness as a therapeutic target still needs to be confirmed. Drugs that independently affect arterial stiffness include antihypertensive drugs, mostly blockers of the renin-angiotensin-aldosterone system, hormone replacement therapy and some antidiabetic drugs such as glitazones. While the quest continues for \\'de-stiffening drugs\\

  8. Intelligent spacecraft module

    Science.gov (United States)

    Oungrinis, Konstantinos-Alketas; Liapi, Marianthi; Kelesidi, Anna; Gargalis, Leonidas; Telo, Marinela; Ntzoufras, Sotiris; Paschidi, Mariana

    2014-12-01

    The paper presents the development of an on-going research project that focuses on a human-centered design approach to habitable spacecraft modules. It focuses on the technical requirements and proposes approaches on how to achieve a spatial arrangement of the interior that addresses sufficiently the functional, physiological and psychosocial needs of the people living and working in such confined spaces that entail long-term environmental threats to human health and performance. Since the research perspective examines the issue from a qualitative point of view, it is based on establishing specific relationships between the built environment and its users, targeting people's bodily and psychological comfort as a measure toward a successful mission. This research has two basic branches, one examining the context of the system's operation and behavior and the other in the direction of identifying, experimenting and formulating the environment that successfully performs according to the desired context. The latter aspect is researched upon the construction of a scaled-model on which we run series of tests to identify the materiality, the geometry and the electronic infrastructure required. Guided by the principles of sensponsive architecture, the ISM research project explores the application of the necessary spatial arrangement and behavior for a user-centered, functional interior where the appropriate intelligent systems are based upon the existing mechanical and chemical support ones featured on space today, and especially on the ISS. The problem is set according to the characteristics presented at the Mars500 project, regarding the living quarters of six crew-members, along with their hygiene, leisure and eating areas. Transformable design techniques introduce spatial economy, adjustable zoning and increased efficiency within the interior, securing at the same time precise spatial orientation and character at any given time. The sensponsive configuration is

  9. Frames in super Hilbert modules

    Directory of Open Access Journals (Sweden)

    Mehdi Rashidi-Kouchi

    2018-01-01

    Full Text Available In this paper, we define super Hilbert module and investigate frames in this space. Super Hilbert modules are  generalization of super Hilbert spaces in Hilbert C*-module setting. Also, we define frames in a super Hilbert module and characterize them by using of the concept of g-frames in a Hilbert C*-module. Finally, disjoint frames in Hilbert C*-modules are introduced and investigated.

  10. Bioelectric modulation of macrophage polarization

    Science.gov (United States)

    Li, Chunmei; Levin, Michael; Kaplan, David L.

    2016-02-01

    Macrophages play a critical role in regulating wound healing and tissue regeneration by changing their polarization state in response to local microenvironmental stimuli. The native roles of polarized macrophages encompass biomaterials and tissue remodeling needs, yet harnessing or directing the polarization response has been largely absent as a potential strategy to exploit in regenerative medicine to date. Recent data have revealed that specific alteration of cells’ resting potential (Vmem) is a powerful tool to direct proliferation and differentiation in a number of complex tissues, such as limb regeneration, craniofacial patterning and tumorigenesis. In this study, we explored the bioelectric modulation of macrophage polarization by targeting ATP sensitive potassium channels (KATP). Glibenclamide (KATP blocker) and pinacidil (KATP opener) treatment not only affect macrophage polarization, but also influence the phenotype of prepolarized macrophages. Furthermore, modulation of cell membrane electrical properties can fine-tune macrophage plasticity. Glibenclamide decreased the secretion and gene expression of selected M1 markers, while pinacidil augmented M1 markers. More interestingly, glibencalmide promoted macrophage alternative activation by enhancing certain M2 markers during M2 polarization. These findings suggest that control of bioelectric properties of macrophages could offer a promising approach to regulate macrophage phenotype as a useful tool in regenerative medicine.

  11. Attentional modulation of reflex cough.

    Science.gov (United States)

    Janssens, Thomas; Silva, Mitchell; Davenport, Paul W; Van Diest, Ilse; Dupont, Lieven J; Van den Bergh, Omer

    2014-07-01

    Reflex cough is a defensive response generated in the brainstem in response to chemical and mechanical stimulation of the airways. However, converging evidence shows that reflex cough is also influenced by central neural control processes. In this study, we investigate whether reflex cough can be modulated by attentional focus on either external stimuli or internal cough-related stimuli. Healthy volunteers (N = 24; seven men; age range, 18-25 years) completed four blocks of citric acid-induced cough challenges while, simultaneously, auditory stimuli were presented. Within each block, four concentrations were administered (30, 100, 300 and 1,000 mM, randomized). During two subsequent blocks, participants focused their attention externally (counting tones). During the other two blocks, participants focused their attention internally (counting coughs). The order of attentional focus was counterbalanced across participants. Ratings of the urge to cough were collected after each challenge. Cough frequency was determined by audio recording. Cough frequency was higher when participants focused their attention internally vs externally (P Reflex cough can be modulated by attentional focus. Internally focused attention may be a mechanism involved in excessive (idiopathic) cough, while an external focus may be introduced as part of treatments targeting excessive cough.

  12. Organelle targeting: third level of drug targeting

    Directory of Open Access Journals (Sweden)

    Sakhrani NM

    2013-07-01

    Full Text Available Niraj M Sakhrani, Harish PadhDepartment of Cell and Molecular Biology, BV Patel Pharmaceutical Education and Research Development (PERD Centre, Gujarat, IndiaAbstract: Drug discovery and drug delivery are two main aspects for treatment of a variety of disorders. However, the real bottleneck associated with systemic drug administration is the lack of target-specific affinity toward a pathological site, resulting in systemic toxicity and innumerable other side effects as well as higher dosage requirement for efficacy. An attractive strategy to increase the therapeutic index of a drug is to specifically deliver the therapeutic molecule in its active form, not only into target tissue, nor even to target cells, but more importantly, into the targeted organelle, ie, to its intracellular therapeutic active site. This would ensure improved efficacy and minimize toxicity. Cancer chemotherapy today faces the major challenge of delivering chemotherapeutic drugs exclusively to tumor cells, while sparing normal proliferating cells. Nanoparticles play a crucial role by acting as a vehicle for delivery of drugs to target sites inside tumor cells. In this review, we spotlight active and passive targeting, followed by discussion of the importance of targeting to specific cell organelles and the potential role of cell-penetrating peptides. Finally, the discussion will address the strategies for drug/DNA targeting to lysosomes, mitochondria, nuclei and Golgi/endoplasmic reticulum.Keywords: intracellular drug delivery, cancer chemotherapy, therapeutic index, cell penetrating peptides

  13. A photovoltaic module

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to a photovoltaic module comprising a carrier substrate, said carrier substrate carrying a purely printed structure comprising printed positive and negative module terminals, a plurality of printed photovoltaic cell units each comprising one or more printed...... photovoltaic cells, wherein the plurality of printed photovoltaic cell units are electrically connected in series between the positive and the negative module terminals such that any two neighbouring photovoltaic cell units are electrically connected by a printed interconnecting electrical conductor....... The carrier substrate comprises a foil and the total thickness of the photovoltaic module is below 500 [mu]m. Moreover, the nominal voltage level between the positive and the negative terminals is at least 5 kV DC....

  14. Strain-Modulated Epitaxy

    National Research Council Canada - National Science Library

    Brown, April

    1999-01-01

    Strain-Modulated Epitaxy (SME) is a novel approach, invented at Georgia Tech, to utilize subsurface stressors to control strain and therefore material properties and growth kinetics in the material above the stressors...

  15. Solid state detector module

    International Nuclear Information System (INIS)

    Hoffman, D. M.

    1985-01-01

    A solid state detector in which each scintillator is optimally configured and coupled with its associated sensing diode in a way which exploits light piping effects to enhance efficiency, and at the same time provide a detector which is modular in nature. To achieve light piping, the scintillator crystal is oriented such that its sides conform with the crystal cleavage plane, and the sides are highly polished. An array of tungsten collimator plates define the individual channels. Multi-channel scintillator/diode modules are mounted behind and in registry with the plurality of collimator plates. A plurality of scintillators are bonded together after coating the surfaces thereof to minimize optical crosstalk. After lapping the face of the scintillator module, it is then bonded to a diode module with individual scintillators in registration with individual diodes. The module is then positioned in the detector array with collimator plates at the junctions between the scintillators

  16. Periodically modulated dark states

    Science.gov (United States)

    Han, Yingying; Zhang, Jun; Zhang, Wenxian

    2018-04-01

    Phenomena of electromagnetically induced transparency (PEIT) may be interpreted by the Autler-Townes Splitting (ATS), where the coupled states are split by the coupling laser field, or by the quantum destructive interference (QDI), where the atomic phases caused by the coupling laser and the probe laser field cancel. We propose modulated experiments to explore the PEIT in an alternative way by periodically modulating the coupling and the probe fields in a Λ-type three-level system initially in a dark state. Our analytical and numerical results rule out the ATS interpretation and show that the QDI interpretation is more appropriate for the modulated experiments. Interestingly, dark state persists in the double-modulation situation where control and probe fields never occur simultaneously, which is significant difference from the traditional dark state condition. The proposed experiments are readily implemented in atomic gases, artificial atoms in superconducting quantum devices, or three-level meta-atoms in meta-materials.

  17. Nestor optical modules blackening

    International Nuclear Information System (INIS)

    Cordelli, M.; Rutili, A.; Trasatti, L.

    1998-09-01

    The optical modules (OM) containing the photomultiplier tubes (PM) for a deep sea neutrino telescope must be protected them from direct sunlight. The problem has been solved using a heat shrink plastic sheet with very good optical and mechanical properties

  18. Random and systematic beam modulator errors in dynamic intensity modulated radiotherapy

    International Nuclear Information System (INIS)

    Parsai, Homayon; Cho, Paul S; Phillips, Mark H; Giansiracusa, Robert S; Axen, David

    2003-01-01

    This paper reports on the dosimetric effects of random and systematic modulator errors in delivery of dynamic intensity modulated beams. A sliding-widow type delivery that utilizes a combination of multileaf collimators (MLCs) and backup diaphragms was examined. Gaussian functions with standard deviations ranging from 0.5 to 1.5 mm were used to simulate random positioning errors. A clinical example involving a clival meningioma was chosen with optic chiasm and brain stem as limiting critical structures in the vicinity of the tumour. Dose calculations for different modulator fluctuations were performed, and a quantitative analysis was carried out based on cumulative and differential dose volume histograms for the gross target volume and surrounding critical structures. The study indicated that random modulator errors have a strong tendency to reduce minimum target dose and homogeneity. Furthermore, it was shown that random perturbation of both MLCs and backup diaphragms in the order of σ = 1 mm can lead to 5% errors in prescribed dose. In comparison, when MLCs or backup diaphragms alone was perturbed, the system was more robust and modulator errors of at least σ = 1.5 mm were required to cause dose discrepancies greater than 5%. For systematic perturbation, even errors in the order of ±0.5 mm were shown to result in significant dosimetric deviations

  19. Programmable synchronous communications module

    International Nuclear Information System (INIS)

    Horelick, D.

    1979-10-01

    The functional characteristics of a programmable, synchronous serial communications CAMAC module with buffering in block format are described. Both bit and byte oriented protocols can be handled in full duplex depending on the program implemented. The main elements of the module are a Signetics 2652 Multi-Protocol Communications Controller, a Zilog Z-808 8 bit microprocessor with PROM and RAM, and FIFOs for buffering

  20. Groups, rings, modules

    CERN Document Server

    Auslander, Maurice

    2014-01-01

    This classic monograph is geared toward advanced undergraduates and graduate students. The treatment presupposes some familiarity with sets, groups, rings, and vector spaces. The four-part approach begins with examinations of sets and maps, monoids and groups, categories, and rings. The second part explores unique factorization domains, general module theory, semisimple rings and modules, and Artinian rings. Part three's topics include localization and tensor products, principal ideal domains, and applications of fundamental theorem. The fourth and final part covers algebraic field extensions

  1. Modulated Current Drive Measurements

    International Nuclear Information System (INIS)

    Petty, C.C.; Lohr, J.; Luce, T.C.; Prater, R.; Cox, W.A.; Forest, C.B.; Jayakumar, R.J.; Makowski, M.A.

    2005-01-01

    A new measurement approach is presented which directly determines the noninductive current profile from the periodic response of the motional Stark effect (MSE) signals to the slow modulation of the external current drive source. A Fourier transform of the poloidal magnetic flux diffusion equation is used to analyze the MSE data. An example of this measurement technique is shown using modulated electron cyclotron current drive (ECCD) discharges from the DIII-D tokamak

  2. Directed network modules

    International Nuclear Information System (INIS)

    Palla, Gergely; Farkas, Illes J; Pollner, Peter; Derenyi, Imre; Vicsek, Tamas

    2007-01-01

    A search technique locating network modules, i.e. internally densely connected groups of nodes in directed networks is introduced by extending the clique percolation method originally proposed for undirected networks. After giving a suitable definition for directed modules we investigate their percolation transition in the Erdos-Renyi graph both analytically and numerically. We also analyse four real-world directed networks, including Google's own web-pages, an email network, a word association graph and the transcriptional regulatory network of the yeast Saccharomyces cerevisiae. The obtained directed modules are validated by additional information available for the nodes. We find that directed modules of real-world graphs inherently overlap and the investigated networks can be classified into two major groups in terms of the overlaps between the modules. Accordingly, in the word-association network and Google's web-pages, overlaps are likely to contain in-hubs, whereas the modules in the email and transcriptional regulatory network tend to overlap via out-hubs

  3. Second generation SLAC modulator

    International Nuclear Information System (INIS)

    Donaldson, A.R.; Cron, J.C.; Hanselman, R.R.

    1986-06-01

    The Stanford Linear Accelerator Laboratory has undertaken the construction of a single pass electron-positron collider. In order to reach required beam energy 235 new klystrons needed upgraded modulator systems. The collider will use 50 GeV electrons and positrons. The increase in accelerator energy from the present 30 GeV necessitates the replacement of existing 35 MW klystrons with new 67 MW units. The doubling of klystron output power required a redesign of the modulator system. The 67 MW klystron needs a 350 kV beam voltage pulse with a 3.7 μs pulse width. A new pulse transformer was designed to deliver the increased voltage and pulse width. Pulse cable design was evaluated to obtain increased reliability of that critical element. The modulator, with the exception of its power supply, was rebuilt to produce the required power increase while enhancing reliability and improving maintainability. An investigation of present thyratron switch tube performance under the new operating conditions resulted in agitation and some warranted panic but these conditions were mitigated after several successful experiments and some evolutionary narrowing of the klystron pulse width. The discussion will cover the upgraded modulator system specifications and some details of the new pulse transformer tank, pulse cable, modulator, and modulator switch tube

  4. Decoupled Modulation Control

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Shaobu; Huang, Renke; Huang, Zhenyu; Diao, Ruisheng

    2016-06-03

    The objective of this research work is to develop decoupled modulation control methods for damping inter-area oscillations with low frequencies, so the damping control can be more effective and easier to design with less interference among different oscillation modes in the power system. A signal-decoupling algorithm was developed that can enable separation of multiple oscillation frequency contents and extraction of a “pure” oscillation frequency mode that are fed into Power System Stabilizers (PSSs) as the modulation input signals. As a result, instead of introducing interferences between different oscillation modes from the traditional approaches, the output of the new PSS modulation control signal mainly affects only one oscillation mode of interest. The new decoupled modulation damping control algorithm has been successfully developed and tested on the standard IEEE 4-machine 2-area test system and a minniWECC system. The results are compared against traditional modulation controls, which demonstrates the validity and effectiveness of the newly-developed decoupled modulation damping control algorithm.

