WorldWideScience

Sample records for heterotrimer selectively targeted

  1. 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

  2. Fuzzy target selection using RFM variables

    NARCIS (Netherlands)

    Kaymak, U.

    2001-01-01

    An important data mining problem from the world of direct marketing is target selection. The main task in target selection is the determination of potential customers for a product from a client database. Target selection algorithms identify the profiles of customer groups for a particular product,

  3. Target selection for direct marketing.

    NARCIS (Netherlands)

    Bult, Jan Roelf

    1993-01-01

    In this thesis we concentrated on the use ol direct mail for targeting potential buyers. The major characteristics that influences the success of a plomotional direct mail campaign are the of-fbr,the communication elements, the timing or sequence of these communication elements, and the list of

  4. Kinase activity determination of specific AMPK complexes/heterotrimers in the skeletal muscle

    DEFF Research Database (Denmark)

    Birk, Jesper Bratz; Wojtaszewski, Jørgen

    2018-01-01

    Measuring the kinase activity of the 5'-AMP-activated protein kinase (AMPK) is an essential part of understanding the regulation of this metabolic master switch. The AMPK heterotrimer can exist in 12 different constellations with potentially diverse activation patterns. It is therefore important ...

  5. Target-selected mutagenesis of the rat

    NARCIS (Netherlands)

    Smits, B.M.; Mudde, J.B.; Plasterk, R.; Cuppen, E.

    2004-01-01

    The rat is one of the most extensively studied model organisms, and with its genome being sequenced, tools to manipulate gene function in vivo have become increasingly important. We here report proof of principle for target-selected mutagenesis as a reverse genetic or knockout approach for the rat.

  6. Target selection for the HRIBF Project

    International Nuclear Information System (INIS)

    Dellwo, J.; Alton, G.D.; Batchelder, J.C.

    1994-01-01

    Experiments are in progress at the Oak Ridge National Laboratory (ORNL) which are designed to select the most appropriate target materials for generating particular radioactive ion beams for the Holifield Radioactive Ion Beam Facility (HRIBF). The 25-MV tandem accelerator is used to implant stable complements of interesting radioactive elements into refractory targets mounted in a high-temperature FEBIAD ion source which is on-line at the UNISOR facility. These experiments permit selection of the target material most appropriate for the rapid release of the element of interest, as well as realistic estimates of the efficiency of the FEBIAD source. From diffusion release data information on the release times and diffusion coefficients can be derived. Diffusion coefficients for CI implanted into and diffused from CeS and Zr 5 Si 3 and As, Br, and Se implanted into and diffused from Zr 5 Ge 3 have been derived from the resulting intensity versus time profiles

  7. Structural Implications for Selective Targeting of PARPs.

    Science.gov (United States)

    Steffen, Jamin D; Brody, Jonathan R; Armen, Roger S; Pascal, John M

    2013-12-20

    Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that use NAD(+) as a substrate to synthesize polymers of ADP-ribose (PAR) as post-translational modifications of proteins. PARPs have important cellular roles that include preserving genomic integrity, telomere maintenance, transcriptional regulation, and cell fate determination. The diverse biological roles of PARPs have made them attractive therapeutic targets, which have fueled the pursuit of small molecule PARP inhibitors. The design of PARP inhibitors has matured over the past several years resulting in several lead candidates in clinical trials. PARP inhibitors are mainly used in clinical trials to treat cancer, particularly as sensitizing agents in combination with traditional chemotherapy to reduce side effects. An exciting aspect of PARP inhibitors is that they are also used to selectivity kill tumors with deficiencies in DNA repair proteins (e.g., BRCA1/2) through an approach termed "synthetic lethality." In the midst of the tremendous efforts that have brought PARP inhibitors to the forefront of modern chemotherapy, most clinically used PARP inhibitors bind to conserved regions that permits cross-selectivity with other PARPs containing homologous catalytic domains. Thus, the differences between therapeutic effects and adverse effects stemming from pan-PARP inhibition compared to selective inhibition are not well understood. In this review, we discuss current literature that has found ways to gain selectivity for one PARP over another. We furthermore provide insights into targeting other domains that make up PARPs, and how new classes of drugs that target these domains could provide a high degree of selectivity by affecting specific cellular functions. A clear understanding of the inhibition profiles of PARP inhibitors will not only enhance our understanding of the biology of individual PARPs, but may provide improved therapeutic options for patients.

  8. A color hierarchy for automatic target selection.

    Directory of Open Access Journals (Sweden)

    Illia Tchernikov

    Full Text Available Visual processing of color starts at the cones in the retina and continues through ventral stream visual areas, called the parvocellular pathway. Motion processing also starts in the retina but continues through dorsal stream visual areas, called the magnocellular system. Color and motion processing are functionally and anatomically discrete. Previously, motion processing areas MT and MST have been shown to have no color selectivity to a moving stimulus; the neurons were colorblind whenever color was presented along with motion. This occurs when the stimuli are luminance-defined versus the background and is considered achromatic motion processing. Is motion processing independent of color processing? We find that motion processing is intrinsically modulated by color. Color modulated smooth pursuit eye movements produced upon saccading to an aperture containing a surface of coherently moving dots upon a black background. Furthermore, when two surfaces that differed in color were present, one surface was automatically selected based upon a color hierarchy. The strength of that selection depended upon the distance between the two colors in color space. A quantifiable color hierarchy for automatic target selection has wide-ranging implications from sports to advertising to human-computer interfaces.

  9. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE)

    DEFF Research Database (Denmark)

    Peyrin-Biroulet, L; Sandborn, W; Sands, B E

    2015-01-01

    OBJECTIVES: The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a "treat-t...... target. CONCLUSIONS: Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients' quality of life....

  10. Sexual selection targets cetacean pelvic bones

    Science.gov (United States)

    Dines, J. P.; Otárola-Castillo, E.; Ralph, P.; Alas, J.; Daley, T.; Smith, A. D.; Dean, M. D.

    2014-01-01

    Male genitalia evolve rapidly, probably as a result of sexual selection. Whether this pattern extends to the internal infrastructure that influences genital movements remains unknown. Cetaceans (whales and dolphins) offer a unique opportunity to test this hypothesis: since evolving from land-dwelling ancestors, they lost external hind limbs and evolved a highly reduced pelvis which seems to serve no other function except to anchor muscles that maneuver the penis. Here we create a novel morphometric pipeline to analyze the size and shape evolution of pelvic bones from 130 individuals (29 species) in the context of inferred mating system. We present two main findings: 1) males from species with relatively intense sexual selection (inferred by relative testes size) have evolved relatively large penises and pelvic bones compared to their body size, and 2) pelvic bone shape diverges more quickly in species pairs that have diverged in inferred mating system. Neither pattern was observed in the anterior-most pair of vertebral ribs, which served as a negative control. This study provides evidence that sexual selection can affect internal anatomy that controls male genitalia. These important functions may explain why cetacean pelvic bones have not been lost through evolutionary time. PMID:25186496

  11. Subunits of the Snf1 kinase heterotrimer show interdependence for association and activity.

    Science.gov (United States)

    Elbing, Karin; Rubenstein, Eric M; McCartney, Rhonda R; Schmidt, Martin C

    2006-09-08

    The Snf1 kinase and its mammalian orthologue, the AMP-activated protein kinase (AMPK), function as heterotrimers composed of a catalytic alpha-subunit and two non-catalytic subunits, beta and gamma. The beta-subunit is thought to hold the complex together and control subcellular localization whereas the gamma-subunit plays a regulatory role by binding to and blocking the function of an auto-inhibitory domain (AID) present in the alpha-subunit. In addition, catalytic activity requires phosphorylation by a distinct upstream kinase. In yeast, any one of three Snf1-activating kinases, Sak1, Tos3, or Elm1, can fulfill this role. We have previously shown that Sak1 is the only Snf1-activating kinase that forms a stable complex with Snf1. Here we show that the formation of the Sak1.Snf1 complex requires the beta- and gamma-subunits in vivo. However, formation of the Sak1.Snf1 complex is not necessary for glucose-regulated phosphorylation of the Snf1 activation loop. Snf1 kinase purified from cells lacking the beta-subunits do not contain any gamma-subunit, indicating that the Snf1 kinase does not form a stable alphagamma dimer in vivo. In vitro kinase assays using purified full-length and truncated Snf1 proteins demonstrate that the kinase domain, which lacks the AID, is significantly more active than the full-length Snf1 protein. Addition of purified beta- and gamma-subunits could stimulate the kinase activity of the full-length alpha-subunit but only when all three subunits were present, suggesting an interdependence of all three subunits for assembly of a functional complex.

  12. Target Selection Models with Preference Variation Between Offenders

    NARCIS (Netherlands)

    Townsley, Michael; Birks, Daniel; Ruiter, Stijn; Bernasco, Wim; White, Gentry

    2016-01-01

    Objectives: This study explores preference variation in location choice strategies of residential burglars. Applying a model of offender target selection that is grounded in assertions of the routine activity approach, rational choice perspective, crime pattern and social disorganization theories,

  13. An algorithm for preferential selection of spectroscopic targets in LEGUE

    International Nuclear Information System (INIS)

    Carlin, Jeffrey L.; Newberg, Heidi Jo; Lépine, Sébastien; Deng Licai; Chen Yuqin; Fu Xiaoting; Gao Shuang; Li Jing; Liu Chao; Beers, Timothy C.; Christlieb, Norbert; Grillmair, Carl J.; Guhathakurta, Puragra; Han Zhanwen; Hou Jinliang; Lee, Hsu-Tai; Liu Xiaowei; Pan Kaike; Sellwood, J. A.; Wang Hongchi

    2012-01-01

    We describe a general target selection algorithm that is applicable to any survey in which the number of available candidates is much larger than the number of objects to be observed. This routine aims to achieve a balance between a smoothly-varying, well-understood selection function and the desire to preferentially select certain types of targets. Some target-selection examples are shown that illustrate different possibilities of emphasis functions. Although it is generally applicable, the algorithm was developed specifically for the LAMOST Experiment for Galactic Understanding and Exploration (LEGUE) survey that will be carried out using the Chinese Guo Shou Jing Telescope. In particular, this algorithm was designed for the portion of LEGUE targeting the Galactic halo, in which we attempt to balance a variety of science goals that require stars at fainter magnitudes than can be completely sampled by LAMOST. This algorithm has been implemented for the halo portion of the LAMOST pilot survey, which began in October 2011.

  14. Target selection biases from recent experience transfer across effectors.

    Science.gov (United States)

    Moher, Jeff; Song, Joo-Hyun

    2016-02-01

    Target selection is often biased by an observer's recent experiences. However, not much is known about whether these selection biases influence behavior across different effectors. For example, does looking at a red object make it easier to subsequently reach towards another red object? In the current study, we asked observers to find the uniquely colored target object on each trial. Randomly intermixed pre-trial cues indicated the mode of action: either an eye movement or a visually guided reach movement to the target. In Experiment 1, we found that priming of popout, reflected in faster responses following repetition of the target color on consecutive trials, occurred regardless of whether the effector was repeated from the previous trial or not. In Experiment 2, we examined whether an inhibitory selection bias away from a feature could transfer across effectors. While priming of popout reflects both enhancement of the repeated target features and suppression of the repeated distractor features, the distractor previewing effect isolates a purely inhibitory component of target selection in which a previewed color is presented in a homogenous display and subsequently inhibited. Much like priming of popout, intertrial suppression biases in the distractor previewing effect transferred across effectors. Together, these results suggest that biases for target selection driven by recent trial history transfer across effectors. This indicates that representations in memory that bias attention towards or away from specific features are largely independent from their associated actions.

  15. Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing

    Science.gov (United States)

    Lee, Ciaran M; Cradick, Thomas J; Fine, Eli J; Bao, Gang

    2016-01-01

    The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web-based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID:26750397

  16. Novel target configurations for selective ionization state studies in molybdenum

    International Nuclear Information System (INIS)

    Ilcisin, K.J.; Feldman, U.; Schwob, J.L.; Wouters, A.; Suckewer, S.; Princeton Univ., NJ

    1990-03-01

    Details of experiments aimed at achieving low ionization state selectivity in molybdenum are presented. Targets are excited with a 10 J CO 2 laser and the resultant VUV spectrum (300--700 Angstrom) has been studied. Combinations of focal spot size, target depth, and target geometries are compared. Simple attenuation of energy is shown not to vary ionization stage composition significantly. Experiments conducted with grazing incidence targets result only in a hot plasma. Modular targets with cooling cylinders of various radii demonstrated good selectivity of the ionization states, but with low absolute signals. Finally, results from combinations of focal spot adjustment and radiative cooling illustrate increased control over desired plasma temperature and density for spectroscopic studies of molybdenum. 7 refs., 14 figs

  17. In-silico Leishmania Target Selectivity of Antiparasitic Terpenoids

    Directory of Open Access Journals (Sweden)

    Ifedayo Victor Ogungbe

    2013-07-01

    Full Text Available Neglected Tropical Diseases (NTDs, like leishmaniasis, are major causes of mortality in resource-limited countries. The mortality associated with these diseases is largely due to fragile healthcare systems, lack of access to medicines, and resistance by the parasites to the few available drugs. Many antiparasitic plant-derived isoprenoids have been reported, and many of them have good in vitro activity against various forms of Leishmania spp. In this work, potential Leishmania biochemical targets of antiparasitic isoprenoids were studied in silico. Antiparasitic monoterpenoids selectively docked to L. infantum nicotinamidase, L. major uridine diphosphate-glucose pyrophosphorylase and methionyl t-RNA synthetase. The two protein targets selectively targeted by germacranolide sesquiterpenoids were L. major methionyl t-RNA synthetase and dihydroorotate dehydrogenase. Diterpenoids generally favored docking to L. mexicana glycerol-3-phosphate dehydrogenase. Limonoids also showed some selectivity for L. mexicana glycerol-3-phosphate dehydrogenase and L. major dihydroorotate dehydrogenase while withanolides docked more selectively with L. major uridine diphosphate-glucose pyrophosphorylase. The selectivity of the different classes of antiparasitic compounds for the protein targets considered in this work can be explored in fragment- and/or structure-based drug design towards the development of leads for new antileishmanial drugs.

  18. Improved targeted immunization strategies based on two rounds of selection

    Science.gov (United States)

    Xia, Ling-Ling; Song, Yu-Rong; Li, Chan-Chan; Jiang, Guo-Ping

    2018-04-01

    In the case of high degree targeted immunization where the number of vaccine is limited, when more than one node associated with the same degree meets the requirement of high degree centrality, how can we choose a certain number of nodes from those nodes, so that the number of immunized nodes will not exceed the limit? In this paper, we introduce a new idea derived from the selection process of second-round exam to solve this problem and then propose three improved targeted immunization strategies. In these proposed strategies, the immunized nodes are selected through two rounds of selection, where we increase the quotas of first-round selection according the evaluation criterion of degree centrality and then consider another characteristic parameter of node, such as node's clustering coefficient, betweenness and closeness, to help choose targeted nodes in the second-round selection. To validate the effectiveness of the proposed strategies, we compare them with the degree immunizations including the high degree targeted and the high degree adaptive immunizations using two metrics: the size of the largest connected component of immunized network and the number of infected nodes. Simulation results demonstrate that the proposed strategies based on two rounds of sorting are effective for heterogeneous networks and their immunization effects are better than that of the degree immunizations.

  19. Feature Extraction and Selection Strategies for Automated Target Recognition

    Science.gov (United States)

    Greene, W. Nicholas; Zhang, Yuhan; Lu, Thomas T.; Chao, Tien-Hsin

    2010-01-01

    Several feature extraction and selection methods for an existing automatic target recognition (ATR) system using JPLs Grayscale Optical Correlator (GOC) and Optimal Trade-Off Maximum Average Correlation Height (OT-MACH) filter were tested using MATLAB. The ATR system is composed of three stages: a cursory region of-interest (ROI) search using the GOC and OT-MACH filter, a feature extraction and selection stage, and a final classification stage. Feature extraction and selection concerns transforming potential target data into more useful forms as well as selecting important subsets of that data which may aide in detection and classification. The strategies tested were built around two popular extraction methods: Principal Component Analysis (PCA) and Independent Component Analysis (ICA). Performance was measured based on the classification accuracy and free-response receiver operating characteristic (FROC) output of a support vector machine(SVM) and a neural net (NN) classifier.

  20. Classification and Target Group Selection Based Upon Frequent Patterns

    NARCIS (Netherlands)

    W.H.L.M. Pijls (Wim); R. Potharst (Rob)

    2000-01-01

    textabstractIn this technical report , two new algorithms based upon frequent patterns are proposed. One algorithm is a classification method. The other one is an algorithm for target group selection. In both algorithms, first of all, the collection of frequent patterns in the training set is

  1. Burglar Target Selection: A Cross-National Comparison

    NARCIS (Netherlands)

    Townsley, M.; Birks, D.; Bernasco, W.; Johnson, S.D.; Ruiter, S.; White, G.

    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

  2. Burglar Target Selection : A Cross-national Comparison

    NARCIS (Netherlands)

    Townsley, Michael; Birks, Daniel; Bernasco, Wim; Ruiter, Stijn; Johnson, Shane D.; White, Gentry; Baum, Scott

    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

  3. Neural Networks for Target Selection in Direct Marketing

    NARCIS (Netherlands)

    R. Potharst (Rob); U. Kaymak (Uzay); W.H.L.M. Pijls (Wim)

    2001-01-01

    textabstractPartly due to a growing interest in direct marketing, it has become an important application field for data mining. Many techniques have been applied to select the targets in commercial applications, such as statistical regression, regression trees, neural computing, fuzzy clustering

  4. Targeted Diazotransfer Reagents Enable Selective Modification of Proteins with Azides.

    Science.gov (United States)

    Lohse, Jonas; Swier, Lotteke J Y M; Oudshoorn, Ruben C; Médard, Guillaume; Kuster, Bernhard; Slotboom, Dirk-Jan; Witte, Martin D

    2017-04-19

    In chemical biology, azides are used to chemically manipulate target structures in a bioorthogonal manner for a plethora of applications ranging from target identification to the synthesis of homogeneously modified protein conjugates. While a variety of methods have been established to introduce the azido group into recombinant proteins, a method that directly converts specific amino groups in endogenous proteins is lacking. Here, we report the first biotin-tethered diazotransfer reagent DtBio and demonstrate that it selectively modifies the model proteins streptavidin and avidin and the membrane protein BioY on cell surface. The reagent converts amines in the proximity of the binding pocket to azides and leaves the remaining amino groups in streptavidin untouched. Reagents of this novel class will find use in target identification as well as the selective functionalization and bioorthogonal protection of proteins.