  5. Nanoparticles for intracellular-targeted drug delivery

    International Nuclear Information System (INIS)

    Paulo, Cristiana S O; Pires das Neves, Ricardo; Ferreira, Lino S

    2011-01-01

    Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

  6. How bees distinguish patterns by green and blue modulation.

    Science.gov (United States)

    Horridge, Adrian

    2015-01-01

    background. The blue content could also be summed over the whole target. There were no achromatic patterns for bees and no evidence that they detected black, white, or gray levels apart from the differences in blue content or modulation at edges. Most of these cues would be sensitive to background color but some were influenced by changes in illumination. The bees usually learned only to avoid the unrewarded target. Exactly the same preferences of the same inputs were used in the detection of single targets as in discrimination between two targets.

  7. Target system materials and engineering problems

    International Nuclear Information System (INIS)

    Fischer, W.E.

    1989-01-01

    This paper discusses the common problems of target design. As a model for the discussion, the author considers a spallation source which is fed by a high power proton beam of the order of one megawatt. The materials used for the target station and particularly for the spallation target itself depend on whether the source is built for pulsed, modulated or continuous operation. The difference of materials used is mainly determined by the neutronics considerations. Depending on the choice of materials for the target systems, the characters of material problems met, are of somewhat different nature. It is recognized that for each target version quite specific difficulties have to be overcome. On the other hand, there is a whole set of problems which is common to all target versions. These are: heat load in region of proton beam interactions; thermal stress and cycling; and radiation damage. It is shown that solutions to the whole package of problems up to a beam power of 0 (1MW) have been found. The whole effort concentrates onto the region of the first few centimeters of beam penetration. Two solutions have been proposed: (1) Keep the power of proton beam limited and produce neutrons elsewhere in the target. and (2) Dilute the power by moving mechanically the target and the window. 8 refs., 11 figs

  8. Superstability for Generalized Module Left Derivations and Generalized Module Derivations on a Banach Module (I

    Directory of Open Access Journals (Sweden)

    Rassias JM

    2009-01-01

    Full Text Available We discuss the superstability of generalized module left derivations and generalized module derivations on a Banach module. Let be a Banach algebra and a Banach -module, and . The mappings , and are defined and it is proved that if (resp., is dominated by then is a generalized (resp., linear module- left derivation and is a (resp., linear module- left derivation. It is also shown that if (resp., is dominated by then is a generalized (resp., linear module- derivation and is a (resp., linear module- derivation.

  9. Deuterium pass through target

    International Nuclear Information System (INIS)

    Alger, D.L.

    1975-01-01

    A neutron emitting target is described for use in neutron generating apparatus including a deuteron source and an accelerator vacuum chamber. The target consists of a tritium-containing target layer, a deuteron accumulation layer, and a target support containing passages providing communication between the accumulation layer and portions of the surface of the support exposed to the accelerator vacuum chamber. With this arrangement, deuterons passing through the target layer and implanting in and diffusing through the accumulation layer, diffuse into the communicating passages and are returned to the accelerator vacuum chamber. The invention allows the continuous removal of deuterons from the target in conventional water cooled neutron generating apparatus. Preferably, the target is provided with thin barrier layers to prevent undesirable tritium diffusion out of the target layer, as well as deuteron diffusion into the target layer

  10. Novel GABA receptor pesticide targets.

    Science.gov (United States)

    Casida, John E; Durkin, Kathleen A

    2015-06-01

    The γ-aminobutyric acid (GABA) receptor has four distinct but overlapping and coupled targets of pesticide action importantly associated with little or no cross-resistance. The target sites are differentiated by binding assays with specific radioligands, resistant strains, site-directed mutagenesis and molecular modeling. Three of the targets are for non-competitive antagonists (NCAs) or channel blockers of widely varied chemotypes. The target of the first generation (20th century) NCAs differs between the larger or elongated compounds (NCA-IA) including many important insecticides of the past (cyclodienes and polychlorocycloalkanes) or present (fiproles) and the smaller or compact compounds (NCA-IB) highly toxic to mammals and known as cage convulsants, rodenticides or chemical threat agents. The target of greatest current interest is designated NCA-II for the second generation (21st century) of NCAs consisting for now of isoxazolines and meta-diamides. This new and uniquely different NCA-II site apparently differs enough between insects and mammals to confer selective toxicity. The fourth target is the avermectin site (AVE) for allosteric modulators of the chloride channel. NCA pesticides vary in molecular surface area and solvent accessible volume relative to avermectin with NCA-IBs at 20-22%, NCA-IAs at 40-45% and NCA-IIs at 57-60%. The same type of relationship relative to ligand-docked length is 27-43% for NCA-IBs, 63-71% for NCA-IAs and 85-105% for NCA-IIs. The four targets are compared by molecular modeling for the Drosophila melanogaster GABA-R. The principal sites of interaction are proposed to be: pore V1' and A2' for NCA-IB compounds; pore A2', L6' and T9' for NCA-IA compounds; pore T9' to S15' in proximity to M1/M3 subunit interface (or alternatively an interstitial site) for NCA-II compounds; and M1/M3, M2 interfaces for AVE. Understanding the relationships of these four binding sites is important in resistance management and in the discovery and use

  11. Molecular Targets for Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Mather, S.J.

    2009-01-01

    Molecular targeted radionuclide cancer therapy is becoming of increasing importance, especially for disseminated diseases. Systemic chemotherapies often lack selectivity while targeted radionuclide therapy has important advantages as the radioactive cytotoxic unit of the targeting vector is specifically directed to the cancer, sparing normal tissues. The principle strategy to improve cancer selectivity is to couple therapeutic agents to tumour-targeting vectors. In targeted radionuclide therapy (TRT), the cytotoxic portion of the conjugates normally contains a therapeutic radiometal immobilised by a bifunctional chelator. The aim is therefore to use as ligand-targeted therapeutics vectors coupled to Auger-, alpha- and/or beta-emitting radionuclides. An advantage of using radiation instead of chemotherapeutics as the cytotoxic agent is the so called 'crossfire effect'. This allows sterilisation of tumour cells that are not directly targeted due to heterogeneity in target molecule expression or inhomogeneous vector delivery. However, before the targeting ligands can be selected, the target molecule on the tumour has to be selected. It should be uniquely expressed, or at least highly overexpressed, on or in the target cells relative to normal tissues. The target should be easily accessible for ligand delivery and should not be shed or down- regulated after ligand binding. An important property of a receptor (or antigen) is its potential to be internalized upon binding of the ligand. This provides an active uptake mechanism and allows the therapeutic agent to be trapped within the tumour cells. Molecular targets of current interest include: Receptors: G-protein coupled receptors are overexpressed on many major human tumours. The prototype of these receptors are somatostatin receptors which show very high density in neuroendocrine tumours, but there are many other most interesting receptors to be applied for TRT. The targeting ligands for these receptors are

  12. High Altitude Supersonic Target (HAST), Phase 2

    Science.gov (United States)

    1974-08-01

    consists of a padded cradle assembly and a tubular steel stand with lockable swivel casters on the front wheels . c Tne recovery module lifting handle is...eds no modification of the ordnance fired at it in order to function. With the HAST system a target will be provided to evaluate the most advanced...Components were tested under environmental extremes. With the completion of the preflight readiness tests and with modification incorporated during the

  13. Development of a 64-channel 100 ps TDC module

    International Nuclear Information System (INIS)

    Liu Xiaohua; An Qi; Liu Shubin; Su Hong; Zhan Wenlong

    2009-01-01

    Multi-wire drift chamber at external target experiment in HIRFL-CSR measures drift time of charged particles to obtain the track information. A 64-channel TDC module hosting high density connectors and high performance TDC chips (HPTDC) are used to perform the time digitization. Data of the module is transferred to computer through PXI bus. The test results show that a 100 ps resolution has been achieved. (authors)

  14. Interactions between amplitude modulation and frequency modulation processing: Effects of age and hearing loss.

    Science.gov (United States)

    Paraouty, Nihaad; Ewert, Stephan D; Wallaert, Nicolas; Lorenzi, Christian

    2016-07-01

    Frequency modulation (FM) and amplitude modulation (AM) detection thresholds were measured for a 500-Hz carrier frequency and a 5-Hz modulation rate. For AM detection, FM at the same rate as the AM was superimposed with varying FM depth. For FM detection, AM at the same rate was superimposed with varying AM depth. The target stimuli always contained both amplitude and frequency modulations, while the standard stimuli only contained the interfering modulation. Young and older normal-hearing listeners, as well as older listeners with mild-to-moderate sensorineural hearing loss were tested. For all groups, AM and FM detection thresholds were degraded in the presence of the interfering modulation. AM detection with and without interfering FM was hardly affected by either age or hearing loss. While aging had an overall detrimental effect on FM detection with and without interfering AM, there was a trend that hearing loss further impaired FM detection in the presence of AM. Several models using optimal combination of temporal-envelope cues at the outputs of off-frequency filters were tested. The interfering effects could only be predicted for hearing-impaired listeners. This indirectly supports the idea that, in addition to envelope cues resulting from FM-to-AM conversion, normal-hearing listeners use temporal fine-structure cues for FM detection.

  15. Effect of synthetic jet modulation schemes on the reduction of a laminar separation bubble

    Science.gov (United States)

    Seo, J. H.; Cadieux, F.; Mittal, R.; Deem, E.; Cattafesta, L.

    2018-03-01

    The response of a laminar separation bubble to synthetic jet forcing with various modulation schemes is investigated via direct numerical simulations. A simple sinusoidal waveform is considered as a reference case, and various amplitude modulation schemes, including the square-wave "burst" modulation, are employed in the simulations. The results indicate that burst modulation is less effective at reducing the length of the flow separation than the sinusoidal forcing primarily because burst modulation is associated with a broad spectrum of input frequencies that are higher than the target frequency for the flow control. It is found that such high-frequency forcing delays vortex roll-up and promotes vortex pairing and merging, which have an adverse effect on reducing the separation bubble length. A commonly used amplitude modulation scheme is also found to have reduced effectiveness due to its spectral content. A new amplitude modulation scheme which is tailored to impart more energy at the target frequency is proposed and shown to be more effective than the other modulation schemes. Experimental measurements confirm that modulation schemes can be preserved through the actuator and used to enhance the energy content at the target modulation frequency. The present study therefore suggests that the effectiveness of synthetic jet-based flow control could be improved by carefully designing the spectral content of the modulation scheme.

  16. Pulse power modulators - an overview

    International Nuclear Information System (INIS)

    Venkatramani, N.

    2006-01-01

    Pulse power modulators are electronic devices to provide, high voltage, high current, power bursts. Ideally, a modulator, with the means to shape and control the pulses, acts as a switch between a high voltage power supply and its load. This article gives an overview of the pulse power modulators: starting with the basics of pulse and modulation, it covers modulation topologies, different types of modulators, major subsystems and pulse measurement techniques. The various applications of pulse power modulators and the recent trends have been included at the end. (author)

  17. Adaptive Modulation and Coding for LTE Wireless Communication

    Science.gov (United States)

    Hadi, S. S.; Tiong, T. C.

    2015-04-01

    Long Term Evolution (LTE) is the new upgrade path for carrier with both GSM/UMTS networks and CDMA2000 networks. The LTE is targeting to become the first global mobile phone standard regardless of the different LTE frequencies and bands use in other countries barrier. Adaptive Modulation and Coding (AMC) is used to increase the network capacity or downlink data rates. Various modulation types are discussed such as Quadrature Phase Shift Keying (QPSK), Quadrature Amplitude Modulation (QAM). Spatial multiplexing techniques for 4×4 MIMO antenna configuration is studied. With channel station information feedback from the mobile receiver to the base station transmitter, adaptive modulation and coding can be applied to adapt to the mobile wireless channels condition to increase spectral efficiencies without increasing bit error rate in noisy channels. In High-Speed Downlink Packet Access (HSDPA) in Universal Mobile Telecommunications System (UMTS), AMC can be used to choose modulation types and forward error correction (FEC) coding rate.

  18. Spatial Terahertz Modulator

    Science.gov (United States)

    Xie, Zhenwei; Wang, Xinke; Ye, Jiasheng; Feng, Shengfei; Sun, Wenfeng; Akalin, Tahsin; Zhang, Yan

    2013-11-01

    Terahertz (THz) technology is a developing and promising candidate for biological imaging, security inspection and communications, due to the low photon energy, the high transparency and the broad band properties of the THz radiation. However, a major encountered bottleneck is lack of efficient devices to manipulate the THz wave, especially to modulate the THz wave front. A wave front modulator should allow the optical or electrical control of the spatial transmission (or reflection) of an input THz wave and hence the ability to encode the information in a wave front. Here we propose a spatial THz modulator (STM) to dynamically control the THz wave front with photo-generated carriers. A computer generated THz hologram is projected onto a silicon wafer by a conventional spatial light modulator (SLM). The corresponding photo-generated carrier spatial distribution will be induced, which forms an amplitude hologram to modulate the wave front of the input THz beam. Some special intensity patterns and vortex beams are generated by using this method. This all-optical controllable STM is structure free, high resolution and broadband. It is expected to be widely used in future THz imaging and communication systems.

  19. Bunch identification module

    International Nuclear Information System (INIS)

    Fox, J.D.

    1981-01-01

    This module provides bunch identification and timing signals for the PEP Interaction areas. Timing information is referenced to the PEP master oscillator, and adjusted in phase as a function of region. Identification signals are generated in a manner that allows observers in all interaction regions to agree on an unambiguous bunch identity. The module provides bunch identification signals via NIM level logic, upon CAMAC command, and through LED indicators. A front panel ''region select'' switch allows the same module to be used in all regions. The module has two modes of operation: a bunch identification mode and a calibration mode. In the identification mode, signals indicate which of the three bunches of electrons and positrons are interacting, and timing information about beam crossing is provided. The calibration mode is provided to assist experimenters making time of flight measurements. In the calibration mode, three distinct gating signals are referenced to a selected bunch, allowing three timing systems to be calibrated against a common standard. Physically, the bunch identifier is constructed as a single width CAMAC module. 2 figs., 1 tab

  20. Integrated unaligned resonant modulator tuning

    Energy Technology Data Exchange (ETDEWEB)

    Zortman, William A.; Lentine, Anthony L.

    2017-10-03

    Methods and systems for tuning a resonant modulator are disclosed. One method includes receiving a carrier signal modulated by the resonant modulator with a stream of data having an approximately equal number of high and low bits, determining an average power of the modulated carrier signal, comparing the average power to a predetermined threshold, and operating a tuning device coupled to the resonant modulator based on the comparison of the average power and the predetermined threshold. One system includes an input structure, a plurality of processing elements, and a digital control element. The input structure is configured to receive, from the resonant modulator, a modulated carrier signal. The plurality of processing elements are configured to determine an average power of the modulated carrier signal. The digital control element is configured to operate a tuning device coupled to the resonant modulator based on the average power of the modulated carrier signal.

  1. Monitoring production target thickness

    International Nuclear Information System (INIS)

    Oothoudt, M.A.

    1993-01-01

    Pion and muon production targets at the Clinton P. Anderson Meson Physics Facility consist of rotating graphite wheels. The previous target thickness monitoring Procedure scanned the target across a reduced intensity beam to determine beam center. The fractional loss in current across the centered target gave a measure of target thickness. This procedure, however, required interruption of beam delivery to experiments and frequently indicated a different fractional loss than at normal beam currents. The new monitoring Procedure compares integrated ups and downs toroid current monitor readings. The current monitors are read once per minute and the integral of readings are logged once per eight-hour shift. Changes in the upstream to downstream fractional difference provide a nonintrusive continuous measurement of target thickness under nominal operational conditions. Target scans are now done only when new targets are installed or when unexplained changes in the current monitor data are observed

  2. The medicinal chemistry of liver X receptor (LXR) modulators.

    Science.gov (United States)

    Tice, Colin M; Noto, Paul B; Fan, Kristi Yi; Zhuang, Linghang; Lala, Deepak S; Singh, Suresh B

    2014-09-11

    LXRs have been of interest as targets for the treatment of atherosclerosis for over a decade. In recent years, LXR modulators have also garnered interest for potential use in the treatment of inflammation, Alzheimer's disease (AD), dermatological conditions, hepatic steatosis, and oncology. To date, no LXR modulator has successfully progressed beyond phase I clinical trials. In this Perspective, we summarize published medicinal chemistry efforts in the context of the available crystallographic data, druglikeness, and isoform selectivity. In addition, we discuss the challenges that need to be overcome before an LXR modulator can reach clinical use.

  3. Modulation of GITR for cancer immunotherapy

    Science.gov (United States)

    Schaer, David A; Murphy, Judith T; Wolchok, Jedd D

    2012-01-01

    Modulation of co-inhibitory and co-stimulatory receptors of the immune system has become a promising new approach for immunotherapy of cancer. With the recent FDA approval of CTLA-4 blockade serving as an important proof of principal, many new targets are now being translated into the clinic. Preclinical research has demonstrated that targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor related gene (GITR), a member of TNF receptor superfamily, by agonist antibodies or natural ligand, can serve as an effective anti-tumor therapy. In this review, we will cover this research and the rationale that has led to initiation of two phase 1 clinical trials targeting GITR as a new immunotherapeutic approach for cancer. PMID:22245556

  4. Charged particle fusion targets

    International Nuclear Information System (INIS)

    Bangerter, R.O.; Meeker, D.J.

    1977-01-01

    The power, voltage, energy and other requirements of electron and ion beam fusion targets are reviewed. Single shell, multiple shell and magnetically insulated target designs are discussed. Questions of stability are also considered. In particular, it is shown that ion beam targets are stabilized by an energy spread in the ion beam

  5. Liquid helium target

    International Nuclear Information System (INIS)

    Fujii, Y.; Kitami, T.; Torikoshi, M.

    1984-12-01

    A liquid helium target system has been built and used for the experiment on the reaction 4 He(γ, p). The target system has worked satisfactorily; the consumption rate of liquid helium is 360 ml/h and the cryogenic system retains liquid helium for about ten hours. The structure, operation and performance of the target system are reported. (author)

  6. Graphite targets at LAMPF

    International Nuclear Information System (INIS)

    Brown, R.D.; Grisham, D.L.

    1983-01-01

    Rotating polycrystalline and stationary pyrolytic graphite target designs for the LAMPF experimental area are described. Examples of finite element calculations of temperatures and stresses are presented. Some results of a metallographic investigation of irradiated pyrolytic graphite target plates are included, together with a brief description of high temperature bearings for the rotating targets

  7. Power module assembly

    Science.gov (United States)

    Campbell, Jeremy B [Torrance, CA; Newson, Steve [Redondo Beach, CA

    2011-11-15

    A power module assembly of the type suitable for deployment in a vehicular power inverter, wherein the power inverter has a grounded chassis, is provided. The power module assembly comprises a conductive base layer electrically coupled to the chassis, an insulating layer disposed on the conductive base layer, a first conductive node disposed on the insulating layer, a second conductive node disposed on the insulating layer, wherein the first and second conductive nodes are electrically isolated from each other. The power module assembly also comprises a first capacitor having a first electrode electrically connected to the conductive base layer, and a second electrode electrically connected to the first conductive node, and further comprises a second capacitor having a first electrode electrically connected to the conductive base layer, and a second electrode electrically connected to the second conductive node.

  8. Waveform Sampler CAMAC Module

    International Nuclear Information System (INIS)

    Freytag, D.R.; Haller, G.M.; Kang, H.; Wang, J.

    1985-09-01

    A Waveform Sampler Module (WSM) for the measurement of signal shapes coming from the multi-hit drift chambers of the SLAC SLC detector is described. The module uses a high speed, high resolution analog storage device (AMU) developed in collaboration between SLAC and Stanford University. The AMU devices together with high speed TTL clocking circuitry are packaged in a hybrid which is also suitable for mounting on the detector. The module is in CAMAC format and provides eight signal channels, each recording signal amplitude versus time in 512 cells at a sampling rate of up to 360 MHz. Data are digitized by a 12-bit ADC with a 1 μs conversion time and stored in an on-board memory accessible through CAMAC

  9. GREET Pretreatment Module

    Energy Technology Data Exchange (ETDEWEB)

    Adom, Felix K. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Dunn, Jennifer B. [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division; Han, Jeongwoo [Argonne National Lab. (ANL), Argonne, IL (United States). Energy Systems Division

    2014-09-01

    A wide range of biofuels and biochemicals can be produced from cellulosic biomass via different pretreatment technologies that yield sugars. Process simulations of dilute acid and ammonia fiber expansion pretreatment processes and subsequent hydrolysis were developed in Aspen Plus for four lignocellulosic feedstocks (corn stover, miscanthus, switchgrass, and poplar). This processing yields sugars that can be subsequently converted to biofuels or biochemical. Material and energy consumption data from Aspen Plus were then compiled in a new Greenhouses Gases, Regulated Emissions, and Energy Use in Transportation (GREETTM) pretreatment module. The module estimates the cradle-to-gate fossil energy consumption (FEC) and greenhouse gas (GHG) emissions associated with producing fermentable sugars. This report documents the data and methodology used to develop this module and the cradle-to-gate FEC and GHG emissions that result from producing fermentable sugars.

  10. Space Experiment Module (SEM)

    Science.gov (United States)

    Brodell, Charles L.

    1999-01-01

    The Space Experiment Module (SEM) Program is an education initiative sponsored by the National Aeronautics and Space Administration (NASA) Shuttle Small Payloads Project. The program provides nationwide educational access to space for Kindergarten through University level students. The SEM program focuses on the science of zero-gravity and microgravity. Within the program, NASA provides small containers or "modules" for students to fly experiments on the Space Shuttle. The experiments are created, designed, built, and implemented by students with teacher and/or mentor guidance. Student experiment modules are flown in a "carrier" which resides in the cargo bay of the Space Shuttle. The carrier supplies power to, and the means to control and collect data from each experiment.

  11. Large enhancement of deuteron polarization with frequency modulated microwaves

    CERN Document Server

    AUTHOR|(CDS)2067425; Arik, S; Arvidson, A; Badelek, B; Ballintijn, M K; Bardin,; Baum, G; Berglund, P; Betev, L; Birda, I G; Birsa, R; Bjrkholm, P; Bonner, B E; de Botton, N; Boutemeur, M; Bradamante, Franco; Bressan, A; Brullc, A; Buchanan, J; Bültmann, S; Burtin, E; Cavata, C; Chen, J P; Clement, J; Clocchiatti, M; Corcoran, M D; Crabb, D; Cranshaw, J; Çuhadar-Dönszelmann, T; Deshpande, S; Dalla Torre, A; Van Dantzig, R; Dhawan, S; Dulya, C; Dyring, A; Eichblatt, S; Faivre, Jean-Claude; Fasching, D; Day, D; Feinstein, F; Fernández, C; Frois, B; Garabatos, C; Garzón, J A; Gaussiran, T; Giorgi, M; von Goeler, E; Goloutvin, Igor A; Gómez, A; Gracia, G; De Groot, N; Grosse-Perdekamp, M; Gülmez, E; Hasegawa, T; Hautle, P; Hayashi, N; Heusch, C A; Horikawa, D; von Harrach, N; Hughes, V W; Igo, G; Ishimoto, S; Iwata, T; De Jong, M; Kabu, E M; Kageya, T; Kaiser, R; Karev, A; Kessler, H J; Ketel, T J; Kiryushin, Yu T; Kishi, A; Kisselev, Yu; Klostermann, L; Krämer, Dietrich; Kukhtin, V; Kyynarinen, J; Lamanna, M; Landgraf, U; Lau, V; Krivokhijinea, K; Layda, T; Le Go, J M; Lehár, F; de Lesquen, A; Lichtenstadt, J; Lindqvist, T; Litmaath, M; López-Ponte, S; Loewe, M; Magnon, A; Mallot, G K; Marie, F; Martin, A; Martino, J; Matsuda, T; Mayes, B; McCarthy, J S; van Middelkoop, K; Medved, G; Miller, D; Mitchell, J; Mori, K; Moromisato, J; Mutchler, G S; Nagaitsev, A; Nassalski, J; Naumann, Lutz; Neganov, B; Niinikoski, T O; Oberski, J E J; Ogawa, A; Okumi, S; Ozben, C S; Penzo, Aldo L; Pérez, C A; Perrot-Kunne, F; Piegaia, R; Pinsky, L; Platchkov, S; Pló, M; Pose, D; Postma, D; Peshekhonov, H; Pretz, J; Pussieux, T; Pyrlik, J; Reyhancan, I; Rieubland, Jean Michel; Rijllart, A; Roberts, J B; Rock, S E; Rodríguez, M; Rondio, E; Rondon, O; Ropelewski, Leszek; Rosado, A; Sabo, I; Saborido, J; Salvato, G; Sandacz, A; Sanders, D; Savin, I; Schiavon, Paolo; Schüler, K P; Segel, R; Seitz, R; Semertzidis, Y; Sergeev, S; Sever, F; Shanahan, P; Sichtermann, E P; Smirnov, G; Staude, A; Steinmetz, A; Stuhrmann, H; Teichert, K M; Tessarotto, F; Thiel, W; Velasco, M; Vogt, J; Voss, R; Weinstein, R; Whitten, C; Willumeit, R; Windmolders, R; Wislicki, W; Witzmann, A; Yañez, A; Zanetti, A M; Zhao, J; Zamiatin, N I

    1996-01-01

    We report a large enhancement of 1.7 in deuteron polarization up to values of 0.6 due to frequency modulation of the polarizing microwaves in a two liters polarized target using the method of dynamic nuclear polarization. This target was used during a deep inelastic polarized muon-deuteron scattering experiment at CERN. Measurements of the electron paramagnetic resonance absorption spectra show that frequency modulation gives rise to additional microwave absorption in the spectral wings. Although these results are not understood theoretically, they may provide a useful testing ground for the deeper understanding of dynamic nuclear polarization.

  12. CAMAC system test module

    International Nuclear Information System (INIS)

    Dawson, W.K.; Gjovig, A.; Naivar, F.; Potter, J.; Smith, W.

    1981-01-01

    Since the CAMAC Branch Highway is used to both send information to and receive information from a CAMAC crate, faults in this highway can be difficult to recognize and diagnose. Similarly faults caused by a Crate Controller corrupting either instructions or data are difficult to distinguish from faults caused by the modules themselves. The CLIVIT (CAMAC Logic Integrity Via Interactive Testing) module is designed to largely eliminate such difficulties and ambiguities by allowing the verification of Branch Highway and Dataway transactions via an independent data communication path. The principle of operation of the CLIVIT is explained. Described are the prototype construction, testing and use

  13. Instant node package module

    CERN Document Server

    Ali, Juzer

    2013-01-01

    Get to grips with a new technology, understand what it is and what it can do for you, and then get to work with the most important features and tasks. A practical exploration of the lifecycle of creating node modules as well as learning all of the top features that npm has to offer.Intended for readers who want to create their first node.js modules. The programming paradigm of JavaScript is not covered so a foundation in these concepts would be beneficial.

  14. Flexible programmable logic module

    Science.gov (United States)

    Robertson, Perry J.; Hutchinson, Robert L.; Pierson, Lyndon G.

    2001-01-01

    The circuit module of this invention is a VME board containing a plurality of programmable logic devices (PLDs), a controlled impedance clock tree, and interconnecting buses. The PLDs are arranged to permit systolic processing of a problem by offering wide data buses and a plurality of processing nodes. The board contains a clock reference and clock distribution tree that can drive each of the PLDs with two critically timed clock references. External clock references can be used to drive additional circuit modules all operating from the same synchronous clock reference.

  15. Fan beam intensity modulated proton therapy

    Science.gov (United States)

    Hill, Patrick M.

    A fan beam proton therapy is developed which delivers intensity modulated proton therapy using distal edge tracking. The system may be retrofit onto existing proton therapy gantries without alterations to infrastructure in order to improve treatments through intensity modulation. A novel range and intensity modulation system is designed using acrylic leaves that are inserted or retracted from subsections of the fan beam. Leaf thicknesses are chosen in a base-2 system and motivated in a binary manner. Dose spots from individual beam channels range between 1 and 5 cm. Integrated collimators attempting to limit crosstalk among beam channels are investigated, but found to be inferior to uncollimated beam channel modulators. A treatment planning system performing data manipulation in MATLAB and dose calculation in MCNPX is developed. Beamlet dose is calculated on patient CT data and a fan beam source is manually defined to produce accurate results. An energy deposition tally follows the CT grid, allowing straightforward registration of dose and image data. Simulations of beam channels assume that a beam channel either delivers dose to a distal edge spot or is intensity modulated. A final calculation is performed separately to determine the deliverable dose accounting for all sources of scatter. Treatment plans investigate the effects that varying system parameters have on dose distributions. Beam channel apertures may be as large as 20 mm because the sharp distal falloff characteristic of proton dose provides sufficient intensity modulation to meet dose objectives, even in the presence of coarse lateral resolution. Dose conformity suffers only when treatments are delivered from less than 10 angles. Jaw widths of 1--2 cm produce comparable dose distributions, but a jaw width of 4 cm produces unacceptable target coverage when maintaining critical structure avoidance. Treatment time for a prostate delivery is estimated to be on the order of 10 minutes. Neutron production

  16. Arrays of surface-normal electroabsorption modulators for the generation and signal processing of microwave photonics signals

    NARCIS (Netherlands)

    Noharet, Bertrand; Wang, Qin; Platt, Duncan; Junique, Stéphane; Marpaung, D.A.I.; Roeloffzen, C.G.H.

    2011-01-01

    The development of an array of 16 surface-normal electroabsorption modulators operating at 1550nm is presented. The modulator array is dedicated to the generation and processing of microwave photonics signals, targeting a modulation bandwidth in excess of 5GHz. The hybrid integration of the

  17. Photovoltaic module and interlocked stack of photovoltaic modules

    Science.gov (United States)

    Wares, Brian S.

    2012-09-04

    One embodiment relates to an arrangement of photovoltaic modules configured for transportation. The arrangement includes a plurality of photovoltaic modules, each photovoltaic module including a frame having at least a top member and a bottom member. A plurality of alignment features are included on the top member of each frame, and a plurality of alignment features are included on the bottom member of each frame. Adjacent photovoltaic modules are interlocked by the alignment features on the top member of a lower module fitting together with the alignment features on the bottom member of an upper module. Other embodiments, features and aspects are also disclosed.

  18. Wake Shield Target Protection

    International Nuclear Information System (INIS)

    Valmianski, Emanuil I.; Petzoldt, Ronald W.; Alexander, Neil B.

    2003-01-01

    The heat flux from both gas convection and chamber radiation on a direct drive target must be limited to avoid target damage from excessive D-T temperature increase. One of the possibilities of protecting the target is a wake shield flying in front of the target. A shield will also reduce drag force on the target, thereby facilitating target tracking and position prediction. A Direct Simulation Monte Carlo (DSMC) code was used to calculate convection heat loads as boundary conditions input into ANSYS thermal calculations. These were used for studying the quality of target protection depending on various shapes of shields, target-shield distance, and protective properties of the shield moving relative to the target. The results show that the shield can reduce the convective heat flux by a factor of 2 to 5 depending on pressure, temperature, and velocity. The protective effect of a shield moving relative to the target is greater than the protective properties of a fixed shield. However, the protective effect of a shield moving under the drag force is not sufficient for bringing the heat load on the target down to the necessary limit. Some other ways of diminishing heat flux using a protective shield are discussed

  19. Development of distributed target

    CERN Document Server

    Yu Hai Jun; Li Qin; Zhou Fu Xin; Shi Jin Shui; Ma Bing; Chen Nan; Jing Xiao Bing

    2002-01-01

    Linear introduction accelerator is expected to generate small diameter X-ray spots with high intensity. The interaction of the electron beam with plasmas generated at the X-ray converter will make the spot on target increase with time and debase the X-ray dose and the imaging resolving power. A distributed target is developed which has about 24 pieces of thin 0.05 mm tantalum films distributed over 1 cm. due to the structure adoption, the distributed target material over a large volume decreases the energy deposition per unit volume and hence reduces the temperature of target surface, then reduces the initial plasma formalizing and its expansion velocity. The comparison and analysis with two kinds of target structures are presented using numerical calculation and experiments, the results show the X-ray dose and normalized angle distribution of the two is basically the same, while the surface of the distributed target is not destroyed like the previous block target

  20. Polarized targets and beams

    International Nuclear Information System (INIS)

    Meyer, W.