  5. Target Selection for the SDSS-IV APOGEE-2 Survey

    Energy Technology Data Exchange (ETDEWEB)

    Zasowski, G. [Department of Physics and Astronomy, University of Utah, Salt Lake City, UT 84112 (United States); Cohen, R. E.; Carlberg, J. K.; Fleming, Scott W. [Space Telescope Science Institute, Baltimore, MD 21218 (United States); Chojnowski, S. D.; Holtzman, J. [Department of Astronomy, New Mexico State University, Las Cruces, NM 88001 (United States); Santana, F. [Departamento de Astronomía, Universidad de Chile, Santiago (Chile); Oelkers, R. J.; Bird, J. C. [Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37235 (United States); Andrews, B. [PITT PACC, Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Beaton, R. L. [The Observatories of the Carnegie Institution for Science, Pasadena, CA 91101 (United States); Bender, C.; Cunha, K. [Steward Observatory, The University of Arizona, Tucson, AZ 85719 (United States); Bovy, J. [Department of Astronomy and Astrophysics and Dunlap Institute for Astronomy and Astrophysics, University of Toronto, Toronto, ON M5S 3H4 (Canada); Covey, K. [Department of Physics and Astronomy, Western Washington University, Bellingham, WA 98225 (United States); Dell’Agli, F.; García-Hernández, D. A. [Departamento de Astrofísica, Universidad de La Laguna, and Instituto de Astrofísica de Canarias, La Laguna, Tenerife (Spain); Frinchaboy, P. M. [Department of Physics and Astronomy, Texas Christian University, Fort Worth, TX 76129 (United States); Harding, P. [Department of Astronomy, Case Western Reserve University, Cleveland, OH 44106 (United States); Johnson, J. A., E-mail: gail.zasowski@gmail.com [Department of Astronomy, The Ohio State University, Columbus, OH 43210 (United States); and others

    2017-11-01

    APOGEE-2 is a high-resolution, near-infrared spectroscopic survey observing ∼3 × 10{sup 5} stars across the entire sky. It is the successor to APOGEE and is part of the Sloan Digital Sky Survey IV (SDSS-IV). APOGEE-2 is expanding on APOGEE’s goals of addressing critical questions of stellar astrophysics, stellar populations, and Galactic chemodynamical evolution using (1) an enhanced set of target types and (2) a second spectrograph at Las Campanas Observatory in Chile. APOGEE-2 is targeting red giant branch and red clump stars, RR Lyrae, low-mass dwarf stars, young stellar objects, and numerous other Milky Way and Local Group sources across the entire sky from both hemispheres. In this paper, we describe the APOGEE-2 observational design, target selection catalogs and algorithms, and the targeting-related documentation included in the SDSS data releases.

  6. Target Selection for the SDSS-IV APOGEE-2 Survey

    International Nuclear Information System (INIS)

    Zasowski, G.; Cohen, R. E.; Carlberg, J. K.; Fleming, Scott W.; Chojnowski, S. D.; Holtzman, J.; Santana, F.; Oelkers, R. J.; Bird, J. C.; Andrews, B.; Beaton, R. L.; Bender, C.; Cunha, K.; Bovy, J.; Covey, K.; Dell’Agli, F.; García-Hernández, D. A.; Frinchaboy, P. M.; Harding, P.; Johnson, J. A.

    2017-01-01

    APOGEE-2 is a high-resolution, near-infrared spectroscopic survey observing ∼3 × 10 5 stars across the entire sky. It is the successor to APOGEE and is part of the Sloan Digital Sky Survey IV (SDSS-IV). APOGEE-2 is expanding on APOGEE’s goals of addressing critical questions of stellar astrophysics, stellar populations, and Galactic chemodynamical evolution using (1) an enhanced set of target types and (2) a second spectrograph at Las Campanas Observatory in Chile. APOGEE-2 is targeting red giant branch and red clump stars, RR Lyrae, low-mass dwarf stars, young stellar objects, and numerous other Milky Way and Local Group sources across the entire sky from both hemispheres. In this paper, we describe the APOGEE-2 observational design, target selection catalogs and algorithms, and the targeting-related documentation included in the SDSS data releases.

  7. Integrative analysis to select cancer candidate biomarkers to targeted validation

    Science.gov (United States)

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  8. Selective tumor cell targeting by the disaccharide moiety of bleomycin.

    Science.gov (United States)

    Yu, Zhiqiang; Schmaltz, Ryan M; Bozeman, Trevor C; Paul, Rakesh; Rishel, Michael J; Tsosie, Krystal S; Hecht, Sidney M

    2013-02-27

    In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells but not the "normal" breast cell line MCF-10A. Furthermore, it was found that the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, did not target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study were the issues of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting and the possible cellular uptake of the disaccharide. In the present study, we conjugated BLM, deglycoBLM, and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreatic cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells and comparable to that of BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

  9. Target Selection for the SDSS-III MARVELS Survey

    Science.gov (United States)

    Paegert, Martin; Stassun, Keivan G.; De Lee, Nathan; Pepper, Joshua; Fleming, Scott W.; Sivarani, Thirupathi; Mahadevan, Suvrath; Mack, Claude E., III; Dhital, Saurav; Hebb, Leslie; Ge, Jian

    2015-06-01

    We present the target selection process for the Multi-object APO Radial Velocity Exoplanets Large-area Survey (MARVELS), which is part of the Sloan Digital Sky Survey (SDSS) III. MARVELS is a medium-resolution (R ∼ 11,000) multi-fiber spectrograph capable of obtaining radial velocities for 60 objects at a time in order to find brown dwarfs and giant planets. The survey was configured to target dwarf stars with effective temperatures approximately between 4500 and 6250 K. For the first 2 years MARVELS relied on low-resolution spectroscopic pre-observations to estimate the effective temperature and log (g) for candidate stars and then selected suitable dwarf stars from this pool. Ultimately, the pre-observation spectra proved ineffective at filtering out giant stars; many giants were incorrectly classified as dwarfs, resulting in a giant contamination rate of ∼30% for the first phase of the MARVELS survey. Thereafter, the survey instead applied a reduced proper motion cut to eliminate giants and used the Infrared Flux Method to estimate effective temperatures, using only extant photmetric and proper-motion catalog information. The target selection method introduced here may be useful for other surveys that need to rely on extant catalog data for selection of specific stellar populations.

  10. Signatures of DNA target selectivity by ETS transcription factors.

    Science.gov (United States)

    Poon, Gregory M K; Kim, Hye Mi

    2017-05-27

    The ETS family of transcription factors is a functionally heterogeneous group of gene regulators that share a structurally conserved, eponymous DNA-binding domain. DNA target specificity derives from combinatorial interactions with other proteins as well as intrinsic heterogeneity among ETS domains. Emerging evidence suggests molecular hydration as a fundamental feature that defines the intrinsic heterogeneity in DNA target selection and susceptibility to epigenetic DNA modification. This perspective invokes novel hypotheses in the regulation of ETS proteins in physiologic osmotic stress, their pioneering potential in heterochromatin, and the effects of passive and pharmacologic DNA demethylation on ETS regulation.

  11. Nanostructured materials for selective recognition and targeted drug delivery

    International Nuclear Information System (INIS)

    Kotrotsiou, O; Kotti, K; Dini, E; Kammona, O; Kiparissides, C

    2005-01-01

    Selective recognition requires the introduction of a molecular memory into a polymer matrix in order to make it capable of rebinding an analyte with a very high specificity. In addition, targeted drug delivery requires drug-loaded vesicles which preferentially localize to the sites of injury and avoid uptake into uninvolved tissues. The rapid evolution of nanotechnology is aiming to fulfill the goal of selective recognition and optimal drug delivery through the development of molecularly imprinted polymeric (MIP) nanoparticles, tailor-made for a diverse range of analytes (e.g., pharmaceuticals, pesticides, amino acids, etc.) and of nanostructured targeted drug carriers (e.g., liposomes and micelles) with increased circulation lifetimes. In the present study, PLGA microparticles containing multilamellar vesicles (MLVs), and MIP nanoparticles were synthesized to be employed as drug carriers and synthetic receptors respectively

  12. THINK OUTSIDE THE COLOR BOX: PROBABILISTIC TARGET SELECTION AND THE SDSS-XDQSO QUASAR TARGETING CATALOG

    International Nuclear Information System (INIS)

    Bovy, Jo; Hogg, David W.; Weaver, Benjamin A.; Hennawi, Joseph F.; Myers, Adam D.; Kirkpatrick, Jessica A.; Schlegel, David J.; Ross, Nicholas P.; Sheldon, Erin S.; McGreer, Ian D.; Schneider, Donald P.

    2011-01-01

    We present the SDSS-XDQSO quasar targeting catalog for efficient flux-based quasar target selection down to the faint limit of the Sloan Digital Sky Survey (SDSS) catalog, even at medium redshifts (2.5 ∼ 3.5) quasar probabilities for all 160,904,060 point sources with dereddened i-band magnitude between 17.75 and 22.45 mag in the 14,555 deg 2 of imaging from SDSS Data Release 8. The catalog can be used to define a uniformly selected and efficient low- or medium-redshift quasar survey, such as that needed for the SDSS-III's Baryon Oscillation Spectroscopic Survey project. We show that the XDQSO technique performs as well as the current best photometric quasar-selection technique at low redshift, and outperforms all other flux-based methods for selecting the medium-redshift quasars of our primary interest. We make code to reproduce the XDQSO quasar target selection publicly available.

  13. Think Outside The Color Box: Probabilistic Target Selection And The SDSS-XDQSO Quasar Targeting Catalog

    International Nuclear Information System (INIS)

    Bovy, J.; Sheldon, E.; Hennawi, J.F.; Hogg, D.W.; Myers, A.D.

    2011-01-01

    We present the SDSS-XDQSO quasar targeting catalog for efficient flux-based quasar target selection down to the faint limit of the Sloan Digital Sky Survey (SDSS) catalog, even at medium redshifts (2.5 ∼ 3.5) quasar probabilities for all 160,904,060 point sources with dereddened i-band magnitude between 17.75 and 22.45 mag in the 14,555 deg 2 of imaging from SDSS Data Release 8. The catalog can be used to define a uniformly selected and efficient low- or medium-redshift quasar survey, such as that needed for the SDSS-III's Baryon Oscillation Spectroscopic Survey project. We show that the XDQSO technique performs as well as the current best photometric quasar-selection technique at low redshift, and outperforms all other flux-based methods for selecting the medium-redshift quasars of our primary interest. We make code to reproduce the XDQSO quasar target selection publicly available.

  14. Dynamic interactions between visual working memory and saccade target selection

    Science.gov (United States)

    Schneegans, Sebastian; Spencer, John P.; Schöner, Gregor; Hwang, Seongmin; Hollingworth, Andrew

    2014-01-01

    Recent psychophysical experiments have shown that working memory for visual surface features interacts with saccadic motor planning, even in tasks where the saccade target is unambiguously specified by spatial cues. Specifically, a match between a memorized color and the color of either the designated target or a distractor stimulus influences saccade target selection, saccade amplitudes, and latencies in a systematic fashion. To elucidate these effects, we present a dynamic neural field model in combination with new experimental data. The model captures the neural processes underlying visual perception, working memory, and saccade planning relevant to the psychophysical experiment. It consists of a low-level visual sensory representation that interacts with two separate pathways: a spatial pathway implementing spatial attention and saccade generation, and a surface feature pathway implementing color working memory and feature attention. Due to bidirectional coupling between visual working memory and feature attention in the model, the working memory content can indirectly exert an effect on perceptual processing in the low-level sensory representation. This in turn biases saccadic movement planning in the spatial pathway, allowing the model to quantitatively reproduce the observed interaction effects. The continuous coupling between representations in the model also implies that modulation should be bidirectional, and model simulations provide specific predictions for complementary effects of saccade target selection on visual working memory. These predictions were empirically confirmed in a new experiment: Memory for a sample color was biased toward the color of a task-irrelevant saccade target object, demonstrating the bidirectional coupling between visual working memory and perceptual processing. PMID:25228628

  15. Dynamic interactions between visual working memory and saccade target selection.

    Science.gov (United States)

    Schneegans, Sebastian; Spencer, John P; Schöner, Gregor; Hwang, Seongmin; Hollingworth, Andrew

    2014-09-16

    Recent psychophysical experiments have shown that working memory for visual surface features interacts with saccadic motor planning, even in tasks where the saccade target is unambiguously specified by spatial cues. Specifically, a match between a memorized color and the color of either the designated target or a distractor stimulus influences saccade target selection, saccade amplitudes, and latencies in a systematic fashion. To elucidate these effects, we present a dynamic neural field model in combination with new experimental data. The model captures the neural processes underlying visual perception, working memory, and saccade planning relevant to the psychophysical experiment. It consists of a low-level visual sensory representation that interacts with two separate pathways: a spatial pathway implementing spatial attention and saccade generation, and a surface feature pathway implementing color working memory and feature attention. Due to bidirectional coupling between visual working memory and feature attention in the model, the working memory content can indirectly exert an effect on perceptual processing in the low-level sensory representation. This in turn biases saccadic movement planning in the spatial pathway, allowing the model to quantitatively reproduce the observed interaction effects. The continuous coupling between representations in the model also implies that modulation should be bidirectional, and model simulations provide specific predictions for complementary effects of saccade target selection on visual working memory. These predictions were empirically confirmed in a new experiment: Memory for a sample color was biased toward the color of a task-irrelevant saccade target object, demonstrating the bidirectional coupling between visual working memory and perceptual processing. © 2014 ARVO.

  16. Targets of balancing selection in the human genome

    DEFF Research Database (Denmark)

    Andrés, Aida M; Hubisz, Melissa J; Indap, Amit

    2009-01-01

    Balancing selection is potentially an important biological force for maintaining advantageous genetic diversity in populations, including variation that is responsible for long-term adaptation to the environment. By serving as a means to maintain genetic variation, it may be particularly relevant...... to maintaining phenotypic variation in natural populations. Nevertheless, its prevalence and specific targets in the human genome remain largely unknown. We have analyzed the patterns of diversity and divergence of 13,400 genes in two human populations using an unbiased single-nucleotide polymorphism data set......, a genome-wide approach, and a method that incorporates demography in neutrality tests. We identified an unbiased catalog of genes with signatures of long-term balancing selection, which includes immunity genes as well as genes encoding keratins and membrane channels; the catalog also shows enrichment...

  17. Positive-negative-selection-mediated gene targeting in rice

    Directory of Open Access Journals (Sweden)

    Zenpei eShimatani

    2015-01-01

    Full Text Available Gene targeting (GT refers to the designed modification of genomic sequence(s through homologous recombination (HR. GT is a powerful tool both for the study of gene function and for molecular breeding. However, in transformation of higher plants, non-homologous end joining (NHEJ occurs overwhelmingly in somatic cells, masking HR-mediated GT. Positive-negative selection (PNS is an approach for finding HR-mediated GT events because it can eliminate NHEJ effectively by expression of a negative-selection marker gene. In rice—a major crop worldwide—reproducible PNS-mediated GT of endogenous genes has now been successfully achieved. The procedure is based on strong PNS using diphtheria toxin A-fragment as a negative marker, and has succeeded in the directed modification of several endogenous rice genes in various ways. In addition to gene knock-outs and knock-ins, a nucleotide substitution in a target gene was also achieved recently. This review presents a summary of the development of the rice PNS system, highlighting its advantages. Different types of gene modification and gene editing aimed at developing new plant breeding technology (NPBT based on PNS are discussed.

  18. The structural basis of the dominant negative phenotype of the Gαi1β1γ2 G203A/A326S heterotrimer

    Science.gov (United States)

    Liu, Ping; Jia, Ming-zhu; Zhou, X Edward; De Waal, Parker W; Dickson, Bradley M; Liu, Bo; Hou, Li; Yin, Yan-ting; Kang, Yan-yong; Shi, Yi; Melcher, Karsten; Xu, H Eric; Jiang, Yi

    2016-01-01

    Aim: Dominant negative mutant G proteins have provided critical insight into the mechanisms of G protein-coupled receptor (GPCR) signaling, but the mechanisms underlying the dominant negative characteristics are not completely understood. The aim of this study was to determine the structure of the dominant negative Gαi1β1γ2 G203A/A326S complex (Gi-DN) and to reveal the structural basis of the mutation-induced phenotype of Gαi1β1γ2. Methods: The three subunits of the Gi-DN complex were co-expressed with a baculovirus expression system. The Gi-DN heterotrimer was purified, and the structure of its complex with GDP was determined through X-ray crystallography. Results: The Gi-DN heterotrimer structure revealed a dual mechanism underlying the dominant negative characteristics. The mutations weakened the hydrogen bonding network between GDP/GTP and the binding pocket residues, and increased the interactions in the Gα-Gβγ interface. Concomitantly, the Gi-DN heterotrimer adopted a conformation, in which the C-terminus of Gαi and the N-termini of both the Gβ and Gγ subunits were more similar to the GPCR-bound state compared with the wild type complex. From these structural observations, two additional mutations (T48F and D272F) were designed that completely abolish the GDP binding of the Gi-DN heterotrimer. Conclusion: Overall, the results suggest that the mutations impede guanine nucleotide binding and Gα-Gβγ protein dissociation and favor the formation of the G protein/GPCR complex, thus blocking signal propagation. In addition, the structure provides a rationale for the design of other mutations that cause dominant negative effects in the G protein, as exemplified by the T48F and D272F mutations. PMID:27498775

  19. CD133, Selectively Targeting the Root of Cancer

    Directory of Open Access Journals (Sweden)

    Jörg U. Schmohl

    2016-05-01

    Full Text Available Cancer stem cells (CSC are capable of promoting tumor initiation and self-renewal, two important hallmarks of carcinoma formation. This population comprises a small percentage of the tumor mass and is highly resistant to chemotherapy, causing the most difficult problem in the field of cancer research, drug refractory relapse. Many CSC markers have been reported. One of the most promising and perhaps least ubiquitous is CD133, a membrane-bound pentaspan glycoprotein that is frequently expressed on CSC. There is evidence that directly targeting CD133 with biological drugs might be the most effective way to eliminate CSC. We have investigated two entirely unrelated, but highly effective approaches for selectively targeting CD133. The first involves using a special anti-CD133 single chain variable fragment (scFv to deliver a catalytic toxin. The second utilizes this same scFv to deliver components of the immune system. In this review, we discuss the development and current status of these CD133 associated biological agents. Together, they show exceptional promise by specific and efficient CSC elimination.

  20. Target and Tissue Selectivity Prediction by Integrated Mechanistic Pharmacokinetic-Target Binding and Quantitative Structure Activity Modeling.