    1985-01-01

    First the experimental situation of the single-pion photoproduction and the photodisintegration of the deuteron is briefly discussed. Then a description of the Bonn polarization facilities is given. The point of main effort is put on the polarized target which plays a vital role in the program. A facility for photon induced double polarization experiments at ELSA will be presented in section 4. Properties of a tensor polarized deuteron target are discussed in section 5. The development in the field of polarized targets, especially on new target materials, enables a new generation of polarized target experiments with (polarized) electrons. Some comments on the use of a polarized target in combination with electron beams will be discussed in section 6. Electron deuteron scattering from a tensor polarized deuteron target is considered and compared with other experimental possibilities. (orig./HSI)

  1. Future Targets for Female Sexual Dysfunction.

    Science.gov (United States)

    Farmer, Melissa; Yoon, Hana; Goldstein, Irwin

    2016-08-01

    Female sexual function reflects a dynamic interplay of central and peripheral nervous, vascular, and endocrine systems. The primary challenge in the development of novel treatments for female sexual dysfunction is the identification and targeted modulation of excitatory sexual circuits using pharmacologic treatments that facilitate the synthesis, release, and/or receptor binding of neurochemicals, peptides, and hormones that promote female sexual function. To develop an evidence-based state-of-the-art consensus report that critically integrates current knowledge of the therapeutic potential for known molecular and cellular targets to facilitate the physiologic processes underlying female sexual function. State-of-the-art review representing the opinions of international experts developed in a consensus process during a 1-year period. Expert opinion was established by grading the evidence-based medical literature, intensive internal committee discussion, public presentation, and debate. Scientific investigation is urgently needed to expand knowledge and foster development of future treatments that maintain genital tissue integrity, enhance genital physiologic responsiveness, and optimize positive subjective appraisal of internal and external sexual cues. This article critically condenses the current knowledge of therapeutic manipulation of molecular and cellular targets within biological systems responsible for female sexual physiologic function. Future treatment targets include pharmacologic modulation of emotional learning circuits, restoration of normal tactile sensation, growth factor therapy, gene therapy, stem cell-based therapies, and regenerative medicine. Concurrent use of centrally and peripherally acting therapies could optimize treatment response. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

  2. Modelling the Photovoltaic Module

    DEFF Research Database (Denmark)

    Katsanevakis, Markos

    2011-01-01

    This paper refers into various ways in simulation the Photovoltaic (PV) module behaviour under any combination of solar irradiation and ambient temperature. There are three different approaches presented here briefly and one of them is chosen because of its good accuracy and relatively low...

  3. Special Attachments. Module 19.

    Science.gov (United States)

    South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

    This module on special attachments, one in a series dealing with industrial sewing machines, their attachments, and operation, covers four topics: gauges; cording attachment; zipper foot; and hemming, shirring, and binding. For each topic these components are provided: an introduction, directions, an objective, learning activities, student…

  4. Special Operation. Module 20.

    Science.gov (United States)

    South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

    This module on special operations, one in a series dealing with industrial sewing machines, their attachments, and operation, covers two topics: topstitching and mitering. For each topic these components are provided: an introduction, directions, an objective, learning activities, student information, a student self-check, and a check-out…

  5. Barrel Module0 Autopsy

    CERN Document Server

    Cobal, M; Nessi, Marzio; Blanch, O; Zamora, Y

    1999-01-01

    Using the information from the Cs calibration runs, many of the problems affecting the response of the barrel Module0 prototype have been spotted out. These can be bad fibre-tile couplings, light losses from fibres bundling, broken fibres, not transparent tiles etc. After a visual inspection, most of these problems have been repaired.

  6. Rescue Manual. Module 6.

    Science.gov (United States)

    Ohio State Univ., Columbus. Instructional Materials Lab.

    This learner manual for rescuers covers the current techniques or practices required in the rescue service. The sixth of 10 modules contains 4 chapters: (1) industrial rescue; (2) rescue from a confined space; (3) extrication from heavy equipment; and (4) rescue operations involving elevators. Key points, an introduction, and conclusion accompany…

  7. Evolutionary and developmental modules.

    Science.gov (United States)

    Lacquaniti, Francesco; Ivanenko, Yuri P; d'Avella, Andrea; Zelik, Karl E; Zago, Myrka

    2013-01-01

    The identification of biological modules at the systems level often follows top-down decomposition of a task goal, or bottom-up decomposition of multidimensional data arrays into basic elements or patterns representing shared features. These approaches traditionally have been applied to mature, fully developed systems. Here we review some results from two other perspectives on modularity, namely the developmental and evolutionary perspective. There is growing evidence that modular units of development were highly preserved and recombined during evolution. We first consider a few examples of modules well identifiable from morphology. Next we consider the more difficult issue of identifying functional developmental modules. We dwell especially on modular control of locomotion to argue that the building blocks used to construct different locomotor behaviors are similar across several animal species, presumably related to ancestral neural networks of command. A recurrent theme from comparative studies is that the developmental addition of new premotor modules underlies the postnatal acquisition and refinement of several different motor behaviors in vertebrates.

  8. Paratransit: An Instructional Module.

    Science.gov (United States)

    Scalici, Anthony

    A concept-based introduction to paratransit is provided in this instructional module for undergraduate and graduate transportation-related courses for disciplines such as engineering, business, marketing, and technology. The concept of paratransit generally refers to modes of transportation other than mass transit and solo-driven automobiles. The…

  9. The Nuclotron internal target control and data acquisition system

    Energy Technology Data Exchange (ETDEWEB)

    Isupov, A.Yu., E-mail: isupov@moonhe.jinr.ru [Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation); Krasnov, V.A.; Ladygin, V.P.; Piyadin, S.M.; Reznikov, S.G. [Joint Institute for Nuclear Research, Dubna 141980 (Russian Federation)

    2013-01-11

    The new control system of the Nuclotron (JINR, Dubna) internal target is described in both hardware and software aspects. The CAMAC hardware is based on the use of the standard CAMAC modules developed and manufactured at JINR. The internal target control and data acquisition (IntTarg CDAQ) system software is implemented using the ngdp framework under the Unix-like operating system (OS) FreeBSD to allow easy network distribution of the online data collected from internal target and accompanying detectors, as well as the internal target remote control.

  10. Targeting the Thioredoxin System for Cancer Therapy.

    Science.gov (United States)

    Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

    2017-09-01

    Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Targeted Delivery of Immunomodulators to Lymph Nodes

    Directory of Open Access Journals (Sweden)

    Jamil Azzi

    2016-05-01

    Full Text Available Active-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node addressin molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.

  12. Design of small molecule epigenetic modulators.

    Science.gov (United States)

    Pachaiyappan, Boobalan; Woster, Patrick M

    2014-01-01

    The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be categorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Young module multiplicities and classifying the indecomposable Young permutation modules

    OpenAIRE

    Gill, Christopher C.

    2012-01-01

    We study the multiplicities of Young modules as direct summands of permutation modules on cosets of Young subgroups. Such multiplicities have become known as the p-Kostka numbers. We classify the indecomposable Young permutation modules, and, applying the Brauer construction for p-permutation modules, we give some new reductions for p-Kostka numbers. In particular we prove that p-Kostka numbers are preserved under multiplying partitions by p, and strengthen a known reduction given by Henke, c...

  14. Fabrication of cryogenic inertial-confinement-fusion targets using target free-fall technique. Report No. 2-82

    International Nuclear Information System (INIS)

    Kim, K.; Murphy, M.J.

    1982-04-01

    Techniques for fabricating cryogenic inertial confinement fusion targets (i.e., spherical shells containing a uniform layer of DT ice) are investigated using target free-fall concept. Detection and characterization of the moving targets are effected by optoelectronic means, of which the principal is an RF ac-interferometer. This interferometer system demonstrates, for the first time, the speed capabilities of the phase-modulation ac-interferometry. New techiques developed for handling, holding, launching, and transporting targets are also described. Results obtained at both room and cryogenic temperatures are presented

  15. Nova target experiments

    International Nuclear Information System (INIS)

    Drake, R.P.

    1985-11-01

    The Nova laser, at the Lawrence Livermore National Laboratory, provides unique opportunities for target experiments. It has unprecedented energy on target and significant flexibility. The paper presented by John Hunt described the capabilities and the status of Nova. This paper discusses plans for future experiments using Nova, and the present status of target experiments. We plan to perform high-quality physics experiments that exploit the unique capabilities of Nova. Because this is our goal, we are fielding an extensive array of well-characterized target diagnostics to measure the emissions from the target. The first section of this paper discusses the basic target diagnostics. We are also taking care to quantify the performance of the laser

  16. Targeting and Persuasive Advertising

    OpenAIRE

    Egli, Alain (Autor/in)

    2015-01-01

    Firms face a prisoner's dilemma when advertising in a competitive environment. In a Hotelling framework with persuasive advertisingfirms counteract this prisoner's dilemma with targeting. The firms even solve the prisoner's problem if targeted advertising is effective enough. Advertising turns from wasteful competition into profits. This is in contrast to wasteful competition as argument for regulations. A further result is maximum advertising differentiation: thefirms target their advertisin...

  17. The ISOLDE target robots

    CERN Multimedia

    Maximilein Brice

    2002-01-01

    ISOLDE targets need to be changed frequently, around 80 times per year. The high radiation levels do not permit this to be done by human hands and the target changes are effected by 2 industrial robots (picture _01). On the left, in the distance, the front-end of the GPS (General Purpose Separator) is seen, while the HRS (High Resolution Separator) is at the right. Also seen are the doors to the irradiated-target storage.

  18. Deuterium high pressure target

    International Nuclear Information System (INIS)

    Perevozchikov, V.V.; Yukhimchuk, A.A.; Vinogradov, Yu.I.

    2001-01-01

    The design of the deuterium high-pressure target is presented. The target having volume of 76 cm 3 serves to provide the experimental research of muon catalyzed fusion reactions in ultra-pure deuterium in the temperature range 80-800 K under pressures of up to 150 MPa. The operation of the main systems of the target is described: generation and purification of deuterium gas, refrigeration, heating, evacuation, automated control system and data collection system

  19. Modulating mind-wandering in dysphoria

    Directory of Open Access Journals (Sweden)

    Fionnuala Catherine Murphy

    2013-11-01

    Full Text Available Depression is associated with significant difficulty staying ‘in the moment’ as the mind tends to wander away from current activity to focus instead on personal concerns. Mind-wandering (MW may in some instances be a precursor for depressive rumination, a thinking style believed to confer vulnerability to the likelihood and extent of depression. Though the majority of evidence examining MW and mood has been correlational, evidence indicates that MW may be not only a consequence but also a cause of low mood. Identifying a paradigm that could modulate MW, particularly in depressed individuals, would allow future studies to test whether elevated rates of MW causally drive cognitive-affective features of depression, such as rumination and anhedonia. This study therefore explored the feasibility of using an existing task manipulation to modulate behavioural and self-report indices of MW in participants with varying levels of self-reported dysphoria. Participants completed two go/no-go tasks – the SART and a high target probability task – and measures of state and trait MW. The two tasks were identical in all respects apart from the lower probability of no-go targets on the SART, a feature considered to encourage mindless, or inattentive, responding. Across participants, errors of commission (a behavioural indicator of MW were elevated on the SART relative to the high probability task, a pattern than was particularly pronounced in dysphoric participants. Dysphoric individuals furthermore reported elevated levels of MW, though the modulation of these subjective reports by task was present to a similar rather than greater extent in the dysphoric individuals. These findings provide encouraging preliminary support for the use of this paradigm as one that modulates MW in depressed individuals. The implications of these results and directions for future research are discussed.

  20. Targeted Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    David Cheng

    2011-10-01

    Full Text Available Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  1. Targeted Radionuclide Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ersahin, Devrim, E-mail: devrimersahin@yahoo.com; Doddamane, Indukala; Cheng, David [Department of Diagnostic Radiology, School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06520 (United States)

    2011-10-11

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  2. Target Assembly Facility

    Data.gov (United States)

    Federal Laboratory Consortium — The Target Assembly Facility integrates new armor concepts into actual armored vehicles. Featuring the capability ofmachining and cutting radioactive materials, it...

  3. Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Ersahin, Devrim; Doddamane, Indukala; Cheng, David

    2011-01-01

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose

  4. Targeting the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.

    2006-11-07

    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  5. From research methods to methodical researcher: Making use of the student voice towards a more comprehensive module evaluation

    OpenAIRE

    Hast, Michael

    2015-01-01

    It is not uncommon for undergraduate students to feel aversion towards research methods teaching. This does not change the fact that research methods play a key role in their education. Targeting module design is imperative to ensure success. However, end-of-module student evaluations may provide a false sense of security regarding satisfaction and learnt knowledge. In order to approach module design more effectively it may instead be necessary to view module evaluations from a delayed perspe...

  6. Modulating aging and longevity

    DEFF Research Database (Denmark)

    Rattan, Suresh

    Provides information and an evaluation of a variety of approaches tried for modulating aging and longevity, including dietary supplementation with antioxidants, vitamins and hormones, genetic engineering, life-style alterations, and hormesis through mild stress. After decades of systematic collec....... The goal of research on ageing is not to increase human longevity regardless of the consequences, but to increase active longevity free from disability and functional dependence......Provides information and an evaluation of a variety of approaches tried for modulating aging and longevity, including dietary supplementation with antioxidants, vitamins and hormones, genetic engineering, life-style alterations, and hormesis through mild stress. After decades of systematic...... collection of data describing age-related changes in organisms, organs, tissues, cells and macromolecules, biogerontologists are now in a position to construct general principles of ageing and explore various possibilities of intervention using rational approaches. While not giving serious consideration...

  7. Weighted network modules

    International Nuclear Information System (INIS)

    Farkas, Illes; Abel, Daniel; Palla, Gergely; Vicsek, Tamas

    2007-01-01

    The inclusion of link weights into the analysis of network properties allows a deeper insight into the (often overlapping) modular structure of real-world webs. We introduce a clustering algorithm clique percolation method with weights (CPMw) for weighted networks based on the concept of percolating k-cliques with high enough intensity. The algorithm allows overlaps between the modules. First, we give detailed analytical and numerical results about the critical point of weighted k-clique percolation on (weighted) Erdos-Renyi graphs. Then, for a scientist collaboration web and a stock correlation graph we compute three-link weight correlations and with the CPMw the weighted modules. After reshuffling link weights in both networks and computing the same quantities for the randomized control graphs as well, we show that groups of three or more strong links prefer to cluster together in both original graphs

  8. Quad nanosecond delay module

    International Nuclear Information System (INIS)

    McDonald, R.J.; Hunter, J.B.; Wozniak, G.J.

    1986-04-01

    Four nanosecond (ns) delay units have been designed to fit in a single-width NIM module. This module is particularly suited for use in conjunction with quad constant fraction timing discriminators (CFTDs) since it has four delay units that can be placed adjacent to the four units of the CFTD. A series of different length cables connected via DIP toggle switches provide delays of 0.60 ns in 4 ns increments. Thus, the CFTD delay can be optimized for pulses of different rise times from approx.10-100 ns. Design work for the PC board and silkscreening of the front panel were done with the MacDraw program on the Apple Mackintosh computer and printed with the Lasewriter printer. 6 refs

  9. Silicon Optical Modulator Simulation

    Directory of Open Access Journals (Sweden)

    Soon Thor LIM

    2015-04-01

    Full Text Available We developed a way of predicting and analyzing high speed optical modulator. Our research adopted a bottom-up approach to consider high-speed optical links using an eye diagram. Our method leverages on modular mapping of electrical characteristics to optical characteristics, while attaining the required accuracy necessary for device footprint approaching sub-micron scales where electrical data distribution varies drastically. We calculate for the bias dependent phase shift (2pi/mm and loss (dB/mm for the optical modulator based on the real and imaginary part of complex effective indices. Subsequently, combine effectively both the electrical and optical profiles to construct the optical eye diagram which is the essential gist of signal integrity of such devices.

  10. Potential clinical efficacy of intensity-modulated conformal therapy

    International Nuclear Information System (INIS)

    Meeks, Sanford L.; Buatti, John M.; Bova, Francis J.; Friedman, William A.; Mendenhall, William M.; Zlotecki, Robert A.

    1998-01-01

    Purpose: The purpose of this study was to examine the potential benefit of using intensity-modulated conformal therapy for a variety of lesions currently treated with stereotactic radiosurgery or conventional radiotherapy. Methods and Materials: Intensity-modulated conformal treatment plans were generated for small intracranial lesions, as well as head and neck, lung, breast, and prostate cases, using the Peacock Plan[reg] treatment-planning system (Nomos Corporation). For small intracranial lesions, intensity-modulated conformal treatment plans were compared with stereotactic radiosurgery treatment plans generated for patient treatment at the University of Florida Shands Cancer Center. For other sites (head and neck, lung, breast, and prostate), plans generated using the Peacock Plan[reg] were compared with conventional treatment plans, as well as beam's-eye-view conformal treatment plans. Plan comparisons were accomplished through conventional qualitative review of two-dimensional (2D) dose distributions in conjunction with quantitative techniques, such as dose-volume histograms, dosimetric statistics, normal tissue complication probabilities, tumor control probabilities, and objective numerical scoring. Results: For small intracranial lesions, there is little difference between intensity-modulated conformal treatment planning and radiosurgery treatment planning in the conformation of high isodose lines with the target volume. However, stereotactic treatment planning provides a steeper dose gradient outside the target volume and, hence, a lower normal tissue toxicity index. For extracranial sites, objective numerical scores for beam's-eye-view and intensity-modulated conformal planning techniques are superior to scores for conventional treatment plans. The beam's-eye-view planning technique prevents geographic target misses and better excludes healthy tissues from the treatment portal. Compared with scores for the beam's-eye-view planning technique, scores for

  11. Investigating Quantum Modulation States

    Science.gov (United States)

    2016-03-01

    Coherent state quantum data encryption is highly interoperable with current classical optical infrastructure in both fiber and free space optical networks...hub’s field of regard has a transmit/receive module that are endpoints of the Lyot filter stage tree within the hub’s backend electro-optics control... mobile airborne and space-borne networking. Just like any laser communication technology, QC links are affected by several sources of distortions

  12. Sparx PCA Module

    Energy Technology Data Exchange (ETDEWEB)

    2017-04-25

    Sparx, a new environment for Cryo-EM image processing; Cryo-EM, Single particle reconstruction, principal component analysis; Hardware Req.: PC, MAC, Supercomputer, Mainframe, Multiplatform, Workstation. Software Req.: operating system is Unix; Compiler C++; type of files: source code, object library, executable modules, compilation instructions; sample problem input data. Location/transmission: http://sparx-em.org; User manual & paper: http://sparx-em.org;

  13. Modulated Pade approximant

    International Nuclear Information System (INIS)

    Ginsburg, C.A.

    1980-01-01

    In many problems, a desired property A of a function f(x) is determined by the behaviour of f(x) approximately equal to g(x,A) as x→xsup(*). In this letter, a method for resuming the power series in x of f(x) and approximating A (modulated Pade approximant) is presented. This new approximant is an extension of a resumation method for f(x) in terms of rational functions. (author)

  14. of Banach modules

    Directory of Open Access Journals (Sweden)

    Anousheh Fatemeh

    2015-10-01

    Full Text Available Let A be a Banach algebra, E be a Banach A-bimodule and Δ E → A be a bounded Banach A-bimodule homomorphism. It is shown that under some mild conditions, the weakΔ''-amenability of E'' (as an A''-bimodule necessitates weak Δ-amenability of E (as an A-bimodule. Some examples of weak-amenable Banach modules are provided as well.

  15. FERMI multi-chip module

    CERN Multimedia

    This FERMI multi-chip module contains five million transistors. 25 000 of these modules will handle the flood of information through parts of the ATLAS and CMS detectors at the LHC. To select interesting events for recording, crucial decisions are taken before the data leaves the detector. FERMI modules are being developed at CERN in partnership with European industry.

  16. Energy spectrum control for modulated proton beams

    International Nuclear Information System (INIS)

    Hsi, Wen C.; Moyers, Michael F.; Nichiporov, Dmitri; Anferov, Vladimir; Wolanski, Mark; Allgower, Chris E.; Farr, Jonathan B.; Mascia, Anthony E.; Schreuder, Andries N.

    2009-01-01

    In proton therapy delivered with range modulated beams, the energy spectrum of protons entering the delivery nozzle can affect the dose uniformity within the target region and the dose gradient around its periphery. For a cyclotron with a fixed extraction energy, a rangeshifter is used to change the energy but this produces increasing energy spreads for decreasing energies. This study investigated the magnitude of the effects of different energy spreads on dose uniformity and distal edge dose gradient and determined the limits for controlling the incident spectrum. A multilayer Faraday cup (MLFC) was calibrated against depth dose curves measured in water for nonmodulated beams with various incident spectra. Depth dose curves were measured in a water phantom and in a multilayer ionization chamber detector for modulated beams using different incident energy spreads. Some nozzle entrance energy spectra can produce unacceptable dose nonuniformities of up to ±21% over the modulated region. For modulated beams and small beam ranges, the width of the distal penumbra can vary by a factor of 2.5. When the energy spread was controlled within the defined limits, the dose nonuniformity was less than ±3%. To facilitate understanding of the results, the data were compared to the measured and Monte Carlo calculated data from a variable extraction energy synchrotron which has a narrow spectrum for all energies. Dose uniformity is only maintained within prescription limits when the energy spread is controlled. At low energies, a large spread can be beneficial for extending the energy range at which a single range modulator device can be used. An MLFC can be used as part of a feedback to provide specified energy spreads for different energies.

  17. Smoothing by spectral dispersion using random phase modulation for inertial confinement fusion

    International Nuclear Information System (INIS)

    Rothenberg, J.E.

    1995-01-01

    Numerical simulations of beam smoothing using random phase modulation and grating dispersion are presented. Spatial spectra of the target illumination show that significantly improved smoothing at low spatial frequency is achieved while maintaining uniform intensity in the laser amplifier

  18. Expression of an expansin carbohydrate-binding module affects ...

    African Journals Online (AJOL)

    Expansins are believed to be involved in disrupting the non-covalent adhesion of cellulose to matrix polysaccharides, thereby promoting wall creep. We have targeted a putative potato expansin (EXPA) carbohydrate-binding module (CBM) to the cell walls of tobacco plants. Histological examinations and electron ...

  19. Optical rangefinding applications using communications modulation technique

    Science.gov (United States)

    Caplan, William D.; Morcom, Christopher John

    2010-10-01

    A novel range detection technique combines optical pulse modulation patterns with signal cross-correlation to produce an accurate range estimate from low power signals. The cross-correlation peak is analyzed by a post-processing algorithm such that the phase delay is proportional to the range to target. This technique produces a stable range estimate from noisy signals. The advantage is higher accuracy obtained with relatively low optical power transmitted. The technique is useful for low cost, low power and low mass sensors suitable for tactical use. The signal coding technique allows applications including IFF and battlefield identification systems.

  20. Dietary Modulation of Inflammation-Induced Colorectal Cancer through PPARγ

    Directory of Open Access Journals (Sweden)

    Ashlee B. Carter

    2009-01-01

    Full Text Available Mounting evidence suggests that the risk of developing colorectal cancer (CRC is dramatically increased for patients with chronic inflammatory diseases. For instance, patients with Crohn's Disease (CD or Ulcerative Colitis (UC have a 12–20% increased risk for developing CRC. Preventive strategies utilizing nontoxic natural compounds that modulate immune responses could be successful in the suppression of inflammation-driven colorectal cancer in high-risk groups. The increase of peroxisome proliferator-activated receptor-γ (PPAR-γ expression and its transcriptional activity has been identified as a target for anti-inflammatory efforts, and the suppression of inflammation-driven colon cancer. PPARγ down-modulates inflammation and elicits antiproliferative and proapoptotic actions in epithelial cells. All of which may decrease the risk for inflammation-induced CRC. This review will focus on the use of orally active, naturally occurring chemopreventive approaches against inflammation-induced CRC that target PPARγ and therefore down-modulate inflammation.

  1. Immune-modulating therapy in acute pancreatitis: Fact or fiction

    Science.gov (United States)

    Akinosoglou, Karolina; Gogos, Charalambos

    2014-01-01

    Acute pancreatitis (AP) is one of the most common diseases of the gastrointestinal tract, bearing significant morbidity and mortality worldwide. Current treatment of AP remains unspecific and supportive and is mainly targeted to aggressively prevent systemic complications and organ failure by intensive care. As acute pancreatitis shares an indistinguishable profile of inflammation with sepsis, therapeutic approaches have turned towards modulating the systemic inflammatory response. Targets, among others, have included pro- and anti-inflammatory modulators, cytokines, chemokines, immune cells, adhesive molecules and platelets. Even though, initial results in experimental models have been encouraging, clinical implementation of immune-regulating therapies in acute pancreatitis has had a slow progress. Main reasons include difficulty in clinical translation of experimental data, poor understanding of inflammatory response time-course, flaws in experimental designs, need for multimodal approaches and commercial drawbacks. Whether immune-modulation in acute pancreatitis remains a fact or just fiction remains to be seen in the future. PMID:25386069

  2. Target reactor development problems

    International Nuclear Information System (INIS)

    Lathrop, K.D.; Vigil, J.C.

    1977-01-01

    Target-blanket design studies are discussed for an accelerator-breeder concept employing a linear accelerator in conjunction with a modified conventional power reactor to produce both fissile fuel and power. The following problems in target and blanket system design are discussed: radiation damage, heat removal, neutronic design, and economics

  3. The CNGS target

    CERN Multimedia

    Patrice Loïez

    2005-01-01

    The CERN Neutrinos to Gran Sasso (CNGS) target ‘magazine’ of five target units. Each unit contains a series of 10-cm long graphite rods distributed over a length of 2 m. It is designed to maximize the number of secondary particles produced and hence the number of neutrinos. One unit is used at a time to prevent over heating.

  4. Targeted radionuclide therapy

    African Journals Online (AJOL)

    target for which a speci c treatment/drug is intended (Fig. 1). eranostics .... Using an anti-CD20 antibody as a delivery device to target the follicular ... systems combine diagnostic imaging (Ga-68-DOTATATE PET/CT) .... Intra-articular injected ...

  5. Modelling Recycling Targets

    DEFF Research Database (Denmark)

    hill, amanda; Leinikka Dall, Ole; Andersen, Frits Møller

    2014-01-01

    % for household waste, and sets an ambitious goal of a 50% recycling rate by 2020. This study integrates the recycling target into the FRIDA model to project how much waste and from which streams should be diverted from incineration to recycling in order to achieve the target. Furthermore, it discusses how...

  6. Strategic Targeted Advertising

    NARCIS (Netherlands)

    A. Galeotti; J.L. Moraga-Gonzalez (José Luis)

    2003-01-01

    textabstractWe present a strategic game of pricing and targeted-advertising. Firms can simultaneously target price advertisements to different groups of customers, or to the entire market. Pure strategy equilibria do not exist and thus market segmentation cannot occur surely. Equilibria exhibit

  7. Seedling root targets

    Science.gov (United States)

    Diane L. Haase

    2011-01-01

    Roots are critical to seedling performance after outplanting. Although root quality is not as quick and simple to measure as shoot quality, target root characteristics should be included in any seedling quality assessment program. This paper provides a brief review of root characteristics most commonly targeted for operational seedling production. These are: root mass...

  8. Internal targets for LEAR

    International Nuclear Information System (INIS)

    Kilian, K.; Gspann, J.; Mohl, D.; Poth, H.

    1984-01-01

    This chapter considers the use of thin internal targets in conjunction with phase-space cooling at the Low-Energy Antiproton Ring (LEAR). Topics considered include the merits of internal target operation; the most efficient use of antiprotons and of proton synchrotron (PS) protons, highest center-of-mass (c.m.) energy resolution; highest angular resolution and access to extreme angles; the transparent environment for all reaction products; a windowless source and pure targets; highest luminosity and count rates; access to lowest energies with increasing resolution; internal target thickness and vacuum requirements; required cooling performance; and modes of operation. It is demonstrated that an internal target in conjunction with phase-space cooling has the potential of better performance in terms of the economic use of antiprotons and consequently of PS protons; energy resolution; angular resolution; maximum reaction rate capability (statistical precision); efficient parasitic operation; transparency of the target for reaction products; access to low energies; and the ease of polarized target experiments. It is concluded that all p - experiments which need high statistics and high p - flux, such as studies of rare channels or broad, weak resonance structures, would profit from internal targets

  9. Fusion target design

    International Nuclear Information System (INIS)

    Bangerter, R.O.

    1978-01-01

    Most detailed fusion target design is done by numerical simulation using large computers. Although numerical simulation is briefly discussed, this lecture deals primarily with the way in which basic physical arguments, driver technology considerations and economical power production requirements are used to guide and augment the simulations. Physics topics discussed include target energetics, preheat, stability and symmetry. A specific design example is discussed

  10. Electron beam fusion targets

    International Nuclear Information System (INIS)

    Clauser, M.J.; Sweeney, M.A.

    1975-01-01

    R The behavior of the DT filled gold shells when irradiated by a variety of pulse shapes was studied. In these pulses the power (and beam current) was varied, but the voltage was kept constant at 1 MeV. In general the performance of the target, for a given peak power, was not significantly affected by the pulse shape. Pulses with rise times of up to half the implosion time do not significantly degrade the target performance. The use of the ''optimal pulse'' of laser fusion with a fixed peak power does not appear to improve the performance of these targets. The main function of the ''optimal pulse'' is to produce a large rho r of the target during the thermonuclear burn. In e-beam targets a total rho r of 5--10 g/cm 2 can be obtained without pulse shaping; the problem here is one of achieving high enough temperatures to ignite the DT. (U.S.)

  11. Receiver Gain Modulation Circuit

    Science.gov (United States)

    Jones, Hollis; Racette, Paul; Walker, David; Gu, Dazhen

    2011-01-01

    A receiver gain modulation circuit (RGMC) was developed that modulates the power gain of the output of a radiometer receiver with a test signal. As the radiometer receiver switches between calibration noise references, the test signal is mixed with the calibrated noise and thus produces an ensemble set of measurements from which ensemble statistical analysis can be used to extract statistical information about the test signal. The RGMC is an enabling technology of the ensemble detector. As a key component for achieving ensemble detection and analysis, the RGMC has broad aeronautical and space applications. The RGMC can be used to test and develop new calibration algorithms, for example, to detect gain anomalies, and/or correct for slow drifts that affect climate-quality measurements over an accelerated time scale. A generalized approach to analyzing radiometer system designs yields a mathematical treatment of noise reference measurements in calibration algorithms. By treating the measurements from the different noise references as ensemble samples of the receiver state, i.e. receiver gain, a quantitative description of the non-stationary properties of the underlying receiver fluctuations can be derived. Excellent agreement has been obtained between model calculations and radiometric measurements. The mathematical formulation is equivalent to modulating the gain of a stable receiver with an externally generated signal and is the basis for ensemble detection and analysis (EDA). The concept of generating ensemble data sets using an ensemble detector is similar to the ensemble data sets generated as part of ensemble empirical mode decomposition (EEMD) with exception of a key distinguishing factor. EEMD adds noise to the signal under study whereas EDA mixes the signal with calibrated noise. It is mixing with calibrated noise that permits the measurement of temporal-functional variability of uncertainty in the underlying process. The RGMC permits the evaluation of EDA by

  12. Creep Burst Testing of a Woven Inflatable Module

    Science.gov (United States)

    Selig, Molly M.; Valle, Gerard D.; James, George H.; Oliveras, Ovidio M.; Jones, Thomas C.; Doggett, William R.