    Science.gov (United States)

    Vlot, Anna H C; de Witte, Wilhelmus E A; Danhof, Meindert; van der Graaf, Piet H; van Westen, Gerard J P; de Lange, Elizabeth C M

    2017-12-04

    Selectivity is an important attribute of effective and safe drugs, and prediction of in vivo target and tissue selectivity would likely improve drug development success rates. However, a lack of understanding of the underlying (pharmacological) mechanisms and availability of directly applicable predictive methods complicates the prediction of selectivity. We explore the value of combining physiologically based pharmacokinetic (PBPK) modeling with quantitative structure-activity relationship (QSAR) modeling to predict the influence of the target dissociation constant (K D ) and the target dissociation rate constant on target and tissue selectivity. The K D values of CB1 ligands in the ChEMBL database are predicted by QSAR random forest (RF) modeling for the CB1 receptor and known off-targets (TRPV1, mGlu5, 5-HT1a). Of these CB1 ligands, rimonabant, CP-55940, and Δ 8 -tetrahydrocanabinol, one of the active ingredients of cannabis, were selected for simulations of target occupancy for CB1, TRPV1, mGlu5, and 5-HT1a in three brain regions, to illustrate the principles of the combined PBPK-QSAR modeling. Our combined PBPK and target binding modeling demonstrated that the optimal values of the K D and k off for target and tissue selectivity were dependent on target concentration and tissue distribution kinetics. Interestingly, if the target concentration is high and the perfusion of the target site is low, the optimal K D value is often not the lowest K D value, suggesting that optimization towards high drug-target affinity can decrease the benefit-risk ratio. The presented integrative structure-pharmacokinetic-pharmacodynamic modeling provides an improved understanding of tissue and target selectivity.

  1. NADP+ binding to the regulatory subunit of methionine adenosyltransferase II increases intersubunit binding affinity in the hetero-trimer.

    Directory of Open Access Journals (Sweden)

    Beatriz González

    Full Text Available Mammalian methionine adenosyltransferase II (MAT II is the only hetero-oligomer in this family of enzymes that synthesize S-adenosylmethionine using methionine and ATP as substrates. Binding of regulatory β subunits and catalytic α2 dimers is known to increase the affinity for methionine, although scarce additional information about this interaction is available. This work reports the use of recombinant α2 and β subunits to produce oligomers showing kinetic parameters comparable to MAT II purified from several tissues. According to isothermal titration calorimetry data and densitometric scanning of the stained hetero-oligomer bands on denatured gels, the composition of these oligomers is that of a hetero-trimer with α2 dimers associated to single β subunits. Additionally, the regulatory subunit is able to bind NADP(+ with a 1:1 stoichiometry, the cofactor enhancing β to α2-dimer binding affinity. Mutants lacking residues involved in NADP(+ binding and N-terminal truncations of the β subunit were able to oligomerize with α2-dimers, although the kinetic properties appeared altered. These data together suggest a role for both parts of the sequence in the regulatory role exerted by the β subunit on catalysis. Moreover, preparation of a structural model for the hetero-oligomer, using the available crystal data, allowed prediction of the regions involved in β to α2-dimer interaction. Finally, the implications that the presence of different N-terminals in the β subunit could have on MAT II behavior are discussed in light of the recent identification of several splicing forms of this subunit in hepatoma cells.

  2. Effects of Mode of Target Task Selection on Learning about Plants in a Mobile Learning Environment: Effortful Manual Selection versus Effortless QR-Code Selection

    Science.gov (United States)

    Gao, Yuan; Liu, Tzu-Chien; Paas, Fred

    2016-01-01

    This study compared the effects of effortless selection of target plants using quick respond (QR) code technology to effortful manual search and selection of target plants on learning about plants in a mobile device supported learning environment. In addition, it was investigated whether the effectiveness of the 2 selection methods was…

  3. Antimicrobial Peptide-PNA Conjugates Selectively Targeting Bacterial Genes

    Science.gov (United States)

    2013-07-22

    antibacterial therapy. Initial publications suggest that conjugates of cell penetrating peptides and PNA’s can overcome the barrier in transporting ...Zhou, Y., Hou, Z., Meng, J., and Luo, X. Targeting RNA polymerase primary σ70 as a therapeutic strategy against methicillin - resistant ... Staphylococcus aureus by antisense peptide nucleic acid. PLoS One. 2012; 7(1):e29886. 2. Good, L., Sandberg, R., Larsson, O., Nielsen, P.E., and Wahlestedt, C

  4. Selective phosphodiesterase inhibitors: a promising target for cognition enhancement

    OpenAIRE

    Reneerkens, Olga A. H.; Rutten, Kris; Steinbusch, Harry W. M.; Blokland, Arjan; Prickaerts, Jos

    2008-01-01

    Rationale One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer?s disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increa...

  5. Evaluating gaze-based interface tools to facilitate point-and-select tasks with small targets

    DEFF Research Database (Denmark)

    Skovsgaard, Henrik; Mateo, Julio C.; Hansen, John Paulin

    2011-01-01

    -and-select tasks. We conducted two experiments comparing the performance of dwell, magnification and zoom methods in point-and-select tasks with small targets in single- and multiple-target layouts. Both magnification and zoom showed higher hit rates than dwell. Hit rates were higher when using magnification than...

  6. A comparative study of fuzzy target selection methods in direct marketing

    NARCIS (Netherlands)

    Costa Sousa, da J.M.; Kaymak, U.; Madeira, S.

    2002-01-01

    Target selection in direct marketing is an important data mining problem for which fuzzy modeling can be used. The paper compares several fuzzy modeling techniques applied to target selection based on recency, frequency and monetary value measures. The comparison uses cross validation applied to

  7. Selection of phage-displayed accessible recombinant targeted antibodies (SPARTA): methodology and applications.

    Science.gov (United States)

    D'Angelo, Sara; Staquicini, Fernanda I; Ferrara, Fortunato; Staquicini, Daniela I; Sharma, Geetanjali; Tarleton, Christy A; Nguyen, Huynh; Naranjo, Leslie A; Sidman, Richard L; Arap, Wadih; Bradbury, Andrew Rm; Pasqualini, Renata

    2018-05-03

    We developed a potentially novel and robust antibody discovery methodology, termed selection of phage-displayed accessible recombinant targeted antibodies (SPARTA). This combines an in vitro screening step of a naive human antibody library against known tumor targets, with in vivo selections based on tumor-homing capabilities of a preenriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human antibodies amenable to rapid translation into medical applications. As a proof of concept, we evaluated SPARTA on 2 well-established tumor cell surface targets, EphA5 and GRP78. We evaluated antibodies that showed tumor-targeting selectivity as a representative panel of antibody-drug conjugates (ADCs) and were highly efficacious. Our results validate a discovery platform to identify and validate monoclonal antibodies with favorable tumor-targeting attributes. This approach may also extend to other diseases with known cell surface targets and affected tissues easily isolated for in vivo selection.

  8. The folate receptor as a molecular target for tumor-selective radionuclide delivery

    International Nuclear Information System (INIS)

    Ke, C.-Y.; Mathias, Carla J.; Green, Mark A.

    2003-01-01

    The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We review here some background on the folate receptor as tumor-associated molecular target for drug delivery, and briefly survey the literature on tumor-targeting with radiolabeled folate-chelate conjugates

  9. In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A

    OpenAIRE

    Stoltenburg, Regina; Schubert, Thomas; Strehlitz, Beate

    2015-01-01

    A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for moni...

  10. Signal Transduction and Molecular Targets of Selected Flavonoids

    Science.gov (United States)

    Bode, Ann M.

    2013-01-01

    Abstract Significance: Diet exerts a major influence on the risk for developing cancer and heart disease. Food factors such as flavonoids are alleged to protect cells from premature aging and disease by shielding DNA, proteins, and lipids from oxidative damage. Recent Advances: Our work has focused on clarifying the effects of dietary components on cancer cell proliferation and tumor growth, discovering mechanisms to explain the effects, and identifying the specific molecular targets of these compounds. Our strategy for identifying specific molecular targets of phytochemicals involves the use of supercomputer technology combined with protein crystallography, molecular biology, and experimental laboratory verification. Critical Issues: One of the greatest challenges for scientists is to reduce the accumulation of distortion and half truths reported in the popular media regarding the health benefits of certain foods or food supplements. The use of these is not new, but interest has increased dramatically because of perceived health benefits that are presumably acquired without unpleasant side effects. Flavonoids are touted to exert many beneficial effects in vitro. However, whether they can produce these effects in vivo is disputed. Future Directions: The World Health Organization indicates that one third of all cancer deaths are preventable and that diet is closely linked to prevention. Based on this idea and epidemiological findings, attention has centered on dietary phytochemicals as an effective intervention in cancer development. However, an unequivocal link between diet and cancer has not been established. Thus, identifying cancer preventive dietary agents with specific molecular targets is essential to move forward toward successful cancer prevention. Antioxid. Redox Signal. 19, 163–180. PMID:23458437

  11. 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

  12. 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

  13. Targeting cancer cells using 3-bromopyruvate for selective cancer treatment

    Directory of Open Access Journals (Sweden)

    Hussam H Baghdadi

    2017-01-01

    Full Text Available Cancer treatment deserves more research efforts despite intensive conventional treatment modalities for many types of malignancies. Metastasis and resistance to chemotherapy and radiotherapy receive a lot of global research efforts. The current advances in cancer biology may improve targeting the critical metabolic differences that distinguish cancer cells from normal cells. Cancer cells are highly glycolytic for energy production, exhibit the Warburg effect, establish aggressive acidic microenvironment, maintain cancer stem cells, exhibit resistance to chemotherapy, have low antioxidant systems but different ΔΨm (delta psi, mitochondrial transmembrane potential, express P-glycoprotein for multidrug resistance, upregulate glucose transporters and monocarboxylate transporters and are under high steady-state reactive oxygen species conditions. Normal cells differ in all these aspects. Lactate produced through the Warburg effect helps cancer metastasis. Targeting glycolysis reactions for energy production in cancer cells seems promising in decreasing the proliferation and metastasis of cancer cells. 3-bromopyruvate makes use of cancer biology in treating cancer cells, cancer stem cells and preventing metastasis in human cancer as discussed in this review. Updated advances are analyzed here, which include research analysis of background, experience, readings in the field of cancer biology, oncology and biochemistry.

  14. Targeting ticks for control of selected hemoparasitic diseases of cattle.

    Science.gov (United States)

    Kocan, K M

    1995-03-01

    Development in and transmission of hemoparasites by tick vectors are phenomena closely synchronized with the tick feeding cycle. In all known life cycles, initial infection of tick tissues occurs in midgut epithelial cells and transmission is effected as ticks feed after parasites have developed and multiplied in salivary glands. Many factors reviewed affect development and transmission of hemoparasites by ticks including age of ticks, artificial temperature, climate and/or season, tick stage or sex, hemoparasite variation, concurrent infection of ticks with other pathogens, host cell susceptibility, transovarial transmission, effect of hemoparasites on tick biology, and the effect of infecting parasitemia level in cattle on infection rates in ticks. Four hemoparasites of cattle, Anaplasma marginale, Cowdria ruminantium, Theileria parva, and Babesia spp., are all dependent on ticks for biological transmission. Babesia is transmitted transovarially whereas the other three are transmitted transstadially. Mechanical transfer of infective blood via fomites and mouthparts of biting arthropods is also a major means of transmission for Anaplasma marginale but not of the others. Potential control methods for hemoparasites that target parasites as they are developing in their respective tick hosts include tick control, vaccines (against ticks and parasites), and drugs (against ticks and parasites). Successful application of control strategies will be dependent upon thorough understanding of parasite developmental cycles, biology of the tick vectors and the immune response of cattle to ticks and to hemoparasites. The most effective control measures will be those that are targeted against both ticks and the hemoparasites they vector.

  15. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.

    2008-01-01

    log K ow. These findings were validated with experimental results and by a comparison to the properties of antimalarial drugs in clinical use. For ten active compounds, nine were predicted to accumulate to a greater extent in lysosomes than in other organelles, six of these were in the optimum range...... predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation...

  16. Dissecting patterns of preparatory activity in the frontal eye fields during pursuit target selection.

    Science.gov (United States)

    Raghavan, Ramanujan T; Joshua, Mati

    2017-10-01

    We investigated the composition of preparatory activity of frontal eye field (FEF) neurons in monkeys performing a pursuit target selection task. In response to the orthogonal motion of a large and a small reward target, monkeys initiated pursuit biased toward the direction of large reward target motion. FEF neurons exhibited robust preparatory activity preceding movement initiation in this task. Preparatory activity consisted of two components, ramping activity that was constant across target selection conditions, and a flat offset in firing rates that signaled the target selection condition. Ramping activity accounted for 50% of the variance in the preparatory activity and was linked most strongly, on a trial-by-trial basis, to pursuit eye movement latency rather than to its direction or gain. The offset in firing rates that discriminated target selection conditions accounted for 25% of the variance in the preparatory activity and was commensurate with a winner-take-all representation, signaling the direction of large reward target motion rather than a representation that matched the parameters of the upcoming movement. These offer new insights into the role that the frontal eye fields play in target selection and pursuit control. They show that preparatory activity in the FEF signals more strongly when to move rather than where or how to move and suggest that structures outside the FEF augment its contributions to the target selection process. NEW & NOTEWORTHY We used the smooth eye movement pursuit system to link between patterns of preparatory activity in the frontal eye fields and movement during a target selection task. The dominant pattern was a ramping signal that did not discriminate between selection conditions and was linked, on trial-by-trial basis, to movement latency. A weaker pattern was composed of a constant signal that discriminated between selection conditions but was only weakly linked to the movement parameters. Copyright © 2017 the American

  17. Metformin selectively targets redox control of complex I energy transduction

    Directory of Open Access Journals (Sweden)

    Amy R. Cameron

    2018-04-01

    Full Text Available Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled. Keywords: Diabetes, Metformin, Mitochondria, NADH, NAD+

  18. Targeting of phage particles towards endothelial cells by antibodies selected through a multi-parameter selection strategy.

    Science.gov (United States)

    Mandrup, Ole A; Lykkemark, Simon; Kristensen, Peter

    2017-02-10

    One of the hallmarks of cancer is sustained angiogenesis. Here, normal endothelial cells are activated, and their formation of new blood vessels leads to continued tumour growth. An improved patient condition is often observed when angiogenesis is prevented or normalized through targeting of these genomically stable endothelial cells. However, intracellular targets constitute a challenge in therapy, as the agents modulating these targets have to be delivered and internalized specifically to the endothelial cells. Selection of antibodies binding specifically to certain cell types is well established. It is nonetheless a challenge to ensure that the binding of antibodies to the target cell will mediate internalization. Previously selection of such antibodies has been performed targeting cancer cell lines; most often using either monovalent display or polyvalent display. In this article, we describe selections that isolate internalizing antibodies by sequential combining monovalent and polyvalent display using two types of helper phages, one which increases display valence and one which reduces background. One of the selected antibodies was found to mediate internalization into human endothelial cells, although our results confirms that the single stranded nature of the DNA packaged into phage particles may limit applications aimed at targeting nucleic acids in mammalian cells.

  19. Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance.

    Directory of Open Access Journals (Sweden)

    John Koren

    Full Text Available MKT-077, a rhodacyanine dye, was shown to produce cancer specific cell death. However, complications prevented the use of this compound beyond clinical trials. Here we describe YM-1, a derivative of MKT-077. We found that YM-1 was more cytotoxic and localized differently than MKT-077. YM-1 demonstrated this cytotoxicity across multiple cancer cell lines. This toxicity was limited to cancer cell lines; immortalized cell models were unaffected. Brief applications of YM-1 were found to be non-toxic. Brief treatment with YM-1 restored tamoxifen sensitivity to a refractory tamoxifen-resistant MCF7 cell model. This effect is potentially due to altered estrogen receptor alpha phosphorylation, an outcome precipitated by selective reductions in Akt levels (Akt/PKB. Thus, modifications to the rhodocyanine scaffold could potentially be made to improve efficacy and pharmacokinetic properties. Moreover, the impact on tamoxifen sensitivity could be a new utility for this compound family.

  20. Visual cells remember earlier applied target: plasticity of orientation selectivity.

    Directory of Open Access Journals (Sweden)

    Narcis Ghisovan

    Full Text Available BACKGROUND: A canonical proposition states that, in mature brain, neurons responsive to sensory stimuli are tuned to specific properties installed shortly after birth. It is amply demonstrated that that neurons in adult visual cortex of cats are orientation-selective that is they respond with the highest firing rates to preferred oriented stimuli. METHODOLOGY/PRINCIPAL FINDINGS: In anesthetized cats, prepared in a conventional fashion for single cell recordings, the present investigation shows that presenting a stimulus uninterruptedly at a non-preferred orientation for twelve minutes induces changes in orientation preference. Across all conditions orientation tuning curves were investigated using a trial by trial method. Contrary to what has been previously reported with shorter adaptation duration, twelve minutes of adaptation induces mostly attractive shifts, i.e. toward the adapter. After a recovery period allowing neurons to restore their original orientation tuning curves, we carried out a second adaptation which produced three major results: (1 more frequent attractive shifts, (2 an increase of their magnitude, and (3 an additional enhancement of responses at the new or acquired preferred orientation. Additionally, we also show that the direction of shifts depends on the duration of the adaptation: shorter adaptation in most cases produces repulsive shifts, whereas adaptation exceeding nine minutes results in attractive shifts, in the same unit. Consequently, shifts in preferred orientation depend on the duration of adaptation. CONCLUSION/SIGNIFICANCE: The supplementary response improvements indicate that neurons in area 17 keep a memory trace of the previous stimulus properties, thereby upgrading cellular performance. It also highlights the dynamic nature of basic neuronal properties in adult cortex since repeated adaptations modified both the orientation tuning selectivity and the response strength to the preferred orientation. These

  1. In Vitro Selection and Characterization of DNA Aptamers to a Small Molecule Target.

    Science.gov (United States)

    Ruscito, Annamaria; McConnell, Erin M; Koudrina, Anna; Velu, Ranganathan; Mattice, Christopher; Hunt, Vernon; McKeague, Maureen; DeRosa, Maria C

    2017-12-14

    Aptamers, synthetic oligonucleotide-based molecular recognition probes, have found use in a wide array of biosensing technologies based on their tight and highly selective binding to a variety of molecular targets. However, the inherent challenges associated with the selection and characterization of aptamers for small molecule targets have resulted in their underrepresentation, despite the need for small molecule detection in fields such as medicine, the environment, and agriculture. This protocol describes the steps in the selection, sequencing, affinity characterization, and truncation of DNA aptamers that are specific for small molecule targets. © 2017 by John Wiley & Sons, Inc. Copyright © 2017 John Wiley & Sons, Inc.

  2. Automatic Target Recognition: Statistical Feature Selection of Non-Gaussian Distributed Target Classes

    Science.gov (United States)

    2011-06-01

    implementing, and evaluating many feature selection algorithms. Mucciardi and Gose compared seven different techniques for choosing subsets of pattern...122 THIS PAGE INTENTIONALLY LEFT BLANK 123 LIST OF REFERENCES [1] A. Mucciardi and E. Gose , “A comparison of seven techniques for

  3. Coping with Atmospheric Turbulence in the Selection of Laser Hardening Technology for FCS Targeting Systems

    National Research Council Canada - National Science Library

    Pritchett, Timothy M

    2004-01-01

    ... by frequency-agile battlefield lasers at both long and short range. Evidently, the selection of sensor protection technologies for incorporation into the final targeting system will be based on their optical limiting performance under field conditions...

  4. The control of attentional target selection in a colour/colour conjunction task

    OpenAIRE

    Berggren, Nick; Eimer, Martin

    2016-01-01

    To investigate the time course of attentional object selection processes in visual search tasks where targets are defined by a combination of features from the same dimension, we measured the N2pc component as an electrophysiological marker of attentional object selection during colour/colour conjunction search. In Experiment 1, participants searched for targets defined by a combination of two colours, while ignoring distractor objects that matched only one of these colours. Reliable N2pc com...

  5. Auditory Stream Segregation Improves Infants' Selective Attention to Target Tones Amid Distracters

    Science.gov (United States)

    Smith, Nicholas A.; Trainor, Laurel J.

    2011-01-01

    This study examined the role of auditory stream segregation in the selective attention to target tones in infancy. Using a task adapted from Bregman and Rudnicky's 1975 study and implemented in a conditioned head-turn procedure, infant and adult listeners had to discriminate the temporal order of 2,200 and 2,400 Hz target tones presented alone,…

  6. Sequence-selective targeting of duplex DNA by peptide nucleic acids

    DEFF Research Database (Denmark)

    Nielsen, Peter E

    2010-01-01

    Sequence-selective gene targeting constitutes an attractive drug-discovery approach for genetic therapy, with the aim of reducing or enhancing the activity of specific genes at the transcriptional level, or as part of a methodology for targeted gene repair. The pseudopeptide DNA mimic peptide...

  7. The control of attentional target selection in a colour/colour conjunction task.

    Science.gov (United States)

    Berggren, Nick; Eimer, Martin

    2016-11-01

    To investigate the time course of attentional object selection processes in visual search tasks where targets are defined by a combination of features from the same dimension, we measured the N2pc component as an electrophysiological marker of attentional object selection during colour/colour conjunction search. In Experiment 1, participants searched for targets defined by a combination of two colours, while ignoring distractor objects that matched only one of these colours. Reliable N2pc components were triggered by targets and also by partially matching distractors, even when these distractors were accompanied by a target in the same display. The target N2pc was initially equal in size to the sum of the two N2pc components to the two different types of partially matching distractors and became superadditive from approximately 250 ms after search display onset. Experiment 2 demonstrated that the superadditivity of the target N2pc was not due to a selective disengagement of attention from task-irrelevant partially matching distractors. These results indicate that attention was initially deployed separately and in parallel to all target-matching colours, before attentional allocation processes became sensitive to the presence of both matching colours within the same object. They suggest that attention can be controlled simultaneously and independently by multiple features from the same dimension and that feature-guided attentional selection processes operate in parallel for different target-matching objects in the visual field.

  8. 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...

  9. Robust Ground Target Detection by SAR and IR Sensor Fusion Using Adaboost-Based Feature Selection

    Directory of Open Access Journals (Sweden)

    Sungho Kim

    2016-07-01

    Full Text Available Long-range ground targets are difficult to detect in a noisy cluttered environment using either synthetic aperture radar (SAR images or infrared (IR images. SAR-based detectors can provide a high detection rate with a high false alarm rate to background scatter noise. IR-based approaches can detect hot targets but are affected strongly by the weather conditions. This paper proposes a novel target detection method by decision-level SAR and IR fusion using an Adaboost-based machine learning scheme to achieve a high detection rate and low false alarm rate. The proposed method consists of individual detection, registration, and fusion architecture. This paper presents a single framework of a SAR and IR target detection method using modified Boolean map visual theory (modBMVT and feature-selection based fusion. Previous methods applied different algorithms to detect SAR and IR targets because of the different physical image characteristics. One method that is optimized for IR target detection produces unsuccessful results in SAR target detection. This study examined the image characteristics and proposed a unified SAR and IR target detection method by inserting a median local average filter (MLAF, pre-filter and an asymmetric morphological closing filter (AMCF, post-filter into the BMVT. The original BMVT was optimized to detect small infrared targets. The proposed modBMVT can remove the thermal and scatter noise by the MLAF and detect extended targets by attaching the AMCF after the BMVT. Heterogeneous SAR and IR images were registered automatically using the proposed RANdom SAmple Region Consensus (RANSARC-based homography optimization after a brute-force correspondence search using the detected target centers and regions. The final targets were detected by feature-selection based sensor fusion using Adaboost. The proposed method showed good SAR and IR target detection performance through feature selection-based decision fusion on a synthetic

  10. Robust Ground Target Detection by SAR and IR Sensor Fusion Using Adaboost-Based Feature Selection

    Science.gov (United States)

    Kim, Sungho; Song, Woo-Jin; Kim, So-Hyun

    2016-01-01

    Long-range ground targets are difficult to detect in a noisy cluttered environment using either synthetic aperture radar (SAR) images or infrared (IR) images. SAR-based detectors can provide a high detection rate with a high false alarm rate to background scatter noise. IR-based approaches can detect hot targets but are affected strongly by the weather conditions. This paper proposes a novel target detection method by decision-level SAR and IR fusion using an Adaboost-based machine learning scheme to achieve a high detection rate and low false alarm rate. The proposed method consists of individual detection, registration, and fusion architecture. This paper presents a single framework of a SAR and IR target detection method using modified Boolean map visual theory (modBMVT) and feature-selection based fusion. Previous methods applied different algorithms to detect SAR and IR targets because of the different physical image characteristics. One method that is optimized for IR target detection produces unsuccessful results in SAR target detection. This study examined the image characteristics and proposed a unified SAR and IR target detection method by inserting a median local average filter (MLAF, pre-filter) and an asymmetric morphological closing filter (AMCF, post-filter) into the BMVT. The original BMVT was optimized to detect small infrared targets. The proposed modBMVT can remove the thermal and scatter noise by the MLAF and detect extended targets by attaching the AMCF after the BMVT. Heterogeneous SAR and IR images were registered automatically using the proposed RANdom SAmple Region Consensus (RANSARC)-based homography optimization after a brute-force correspondence search using the detected target centers and regions. The final targets were detected by feature-selection based sensor fusion using Adaboost. The proposed method showed good SAR and IR target detection performance through feature selection-based decision fusion on a synthetic database generated

  11. Selection of targets and ion sources for RIB generation at the Holifield Radioactive Ion Beam Facility

    International Nuclear Information System (INIS)

    Alton, G.D.

    1995-01-01

    In this report, the authors describe the performance characteristics for a selected number of target ion sources that will be employed for initial use at the Holifield Radioactive Ion Beam Facility (HRIBF) as well as prototype ion sources that show promise for future use for RIB applications. A brief review of present efforts to select target materials and to design composite target matrix/heat-sink systems that simultaneously incorporate the short diffusion lengths, high permeabilities, and controllable temperatures required to effect fast and efficient diffusion release of the short-lived species is also given

  12. Predictive distractor context facilitates attentional selection of high, but not intermediate and low, salience targets.

    Science.gov (United States)

    Töllner, Thomas; Conci, Markus; Müller, Hermann J

    2015-03-01

    It is well established that we can focally attend to a specific region in visual space without shifting our eyes, so as to extract action-relevant sensory information from covertly attended locations. The underlying mechanisms that determine how fast we engage our attentional spotlight in visual-search scenarios, however, remain controversial. One dominant view advocated by perceptual decision-making models holds that the times taken for focal-attentional selection are mediated by an internal template that biases perceptual coding and selection decisions exclusively through target-defining feature coding. This notion directly predicts that search times remain unaffected whether or not participants can anticipate the upcoming distractor context. Here we tested this hypothesis by employing an illusory-figure localization task that required participants to search for an invariant target amongst a variable distractor context, which gradually changed--either randomly or predictably--as a function of distractor-target similarity. We observed a graded decrease in internal focal-attentional selection times--correlated with external behavioral latencies--for distractor contexts of higher relative to lower similarity to the target. Critically, for low but not intermediate and high distractor-target similarity, these context-driven effects were cortically and behaviorally amplified when participants could reliably predict the type of distractors. This interactive pattern demonstrates that search guidance signals can integrate information about distractor, in addition to target, identities to optimize distractor-target competition for focal-attentional selection. © 2014 Wiley Periodicals, Inc.

  13. Directional enhancement of selected high-order-harmonics from intense laser irradiated blazed grating targets.

    Science.gov (United States)

    Zhang, Guobo; Chen, Min; Liu, Feng; Yuan, Xiaohui; Weng, Suming; Zheng, Jun; Ma, Yanyun; Shao, Fuqiu; Sheng, Zhengming; Zhang, Jie

    2017-10-02

    Relativistically intense laser solid target interaction has been proved to be a promising way to generate high-order harmonics, which can be used to diagnose ultrafast phenomena. However, their emission direction and spectra still lack tunability. Based upon two-dimensional particle-in-cell simulations, we show that directional enhancement of selected high-order-harmonics can be realized using blazed grating targets. Such targets can select harmonics with frequencies being integer times of the grating frequency. Meanwhile, the radiation intensity and emission area of the harmonics are increased. The emission direction is controlled by tailoring the local blazed structure. Theoretical and electron dynamics analysis for harmonics generation, selection and directional enhancement from the interaction between multi-cycle laser and grating target are carried out. These studies will benefit the generation and application of laser plasma-based high order harmonics.

  14. Purification-Free, Target-Selective Immobilization of a Protein from Cell Lysates.

    Science.gov (United States)

    Cha, Jaehyun; Kwon, Inchan

    2018-02-27

    Protein immobilization has been widely used for laboratory experiments and industrial processes. Preparation of a recombinant protein for immobilization usually requires laborious and expensive purification steps. Here, a novel purification-free, target-selective immobilization technique of a protein from cell lysates is reported. Purification steps are skipped by immobilizing a target protein containing a clickable non-natural amino acid (p-azidophenylalanine) in cell lysates onto alkyne-functionalized solid supports via bioorthogonal azide-alkyne cycloaddition. In order to achieve a target protein-selective immobilization, p-azidophenylalanine was introduced into an exogenous target protein, but not into endogenous non-target proteins using host cells with amber codon-free genomic DNAs. Immobilization of superfolder fluorescent protein (sfGFP) from cell lysates is as efficient as that of the purified sfGFP. Using two fluorescent proteins (sfGFP and mCherry), the authors also demonstrated that the target proteins are immobilized with a minimal immobilization of non-target proteins (target-selective immobilization). © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Altering spatial priority maps via statistical learning of target selection and distractor filtering.

    Science.gov (United States)

    Ferrante, Oscar; Patacca, Alessia; Di Caro, Valeria; Della Libera, Chiara; Santandrea, Elisa; Chelazzi, Leonardo

    2018-05-01

    The cognitive system has the capacity to learn and make use of environmental regularities - known as statistical learning (SL), including for the implicit guidance of attention. For instance, it is known that attentional selection is biased according to the spatial probability of targets; similarly, changes in distractor filtering can be triggered by the unequal spatial distribution of distractors. Open questions remain regarding the cognitive/neuronal mechanisms underlying SL of target selection and distractor filtering. Crucially, it is unclear whether the two processes rely on shared neuronal machinery, with unavoidable cross-talk, or they are fully independent, an issue that we directly addressed here. In a series of visual search experiments, participants had to discriminate a target stimulus, while ignoring a task-irrelevant salient distractor (when present). We systematically manipulated spatial probabilities of either one or the other stimulus, or both. We then measured performance to evaluate the direct effects of the applied contingent probability distribution (e.g., effects on target selection of the spatial imbalance in target occurrence across locations) as well as its indirect or "transfer" effects (e.g., effects of the same spatial imbalance on distractor filtering across locations). By this approach, we confirmed that SL of both target and distractor location implicitly bias attention. Most importantly, we described substantial indirect effects, with the unequal spatial probability of the target affecting filtering efficiency and, vice versa, the unequal spatial probability of the distractor affecting target selection efficiency across locations. The observed cross-talk demonstrates that SL of target selection and distractor filtering are instantiated via (at least partly) shared neuronal machinery, as further corroborated by strong correlations between direct and indirect effects at the level of individual participants. Our findings are compatible

  16. Molecular Connectivity Predefines Polypharmacology: Aliphatic Rings, Chirality, and sp3 Centers Enhance Target Selectivity

    Directory of Open Access Journals (Sweden)

    Stefania Monteleone

    2017-08-01

    Full Text Available Dark chemical matter compounds are small molecules that have been recently identified as highly potent and selective hits. For this reason, they constitute a promising class of possible candidates in the process of drug discovery and raise the interest of the scientific community. To this purpose, Wassermann et al. (2015 have described the application of 2D descriptors to characterize dark chemical matter. However, their definition was based on the number of reported positive assays rather than the number of known targets. As there might be multiple assays for one single target, the number of assays does not fully describe target selectivity. Here, we propose an alternative classification of active molecules that is based on the number of known targets. We cluster molecules in four classes: black, gray, and white compounds are active on one, two to four, and more than four targets respectively, whilst inactive compounds are found to be inactive in the considered assays. In this study, black and inactive compounds are found to have not only higher solubility, but also a higher number of chiral centers, sp3 carbon atoms and aliphatic rings. On the contrary, white compounds contain a higher number of double bonds and fused aromatic rings. Therefore, the design of a screening compound library should consider these molecular properties in order to achieve target selectivity or polypharmacology. Furthermore, analysis of four main target classes (GPCRs, kinases, proteases, and ion channels shows that GPCR ligands are more selective than the other classes, as the number of black compounds is higher in this target superfamily. On the other side, ligands that hit kinases, proteases, and ion channels bind to GPCRs more likely than to other target classes. Consequently, depending on the target protein family, appropriate screening libraries can be designed in order to minimize the likelihood of unwanted side effects early in the drug discovery process

  17. Occurrence Prospect of HDR and Target Site Selection Study in Southeastern of China

    Science.gov (United States)

    Lin, W.; Gan, H.

    2017-12-01

    Hot dry rock (HDR) geothermal resource is one of the most important clean energy in future. Site selection a HDR resource is a fundamental work to explore the HDR resources. This paper compiled all the HDR development projects domestic and abroad, and summarized the location of HDR geothermal geological index. After comparing the geological background of HDR in the southeast coastal area of China, Yangjiang Xinzhou in Guangdong province, Leizhou Peninsula area, Lingshui in Hainan province and Huangshadong in Guangzhou were selected from some key potential target area along the southeast coast of China. Deep geothermal field model of the study area is established based on the comprehensive analysis of the target area of deep geothermal geological background and deep thermal anomalies. This paper also compared the hot dry rock resources target locations, and proposed suggestions for the priority exploration target area and exploration scheme.

  18. Selection of IFE target materials from a safety and environmental perspective

    Energy Technology Data Exchange (ETDEWEB)

    Latkowski, J.F. E-mail: latkowski1@llnl.gov; Sanz, J.; Reyes, S.; Gomez del Rio, J

    2001-05-21

    Target materials for inertial fusion energy (IFE) power plant designs might be selected for a wide variety of reasons including wall absorption of driver energy, material opacity, cost and ease of fabrication. While each of these issues are of great importance, target materials should also be selected based upon their safety and environmental (S and E) characteristics. The present work focuses on the recycling, waste management and accident dose characteristics of potential target materials. If target materials are recycled so that the quantity is small, isotopic separation may be economically viable. Therefore, calculations have been completed for all stable isotopes for all elements from lithium to polonium. The results of these calculations are used to identify specific isotopes and elements that are most likely to be offensive as well as those most likely to be acceptable in terms of their S and E characteristics.

  19. Selection of IFE target materials from a safety and environmental perspective

    Science.gov (United States)

    Latkowski, J. F.; Sanz, J.; Reyes, S.; Gomez del Rio, J.

    2001-05-01

    Target materials for inertial fusion energy (IFE) power plant designs might be selected for a wide variety of reasons including wall absorption of driver energy, material opacity, cost and ease of fabrication. While each of these issues are of great importance, target materials should also be selected based upon their safety and environmental (S&E) characteristics. The present work focuses on the recycling, waste management and accident dose characteristics of potential target materials. If target materials are recycled so that the quantity is small, isotopic separation may be economically viable. Therefore, calculations have been completed for all stable isotopes for all elements from lithium to polonium. The results of these calculations are used to identify specific isotopes and elements that are most likely to be offensive as well as those most likely to be acceptable in terms of their S&E characteristics.

  20. The spatially global control of attentional target selection in visual search

    OpenAIRE

    Berggren, Nick; Jenkins, M.; McCants, C.W.; Eimer, Martin

    2017-01-01

    Glyn Humphreys and his co-workers have made numerous important theoretical and empirical contributions to research on visual search. They have introduced the concept of attentional target templates and investigated the nature of these templates and how they are involved in the control of search performance. In the experiments reported here, we investigated whether feature-specific search template for particular colours can guide target selection independently for different regions of visual s...

  1. Impact of high-risk conjunctions on Active Debris Removal target selection

    OpenAIRE

    Lidtke, Aleksander A.; Lewis, Hugh G.; Armellin, Roberto

    2015-01-01

    All rights reserved.Space debris simulations show that if current space launches continue unchanged, spacecraft operations might become difficult in the congested space environment. It has been suggested that Active Debris Removal (ADR) might be necessary in order to prevent such a situation. Selection of objects to be targeted by ADR is considered important because removal of non-relevant objects will unnecessarily increase the cost of ADR. One of the factors to be used in this ADR target se...

  2. Contextual control over selective attention: evidence from a two-target method.

    Science.gov (United States)

    MacLellan, Ellen; Shore, David I; Milliken, Bruce

    2015-07-01

    Selective attention is generally studied with conflict tasks, using response time as the dependent measure. Here, we study the impact of selective attention to a first target, T1, presented simultaneously with a distractor, on the accuracy of subsequent encoding of a second target item, T2. This procedure produces an "attentional blink" (AB) effect much like that reported in other studies, and allowed us to study the influence of context on cognitive control with a novel method. In particular, we examined whether preparation to attend selectively to T1 had an impact on the selective encoding of T1 that would translate to report of T2. Preparation to attend selectively was manipulated by varying whether difficult selective attention T1 trials were presented in the context of other difficult selective attention T1 trials. The results revealed strong context effects of this nature, with smaller AB effects when difficult selective attention T1 trials were embedded in a context with many, rather than few, other difficult selective attention T1 trials. Further, the results suggest that both the trial-to-trial local context and the block-wide global context modulate performance in this task.

  3. Social exclusion impairs distractor suppression but not target enhancement in selective attention.

    Science.gov (United States)

    Xu, Mengsi; Li, Zhiai; Diao, Liuting; Fan, Lingxia; Zhang, Lijie; Yuan, Shuge; Yang, Dong

    2017-11-01

    Social exclusion has been thought to weaken one's ability to exert inhibitory control. Existing studies have primarily focused on the relationship between exclusion and behavioral inhibition, and have reported that exclusion impairs behavioral inhibition. However, whether exclusion also affects selective attention, another important aspect of inhibitory control, remains unknown. Therefore, the current study aimed to explore whether social exclusion impairs selective attention, and to specifically examine its effect on two hypothesized mechanisms of selective attention: target enhancement and distractor suppression. The Cyberball game was used to manipulate social exclusion. Participants then performed a visual search task while event-related potentials were recorded. In the visual search task, target and salient distractor were either both presented laterally or one was presented on the vertical midline and the other laterally. Results showed that social exclusion differentially affected target and distractor processing. While exclusion impaired distractor suppression, reflected as smaller distractor-positivity (Pd) amplitudes for the exclusion group compared to the inclusion group, it did not affect target enhancement, reflected as similar target-negativity (Nt) amplitudes for both the exclusion and inclusion groups. Together, these results extend our understanding of the relationship between exclusion and inhibitory control, and suggest that social exclusion affects selective attention in a more complex manner than previously thought. Copyright © 2017. Published by Elsevier B.V.