    2015-01-01

    A woven Vectran inflatable module 88 inches in diameter and 10 feet long was tested at the NASA Johnson Space Center until failure from creep. The module was pressurized pneumatically to an internal pressure of 145 psig, and was held at pressure until burst. The external environment remained at standard atmospheric temperature and pressure. The module burst occurred after 49 minutes at the target pressure. The test article pressure and temperature were monitored, and video footage of the burst was captured at 60 FPS. Photogrammetry was used to obtain strain measurements of some of the webbing. Accelerometers on the test article measured the dynamic response. This paper discusses the test article, test setup, predictions, observations, photogrammetry technique and strain results, structural dynamics methods and quick-look results, and a comparison of the module level creep behavior to the strap level creep behavior.

  13. Target Trailing With Safe Navigation for Maritime Autonomous Surface Vehicles

    Science.gov (United States)

    Wolf, Michael; Kuwata, Yoshiaki; Zarzhitsky, Dimitri V.

    2013-01-01

    This software implements a motion-planning module for a maritime autonomous surface vehicle (ASV). The module trails a given target while also avoiding static and dynamic surface hazards. When surface hazards are other moving boats, the motion planner must apply International Regulations for Avoiding Collisions at Sea (COLREGS). A key subset of these rules has been implemented in the software. In case contact with the target is lost, the software can receive and follow a "reacquisition route," provided by a complementary system, until the target is reacquired. The programmatic intention is that the trailed target is a submarine, although any mobile naval platform could serve as the target. The algorithmic approach to combining motion with a (possibly moving) goal location, while avoiding local hazards, may be applicable to robotic rovers, automated landing systems, and autonomous airships. The software operates in JPL s CARACaS (Control Architecture for Robotic Agent Command and Sensing) software architecture and relies on other modules for environmental perception data and information on the predicted detectability of the target, as well as the low-level interface to the boat controls.

  14. Bent Electro-Absorption Modulator

    DEFF Research Database (Denmark)

    2002-01-01

    by applying a variable electric or electronmagnetic field. The modulation of the complex refractive index results in a modulation of the refractive index contrast and the absorption coefficient for the waveguide at the frequency of the light. By carefully adjusting the composition of the semiconducting...... components and the applied electric field in relation to the frequency of the modulated radiation, the bending losses (and possibly coupling losses) will provide extinction of light guided by the bent waveguide section. The refractive index contract may be modulated while keeping the absorption coefficient......The present invention relates to a method and a device for modulating optical signals based on modulating bending losses in bend, quantum well semiconductor waveguide sections. The complex refractive index of the optical active semiconducting components of the waveguide section is modulated...

  15. Detection and localization of multiple short range targets using FMCW radar signal

    KAUST Repository

    Jardak, Seifallah; Kiuru, Tero; Metso, Mikko; Pursula, Pekka; Hakli, Janne; Hirvonen, Mervi; Ahmed, Sajid; Alouini, Mohamed-Slim

    2016-01-01

    In this paper, a 24 GHz frequency-modulated continuous wave radar is used to detect and localize both stationary and moving targets. Depending on the application, the implemented software offers different modes of operation. For example, it can

  16. Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis

    NARCIS (Netherlands)

    Ai, Ding; Jiang, Hongfeng; Westerterp, Marit; Murphy, Andrew J.; Wang, Mi; Ganda, Anjali; Abramowicz, Sandra; Welch, Carrie; Almazan, Felicidad; Zhu, Yi; Miller, Yury I.; Tall, Alan R.

    2014-01-01

    The mammalian target of rapamycin complex 1 inhibitor, rapamycin, has been shown to decrease atherosclerosis, even while increasing plasma low-density lipoprotein levels. This suggests an antiatherogenic effect possibly mediated by the modulation of inflammatory responses in atherosclerotic plaques.

  17. On staggered indecomposable Virasoro modules

    International Nuclear Information System (INIS)

    Kytoelae, Kalle; Ridout, David

    2009-01-01

    In this article, certain indecomposable Virasoro modules are studied. Specifically, the Virasoro mode L 0 is assumed to be nondiagonalizable, possessing Jordan blocks of rank 2. Moreover, the module is further assumed to have a highest weight submodule, the 'left module', and that the quotient by this submodule yields another highest weight module, the 'right module'. Such modules, which have been called staggered, have appeared repeatedly in the logarithmic conformal field theory literature, but their theory has not been explored in full generality. Here, such a theory is developed for the Virasoro algebra using rather elementary techniques. The focus centers on two different but related questions typically encountered in practical studies: How can one identify a given staggered module, and how can one demonstrate the existence of a proposed staggered module. Given just the values of the highest weights of the left and right modules, themselves subject to simple necessary conditions, invariants are defined which together with the knowledge of the left and right modules uniquely identify a staggered module. The possible values of these invariants form a vector space of dimension 0, 1, or 2, and the structures of the left and right modules limit the isomorphism classes of the corresponding staggered modules to an affine subspace (possibly empty). The number of invariants and affine restrictions is purely determined by the structures of the left and right modules. Moreover, in order to facilitate applications, the expressions for the invariants and restrictions are given by formulas as explicit as possible (they generally rely on expressions for Virasoro singular vectors). Finally, the text is liberally peppered throughout with examples illustrating the general concepts. These have been carefully chosen for their physical relevance or for the novel features they exhibit.

  18. On staggered indecomposable Virasoro modules

    Energy Technology Data Exchange (ETDEWEB)

    Kytoelae, Kalle [Geneve Univ. (Switzerland); Ridout, David [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany)

    2009-06-15

    In this article, certain indecomposable Virasoro modules are studied. Specifically, the Virasoro mode L0 is assumed to be non-diagonalisable, possessing Jordan blocks of rank two. Moreover, the module is further assumed to have a highest weight submodule, the ''left module'', and that the quotient by this submodule yields another highest weight module, the ''right module''. Such modules, which have been called staggered, have appeared repeatedly in the logarithmic conformal field theory literature, but their theory has not been explored in full generality. Here, such a theory is developed for the Virasoro algebra using rather elementary techniques. The focus centres on two different but related questions typically encountered in practical studies: How can one identify a given staggered module, and how can one demonstrate the existence of a proposed staggered module. Given just the values of the highest weights of the left and right modules, themselves subject to simple necessary conditions, invariants are defined which together with the knowledge of the left and right modules uniquely identify a staggered module. The possible values of these invariants form a vector space of dimension zero, one or two, and the structures of the left and right modules limit the isomorphism classes of the corresponding staggered modules to an affine subspace (possibly empty). The number of invariants and affine restrictions is purely determined by the structures of the left and right modules. Moreover, in order to facilitate applications, the expressions for the invariants and restrictions are given by formulae as explicit as possible (they generally rely on expressions for Virasoro singular vectors). Finally, the text is liberally peppered throughout with examples illustrating the general concepts. These have been carefully chosen for their physical relevance or for the novel features they exhibit. (orig.)

  19. On staggered indecomposable Virasoro modules

    International Nuclear Information System (INIS)

    Kytoelae, Kalle; Ridout, David

    2009-06-01

    In this article, certain indecomposable Virasoro modules are studied. Specifically, the Virasoro mode L0 is assumed to be non-diagonalisable, possessing Jordan blocks of rank two. Moreover, the module is further assumed to have a highest weight submodule, the ''left module'', and that the quotient by this submodule yields another highest weight module, the ''right module''. Such modules, which have been called staggered, have appeared repeatedly in the logarithmic conformal field theory literature, but their theory has not been explored in full generality. Here, such a theory is developed for the Virasoro algebra using rather elementary techniques. The focus centres on two different but related questions typically encountered in practical studies: How can one identify a given staggered module, and how can one demonstrate the existence of a proposed staggered module. Given just the values of the highest weights of the left and right modules, themselves subject to simple necessary conditions, invariants are defined which together with the knowledge of the left and right modules uniquely identify a staggered module. The possible values of these invariants form a vector space of dimension zero, one or two, and the structures of the left and right modules limit the isomorphism classes of the corresponding staggered modules to an affine subspace (possibly empty). The number of invariants and affine restrictions is purely determined by the structures of the left and right modules. Moreover, in order to facilitate applications, the expressions for the invariants and restrictions are given by formulae as explicit as possible (they generally rely on expressions for Virasoro singular vectors). Finally, the text is liberally peppered throughout with examples illustrating the general concepts. These have been carefully chosen for their physical relevance or for the novel features they exhibit. (orig.)

  20. On staggered indecomposable Virasoro modules

    Science.gov (United States)

    Kytölä, Kalle; Ridout, David

    2009-12-01

    In this article, certain indecomposable Virasoro modules are studied. Specifically, the Virasoro mode L0 is assumed to be nondiagonalizable, possessing Jordan blocks of rank 2. Moreover, the module is further assumed to have a highest weight submodule, the "left module," and that the quotient by this submodule yields another highest weight module, the "right module." Such modules, which have been called staggered, have appeared repeatedly in the logarithmic conformal field theory literature, but their theory has not been explored in full generality. Here, such a theory is developed for the Virasoro algebra using rather elementary techniques. The focus centers on two different but related questions typically encountered in practical studies: How can one identify a given staggered module, and how can one demonstrate the existence of a proposed staggered module. Given just the values of the highest weights of the left and right modules, themselves subject to simple necessary conditions, invariants are defined which together with the knowledge of the left and right modules uniquely identify a staggered module. The possible values of these invariants form a vector space of dimension 0, 1, or 2, and the structures of the left and right modules limit the isomorphism classes of the corresponding staggered modules to an affine subspace (possibly empty). The number of invariants and affine restrictions is purely determined by the structures of the left and right modules. Moreover, in order to facilitate applications, the expressions for the invariants and restrictions are given by formulas as explicit as possible (they generally rely on expressions for Virasoro singular vectors). Finally, the text is liberally peppered throughout with examples illustrating the general concepts. These have been carefully chosen for their physical relevance or for the novel features they exhibit.

  1. AA antiproton production target

    CERN Multimedia

    CERN PhotoLab

    1979-01-01

    The first version of the antiproton production target was a tungsten rod, 11 cm long and 3 mm in diameter. The rod was embedded in graphite, pressure-seated into an outer casing of stainless steel. At the entrance to the target assembly was a scintillator screen, imprinted with circles every 5 mm in radius, which allowed to precisely aim the 26 GeV high-intensity proton beam from the PS onto the centre of the target rod. The scintillator screen was a 1 mm thick plate of Cr-doped alumina. See also 7903034 and 7905091.

  2. Shiva target irradiation facility

    International Nuclear Information System (INIS)

    Manes, K.R.; Ahlstrom, H.G.; Coleman, L.W.; Storm, E.K.; Glaze, J.A.; Hurley, C.A.; Rienecker, F.; O'Neal, W.C.

    1977-01-01

    The first laser/plasma studies performed with the Shiva laser system will be two sided irradiations extending the data obtained by other LLL lasers to higher powers. The twenty approximately 1 TW laser pulses will reach the target simultaneously from above and below in nested pentagonal clusters. The upper and lower clusters of ten beams each are radially polarized so that they strike the target in p-polarization and maximize absorption. This geometry introduces laser system isolation problems which will be briefly discussed. The layout and types of target diagnostics will be described and a brief status report on the facility given

  3. STANFORD: Internal targets

    Energy Technology Data Exchange (ETDEWEB)

    Riordan, Michael

    1989-05-15

    Of burgeoning interest to many nuclear and particle physicists is a storage ring technique for fixed target experiments. It hinges on the use of gas-jet targets, shooting a narrow stream of atoms through a circulating beam of electrons or protons. Pioneered at CERN and the Soviet Novosibirsk Laboratory, more such 'internal targets' are being built or contemplated for storage rings in Europe, the Soviet Union, and the United States. From 9-12 January, physicists from around the world met at the Stanford Linear Accelerator Center (SLAC) to discuss prospects and problems in this expanding field.

  4. TARGET Research Goals

    Science.gov (United States)

    TARGET researchers use various sequencing and array-based methods to examine the genomes, transcriptomes, and for some diseases epigenomes of select childhood cancers. This “multi-omic” approach generates a comprehensive profile of molecular alterations for each cancer type. Alterations are changes in DNA or RNA, such as rearrangements in chromosome structure or variations in gene expression, respectively. Through computational analyses and assays to validate biological function, TARGET researchers predict which alterations disrupt the function of a gene or pathway and promote cancer growth, progression, and/or survival. Researchers identify candidate therapeutic targets and/or prognostic markers from the cancer-associated alterations.

  5. Weyl modules, demazure modules, KR-modules, crystals, fusion products and limit constructions

    OpenAIRE

    Fourier, G.; Littelmann, P.

    2007-01-01

    We study finite dimensional representations of current algebras, loop algebras and their quantized versions. For the current algebra of a simple Lie algebra of type {\\tt ADE}, we show that Kirillov-Reshetikhin modules and Weyl modules are in fact all Demazure modules. As a consequence one obtains an elementary proof of the dimension formula for Weyl modules for the current and the loop algebra. Further, we show that the crystals of the Weyl and the Demazure module are the same up to some addi...

  6. TALE-mediated modulation of transcriptional enhancers in vivo.

    Science.gov (United States)

    Crocker, Justin; Stern, David L

    2013-08-01

    We tested whether transcription activator-like effectors (TALEs) could mediate repression and activation of endogenous enhancers in the Drosophila genome. TALE repressors (TALERs) targeting each of the five even-skipped (eve) stripe enhancers generated repression specifically of the focal stripes. TALE activators (TALEAs) targeting the eve promoter or enhancers caused increased expression primarily in cells normally activated by the promoter or targeted enhancer, respectively. This effect supports the view that repression acts in a dominant fashion on transcriptional activators and that the activity state of an enhancer influences TALE binding or the ability of the VP16 domain to enhance transcription. In these assays, the Hairy repression domain did not exhibit previously described long-range transcriptional repression activity. The phenotypic effects of TALER and TALEA expression in larvae and adults are consistent with the observed modulations of eve expression. TALEs thus provide a novel tool for detection and functional modulation of transcriptional enhancers in their native genomic context.

  7. Brownian modulated optical nanoprobes

    International Nuclear Information System (INIS)

    Behrend, C.J.; Anker, J.N.; Kopelman, R.

    2004-01-01

    Brownian modulated optical nanoprobes (Brownian MOONs) are fluorescent micro- and nanoparticles that resemble moons: one hemisphere emits a bright fluorescent signal, while an opaque metal darkens the other hemisphere. Brownian motion causes the particles to tumble and blink erratically as they rotate literally through the phases of the moon. The fluctuating probe signals are separated from optical and electronic backgrounds using principal components analysis or images analysis. Brownian MOONs enable microrheological measurements on size scales and timescales that are difficult to study with other methods. Local chemical concentrations can be measured simultaneously, using spectral characteristics of indicator dyes embedded within the MOONs

  8. Oscillator, neutron modulator

    International Nuclear Information System (INIS)

    Agaisse, R.; Leguen, R.; Ombredane, D.

    1960-01-01

    The authors present a mechanical device and an electronic control circuit which have been designed to sinusoidally modulate the reactivity of the Proserpine atomic pile. The mechanical device comprises an oscillator and a mechanism assembly. The oscillator is made of cadmium blades which generate the reactivity oscillation. The mechanism assembly comprises a pulse generator for cycle splitting, a gearbox and an engine. The electronic device comprises or performs pulse detection, an on-off device, cycle pulse shaping, phase separation, a dephasing amplifier, electronic switches, counting scales, and control devices. All these elements are briefly presented

  9. CDC 7600 Module

    CERN Multimedia

    1970-01-01

    The CDC 7600 has been created by Seymour Cray. It was designed to be compatible with the 6600, which allows for a substantial increase in performance. Furthermore the rise of new technologies has enabled this performance by reducing the minor cycle clock period from 100 ns to 27.5 ns (4 time faster). A very large machine, the 7600 had over 120 miles of hand-wired interconnections. It was the most powerful computer of its time. However, this speed caused a ground-loop problem causing intermittent faults, and eventually requiring all modules to be fitted with sheathed rubber bands. The CDC 7600 was replaced in 1983 by CRAY-1A.

  10. Submillimeter Confocal Imaging Active Module

    Science.gov (United States)

    Hong, John; Mehdi, Imran; Siegel, Peter; Chattopadhyay, Goutam; Cwik, Thomas; Rowell, Mark; Hacker, John

    2009-01-01

    The term submillimeter confocal imaging active module (SCIAM) denotes a proposed airborne coherent imaging radar system that would be suitable for use in reconnaissance, surveillance, and navigation. The development of the SCIAM would include utilization and extension of recent achievements in monolithic microwave integrated circuits capable of operating at frequencies up to and beyond a nominal radio frequency of 340 GHz. Because the SCIAM would be primarily down-looking (in contradistinction to primarily side-looking), it could be useful for imaging shorter objects located between taller ones (for example, objects on streets between buildings). The SCIAM would utilize a confocal geometry to obtain high cross-track resolution, and would be amenable to synthetic-aperture processing of its output to obtain high along-track resolution. The SCIAM (see figure) would include multiple (two in the initial version) antenna apertures, separated from each other by a cross-track baseline of suitable length (e.g., 1.6 m). These apertures would both transmit the illuminating radar pulses and receive the returns. A common reference oscillator would generate a signal at a controllable frequency of (340 GHz + (Delta)f)/N, where (Delta)f is an instantaneous swept frequency difference and N is an integer. The output of this oscillator would be fed to a frequency- multiplier-and-power-amplifier module to obtain a signal, at 340 GHz + (Delta)f, that would serve as both the carrier signal for generating the transmitted pulses and a local-oscillator (LO) signal for a receiver associated with each antenna aperture. Because duplexers in the form of circulators or transmit/receive (T/R) switches would be lossy and extremely difficult to implement, the antenna apertures would be designed according to a spatial-diplexing scheme, in which signals would be coupled in and out via separate, adjacent transmitting and receiving feed horns. This scheme would cause the transmitted and received beams

  11. Structured cylindrical targets

    International Nuclear Information System (INIS)

    Arnold, R.

    1986-01-01

    A variety of experimental concepts using high-energy heavy-ion beams in cylindrical targets have been studied through numerical simulation. With an accelerator planned for GSl, plasma temperatures of 100 eV can be reached by cylindrical compression, using inhomogeneous hollow-shell targets. Magnetic insulation, using external fields, has been explored as an aid in reaching high core temperatures. Experiments on collision-pumped x-ray laser physics are also discussed. (ii) Two-dimensional PlC code simulations of homogeneous solid targets show hydrodynamic effects not found in previous 1-D calculations. (iii) Preliminary ideas for an experiment on non-equilibrium heavy-ion charge-states using an existing accelerator and a pre-formed plasma target are outlined. (author)

  12. Structured cylindrical targets

    International Nuclear Information System (INIS)

    Arnold, R.; Lackner-Russo, D.; Meyer-ter-Vehn, J.; Hoffmann, I.

    1986-01-01

    A variety of experimental concepts using high-energy heavy-ion beams in cylindrical targets have been studied through numerical simulation. With an accelerator planned for GSl, plasma temperatures of 100 eV can be reached by cylindrical compression, using inhomogenous hollow-shell targets. Magnetic insulation, using external fields, has been explored as an aid in reaching high core temperatures. Experiments on collision-pumped x-ray laser physics are also discussed. (ii) Two-dimensional PlC code simulations of homogeneous solid targets show hydrodynamic effects not found in previous l-D calculations. (iii) Preliminary ideas for an experiment on non-equilibrium heavy-ion charge-states using an existing accelerator and a pre-formed plasma target are outlined. (author)

  13. Target Price Accuracy

    Directory of Open Access Journals (Sweden)

    Alexander G. Kerl

    2011-04-01

    Full Text Available This study analyzes the accuracy of forecasted target prices within analysts’ reports. We compute a measure for target price forecast accuracy that evaluates the ability of analysts to exactly forecast the ex-ante (unknown 12-month stock price. Furthermore, we determine factors that explain this accuracy. Target price accuracy is negatively related to analyst-specific optimism and stock-specific risk (measured by volatility and price-to-book ratio. However, target price accuracy is positively related to the level of detail of each report, company size and the reputation of the investment bank. The potential conflicts of interests between an analyst and a covered company do not bias forecast accuracy.

  14. Autonomous Target Ranging Techniques

    DEFF Research Database (Denmark)

    Jørgensen, Peter Siegbjørn; Jørgensen, John Leif; Denver, Troelz

    2003-01-01

    of this telescope, a fast determination of the range to and the motion of the detected targets are important. This is needed in order to prepare the future observation strategy for each target, i.e. when is the closest approach where imaging will be optimal. In order to quickly obtain such a determination two...... ranging strategies are presented. One is an improved laser ranger with an effective range with non-cooperative targets of at least 10,000 km, demonstrated in ground tests. The accuracy of the laser ranging will be approximately 1 m. The laser ranger may furthermore be used for trajectory determination...... of nano-gravity probes, which will perform direct mass measurements of selected targets. The other is triangulation from two spacecraft. For this method it is important to distinguish between detection and tracking range, which will be different for Bering since different instruments are used...

  15. Targeted Cancer Therapies

    Science.gov (United States)

    ... are sometimes referred to as the product of "rational" drug design.) One approach to identify potential targets ... molecules that stimulate new blood vessel growth. Immunotherapies trigger the immune system to destroy cancer cells. Some ...

  16. Targeting radiation to tumours

    International Nuclear Information System (INIS)

    Wheldon, T.E.; Greater Glasgow Health Board, Glasgow

    1994-01-01

    Biologically targeted radiotherapy entails the preferential delivery of radiation to solid tumours or individual tumour cells by means of tumour-seeking delivery vehicles to which radionuclides can be conjugated. Monoclonal antibodies have attracted attention for some years as potentially selective targeting agents, but advances in tumour and molecular biology are now providing a much wider choice of molecular species. General radiobiological principles may be derived which are applicable to most forms of targeted radiotherapy. These principles provide guidelines for the appropriate choice of radionuclide in specific treatment situations and its optimal combination with other treatment modalities. In future, the availability of gene targeting agents will focus attention on the use of Auger electron emitters whose high potency and short range selectivity makes them attractive choices for specific killing of cancer cells whose genetic peculiarities are known. (author)

  17. Intensity-modulated arc therapy simplified

    International Nuclear Information System (INIS)

    Wong, Eugene; Chen, Jeff Z.; Greenland, Jonathan

    2002-01-01

    Purpose: We present a treatment planning strategy for intensity-modulated radiation therapy using gantry arcs with dynamic multileaf collimator, previously termed intensity-modulated arc therapy (IMAT). Methods and Materials: The planning strategy is an extension of the photon bar arc and asymmetric arc techniques and is classified into three levels of complexity, with increasing number of gantry arcs. This principle allows us to generalize the analysis of the number of arcs required for intensity modulation for a given treatment site. Using a phantom, we illustrate how the current technique is more flexible than the photon bar arc technique. We then compare plans from our strategy with conventional three-dimensional conformal treatment plans for three sites: prostate (prostate plus seminal vesicles), posterior pharyngeal wall, and chest wall. Results: Our strategy generates superior IMAT treatment plans compared to conventional three-dimensional conformal plans. The IMAT plans spare critical organs well, and the trade-off for simplicity is that the dose uniformity in the target volume may not rival that of true inverse treatment plans. Conclusions: The analyses presented in this paper give a better understanding of IMAT plans. Our strategy is easier to understand and more efficient in generating plans than inverse planning systems; our plans are also simpler to modify, and quality assurance is more intuitive

  18. Curcumin: the spicy modulator of breast carcinogenesis.

    Science.gov (United States)

    Banik, Urmila; Parasuraman, Subramani; Adhikary, Arun Kumar; Othman, Nor Hayati

    2017-07-19

    Worldwide breast cancer is the most common cancer in women. For many years clinicians and the researchers are examining and exploring various therapeutic modalities for breast cancer. Yet the disease has remained unconquered and the quest for cure is still going on. Present-day strategy of breast cancer therapy and prevention is either combination of a number of drugs or a drug that modulates multiple targets. In this regard natural products are now becoming significant options. Curcumin exemplifies a promising natural anticancer agent for this purpose. This review primarily underscores the modulatory effect of curcumin on the cancer hallmarks. The focus is its anticancer effect in the complex pathways of breast carcinogenesis. Curcumin modulates breast carcinogenesis through its effect on cell cycle and proliferation, apoptosis, senescence, cancer spread and angiogenesis. Largely the NFkB, PI3K/Akt/mTOR, MAPK and JAK/STAT are the key signaling pathways involved. The review also highlights the curcumin mediated modulation of tumor microenvironment, cancer immunity, breast cancer stem cells and cancer related miRNAs. Using curcumin as a therapeutic and preventive agent in breast cancer is perplexed by its diverse biological activity, much of which remains inexplicable. The information reviewed here should point toward potential scope of future curcumin research in breast cancer.

  19. Processing module operating methods, processing modules, and communications systems

    Science.gov (United States)

    McCown, Steven Harvey; Derr, Kurt W.; Moore, Troy

    2014-09-09

    A processing module operating method includes using a processing module physically connected to a wireless communications device, requesting that the wireless communications device retrieve encrypted code from a web site and receiving the encrypted code from the wireless communications device. The wireless communications device is unable to decrypt the encrypted code. The method further includes using the processing module, decrypting the encrypted code, executing the decrypted code, and preventing the wireless communications device from accessing the decrypted code. Another processing module operating method includes using a processing module physically connected to a host device, executing an application within the processing module, allowing the application to exchange user interaction data communicated using a user interface of the host device with the host device, and allowing the application to use the host device as a communications device for exchanging information with a remote device distinct from the host device.

  20. Strategic Targeted Advertising

    OpenAIRE

    Andrea Galeotti; Jose Luis Moraga

    2003-01-01

    textabstractWe present a strategic game of pricing and targeted-advertising. Firms can simultaneously target price advertisements to different groups of customers, or to the entire market. Pure strategy equilibria do not exist and thus market segmentation cannot occur surely. Equilibria exhibit random advertising --to induce an unequal distribution of information in the market-- and random pricing --to obtain profits from badly informed buyers--. We characterize a positive profits equilibrium...

  1. Targets and teamwork

    DEFF Research Database (Denmark)

    Skinner, Timothy C.; Lange, Karin S.; Hoey, Hilary

    2017-01-01

    differences in mean HbA1c between centers ranging from 7.3±0.8% (53mmol/mol±8.7) to 8.9±1.1% (74mmol/mol±12.0). Centers with lower mean HbA1c had (1) parents who reported lower targets for their children, (2) health-care professionals that reported lower targets and more frequent testing, and (3) teams...

  2. Targets and special materials

    International Nuclear Information System (INIS)

    Blanc, R.; Bouriant, M.; Richaud, J.P.

    1997-01-01

    The target preparation group supplied a large number of samples to nuclear physicists for experiments using SARA and also other accelerators throughout the world. Particular preparation and projects include: 208 Pb, 116 Cd, 6 LiF, 123 Sb, In and Ta targets, strippers for SARA and GANIL, optical silicone disks for POLDER and GRAAL experiments, active participations for the AMS project and finally filament preparation for the GENEPI project. (authors)

  3. The ISIS target

    International Nuclear Information System (INIS)

    Carne, A.; Broome, T.A.; Hogston, J.R.; Holding, M.

    1989-01-01

    This presentation discusses the two target failures that have occurred, gives the understanding of the causes and indicates the steps being taken to alleviate the problems. At the outset of the design it was understood that the target would have a finite lifetime, due to radiation damage effects, exacerbated by mechanical damage due to thermal cycling and fatigue. Estimates of target lifetime at full intensity are about 2 years for radiation damage swelling and about 10E4 gross thermal excursions. The latter number is the one which gives uncertainty in defining the life of the target, since it is dependent on the reliability of the accelerator and quality of the proton beam. The commissioning of an accelerator system and bringing it up to high beam intensities have their own special problems. There must be protection of components against uncontrolled beam loss, which produces thermal damage, prompt radiation and induced activity. Fast beam trips for beam loss protection, or equipment failures, result in quenches from high temperature in the target which get bigger with increasing beam intensity. But the target itself is a difficult device to make, taking about 12 months to manufacture. Further, changing one is a complex and time consuming task, not without its hazards. There is thus something of a balancing act to bring the accelerator towards specification before the target fails due to thermal cycling fatigue. In the early days of ISIS beam loss protection was the dominant consideration and the target was regarded somewhat as a sacrificial lamb to the goddess of machine reliability. 2 refs., 6 figs

  4. Improved target detection algorithm using Fukunaga-Koontz transform and distance classifier correlation filter

    Science.gov (United States)

    Bal, A.; Alam, M. S.; Aslan, M. S.

    2006-05-01

    Often sensor ego-motion or fast target movement causes the target to temporarily go out of the field-of-view leading to reappearing target detection problem in target tracking applications. Since the target goes out of the current frame and reenters at a later frame, the reentering location and variations in rotation, scale, and other 3D orientations of the target are not known thus complicating the detection algorithm has been developed using Fukunaga-Koontz Transform (FKT) and distance classifier correlation filter (DCCF). The detection algorithm uses target and background information, extracted from training samples, to detect possible candidate target images. The detected candidate target images are then introduced into the second algorithm, DCCF, called clutter rejection module, to determine the target coordinates are detected and tracking algorithm is initiated. The performance of the proposed FKT-DCCF based target detection algorithm has been tested using real-world forward looking infrared (FLIR) video sequences.

  5. An ISOLDE target unit

    CERN Multimedia

    Maximilien Brice

    2002-01-01

    A good dozen different targets are available for ISOLDE, made of different materials and equipped with different kinds of ion-sources, according to the needs of the experiments. Each separator (GPS: general purpose; HRS: high resolution) has its own target. Because of the high radiation levels, robots effect the target changes, about 80 times per year. In the standard unit shown in picture _01, the target is the cylindrical object in the front. It contains uranium-carbide kept at a temperature of 2200 deg C, necessary for the isotopes to be able to escape. At either end, one sees the heater current leads, carrying 700 A. The Booster beam, some 3E13 protons per pulse, enters the target from left. The evaporated isotope atoms enter a hot-plasma ion source (the black object behind the target). The whole unit sits at 60 kV potential (pulsed in synchronism with the arrival of the Booster beam) which accelerates the ions (away from the viewer) towards one of the 2 separators.

  6. Laser targets: introduction

    International Nuclear Information System (INIS)

    Rosen, M.D.