  4. Candidate Targets for New Anti-Virulence Drugs: Selected Cases of Bacterial Adhesion and Biofilm Formation

    DEFF Research Database (Denmark)

    Klemm, Per; Hancock, Viktoria; Kvist, Malin

    2007-01-01

    is particularly problematic in medical contexts because biofilm-associated bacteria are particularly hard to eradicate. Several promising candidate drugs that target bacterial adhesion and biofilm formation are being developed. Some of these might be valuable weapons for fighting infectious diseases in the future...... formation are highly attractive targets for new drugs. Specific adhesion provides bacteria with target selection and prevents removal by hydrodynamic flow forces. Bacterial adhesion is of paramount importance for bacterial pathogenesis. Adhesion is also the first step in biofilm formation. Biofilm formation...

  5. TARGET MARKET SELECTION IN FRESH FRUIT-VEGETABLE SECTOR USING FUZZY VIKOR METHOD

    OpenAIRE

    Tosun, Nedret

    2017-01-01

    Purpose- Companieshave to open up to new markets in order to develop and increase theircompetitiveness in the face of globalization and technological revolution.Target market selection is an important issue that needs to be addressed withpriority in terms of efficient use of resources. Methodology- The problemof market selection is a multi-criteria decision-making problem due to itsnature which requires the evaluation of different and sometimes conflictingcriteria in the decision-making proce...

  6. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    DEFF Research Database (Denmark)

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel

    2017-01-01

    Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment ...

  7. THE SDSS-IV EXTENDED BARYON OSCILLATION SPECTROSCOPIC SURVEY: LUMINOUS RED GALAXY TARGET SELECTION

    Energy Technology Data Exchange (ETDEWEB)

    Prakash, Abhishek; Licquia, Timothy C.; Newman, Jeffrey A.; Rao, Sandhya M. [PITT PACC, Department of Physics and Astronomy, University of Pittsburgh, Pittsburgh, PA 15260 (United States); Ross, Ashley J. [Center for Cosmology and Astro-Particle Physics, Ohio State University, Columbus, OH 43210 (United States); Myers, Adam D. [Department of Physics and Astronomy, University of Wyoming, Laramie, WY 82071 (United States); Dawson, Kyle S.; Bautista, Julian E.; Brownstein, Joel R. [Department of Physics and Astronomy, University of Utah, Salt Lake City, UT 84112 (United States); Kneib, Jean-Paul [Laboratoire d’Astrophysique, Ecole Polytechnique Fédérale de Lausanne Observatoire de Sauverny, 1290 Versoix (Switzerland); Percival, Will J. [Institute of Cosmology and Gravitation, Dennis Sciama Building, University of Portsmouth, Portsmouth, PO1 3FX (United Kingdom); Comparat, Johan [Instituto de Física Teórica, (UAM/CSIC), Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid (Spain); Tinker, Jeremy L. [Center for Cosmology and Particle Physics, Department of Physics, New York University, 4 Washington Place, New York, NY 10003 (United States); Schlegel, David J. [Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, CA 94720 (United States); Tojeiro, Rita [School of Physics and Astronomy, St Andrews, KY16 9SS (United Kingdom); Ho, Shirley; Lang, Dustin [Bruce and Astrid McWilliams Center for Cosmology, Department of Physics, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, PA 15213 (United States); McBride, Cameron K. [Harvard-Smithsonian Center for Astrophysics, Harvard University, 60 Garden Street, Cambridge, MA 02138 (United States); Zhu, Guangtun Ben, E-mail: abp15@pitt.edu [Department of Physics and Astronomy, Johns Hopkins University, Baltimore, MD 21218 (United States); and others

    2016-06-01

    We describe the algorithm used to select the luminous red galaxy (LRG) sample for the extended Baryon Oscillation Spectroscopic Survey (eBOSS) of the Sloan Digital Sky Survey IV (SDSS-IV) using photometric data from both the SDSS and the Wide-field Infrared Survey Explorer . LRG targets are required to meet a set of color selection criteria and have z -band and i -band MODEL magnitudes z < 19.95 and 19.9 < i < 21.8, respectively. Our algorithm selects roughly 50 LRG targets per square degree, the great majority of which lie in the redshift range 0.6 < z < 1.0 (median redshift 0.71). We demonstrate that our methods are highly effective at eliminating stellar contamination and lower-redshift galaxies. We perform a number of tests using spectroscopic data from SDSS-III/BOSS ancillary programs to determine the redshift reliability of our target selection and its ability to meet the science requirements of eBOSS. The SDSS spectra are of high enough signal-to-noise ratio that at least ∼89% of the target sample yields secure redshift measurements. We also present tests of the uniformity and homogeneity of the sample, demonstrating that it should be clean enough for studies of the large-scale structure of the universe at higher redshifts than SDSS-III/BOSS LRGs reached.

  8. In silico tools used for compound selection during target-based drug discovery and development.

    Science.gov (United States)

    Caldwell, Gary W

    2015-01-01

    The target-based drug discovery process, including target selection, screening, hit-to-lead (H2L) and lead optimization stage gates, is the most common approach used in drug development. The full integration of in vitro and/or in vivo data with in silico tools across the entire process would be beneficial to R&D productivity by developing effective selection criteria and drug-design optimization strategies. This review focuses on understanding the impact and extent in the past 5 years of in silico tools on the various stage gates of the target-based drug discovery approach. There are a large number of in silico tools available for establishing selection criteria and drug-design optimization strategies in the target-based approach. However, the inconsistent use of in vitro and/or in vivo data integrated with predictive in silico multiparameter models throughout the process is contributing to R&D productivity issues. In particular, the lack of reliable in silico tools at the H2L stage gate is contributing to the suboptimal selection of viable lead compounds. It is suggested that further development of in silico multiparameter models and organizing biologists, medicinal and computational chemists into one team with a single accountable objective to expand the utilization of in silico tools in all phases of drug discovery would improve R&D productivity.

  9. Competition between color and luminance for target selection in smooth pursuit and saccadic eye movements.

    Science.gov (United States)

    Spering, Miriam; Montagnini, Anna; Gegenfurtner, Karl R

    2008-11-24

    Visual processing of color and luminance for smooth pursuit and saccadic eye movements was investigated using a target selection paradigm. In two experiments, stimuli were varied along the dimensions color and luminance, and selection of the more salient target was compared in pursuit and saccades. Initial pursuit was biased in the direction of the luminance component whereas saccades showed a relative preference for color. An early pursuit response toward luminance was often reversed to color by a later saccade. Observers' perceptual judgments of stimulus salience, obtained in two control experiments, were clearly biased toward luminance. This choice bias in perceptual data implies that the initial short-latency pursuit response agrees with perceptual judgments. In contrast, saccades, which have a longer latency than pursuit, do not seem to follow the perceptual judgment of salience but instead show a stronger relative preference for color. These substantial differences in target selection imply that target selection processes for pursuit and saccadic eye movements use distinctly different weights for color and luminance stimuli.

  10. Stimulus selection and tracking during urination: autoshaping directed behavior with toilet targets.

    Science.gov (United States)

    Siegel, R K

    1977-01-01

    A simple procedure is described for investigating stimuli selected as targets during urination in the commode. Ten normal males preferred a floating target that could be tracked to a series of stationary targets. This technique was used to bring misdirected urinations in a severely retarded male under rapid stimulus control of a floating target in the commode. The float stimulus was also evaluated with nine institionalized, moderately retarded males and results indicated rapid autoshaping of directed urination without the use of verbal instructions or conventional toilet training. The technique can be applied in training children to control misdirected urinations in institution for the retarded, in psychiatric wards with regressed populations, and in certain male school dormitories. PMID:885828

  11. Band selection method based on spectrum difference in targets of interest in hyperspectral imagery

    Science.gov (United States)

    Zhang, Xiaohan; Yang, Guang; Yang, Yongbo; Huang, Junhua

    2016-10-01

    While hyperspectral data shares rich spectrum information, it has numbers of bands with high correlation coefficients, causing great data redundancy. A reasonable band selection is important for subsequent processing. Bands with large amount of information and low correlation should be selected. On this basis, according to the needs of target detection applications, the spectral characteristics of the objects of interest are taken into consideration in this paper, and a new method based on spectrum difference is proposed. Firstly, according to the spectrum differences of targets of interest, a difference matrix which represents the different spectral reflectance of different targets in different bands is structured. By setting a threshold, the bands satisfying the conditions would be left, constituting a subset of bands. Then, the correlation coefficients between bands are calculated and correlation matrix is given. According to the size of the correlation coefficient, the bands can be set into several groups. At last, the conception of normalized variance is used on behalf of the information content of each band. The bands are sorted by the value of its normalized variance. Set needing number of bands, and the optimum band combination solution can be get by these three steps. This method retains the greatest degree of difference between the target of interest and is easy to achieve by computer automatically. Besides, false color image synthesis experiment is carried out using the bands selected by this method as well as other 3 methods to show the performance of method in this paper.

  12. Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Idit Dotan

    Full Text Available The incidence of papillary thyroid carcinoma (PTC has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.Thyroid Stimulating Hormone Receptor (TSHR was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with

  13. In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A.

    Directory of Open Access Journals (Sweden)

    Regina Stoltenburg

    Full Text Available A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5'-end including the 5'-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins like Protein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer.

  14. In vitro Selection and Interaction Studies of a DNA Aptamer Targeting Protein A.

    Science.gov (United States)

    Stoltenburg, Regina; Schubert, Thomas; Strehlitz, Beate

    2015-01-01

    A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5'-end including the 5'-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins like Protein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer.

  15. Design, construction, and characterization of high-performance membrane fusion devices with target-selectivity.

    Science.gov (United States)

    Kashiwada, Ayumi; Yamane, Iori; Tsuboi, Mana; Ando, Shun; Matsuda, Kiyomi

    2012-01-31

    Membrane fusion proteins such as the hemagglutinin glycoprotein have target recognition and fusion accelerative domains, where some synergistically working elements are essential for target-selective and highly effective native membrane fusion systems. In this work, novel membrane fusion devices bearing such domains were designed and constructed. We selected a phenylboronic acid derivative as a recognition domain for a sugar-like target and a transmembrane-peptide (Leu-Ala sequence) domain interacting with the target membrane, forming a stable hydrophobic α-helix and accelerating the fusion process. Artificial membrane fusion behavior between the synthetic devices in which pilot and target liposomes were incorporated was characterized by lipid-mixing and inner-leaflet lipid-mixing assays. Consequently, the devices bearing both the recognition and transmembrane domains brought about a remarkable increase in the initial rate for the membrane fusion compared with the devices containing the recognition domain alone. In addition, a weakly acidic pH-responsive device was also constructed by replacing three Leu residues in the transmembrane-peptide domain by Glu residues. The presence of Glu residues made the acidic pH-dependent hydrophobic α-helix formation possible as expected. The target-selective liposome-liposome fusion was accelerated in a weakly acidic pH range when the Glu-substituted device was incorporated in pilot liposomes. The use of this pH-responsive device seems to be a potential strategy for novel applications in a liposome-based delivery system. © 2011 American Chemical Society

  16. Out with the old? The role of selective attention in retaining targets in partial report.

    Science.gov (United States)

    Lindsey, Dakota R B; Bundesen, Claus; Kyllingsbæk, Søren; Petersen, Anders; Logan, Gordon D

    2017-01-01

    In the partial-report task, subjects are asked to report only a portion of the items presented. Selective attention chooses which objects to represent in short-term memory (STM) on the basis of their relevance. Because STM is limited in capacity, one must sometimes choose which objects are removed from memory in light of new relevant information. We tested the hypothesis that the choices among newly presented information and old information in STM involve the same process-that both are acts of selective attention. We tested this hypothesis using a two-display partial-report procedure. In this procedure, subjects had to select and retain relevant letters (targets) from two sequentially presented displays. If selection in perception and retention in STM are the same process, then irrelevant letters (distractors) in the second display, which demanded attention because of their similarity to the targets, should have decreased target report from the first display. This effect was not obtained in any of four experiments. Thus, choosing objects to keep in STM is not the same process as choosing new objects to bring into STM.

  17. Selective whole genome amplification for resequencing target microbial species from complex natural samples.

    Science.gov (United States)

    Leichty, Aaron R; Brisson, Dustin

    2014-10-01

    Population genomic analyses have demonstrated power to address major questions in evolutionary and molecular microbiology. Collecting populations of genomes is hindered in many microbial species by the absence of a cost effective and practical method to collect ample quantities of sufficiently pure genomic DNA for next-generation sequencing. Here we present a simple method to amplify genomes of a target microbial species present in a complex, natural sample. The selective whole genome amplification (SWGA) technique amplifies target genomes using nucleotide sequence motifs that are common in the target microbe genome, but rare in the background genomes, to prime the highly processive phi29 polymerase. SWGA thus selectively amplifies the target genome from samples in which it originally represented a minor fraction of the total DNA. The post-SWGA samples are enriched in target genomic DNA, which are ideal for population resequencing. We demonstrate the efficacy of SWGA using both laboratory-prepared mixtures of cultured microbes as well as a natural host-microbe association. Targeted amplification of Borrelia burgdorferi mixed with Escherichia coli at genome ratios of 1:2000 resulted in >10(5)-fold amplification of the target genomes with genomic extracts from Wolbachia pipientis-infected Drosophila melanogaster resulted in up to 70% of high-throughput resequencing reads mapping to the W. pipientis genome. By contrast, 2-9% of sequencing reads were derived from W. pipientis without prior amplification. The SWGA technique results in high sequencing coverage at a fraction of the sequencing effort, thus allowing population genomic studies at affordable costs. Copyright © 2014 by the Genetics Society of America.

  18. Specific and selective target detection of supra-genome 21 Mers Salmonella via silicon nanowires biosensor

    Science.gov (United States)

    Mustafa, Mohammad Razif Bin; Dhahi, Th S.; Ehfaed, Nuri. A. K. H.; Adam, Tijjani; Hashim, U.; Azizah, N.; Mohammed, Mohammed; Noriman, N. Z.

    2017-09-01

    The nano structure based on silicon can be surface modified to be used as label-free biosensors that allow real-time measurements. The silicon nanowire surface was functionalized using 3-aminopropyltrimethoxysilane (APTES), which functions as a facilitator to immobilize biomolecules on the silicon nanowire surface. The process is simple, economical; this will pave the way for point-of-care applications. However, the surface modification and subsequent detection mechanism still not clear. Thus, study proposed step by step process of silicon nano surface modification and its possible in specific and selective target detection of Supra-genome 21 Mers Salmonella. The device captured the molecule with precisely; the approach took the advantages of strong binding chemistry created between APTES and biomolecule. The results indicated how modifications of the nanowires provide sensing capability with strong surface chemistries that can lead to specific and selective target detection.

  19. Designing the nanobiointerface of fluorescent nanodiamonds: highly selective targeting of glioma cancer cells.

    Science.gov (United States)

    Slegerova, Jitka; Hajek, Miroslav; Rehor, Ivan; Sedlak, Frantisek; Stursa, Jan; Hruby, Martin; Cigler, Petr

    2015-01-14

    Core-shell nanoparticles based on fluorescent nanodiamonds coated with a biocompatible N-(2-hydroxypropyl)methacrylamide copolymer shell were developed for background-free near-infrared imaging of cancer cells. The particles showed excellent colloidal stability in buffers and culture media. After conjugation with a cyclic RGD peptide they selectively targeted integrin αvβ3 receptors on glioblastoma cells with high internalization efficacy.

  20. Mature Epitope Density - A strategy for target selection based on immunoinformatics and exported prokaryotic proteins

    DEFF Research Database (Denmark)

    Santos, Anderson R; Pereira, Vanessa Bastos; Barbosa, Eudes

    2013-01-01

    . However, currently available tools do not account for the concentration of epitope products in the mature protein product and its relation to the reliability of target selection. RESULTS: We developed a computational strategy based on measuring the epitope's concentration in the mature protein, called...... Mature Epitope Density (MED). Our method, though simple, is capable of identifying promising vaccine targets. Our online software implementation provides a computationally light and reliable analysis of bacterial exoproteins and their potential for vaccines or diagnosis projects against pathogenic...... proteins were confirmed as related. There was no experimental evidence of antigenic or pathogenic contributions for three of the highest MED-scored Mtb proteins. Hence, these three proteins could represent novel putative vaccine and drug targets for Mtb. A web version of MED is publicly available online...

  1. Social comparisons in adults with type 2 diabetes: Patients' reasons for target selection.

    Science.gov (United States)

    Arigo, Danielle; Cornell, Max; Smyth, Joshua M

    2018-07-01

    To examine reasons for selecting a social comparison target (i.e. a specific other for relative self-evaluation), and their influence on affect and motivation for self-care, in type 2 diabetes (T2DM). Adults with T2DM (n = 180, M A1c  = 7.6%) chose to read about one of four targets. Participants rated five reasons for their choice (strongly disagree - strongly agree), and rated affect and self-care motivation before and after reading. To boost confidence in my ability to manage diabetes was rated highest overall (ps motivation (p motivation only among those who chose better-off targets (p = 0.01). Patients' reasons for a particular comparison are associated with short-term changes in affect and self-care motivation, and warrant greater empirical and clinical attention.

  2. Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase.

    Science.gov (United States)

    Keohane, Colleen E; Steele, Andrew D; Fetzer, Christian; Khowsathit, Jittasak; Van Tyne, Daria; Moynié, Lucile; Gilmore, Michael S; Karanicolas, John; Sieber, Stephan A; Wuest, William M

    2018-02-07

    Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa, a significant pathogen in clinical settings.

  3. The TESS Input Catalog and Selection of Targets for the TESS Transit Search

    Science.gov (United States)

    Pepper, Joshua; Stassun, Keivan G.; Paegert, Martin; Oelkers, Ryan; De Lee, Nathan Michael; Torres, Guillermo; TESS Target Selection Working Group

    2018-01-01

    The TESS mission will photometrically survey millions of the brightest stars over almost the entire the sky to detect transiting exoplanets. A key step to enable that search is the creation of the TESS Input Catalog (TIC), a compiled catalog of 700 million stars and galaxies with observed and calculated parameters. From the TIC we derive the Candidate Target List (CTL) to identify target stars for the 2-minute TESS postage stamps. The CTL is designed to identify the best stars for the detection of small planets, which includes all bright cool dwarf stars in the sky. I will describe the target selection strategy, the distribution of stars in the current CTL, and how both the TIC and CTL will expand and improve going forward.