    1985-01-01

    The laser target design group was engaged in three main tasks in 1984: (1) analyzing Novette implosion and hohlraum-scaling data, (2) planning for the first experiments on Nova, and (3) designing laboratory x-ray laser targets and experiments. The Novette implosion and hohlraum scaling data are mostly classified and are therefore not discussed in detail here. The authors achieved average final/initial pusher pr ratios of about 50, some 3 times higher than the value achieved in the best Shiva shots. These pr values imply a fuel compression to 100 times liquid density, although this figure and other aspects of the experiments are subject to further interpretation because of detailed questions of target symmetry and stability. Their main long-term goal for Nova is to produce a so-called hydrodynamically equivalent target (HET) - that is, a target whose hydrodynamic behavior (implosion velocity, convergence ratio, symmetry and stability requirements, etc.) is very much like that of a high-gain target, but one that is scaled down in size to match the energy available from Nova and is too small to achieve enough hot-spot pr to ignite the cold, near-Fermi-degenerate fuel around it. Their goal for Nova's first year is to do experiments that will teach them how to achieve the symmetry and stability conditions required by an HET

  7. Argus target chamber

    International Nuclear Information System (INIS)

    Rienecker, F. Jr.; Glaros, S.S.; Kobierecki, M.

    1975-01-01

    A target chamber for application in the laser fusion program must satisfy some very basic requirements. (1) Provide a vacuum on the order of 10 -6 torr. (2) Support a microscopically small target in a fixed point in space and verify its location within 5 micrometers. (3) Contain an adjustable beam focusing system capable of delivering a number of laser beams onto the target simultaneously, both in time and space. (4) Provide access for diagnostics to evaluate the results of target irradiation. (5) Have flexibility to allow changes in targets, focusing optics and number of beams. The ARGUS laser which is now under construction at LLL will have a target chamber which meets these requirements in a simple economic manner. The chamber and auxiliary equipment are described, with reference to two double beam focusing systems; namely, lenses and ellipsoidal mirrors. Provision is made for future operation with four beams, using ellipsoidal mirrors for two-sided illumination and lens systems for tetragonal and tetrahedral irradiation

  8. HCN Channels Modulators: The Need for Selectivity

    Science.gov (United States)

    Romanelli, Maria Novella; Sartiani, Laura; Masi, Alessio; Mannaioni, Guido; Manetti, Dina; Mugelli, Alessandro; Cerbai, Elisabetta

    2016-01-01

    Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects. HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators. PMID:26975509

  9. Whole Module Offgas Test Report: Space-Xl Dragon Module

    Science.gov (United States)

    James, John T.

    2012-01-01

    On September 26 and September 28,2012 a chemist from the JSC Toxicology Group acquired samples of air in 500 m1 evacuated canisters from the sealed Space-Xl Dragon Module. One sample was also acquired from Space-X Facility near the module at the start of the test. Samples of the module air were taken in triplicate once the module had been sealed, and then taken again in triplicate 1.98 days later. Ofthe triplicate samples, the first served as a line purge, and the last two were analyzed. The results of 5 samples are reported.

  10. Recent Advances in Aptamers Targeting Immune System.

    Science.gov (United States)

    Hu, Piao-Ping

    2017-02-01

    The immune system plays important role in protecting the organism by recognizing non-self molecules from pathogen such as bacteria, parasitic worms, and viruses. When the balance of the host defense system is disturbed, immunodeficiency, autoimmunity, and inflammation occur. Nucleic acid aptamers are short single-stranded DNA (ssDNA) or RNA ligands that interact with complementary molecules with high specificity and affinity. Aptamers that target the molecules involved in immune system to modulate their function have great potential to be explored as new diagnostic and therapeutic agents for immune disorders. This review summarizes recent advances in the development of aptamers targeting immune system. The selection of aptamers with superior chemical and biological characteristics will facilitate their application in the diagnosis and treatment of immune disorders.

  11. Modular crystals as modulated structures

    DEFF Research Database (Denmark)

    Elcoro, L.; Perez-Mato, J.M.; Friese, K.

    2008-01-01

    The use of the superspace formalism is extended to the description and refinement of the homologous series of modular structures with two symmetry-related modules with different orientations. The lillianite homologous series has been taken as a study case. Starting from a commensurate modulated...... composite description with two basic subsystems corresponding to the two different modules, it is shown how a more efficient description can be achieved using so-called zigzag modulation functions. These linear zigzag modulations, newly implemented in the program JANA2006, have very large fixed amplitudes...... and introduce in the starting model the two orientations of the underlying module sublattices. We show that a composite approach with this type of function, which treats the cations and anions as two separate subsystems forming a misfit compound, is the most appropriate and robust method for the refinements....

  12. Apparatuses to support photovoltaic modules

    Science.gov (United States)

    Ciasulli, John; Jones, Jason

    2017-08-22

    Methods and apparatuses to support photovoltaic ("PV") modules are described. A saddle bracket has a mounting surface to support one or more PV modules over a tube, a gusset coupled to the mounting surface, and a mounting feature coupled to the gusset to couple to the tube. A grounding washer has a first portion to couple to a support; and a second portion coupled to the first portion to provide a ground path to a PV module. A PV system has a saddle bracket; a PV module over the saddle bracket; and a grounding washer coupled to the saddle bracket and the PV module. Saddle brackets can be coupled to a torque tube at predetermined locations. PV modules can be coupled to the saddle brackets.

  13. Mixed twistor D-modules

    CERN Document Server

    Mochizuki, Takuro

    2015-01-01

    We introduce mixed twistor D-modules and establish their fundamental functorial properties. We also prove that they can be described as the gluing of admissible variations of mixed twistor structures. In a sense, mixed twistor D-modules can be regarded as a twistor version of M. Saito's mixed Hodge modules. Alternatively, they can be viewed as a mixed version of the pure twistor D-modules studied by C. Sabbah and the author. The theory of mixed twistor D-modules is one of the ultimate goals in the study suggested by Simpson's Meta Theorem, and it would form a foundation for the Hodge theory of holonomic D-modules which are not necessarily regular singular.  .

  14. Volumetric modulated arc radiotherapy for esophageal cancer

    International Nuclear Information System (INIS)

    Vivekanandan, Nagarajan; Sriram, Padmanaban; Syam Kumar, S.A.; Bhuvaneswari, Narayanan; Saranya, Kamalakannan

    2012-01-01

    A treatment planning study was performed to evaluate the performance of volumetric arc modulation with RapidArc (RA) against 3D conformal radiation therapy (3D-CRT) and conventional intensity-modulated radiation therapy (IMRT) techniques for esophageal cancer. Computed tomgraphy scans of 10 patients were included in the study. 3D-CRT, 4-field IMRT, and single-arc and double-arc RA plans were generated with the aim to spare organs at risk (OAR) and healthy tissue while enforcing highly conformal target coverage. The planning objective was to deliver 54 Gy to the planning target volume (PTV) in 30 fractions. Plans were evaluated based on target conformity and dose-volume histograms of organs at risk (lung, spinal cord, and heart). The monitor unit (MU) and treatment delivery time were also evaluated to measure the treatment efficiency. The IMRT plan improves target conformity and spares OAR when compared with 3D-CRT. Target conformity improved with RA plans compared with IMRT. The mean lung dose was similar in all techniques. However, RA plans showed a reduction in the volume of the lung irradiated at V 20Gy and V 30Gy dose levels (range, 4.62–17.98%) compared with IMRT plans. The mean dose and D 35% of heart for the RA plans were better than the IMRT by 0.5–5.8%. Mean V 10Gy and integral dose to healthy tissue were almost similar in all techniques. But RA plans resulted in a reduced low-level dose bath (15–20 Gy) in the range of 14–16% compared with IMRT plans. The average MU needed to deliver the prescribed dose by RA technique was reduced by 20–25% compared with IMRT technique. The preliminary study on RA for esophageal cancers showed improvements in sparing OAR and healthy tissue with reduced beam-on time, whereas only double-arc RA offered improved target coverage compared with IMRT and 3D-CRT plans.

  15. Modules to enhance smart lighting education

    Science.gov (United States)

    Bunch, Robert M.; Joenathan, Charles; Connor, Kenneth; Chouikha, Mohamed

    2012-10-01

    Over the past several years there has been a rapid advancement in solid state lighting applications brought on by the development of high efficiency light emitting diodes. Development of lighting devices, systems and products that meet the demands of the future lighting marketplace requires workers from many disciplines including engineers, scientists, designers and architects. The National Science Foundation has recognized this fact and established the Smart Lighting Engineering Research Center that promotes research leading to smart lighting systems, partners with industry to enhance innovation and educates a diverse, world-class workforce. The lead institution is Rensselaer Polytechnic Institute with core partners Boston University and The University of New Mexico. Outreach partners include Howard University, Morgan State University, and Rose-Hulman Institute of Technology. Because of the multidisciplinary nature of advanced smart lighting systems workers often have little or no formal education in basic optics, lighting and illumination. This paper describes the initial stages of the development of self-contained and universally applicable educational modules that target essential optics topics needed for lighting applications. The modules are intended to be easily incorporated into new and existing courses by a variety of educators and/or to be used in a series of stand-alone, asynchronous training exercises by new graduate students. The ultimate goal of this effort is to produce resources such as video lectures, video presentations of students-teaching-students, classroom activities, assessment tools, student research projects and laboratories integrated into learning modules. Sample modules and resources will be highlighted. Other outreach activities such as plans for coursework, undergraduate research, design projects, and high school enrichment programs will be discussed.

  16. Modulator considerations for the SNS RF system

    International Nuclear Information System (INIS)

    Tallerico, P.J.; Reass, W.A.

    1998-01-01

    The Spallation Neutron Source (SNS) is an intense neutron source for neutron scattering experiments. The project is in the research stage, with construction funding beginning next year. The SNS is comprised of an ion source, a 1,000 MeV, H - linear accelerator, an accumulator ring, a neutron producing target, and experimental area to utilize the scattering of the neutrons. The linear accelerator is RF driven, and the peak beam current is 27 mA and the beam duty factor is 5.84%. The peak RF power required is 104 MW, and the H - beam pulse length is 0.97 ms at a 60 Hz repetition rate. The RF pulses must be about 0.1 ms longer than the beam pulses, due to the Q of the accelerating cavities, and the time required to establish control of the cavity fields. The modulators for the klystrons in this accelerator are discussed in this paper. The SNS is designed to be expandable, so the beam power can be doubled or even quadrupled in the future. One of the double-power options is to double the beam pulse length and duty factor. The authors are specifying the klystrons to operate in this twice-duty-factor mode, and the modulator also should be expandable to 2 ms pulses at 60 Hz. Due to the long pulse length and low RF frequency of 805 MHz, the klystron power is specified at 2.5 MW peak, and the RF system will have 56 klystrons at 805 MHz, and three 1.25 MW peak power klystrons at 402.5 MHz for the low energy portion of the accelerator. The low frequency modulators are conventional floating-deck modulation anode control systems

  17. Emerging Paradigm of Intracellular Targeting of G Protein-Coupled Receptors.

    Science.gov (United States)

    Chaturvedi, Madhu; Schilling, Justin; Beautrait, Alexandre; Bouvier, Michel; Benovic, Jeffrey L; Shukla, Arun K

    2018-05-04

    G protein-coupled receptors (GPCRs) recognize a diverse array of extracellular stimuli, and they mediate a broad repertoire of signaling events involved in human physiology. Although the major effort on targeting GPCRs has typically been focused on their extracellular surface, a series of recent developments now unfold the possibility of targeting them from the intracellular side as well. Allosteric modulators binding to the cytoplasmic surface of GPCRs have now been described, and their structural mechanisms are elucidated by high-resolution crystal structures. Furthermore, pepducins, aptamers, and intrabodies targeting the intracellular face of GPCRs have also been successfully utilized to modulate receptor signaling. Moreover, small molecule compounds, aptamers, and synthetic intrabodies targeting β-arrestins have also been discovered to modulate GPCR endocytosis and signaling. Here, we discuss the emerging paradigm of intracellular targeting of GPCRs, and outline the current challenges, potential opportunities, and future outlook in this particular area of GPCR biology. Copyright © 2018 Elsevier Ltd. All rights reserved.

  18. Burglar Target Selection

    Science.gov (United States)

    Townsley, Michael; Bernasco, Wim; Ruiter, Stijn; Johnson, Shane D.; White, Gentry; Baum, Scott

    2015-01-01

    Objectives: This study builds on research undertaken by Bernasco and Nieuwbeerta and explores the generalizability of a theoretically derived offender target selection model in three cross-national study regions. Methods: Taking a discrete spatial choice approach, we estimate the impact of both environment- and offender-level factors on residential burglary placement in the Netherlands, the United Kingdom, and Australia. Combining cleared burglary data from all study regions in a single statistical model, we make statistical comparisons between environments. Results: In all three study regions, the likelihood an offender selects an area for burglary is positively influenced by proximity to their home, the proportion of easily accessible targets, and the total number of targets available. Furthermore, in two of the three study regions, juvenile offenders under the legal driving age are significantly more influenced by target proximity than adult offenders. Post hoc tests indicate the magnitudes of these impacts vary significantly between study regions. Conclusions: While burglary target selection strategies are consistent with opportunity-based explanations of offending, the impact of environmental context is significant. As such, the approach undertaken in combining observations from multiple study regions may aid criminology scholars in assessing the generalizability of observed findings across multiple environments. PMID:25866418

  19. LANSCE target system performance

    International Nuclear Information System (INIS)

    Russell, G.J.; Gilmore, J.S.; Robinson, H.; Legate, G.L.; Bridge, A.; Sanchez, R.J.; Brewton, R.J.; Woods, R.; Hughes, H.G. III

    1989-01-01

    We measured neutron beam fluxes at LANSCE using gold foil activation techniques. We did an extensive computer simulation of the as-built LANSCE Target/Moderator/Reflector/Shield geometry. We used this mockup in a Monte Carlo calculation to predict LANSCE neutronic performance for comparison with measured results. For neutron beam fluxes at 1 eV, the ratio of measured data to calculated varies from ∼0.6-0.9. The computed 1 eV neutron leakage at the moderator surface is 3.9 x 10 10 n/eV-sr-s-μA for LANSCE high-intensity water moderators. The corresponding values for the LANSCE high-resolution water moderator and the liquid hydrogen moderator are 3.3 and 2.9 x 10 10 , respectively. LANSCE predicted moderator intensities (per proton) for a tungsten target are essentially the same as ISIS predicted moderator intensities for a depleted uranium target. The calculated LANSCE steady state unperturbed thermal (E 13 n/cm 2 -s. The unique LANSCE split-target/flux-trap-moderator system is performing exceedingly well. The system has operated without a target or moderator change for over three years at nominal proton currents of ∼25 μA of 800-MeV protons. (author)

  20. Development of allosteric modulators of GPCRs for treatment of CNS disorders.

    Science.gov (United States)

    Nickols, Hilary Highfield; Conn, P Jeffrey

    2014-01-01

    The discovery of allosteric modulators of G protein-coupled receptors (GPCRs) provides a promising new strategy with potential for developing novel treatments for a variety of central nervous system (CNS) disorders. Traditional drug discovery efforts targeting GPCRs have focused on developing ligands for orthosteric sites which bind endogenous ligands. Allosteric modulators target a site separate from the orthosteric site to modulate receptor function. These allosteric agents can either potentiate (positive allosteric modulator, PAM) or inhibit (negative allosteric modulator, NAM) the receptor response and often provide much greater subtype selectivity than orthosteric ligands for the same receptors. Experimental evidence has revealed more nuanced pharmacological modes of action of allosteric modulators, with some PAMs showing allosteric agonism in combination with positive allosteric modulation in response to endogenous ligand (ago-potentiators) as well as "bitopic" ligands that interact with both the allosteric and orthosteric sites. Drugs targeting the allosteric site allow for increased drug selectivity and potentially decreased adverse side effects. Promising evidence has demonstrated potential utility of a number of allosteric modulators of GPCRs in multiple CNS disorders, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as psychiatric or neurobehavioral diseases such as anxiety, schizophrenia, and addiction. © 2013.