  4. Targeting hunter distribution based on host resource selection and kill sites to manage disease risk.

    Science.gov (United States)

    Dugal, Cherie J; van Beest, Floris M; Vander Wal, Eric; Brook, Ryan K

    2013-10-01

    Endemic and emerging diseases are rarely uniform in their spatial distribution or prevalence among cohorts of wildlife. Spatial models that quantify risk-driven differences in resource selection and hunter mortality of animals at fine spatial scales can assist disease management by identifying high-risk areas and individuals. We used resource selection functions (RSFs) and selection ratios (SRs) to quantify sex- and age-specific resource selection patterns of collared (n = 67) and hunter-killed (n = 796) nonmigratory elk (Cervus canadensis manitobensis) during the hunting season between 2002 and 2012, in southwestern Manitoba, Canada. Distance to protected area was the most important covariate influencing resource selection and hunter-kill sites of elk (AICw = 1.00). Collared adult males (which are most likely to be infected with bovine tuberculosis (Mycobacterium bovis) and chronic wasting disease) rarely selected for sites outside of parks during the hunting season in contrast to adult females and juvenile males. The RSFs showed selection by adult females and juvenile males to be negatively associated with landscape-level forest cover, high road density, and water cover, whereas hunter-kill sites of these cohorts were positively associated with landscape-level forest cover and increasing distance to streams and negatively associated with high road density. Local-level forest was positively associated with collared animal locations and hunter-kill sites; however, selection was stronger for collared juvenile males and hunter-killed adult females. In instances where disease infects a metapopulation and eradication is infeasible, a principle goal of management is to limit the spread of disease among infected animals. We map high-risk areas that are regularly used by potentially infectious hosts but currently underrepresented in the distribution of kill sites. We present a novel application of widely available data to target hunter distribution based on host resource

  5. Retroviral DNA integration: viral and cellular determinants of target-site selection.

    Directory of Open Access Journals (Sweden)

    Mary K Lewinski

    2006-06-01

    Full Text Available Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV integrates preferentially within active transcription units, whereas murine leukemia virus (MLV integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN coding region into HIV (to make HIVmIN caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I-hypersensitive sites (i.e., +/- 1 kb, and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins.

  6. Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation

    Directory of Open Access Journals (Sweden)

    Sven Kruspe

    2014-01-01

    Full Text Available Photodynamic therapy (PDT uses the therapeutic properties of light in combination with certain chemicals, called photosensitizers, to successfully treat brain, breast, prostate, and skin cancers. To improve PDT, current research focuses on the development of photosensitizers to specifically target cancer cells. In the past few years, aptamers have been developed to directly deliver cargo molecules into target cells. We conjugated the photosensitizer chlorin e6 (ce6 with a human interleukin-6 receptor (IL-6R binding RNA aptamer, AIR-3A yielding AIR-3A-ce6 for application in high efficient PDT. AIR-3A-ce6 was rapidly and specifically internalized by IL-6R presenting (IL-6R+ cells. Upon light irradiation, targeted cells were selectively killed, while free ce6 did not show any toxic effect. Cells lacking the IL-6R were also not affected by AIR-3A-ce6. With this approach, we improved the target specificity of ce6-mediated PDT. In the future, other tumor-specific aptamers might be used to selectively localize photosensitizers into cells of interest and improve the efficacy and specificity of PDT in cancer and other diseases.

  7. Selection of RIB targets using ion implantation at the Holifield radioactive ion beam facility

    International Nuclear Information System (INIS)

    Alton, G.D.; Dellwo, J.

    1995-01-01

    Among several major challenges posed by generating and accelerating adequate intensities of RIBs, selection of the most appropriate target material is perhaps the most difficult because of the requisite fast and selective thermal release of minute amounts of the short-lived product atoms from the ISOL target in the presence of bulk amounts of target material. Experimental studies are under way at the Oak Ridge National Laboratory (ORNL) which are designed to measure the time evolution of implanted elements diffused from refractory target materials which are candidates for forming radioactive ion beams (RIBs) at the Holifield Radioactive Ion Beam Facility (HRIBF). The diffusion coefficients are derived by comparing experimental data with numerical solutions to a one-dimensional form of Fick's second law for ion implanted distributions. In this report, we describe the experimental arrangement, experimental procedures, and provide time release data and diffusion coefficients for releasing ion implanted 37 Cl from Zr 5 Si 3 and 75 As, 79 Br, and 78 Se from Zr 5 Ge 3 and estimates of the diffusion coefficients for 35 Cl, 63 Cu, 65 Cu, 69 Ga and 71 Ga diffused from BN; 35 Cl, 63 Cu, 65 Cu, 69 Ga, 75 As, and 78 Se diffused from C; 35 Cl, 68 Cu, 69 Ga, 75 As, and 78 Se diffused from Ta

  8. Efficient and Adaptive Node Selection for Target Tracking in Wireless Sensor Network

    Directory of Open Access Journals (Sweden)

    Juan Feng

    2016-01-01

    Full Text Available In target tracking wireless sensor network, choosing the proper working nodes can not only minimize the number of active nodes, but also satisfy the tracking reliability requirement. However, most existing works focus on selecting sensor nodes which are the nearest to the target for tracking missions and they did not consider the correlation of the location of the sensor nodes so that these approaches can not meet all the goals of the network. This work proposes an efficient and adaptive node selection approach for tracking a target in a distributed wireless sensor network. The proposed approach combines the distance-based node selection strategy and particle filter prediction considering the spatial correlation of the different sensing nodes. Moreover, a joint distance weighted measurement is proposed to estimate the information utility of sensing nodes. Experimental results show that EANS outperformed the state-of-the-art approaches by reducing the energy cost and computational complexity as well as guaranteeing the tracking accuracy.

  9. Merger and Acquisition Target Selection Based on Interval Neutrosophic Multigranulation Rough Sets over Two Universes

    Directory of Open Access Journals (Sweden)

    Chao Zhang

    2017-07-01

    Full Text Available As a significant business activity, merger and acquisition (M&A generally means transactions in which the ownership of companies, other business organizations or their operating units are transferred or combined. In a typical M&A procedure, M&A target selection is an important issue that tends to exert an increasingly significant impact on different business areas. Although some research works based on fuzzy methods have been explored on this issue, they can only deal with incomplete and uncertain information, but not inconsistent and indeterminate information that exists universally in the decision making process. Additionally, it is advantageous to solve M&A problems under the group decision making context. In order to handle these difficulties in M&A target selection background, we introduce a novel rough set model by combining interval neutrosophic sets (INSs with multigranulation rough sets over two universes, called an interval neutrosophic (IN multigranulation rough set over two universes. Then, we discuss the definition and some fundamental properties of the proposed model. Finally, we establish decision making rules and computing approaches for the proposed model in M&A target selection background, and the effectiveness of the decision making approach is demonstrated by an illustrative case analysis.

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

    Science.gov (United States)

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

    2016-01-22

    Increasing antibacterial resistance presents a major challenge in antibiotic discovery. One attractive target in Gram-negative bacteria is the unique asymmetric outer membrane (OM), which acts as a permeability barrier that protects the cell from external stresses, such as the presence of antibiotics. We describe a novel β-hairpin macrocyclic peptide JB-95 with potent antimicrobial activity against Escherichia coli. This peptide exhibits no cellular lytic activity, but electron microscopy and fluorescence studies reveal an ability to selectively disrupt the OM but not the inner membrane of E. coli. The selective targeting of the OM probably occurs through interactions of JB-95 with selected β-barrel OM proteins, including BamA and LptD as shown by photolabeling experiments. Membrane proteomic studies reveal rapid depletion of many β-barrel OM proteins from JB-95-treated E. coli, consistent with induction of a membrane stress response and/or direct inhibition of the Bam folding machine. The results suggest that lethal disruption of the OM by JB-95 occurs through a novel mechanism of action at key interaction sites within clusters of β-barrel proteins in the OM. These findings open new avenues for developing antibiotics that specifically target β-barrel proteins and the integrity of the Gram-negative OM. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Selective autophagy of non-ubiquitylated targets in plants: looking for cognate receptor/adaptor proteins

    Directory of Open Access Journals (Sweden)

    Vasko eVeljanovski

    2014-06-01

    Full Text Available Cellular homeostasis is essential for the physiology of eukaryotic cells. Eukaryotic cells, including plant cells, utilize two main pathways to adjust the level of cytoplasmic components, namely the proteasomal and the lysosomal/vacuolar pathways. Macroautophagy is a lysosomal/vacuolar pathway which, until recently, was thought to be non-specific and a bulk degradation process. However, selective autophagy which can be activated in the cell under various physiological conditions, involves the specific degradation of defined macromolecules or organelles by a conserved molecular mechanism. For this process to be efficient, the mechanisms underlying the recognition and selection of the cargo to be engulfed by the double-membrane autophagosome are critical, and not yet well understood. Ubiquitin (poly-ubiquitin conjugation to the target appears to be a conserved ligand mechanism in many types of selective autophagy, and defined receptors/adaptors recognizing and regulating the autophagosomal capture of the ubiquitylated target have been characterized. However, non-proteinaceous and non-ubiquitylated cargoes are also selectively degraded by this pathway. This ubiquitin-independent selective autophagic pathway also involves receptor and/or adaptor proteins linking the cargo to the autophagic machinery. Some of these receptor/adaptor proteins including accessory autophagy-related (Atg and non-Atg proteins have been described in yeast and animal cells but not yet in plants. In this review we discuss the ubiquitin-independent cargo selection mechanisms in selective autophagy degradation of organelles and macromolecules and speculate on potential plant receptor/adaptor proteins.

  12. THE SDSS-III BARYON OSCILLATION SPECTROSCOPIC SURVEY: QUASAR TARGET SELECTION FOR DATA RELEASE NINE

    Energy Technology Data Exchange (ETDEWEB)

    Ross, Nicholas P.; Kirkpatrick, Jessica A.; Carithers, William C.; Ho, Shirley [Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720 (United States); Myers, Adam D. [Department of Astronomy, MC-221, University of Illinois, 1002 West Green Street, Urbana, IL 61801 (United States); Sheldon, Erin S. [Brookhaven National Laboratory, Blgd 510, Upton, NY 11375 (United States); Yeche, Christophe; Aubourg, Eric [CEA, Centre de Saclay, IRFU, 91191 Gif-sur-Yvette (France); Strauss, Michael A.; Lee, Khee-Gan [Department of Astrophysical Sciences, Princeton University, Princeton, NJ 08544 (United States); Bovy, Jo; Blanton, Michael R.; Hogg, David W. [Center for Cosmology and Particle Physics, New York University, 4 Washington Place, New York, NY 10003 (United States); Richards, Gordon T. [Department of Physics, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104 (United States); Brandt, W. N. [Department of Astronomy and Astrophysics, The Pennsylvania State University, 525 Davey Laboratory, University Park, PA 16802 (United States); Croft, Rupert A. C. [Bruce and Astrid McWilliams Center for Cosmology, Carnegie Mellon University, Pittsburgh, PA 15213 (United States); Da Silva, Robert [Department of Astronomy and Astrophysics, University of California, Santa Cruz, Santa Cruz, CA 95064 (United States); Dawson, Kyle [Department of Physics and Astronomy, University of Utah, UT (United States); Eisenstein, Daniel J. [Steward Observatory, 933 North Cherry Avenue, Tucson, AZ 85721 (United States); Hennawi, Joseph F., E-mail: npross@lbl.gov [Max-Planck-Institut fuer Astronomie, Konigstuhl 17, 69117 Heidelberg (Germany); and others

    2012-03-01

    The SDSS-III Baryon Oscillation Spectroscopic Survey (BOSS), a five-year spectroscopic survey of 10,000 deg{sup 2}, achieved first light in late 2009. One of the key goals of BOSS is to measure the signature of baryon acoustic oscillations (BAOs) in the distribution of Ly{alpha} absorption from the spectra of a sample of {approx}150,000 z > 2.2 quasars. Along with measuring the angular diameter distance at z Almost-Equal-To 2.5, BOSS will provide the first direct measurement of the expansion rate of the universe at z > 2. One of the biggest challenges in achieving this goal is an efficient target selection algorithm for quasars in the redshift range 2.2 < z < 3.5, where their colors tend to overlap those of the far more numerous stars. During the first year of the BOSS survey, quasar target selection (QTS) methods were developed and tested to meet the requirement of delivering at least 15 quasars deg{sup -2} in this redshift range, with a goal of 20 out of 40 targets deg{sup -2} allocated to the quasar survey. To achieve these surface densities, the magnitude limit of the quasar targets was set at g {<=} 22.0 or r {<=} 21.85. While detection of the BAO signature in the distribution of Ly{alpha} absorption in quasar spectra does not require a uniform target selection algorithm, many other astrophysical studies do. We have therefore defined a uniformly selected subsample of 20 targets deg{sup -2}, for which the selection efficiency is just over 50% ({approx}10 z > 2.20 quasars deg{sup -2}). This 'CORE' subsample will be fixed for Years Two through Five of the survey. For the remaining 20 targets deg{sup -2}, we will continue to develop improved selection techniques, including the use of additional data sets beyond the Sloan Digital Sky Survey (SDSS) imaging data. In this paper, we describe the evolution and implementation of the BOSS QTS algorithms during the first two years of BOSS operations (through 2011 July), in support of the science investigations

  13. Target Selection and Deselection at the Berkeley StructuralGenomics Center

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Kim, Sung-Hou; Brenner, Steven E.

    2005-03-22

    At the Berkeley Structural Genomics Center (BSGC), our goalis to obtain a near-complete structural complement of proteins in theminimal organisms Mycoplasma genitalium and M. pneumoniae, two closelyrelated pathogens. Current targets for structure determination have beenselected in six major stages, starting with those predicted to be mosttractable to high throughput study and likely to yield new structuralinformation. We report on the process used to select these proteins, aswell as our target deselection procedure. Target deselection reducesexperimental effort by eliminating targets similar to those recentlysolved by the structural biology community or other centers. We measurethe impact of the 69 structures solved at the BSGC as of July 2004 onstructure prediction coverage of the M. pneumoniae and M. genitaliumproteomes. The number of Mycoplasma proteins for which thefold couldfirst be reliably assigned based on structures solved at the BSGC (24 M.pneumoniae and 21 M. genitalium) is approximately 25 percent of the totalresulting from work at all structural genomics centers and the worldwidestructural biology community (94 M. pneumoniae and 86M. genitalium)during the same period. As the number of structures contributed by theBSGC during that period is less than 1 percent of the total worldwideoutput, the benefits of a focused target selection strategy are apparent.If the structures of all current targets were solved, the percentage ofM. pneumoniae proteins for which folds could be reliably assigned wouldincrease from approximately 57 percent (391 of 687) at present to around80 percent (550 of 687), and the percentage of the proteome that could beaccurately modeled would increase from around 37 percent (254 of 687) toabout 64 percent (438 of 687). In M. genitalium, the percentage of theproteome that could be structurally annotated based on structures of ourremaining targets would rise from 72 percent (348 of 486) to around 76percent (371 of 486), with the

  14. Implications of structural genomics target selection strategies: Pfam5000, whole genome, and random approaches

    Energy Technology Data Exchange (ETDEWEB)

    Chandonia, John-Marc; Brenner, Steven E.

    2004-07-14

    The structural genomics project is an international effort to determine the three-dimensional shapes of all important biological macromolecules, with a primary focus on proteins. Target proteins should be selected according to a strategy which is medically and biologically relevant, of good value, and tractable. As an option to consider, we present the Pfam5000 strategy, which involves selecting the 5000 most important families from the Pfam database as sources for targets. We compare the Pfam5000 strategy to several other proposed strategies that would require similar numbers of targets. These include including complete solution of several small to moderately sized bacterial proteomes, partial coverage of the human proteome, and random selection of approximately 5000 targets from sequenced genomes. We measure the impact that successful implementation of these strategies would have upon structural interpretation of the proteins in Swiss-Prot, TrEMBL, and 131 complete proteomes (including 10 of eukaryotes) from the Proteome Analysis database at EBI. Solving the structures of proteins from the 5000 largest Pfam families would allow accurate fold assignment for approximately 68 percent of all prokaryotic proteins (covering 59 percent of residues) and 61 percent of eukaryotic proteins (40 percent of residues). More fine-grained coverage which would allow accurate modeling of these proteins would require an order of magnitude more targets. The Pfam5000 strategy may be modified in several ways, for example to focus on larger families, bacterial sequences, or eukaryotic sequences; as long as secondary consideration is given to large families within Pfam, coverage results vary only slightly. In contrast, focusing structural genomics on a single tractable genome would have only a limited impact in structural knowledge of other proteomes: a significant fraction (about 30-40 percent of the proteins, and 40-60 percent of the residues) of each proteome is classified in small

  15. The diffusion properties of ion implanted species in selected target materials

    International Nuclear Information System (INIS)

    Alton, G.D.; Dellwo, J.; Carter, H.K.; Kormicki, J.; Bartolo, G. di; Batchelder, J.C.; Breitenbach, J.; Chediak, J.A.; Jentoff-Nilsen, K.; Ichikawa, S.

    1995-01-01

    Experiments important to the future success of the Holifield Radioactive Ion Beam Facility (HRIBF) are in progress at the Oak Ridge National Laboratory which are designed to select the most appropriate target material for generating a particular radioactive ion beam (RIB). The 25-MV HHIRF tandem accelerator is used to implant stable complements of interesting radioactive elements into refractory targets mounted in a high-temperature FEBIAD ion source which is open-quotes on-lineclose quotes at the UNISOR facility. The intensity versus time of implanted species, which diffuse from the high-temperature target material (∼1700 degrees C) and are ionized in the FEBIAD ion source, is used to determine release times for a particular projectile/target material combination. From such release data, diffusion coefficients can be derived by fitting the theoretical results obtained by computational solution of Fick's second equation to experimental data. The diffusion coefficient can be used subsequently to predict the release properties of the particular element from the same material in other target geometries and at other temperatures, provided that the activation energy is also known. Diffusion coefficients for Cl implanted into and diffused from CeS and Zr 5 Si 3 and As, Br, and Se implanted into and diffused from Zr 5 Ge 3 have been derived from the resulting intensity versus time profiles. Brief descriptions of the experimental apparatus and procedures utilized in the present experiments and plans for future related experiments are presented

  16. Selective Inhibition of Histone Deacetylation in Melanoma Increases Targeted Gene Delivery by a Bacteriophage Viral Vector

    Directory of Open Access Journals (Sweden)

    Samuel Campbell

    2018-04-01

    Full Text Available The previously developed adeno-associated virus/phage (AAVP vector, a hybrid between M13 bacteriophage (phage viruses that infect bacteria only and human Adeno-Associated Virus (AAV, is a promising tool in targeted gene therapy against cancer. AAVP can be administered systemically and made tissue specific through the use of ligand-directed targeting. Cancer cells and tumor-associated blood vessels overexpress the αν integrin receptors, which are involved in tumor angiogenesis and tumor invasion. AAVP is targeted to these integrins via a double cyclic RGD4C ligand displayed on the phage capsid. Nevertheless, there remain significant host-defense hurdles to the use of AAVP in targeted gene delivery and subsequently in gene therapy. We previously reported that histone deacetylation in cancer constitutes a barrier to AAVP. Herein, to improve AAVP-mediated gene delivery to cancer cells, we combined the vector with selective adjuvant chemicals that inhibit specific histone deacetylases (HDAC. We examined the effects of the HDAC inhibitor C1A that mainly targets HDAC6 and compared this to sodium butyrate, a pan-HDAC inhibitor with broad spectrum HDAC inhibition. We tested the effects on melanoma, known for HDAC6 up-regulation, and compared this side by side with a normal human kidney HEK293 cell line. Varying concentrations were tested to determine cytotoxic levels as well as effects on AAVP gene delivery. We report that the HDAC inhibitor C1A increased AAVP-mediated transgene expression by up to ~9-fold. These findings indicate that selective HDAC inhibition is a promising adjuvant treatment for increasing the therapeutic value of AAVP.

  17. A dual selection based, targeted gene replacement tool for Magnaporthe grisea and Fusarium oxysporum.

    Science.gov (United States)

    Khang, Chang Hyun; Park, Sook-Young; Lee, Yong-Hwan; Kang, Seogchan

    2005-06-01

    Rapid progress in fungal genome sequencing presents many new opportunities for functional genomic analysis of fungal biology through the systematic mutagenesis of the genes identified through sequencing. However, the lack of efficient tools for targeted gene replacement is a limiting factor for fungal functional genomics, as it often necessitates the screening of a large number of transformants to identify the desired mutant. We developed an efficient method of gene replacement and evaluated factors affecting the efficiency of this method using two plant pathogenic fungi, Magnaporthe grisea and Fusarium oxysporum. This method is based on Agrobacterium tumefaciens-mediated transformation with a mutant allele of the target gene flanked by the herpes simplex virus thymidine kinase (HSVtk) gene as a conditional negative selection marker against ectopic transformants. The HSVtk gene product converts 5-fluoro-2'-deoxyuridine to a compound toxic to diverse fungi. Because ectopic transformants express HSVtk, while gene replacement mutants lack HSVtk, growing transformants on a medium amended with 5-fluoro-2'-deoxyuridine facilitates the identification of targeted mutants by counter-selecting against ectopic transformants. In addition to M. grisea and F. oxysporum, the method and associated vectors are likely to be applicable to manipulating genes in a broad spectrum of fungi, thus potentially serving as an efficient, universal functional genomic tool for harnessing the growing body of fungal genome sequence data to study fungal biology.

  18. Perceptions of similarity and response to selected comparison targets in type 2 diabetes.

    Science.gov (United States)

    Arigo, Danielle; Smyth, Joshua M; Suls, Jerry M

    2015-01-01

    Social comparisons (i.e. self-evaluations relative to others) may affect motivation for diabetes self-care behaviours. Comparisons can have either positive or negative effects, but it is not clear what differentiates these responses. This study tested the effect of a patient's perceived similarity to a comparison target on motivation for self-care. Individuals with type 2 diabetes (n = 180, MA1c = 7.59%) selected to read one of four brief descriptions of a patient with diabetes. Participants rated their motivation for self-care behaviours prior and subsequent to reading and reported the extent to which they focused on similarities between the self and the selected patient while reading. Perceived similarity moderated the effect of selection on motivation for self-care (p = .01, η2 = .06). Increased motivation was observed if participants focused on similarities with patients 'doing better' (i.e. high coping effectiveness/low symptom severity) and decreased motivation if they focused on similarities with patients 'doing worse' (low coping effectiveness/high symptom severity). Providing social comparison information in diabetes management (and perhaps other chronic diseases) may improve motivation for self-care among some patients. A subset of patients, however, may benefit from guidance to focus on similarities with certain targets.

  19. Antisense oligonucleotides targeting translation inhibitory elements in 5' UTRs can selectively increase protein levels.

    Science.gov (United States)

    Liang, Xue-Hai; Sun, Hong; Shen, Wen; Wang, Shiyu; Yao, Joyee; Migawa, Michael T; Bui, Huynh-Hoa; Damle, Sagar S; Riney, Stan; Graham, Mark J; Crooke, Rosanne M; Crooke, Stanley T

    2017-09-19

    A variety of diseases are caused by deficiencies in amounts or activity of key proteins. An approach that increases the amount of a specific protein might be of therapeutic benefit. We reasoned that translation could be specifically enhanced using trans-acting agents that counter the function of negative regulatory elements present in the 5' UTRs of some mRNAs. We recently showed that translation can be enhanced by antisense oligonucleotides (ASOs) that target upstream open reading frames. Here we report the amount of a protein can also be selectively increased using ASOs designed to hybridize to other translation inhibitory elements in 5' UTRs. Levels of human RNASEH1, LDLR, and ACP1 and of mouse ACP1 and ARF1 were increased up to 2.7-fold in different cell types and species upon treatment with chemically modified ASOs targeting 5' UTR inhibitory regions in the mRNAs encoding these proteins. The activities of ASOs in enhancing translation were sequence and position dependent and required helicase activity. The ASOs appear to improve the recruitment of translation initiation factors to the target mRNA. Importantly, ASOs targeting ACP1 mRNA significantly increased the level of ACP1 protein in mice, suggesting that this approach has therapeutic and research potentials. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  20. "Killer" Microcapsules That Can Selectively Destroy Target Microparticles in Their Vicinity.

    Science.gov (United States)

    Arya, Chandamany; Oh, Hyuntaek; Raghavan, Srinivasa R

    2016-11-02

    We have developed microscale polymer capsules that are able to chemically degrade a certain type of polymeric microbead in their immediate vicinity. The inspiration here is from the body's immune system, where killer T cells selectively destroy cancerous cells or cells infected by pathogens while leaving healthy cells alone. The "killer" capsules are made from the cationic biopolymer chitosan by a combination of ionic cross-linking (using multivalent tripolyposphate anions) and subsequent covalent cross-linking (using glutaraldehyde). During capsule formation, the enzyme glucose oxidase (GOx) is encapsulated in these capsules. The target beads are made by ionic cross-linking of the biopolymer alginate using copper (Cu 2+ ) cations. The killer capsules harvest glucose from their surroundings, which is then enzymatically converted by GOx into gluconate ions. These ions are known for their ability to chelate Cu 2+ cations. Thus, when a killer capsule is next to a target alginate bead, the gluconate ions diffuse into the bead and extract the Cu 2+ cross-links, causing the disintegration of the target bead. Such destruction is visualized in real-time using optical microscopy. The destruction is specific, i.e., other microparticles that do not contain Cu 2+ are left undisturbed. Moreover, the destruction is localized, i.e., the targets destroyed in the short term are the ones right next to the killer beads. The time scale for destruction depends on the concentration of encapsulated enzyme in the capsules.

  1. Selection of target mutation in rat gastrointestinal tract E. coli by minute dosage of enrofloxacin.

    Science.gov (United States)

    Lin, Dachuan; Chen, Kaichao; Li, Ruichao; Liu, Lizhang; Guo, Jiubiao; Yao, Wen; Chen, Sheng

    2014-01-01

    It has been suggested that bacterial resistance is selected within a mutation selection window of antibiotics. More recent studies showed that even extremely low concentration of antibiotic could select resistant bacteria in vitro. Yet little is known about the exact antibiotic concentration range that can effectively select for resistant organisms in animal gastrointestinal (GI) tract. In this study, the effect of different dosages of enrofloxacin on resistance and mutation development in rat GI tract E. coli was investigated by determining the number of resistant E. coli recoverable from rat fecal samples. Our data showed that high dose antibiotic treatment could effectively eliminate E. coli with single gyrA mutation in the early course of treatment, yet the eradication effects diminished upon prolonged treatment. Therapeutic and sub-therapeutic dose (1/10 and 1/100 of therapeutic doses) of enrofloxacin could effectively select for mutation in GI tract E. coli at the later course of enrofloxacin treatment and during the cessation periods. Surprisingly, very low dose of enrofloxacin (1/1000 therapeutic dose) could also select for mutation in GI tract E. coli at the later course of enrofloxacin treatment, only with slightly lower efficiency. No enrofloxacin-resistant E. coli could be selected at all test levels of enrofloxacin during long term treatment and the strength of antibiotic treatment does not alter the overall level of E. coli in rat GI tract. This study demonstrated that long term antibiotic treatment seems to be the major trigger for the development of target mutations in GI tract E. coli, which provided insight into the rational use of antibiotics in animal husbandry.

  2. Target selection and mass estimation for manned NEO exploration using a baseline mission design

    Science.gov (United States)

    Boden, Ralf C.; Hein, Andreas M.; Kawaguchi, Junichiro

    2015-06-01

    In recent years Near-Earth Objects (NEOs) have received an increased amount of interest as a target for human exploration. NEOs offer scientifically interesting targets, and at the same time function as a stepping stone for achieving future Mars missions. The aim of this research is to identify promising targets from the large number of known NEOs that qualify for a manned sample-return mission with a maximum duration of one year. By developing a baseline mission design and a mass estimation model, mission opportunities are evaluated based on on-orbit mass requirements, safety considerations, and the properties of the potential targets. A selection of promising NEOs is presented and the effects of mission requirements and restrictions are discussed. Regarding safety aspects, the use of free-return trajectories provides the lowest on-orbit mass, when compared to an alternative design that uses system redundancies to ensure return of the spacecraft to Earth. It is discovered that, although a number of targets are accessible within the analysed time frame, no NEO offers both easy access and high incentive for its exploration. Under the discussed aspects a first human exploration mission going beyond the vicinity of Earth will require a trade off between targets that provide easy access and those that are of scientific interest. This lack of optimal mission opportunities can be seen in the small number of only 4 NEOs that meet all requirements for a sample-return mission and remain below an on-orbit mass of 500 metric Tons (mT). All of them require a mass between 315 and 492 mT. Even less ideal, smaller asteroids that are better accessible require an on-orbit mass that exceeds the launch capability of future heavy lift vehicles (HLV) such as SLS by at least 30 mT. These mass requirements show that additional efforts are necessary to increase the number of available targets and reduce on-orbit mass requirements through advanced mission architectures. The need for on

  3. Target-matched insertion gain derived from three different hearing aid selection procedures.

    Science.gov (United States)

    Punch, J L; Shovels, A H; Dickinson, W W; Calder, J H; Snead, C

    1995-11-01

    Three hearing aid selection procedures were compared to determine if any one was superior in producing prescribed real-ear insertion gain. For each of three subject groups, 12 in-the-ear style hearing aids with Class D circuitry and similar dispenser controls were ordered from one of three manufacturers. Subject groups were classified based on the type of information included on the hearing aid order form: (1) the subject's audiogram, (2) a three-part matrix specifying the desired maximum output, full-on gain, and frequency response slope of the hearing aid, or (3) the desired 2-cc coupler full-in grain of the hearing aid, based on real-ear coupler difference (RECD) measurements. Following electroacoustic adjustments aimed at approximating a commonly used target insertion gain formula, results revealed no significant differences among any of the three selection procedures with respect to obtaining acceptable insertion gain values.

  4. Rapid and targeted introgression of genes into popular wheat cultivars using marker-assisted background selection.

    Directory of Open Access Journals (Sweden)

    Harpinder S Randhawa

    Full Text Available A marker-assisted background selection (MABS-based gene introgression approach in wheat (Triticum aestivum L. was optimized, where 97% or more of a recurrent parent genome (RPG can be recovered in just two backcross (BC generations. A four-step MABS method was developed based on 'Plabsim' computer simulations and wheat genome structure information. During empirical optimization of this method, double recombinants around the target gene were selected in a step-wise fashion during the two BC cycles followed by selection for recurrent parent genotype on non-carrier chromosomes. The average spacing between carrier chromosome markers was <4 cM. For non-carrier chromosome markers that flanked each of the 48 wheat gene-rich regions, this distance was approximately 12 cM. Employed to introgress seedling stripe rust (Puccinia striiformis f. sp. tritici resistance gene Yr15 into the spring wheat cultivar 'Zak', marker analysis of 2,187 backcross-derived progeny resulted in the recovery of a BC(2F(2ratio3 plant with 97% of the recurrent parent genome. In contrast, only 82% of the recurrent parent genome was recovered in phenotypically selected BC(4F(7 plants developed without MABS. Field evaluation results from 17 locations indicated that the MABS-derived line was either equal or superior to the recurrent parent for the tested agronomic characteristics. Based on these results, MABS is recommended as a strategy for rapidly introgressing a targeted gene into a wheat genotype in just two backcross generations while recovering 97% or more of the recurrent parent genotype.

  5. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

    International Nuclear Information System (INIS)

    Han, Seula; Woo, Jong Kyu; Jung, Yuchae; Jeong, Dawoon; Kang, Minsook; Yoo, Young-Ji; Lee, Hani; Oh, Seung Hyun; Ryu, Jae-Ha; Kim, Woo-Young

    2016-01-01

    In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulk cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer. - Highlights: • Evodiamine selectively kills breast cancer stem like cells at G1 phase. • Evodiamine utilizes different mechanism of cell cycle modulation in CSLC and in bulk cancer cells. • Evodiamine activate the p53, p21 and Rb pathway.

  6. Evodiamine selectively targets cancer stem-like cells through the p53-p21-Rb pathway

    Energy Technology Data Exchange (ETDEWEB)

    Han, Seula [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Woo, Jong Kyu [College of Pharmacy, Gachon University, Incheon (Korea, Republic of); Jung, Yuchae; Jeong, Dawoon; Kang, Minsook; Yoo, Young-Ji; Lee, Hani [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Oh, Seung Hyun [College of Pharmacy, Gachon University, Incheon (Korea, Republic of); Ryu, Jae-Ha [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of); Kim, Woo-Young, E-mail: wykim@sookmyung.ac.kr [The Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul (Korea, Republic of)

    2016-01-22

    In spite of the recent improvements, the resistance to chemotherapy/radiotherapy followed by relapse is the main hurdle for the successful treatment of breast cancer, a leading cause of death in women. A small population of breast cancer cells that have stem-like characteristics (cancer stem-like cells; CSLC) may contribute to this resistance and relapse. Here, we report on a component of a traditional Chinese medicine, evodiamine, which selectively targets CSLC of breast cancer cell lines MCF7 and MDAMB 231 at a concentration that does show a little or no cytotoxic effect on bulk cancer cells. While evodiamine caused the accumulation of bulk cancer cells at the G2/M phase, it did not hold CSLC in a specific cell cycle phase but instead, selectively killed CSLC. This was not due to the culture of CSLC in suspension or without FBS. A proteomic analysis and western blotting revealed that evodiamine changed the expression of cell cycle regulating molecules more efficiently in CSLC cells than in bulk cancer cells. Surprisingly, evodiamine selectively activated p53 and p21 and decreased inactive Rb, the master molecules in G1/S checkpoint. These data collectively suggest a novel mechanism involving CSLC-specific targeting by evodiamine and its possible use to the therapy of breast cancer. - Highlights: • Evodiamine selectively kills breast cancer stem like cells at G1 phase. • Evodiamine utilizes different mechanism of cell cycle modulation in CSLC and in bulk cancer cells. • Evodiamine activate the p53, p21 and Rb pathway.

  7. Criteria for selection of target materials and design of high-efficiency-release targets for radioactive ion beam generation

    CERN Document Server

    Alton, G D; Liu, Y

    1999-01-01

    In this report, we define criteria for choosing target materials and for designing, mechanically stable, short-diffusion-length, highly permeable targets for generation of high-intensity radioactive ion beams (RIBs) for use at nuclear physics and astrophysics research facilities based on the ISOL principle. In addition, lists of refractory target materials are provided and examples are given of a number of successful targets, based on these criteria, that have been fabricated and tested for use at the Holifield Radioactive Ion Beam Facility (HRIBF).

  8. The selective processing of emotional visual stimuli while detecting auditory targets: an ERP analysis.

    Science.gov (United States)

    Schupp, Harald T; Stockburger, Jessica; Bublatzky, Florian; Junghöfer, Markus; Weike, Almut I; Hamm, Alfons O

    2008-09-16

    Event-related potential studies revealed an early posterior negativity (EPN) for emotional compared to neutral pictures. Exploring the emotion-attention relationship, a previous study observed that a primary visual discrimination task interfered with the emotional modulation of the EPN component. To specify the locus of interference, the present study assessed the fate of selective visual emotion processing while attention is directed towards the auditory modality. While simply viewing a rapid and continuous stream of pleasant, neutral, and unpleasant pictures in one experimental condition, processing demands of a concurrent auditory target discrimination task were systematically varied in three further experimental conditions. Participants successfully performed the auditory task as revealed by behavioral performance and selected event-related potential components. Replicating previous results, emotional pictures were associated with a larger posterior negativity compared to neutral pictures. Of main interest, increasing demands of the auditory task did not modulate the selective processing of emotional visual stimuli. With regard to the locus of interference, selective emotion processing as indexed by the EPN does not seem to reflect shared processing resources of visual and auditory modality.

  9. Selective Targeting of SH2 Domain–Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies

    Energy Technology Data Exchange (ETDEWEB)

    Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

    2017-05-01

    The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody–SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells.

  10. Selective Targeting of SH2 Domain-Phosphotyrosine Interactions of Src Family Tyrosine Kinases with Monobodies.

    Science.gov (United States)

    Kükenshöner, Tim; Schmit, Nadine Eliane; Bouda, Emilie; Sha, Fern; Pojer, Florence; Koide, Akiko; Seeliger, Markus; Koide, Shohei; Hantschel, Oliver

    2017-05-05

    The binding of Src-homology 2 (SH2) domains to phosphotyrosine (pY) sites is critical for the autoinhibition and substrate recognition of the eight Src family kinases (SFKs). The high sequence conservation of the 120 human SH2 domains poses a significant challenge to selectively perturb the interactions of even the SFK SH2 family against the rest of the SH2 domains. We have developed synthetic binding proteins, termed monobodies, for six of the SFK SH2 domains with nanomolar affinity. Most of these monobodies competed with pY ligand binding and showed strong selectivity for either the SrcA (Yes, Src, Fyn, Fgr) or SrcB subgroup (Lck, Lyn, Blk, Hck). Interactome analysis of intracellularly expressed monobodies revealed that they bind SFKs but no other SH2-containing proteins. Three crystal structures of monobody-SH2 complexes unveiled different and only partly overlapping binding modes, which rationalized the observed selectivity and enabled structure-based mutagenesis to modulate inhibition mode and selectivity. In line with the critical roles of SFK SH2 domains in kinase autoinhibition and T-cell receptor signaling, monobodies binding the Src and Hck SH2 domains selectively activated respective recombinant kinases, whereas an Lck SH2-binding monobody inhibited proximal signaling events downstream of the T-cell receptor complex. Our results show that SFK SH2 domains can be targeted with unprecedented potency and selectivity using monobodies. They are excellent tools for dissecting SFK functions in normal development and signaling and to interfere with aberrant SFK signaling networks in cancer cells. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  11. Sejong Open Cluster Survey (SOS). 0. Target Selection and Data Analysis

    Science.gov (United States)

    Sung, Hwankyung; Lim, Beomdu; Bessell, Michael S.; Kim, Jinyoung S.; Hur, Hyeonoh; Chun, Moo-Young; Park, Byeong-Gon

    2013-06-01

    Star clusters are superb astrophysical laboratories containing cospatial and coeval samples of stars with similar chemical composition. We initiate the Sejong Open cluster Survey (SOS) - a project dedicated to providing homogeneous photometry of a large number of open clusters in the SAAO Johnson-Cousins' UBVI system. To achieve our main goal, we pay much attention to the observation of standard stars in order to reproduce the SAAO standard system. Many of our targets are relatively small sparse clusters that escaped previous observations. As clusters are considered building blocks of the Galactic disk, their physical properties such as the initial mass function, the pattern of mass segregation, etc. give valuable information on the formation and evolution of the Galactic disk. The spatial distribution of young open clusters will be used to revise the local spiral arm structure of the Galaxy. In addition, the homogeneous data can also be used to test stellar evolutionary theory, especially concerning rare massive stars. In this paper we present the target selection criteria, the observational strategy for accurate photometry, and the adopted calibrations for data analysis such as color-color relations, zero-age main sequence relations, Sp - M_V relations, Sp - T_{eff} relations, Sp - color relations, and T_{eff} - BC relations. Finally we provide some data analysis such as the determination of the reddening law, the membership selection criteria, and distance determination.

  12. Advancing the sensitivity of selected reaction monitoring-based targeted quantitative proteomics

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Tujin; Su, Dian; Liu, Tao; Tang, Keqi; Camp, David G.; Qian, Weijun; Smith, Richard D.

    2012-04-01

    Selected reaction monitoring (SRM)—also known as multiple reaction monitoring (MRM)—has emerged as a promising high-throughput targeted protein quantification technology for candidate biomarker verification and systems biology applications. A major bottleneck for current SRM technology, however, is insufficient sensitivity for e.g., detecting low-abundance biomarkers likely present at the pg/mL to low ng/mL range in human blood plasma or serum, or extremely low-abundance signaling proteins in the cells or tissues. Herein we review recent advances in methods and technologies, including front-end immunoaffinity depletion, fractionation, selective enrichment of target proteins/peptides or their posttranslational modifications (PTMs), as well as advances in MS instrumentation, which have significantly enhanced the overall sensitivity of SRM assays and enabled the detection of low-abundance proteins at low to sub- ng/mL level in human blood plasma or serum. General perspectives on the potential of achieving sufficient sensitivity for detection of pg/mL level proteins in plasma are also discussed.

  13. Does Angling Technique Selectively Target Fishes Based on Their Behavioural Type?

    Directory of Open Access Journals (Sweden)

    Alexander D M Wilson

    Full Text Available Recently, there has been growing recognition that fish harvesting practices can have important impacts on the phenotypic distributions and diversity of natural populations through a phenomenon known as fisheries-induced evolution. Here we experimentally show that two common recreational angling techniques (active crank baits versus passive soft plastics differentially target wild largemouth bass (Micropterus salmoides and rock bass (Ambloplites rupestris based on variation in their behavioural tendencies. Fish were first angled in the wild using both techniques and then brought back to the laboratory and tested for individual-level differences in common estimates of personality (refuge emergence, flight-initiation-distance, latency-to-recapture and with a net, and general activity in an in-lake experimental arena. We found that different angling techniques appear to selectively target these species based on their boldness (as characterized by refuge emergence, a standard measure of boldness in fishes but not other assays of personality. We also observed that body size was independently a significant predictor of personality in both species, though this varied between traits and species. Our results suggest a context-dependency for vulnerability to capture relative to behaviour in these fish species. Ascertaining the selective pressures angling practices exert on natural populations is an important area of fisheries research with significant implications for ecology, evolution, and resource management.

  14. Target objects defined by a conjunction of colour and shape can be selected independently and in parallel.

    Science.gov (United States)

    Jenkins, Michael; Grubert, Anna; Eimer, Martin

    2017-11-01

    It is generally assumed that during search for targets defined by a feature conjunction, attention is allocated sequentially to individual objects. We tested this hypothesis by tracking the time course of attentional processing biases with the N2pc component in tasks where observers searched for two targets defined by a colour/shape conjunction. In Experiment 1, two displays presented in rapid succession (100 ms or 10 ms SOA) each contained a target and a colour-matching or shape-matching distractor on opposite sides. Target objects in both displays elicited N2pc components of similar size that overlapped in time when the SOA was 10 ms, suggesting that attention was allocated in parallel to both targets. Analogous results were found in Experiment 2, where targets and partially matching distractors were both accompanied by an object without target-matching features. Colour-matching and shape-matching distractors also elicited N2pc components, and the target N2pc was initially identical to the sum of the two distractor N2pcs, suggesting that the initial phase of attentional object selection was guided independently by feature templates for target colour and shape. Beyond 230 ms after display onset, the target N2pc became superadditive, indicating that attentional selection processes now started to be sensitive to the presence of feature conjunctions. Results show that independent attentional selection processes can be activated in parallel by two target objects in situations where these objects are defined by a feature conjunction.

  15. Selective synaptic targeting of the excitatory and inhibitory presynaptic organizers FGF22 and FGF7.

    Science.gov (United States)

    Terauchi, Akiko; Timmons, Kendall M; Kikuma, Koto; Pechmann, Yvonne; Kneussel, Matthias; Umemori, Hisashi

    2015-01-15

    Specific formation of excitatory and inhibitory synapses is crucial for proper functioning of the brain. Fibroblast growth factor 22 (FGF22) and FGF7 are postsynaptic-cell-derived presynaptic organizers necessary for excitatory and inhibitory presynaptic differentiation, respectively, in the hippocampus. For the establishment of specific synaptic networks, these FGFs must localize to appropriate synaptic locations - FGF22 to excitatory and FGF7 to inhibitory postsynaptic sites. Here, we show that distinct motor and adaptor proteins contribute to intracellular microtubule transport of FGF22 and FGF7. Excitatory synaptic targeting of FGF22 requires the motor proteins KIF3A and KIF17 and the adaptor protein SAP102 (also known as DLG3). By contrast, inhibitory synaptic targeting of FGF7 requires the motor KIF5 and the adaptor gephyrin. Time-lapse imaging shows that FGF22 moves with SAP102, whereas FGF7 moves with gephyrin. These results reveal the basis of selective targeting of the excitatory and inhibitory presynaptic organizers that supports their different synaptogenic functions. Finally, we found that knockdown of SAP102 or PSD95 (also known as DLG4), which impairs the differentiation of excitatory synapses, alters FGF7 localization, suggesting that signals from excitatory synapses might regulate inhibitory synapse formation by controlling the distribution of the inhibitory presynaptic organizer. © 2015. Published by The Company of Biologists Ltd.

  16. Scientific objectives and selection of targets for the SMART-1 Infrared Spectrometer (SIR)

    Science.gov (United States)

    Basilevsky, A. T.; Keller, H. U.; Nathues, A.; Mall, U.; Hiesinger, H.; Rosiek, M.

    2004-12-01

    The European SMART-1 mission to the Moon, primarily a testbed for innovative technologies, was launched in September 2003 and will reach the Moon in 2005. On board are several scientific instruments, including the point-spectrometer SMART-1 Infrared Spectrometer (SIR). Taking into account the capabilities of the SMART-1 mission and the SIR instrument in particular, as well as the open questions in lunar science, a selection of targets for SIR observations has been compiled. SIR can address at least five topics: (1) Surface/regolith processes; (2) Lunar volcanism; (3) Lunar crust structure; (4) Search for spectral signatures of ices at the lunar poles; and (5) Ground truth and study of geometric effects on the spectral shape. For each topic we will discuss specific observation modes, necessary to achieve our scientific goals. The majority of SIR targets will be observed in the nadir-tracking mode. More than 100 targets, which require off-nadir pointing and off-nadir tracking, are planned. It is expected that results of SIR observations will significantly increase our understanding of the Moon. Since the exact arrival date and the orbital parameters of the SMART-1 spacecraft are not known yet, a more detailed planning of the scientific observations will follow in the near future.

  17. Selection of flowing liquid lead target structural materials for accelerator driven transmutation applications

    International Nuclear Information System (INIS)

    Park, J.J.; Buksa, J.J.

    1994-01-01

    The beam entry window and container for a liquid lead spallation target will be exposed to high fluxes of protons and neutrons that are both higher in magnitude and energy than have been experienced in proton accelerators and fission reactors, as well as in a corrosive environment. The structural material of the target should have a good compatibility with liquid lead, a sufficient mechanical strength at elevated temperatures, a good performance under an intense irradiation environment, and a low neutron absorption cross section; these factors have been used to rank the applicability of a wide range of materials for structural containment Nb-1Zr has been selected for use as the structural container for the LANL ABC/ATW molten lead target. Corrosion and mass transfer behavior for various candidate structural materials in liquid lead are reviewed, together with the beneficial effects of inhibitors and various coatings to protect substrate against liquid lead corrosion. Mechanical properties of some candidate materials at elevated temperatures and the property changes resulting from 800 MeV proton irradiation are also reviewed

  18. HisB as novel selection marker for gene targeting approaches in Aspergillus niger.

    Science.gov (United States)

    Fiedler, Markus R M; Gensheimer, Tarek; Kubisch, Christin; Meyer, Vera

    2017-03-08

    For Aspergillus niger, a broad set of auxotrophic and dominant resistance markers is available. However, only few offer targeted modification of a gene of interest into or at a genomic locus of choice, which hampers functional genomics studies. We thus aimed to extend the available set by generating a histidine auxotrophic strain with a characterized hisB locus for targeted gene integration and deletion in A. niger. A histidine-auxotrophic strain was established via disruption of the A. niger hisB gene by using the counterselectable pyrG marker. After curing, a hisB - , pyrG - strain was obtained, which served as recipient strain for further studies. We show here that both hisB orthologs from A. nidulans and A. niger can be used to reestablish histidine prototrophy in this recipient strain. Whereas the hisB gene from A. nidulans was suitable for efficient gene targeting at different loci in A. niger, the hisB gene from A. niger allowed efficient integration of a Tet-on driven luciferase reporter construct at the endogenous non-functional hisB locus. Subsequent analysis of the luciferase activity revealed that the hisB locus is tight under non-inducing conditions and allows even higher luciferase expression levels compared to the pyrG integration locus. Taken together, we provide here an alternative selection marker for A. niger, hisB, which allows efficient homologous integration rates as well as high expression levels which compare favorably to the well-established pyrG selection marker.

  19. Selective Vitamin D Receptor Activation as Anti-Inflammatory Target in Chronic Kidney Disease

    Directory of Open Access Journals (Sweden)

    J. Donate-Correa

    2014-01-01

    Full Text Available Paricalcitol, a selective vitamin D receptor (VDR activator used for treatment of secondary hyperparathyroidism in chronic kidney disease (CKD, has been associated with survival advantages, suggesting that this drug, beyond its ability to suppress parathyroid hormone, may have additional beneficial actions. In this prospective, nonrandomised, open-label, proof-of-concept study, we evaluated the hypothesis that selective vitamin D receptor activation with paricalcitol is an effective target to modulate inflammation in CKD patients. Eight patients with an estimated glomerular filtration rate between 15 and 44 mL/min/1.73 m2 and an intact parathyroid hormone (PTH level higher than 110 pg/mL received oral paricalcitol (1 μg/48 hours as therapy for secondary hyperparathyroidism. Nine patients matched by age, sex, and stage of CKD, but a PTH level <110 pg/mL, were enrolled as a control group. Our results show that five months of paricalcitol administration were associated with a reduction in serum concentrations of hs-CRP (13.9%, P<0.01, TNF-α (11.9%, P=0.01, and IL-6 (7%, P<0.05, with a nonsignificant increase of IL-10 by 16%. In addition, mRNA expression levels of the TNFα and IL-6 genes in peripheral blood mononuclear cells decreased significantly by 30.8% (P=0.01 and 35.4% (P=0.01, respectively. In conclusion, selective VDR activation is an effective target to modulate inflammation in CKD.

  20. Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

    DEFF Research Database (Denmark)

    Spiess, Katja; Jeppesen, Mads G.; Malmgaard-Clausen, Mikkel

    2017-01-01

    of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin...... A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher...... selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate...

  1. Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology.

    Science.gov (United States)

    Galdeano, Carles; Ciulli, Alessio

    2016-09-01

    Targeting epigenetic proteins is a rapidly growing area for medicinal chemistry and drug discovery. Recent years have seen an explosion of interest in developing small molecules binding to bromodomains, the readers of acetyl-lysine modifications. A plethora of co-crystal structures has motivated focused fragment-based design and optimization programs within both industry and academia. These efforts have yielded several compounds entering the clinic, and many more are increasingly being used as chemical probes to interrogate bromodomain biology. High selectivity of chemical probes is necessary to ensure biological activity is due to an on-target effect. Here, we review the state-of-the-art of bromodomain-targeting compounds, focusing on the structural basis for their on-target selectivity or lack thereof. We also highlight chemical biology approaches to enhance on-target selectivity.

  2. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

    Energy Technology Data Exchange (ETDEWEB)

    Lasko, Loren M.; Jakob, Clarissa G.; Edalji, Rohinton P.; Qiu, Wei; Montgomery, Debra; Digiammarino, Enrico L.; Hansen, T. Matt; Risi, Roberto M.; Frey, Robin; Manaves, Vlasios; Shaw, Bailin; Algire, Mikkel; Hessler, Paul; Lam, Lloyd T.; Uziel, Tamar; Faivre, Emily; Ferguson, Debra; Buchanan, Fritz G.; Martin, Ruth L.; Torrent, Maricel; Chiang, Gary G.; Karukurichi, Kannan; Langston, J. William; Weinert, Brian T.; Choudhary, Chunaram; de Vries, Peter; Van Drie, John H.; McElligott, David; Kesicki, Ed; Marmorstein, Ronen; Sun, Chaohong; Cole, Philip A.; Rosenberg, Saul H.; Michaelides, Michael R.; Lai, Albert; Bromberg, Kenneth D. (AbbVie); (UCopenhagen); (Petra Pharma); (UPENN); (JHU); (Van Drie); (Faraday)

    2017-09-27

    The dynamic and reversible acetylation of proteins, catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is a major epigenetic regulatory mechanism of gene transcription1 and is associated with multiple diseases. Histone deacetylase inhibitors are currently approved to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind2. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have also been implicated in human pathological conditions (including cancer3). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products4, bi-substrate analogues5 and the widely used small molecule C6466,7, lack potency or selectivity. Here, we describe A-485, a potent, selective and drug-like catalytic inhibitor of p300 and CBP. We present a high resolution (1.95 Å) co-crystal structure of a small molecule bound to the catalytic active site of p300 and demonstrate that A-485 competes with acetyl coenzyme A (acetyl-CoA). A-485 selectively inhibited proliferation in lineage-specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft model. These results demonstrate the feasibility of using small molecule inhibitors to selectively target the catalytic activity of histone acetyltransferases, which may provide effective treatments for transcriptional activator-driven malignancies and diseases.

  3. Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2

    DEFF Research Database (Denmark)

    Hubackova, Sona; Davidova, Eliska; Rohlenova, Katerina

    2018-01-01

    and development of age-related diseases. We found that the anticancer agent mitochondria-targeted tamoxifen (MitoTam), unlike conventional anticancer agents, kills cancer cells without inducing senescence in vitro and in vivo. Surprisingly, it also selectively eliminates both malignant and non-cancerous senescent...... cells. In naturally aged mice treated with MitoTam for 4 weeks, we observed a significant decrease of senescence markers in all tested organs compared to non-treated animals. Mechanistically, we found that the susceptibility of senescent cells to MitoTam is linked to a very low expression level...... of adenine nucleotide translocase-2 (ANT2), inherent to the senescent phenotype. Restoration of ANT2 in senescent cells resulted in resistance to MitoTam, while its downregulation in non-senescent cells promoted their MitoTam-triggered elimination. Our study documents a novel, translationally intriguing role...

  4. Multi-data integration of exploration criteria and selection of prospecting targets

    International Nuclear Information System (INIS)

    Dechang, L.; Jingke, Z.; Maorong, S.; Guojuan, W.

    1991-01-01

    In this paper based on the analysis of the exploration criteria for Shengyuan Basin-a uranium ore field, the multi-data integration and information extraction of exploration criteria are carried out on computer and image processing system so that the areas with best combinations of exploration criteria are directly displayed on the screen. Six prospecting targets are selected through the field examination. Shengyuan basin in Jiangxi province is a uranium-producing, Jurassic Cretaceous volcanic-sedimentary basin with an area of about 400 sq km. Its basement consists of Sinian-Cambrian rocks with Caledonian granites intruded. Several uranium deposits, occurrences and anomalies were discovered over the basin region which, therefore, becomes a very important uranium ore field in China

  5. New Molecules and Old Drugs as Emerging Approaches to Selectively Target Human Glioblastoma Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Roberto Würth

    2014-01-01

    Full Text Available Despite relevant progress obtained by multimodal treatment, glioblastoma (GBM, the most aggressive primary brain tumor, is still incurable. The most encouraging advancement of GBM drug research derives from the identification of cancer stem cells (CSCs, since these cells appear to represent the determinants of resistance to current standard therapies. The goal of most ongoing studies is to identify drugs able to affect CSCs biology, either inducing selective toxicity or differentiating this tumor cell population into nontumorigenic cells. Moreover, the therapeutic approach for GBM could be improved interfering with chemo- or radioresistance mechanisms, microenvironment signals, and the neoangiogenic process. During the last years, molecular targeted compounds such as sorafenib and old drugs, like metformin, displayed interesting efficacy in preclinical studies towards several tumors, including GBM, preferentially affecting CSC viability. In this review, the latest experimental results, controversies, and prospective application concerning these promising anticancer drugs will be discussed.

  6. Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

    Directory of Open Access Journals (Sweden)

    Joana R. Viola

    2013-01-01

    Full Text Available Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed.

  7. Deontic reasoning as a target of selection: reply to Astington and Dack.

    Science.gov (United States)

    Cummins, Denise Dellarosa

    2013-12-01

    In their discussion of young children's deontic reasoning performance, Astington and Dack (2013) made the following claims: (1) Children need more cues to elicit cogent social norm reasoning than adults require, namely, explicit reference to authority; (2) Deontic reasoning improves with age, and this is evidence against a nativist view; (3) All evolutionary explanations of deontic reasoning advantages require positing a ''domain-specific deontic reasoning module."; and (4) young children excel at deontic reasoning because it is easier. Here, I refute each claim. Instead, I argue that (1) Social norm reasoning is one type of deontic reasoning that has been the target of selective pressure; (2) Development does not preclude nativism; (3) Epistemic utterances make no greater processing demands than deontic utterances; and (4) both adult and child norm reasoning performance is strongly influenced by reference to or implication of authority. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Construction and applications of exon-trapping gene-targeting vectors with a novel strategy for negative selection.

    Science.gov (United States)

    Saito, Shinta; Ura, Kiyoe; Kodama, Miho; Adachi, Noritaka

    2015-06-30

    Targeted gene modification by homologous recombination provides a powerful tool for studying gene function in cells and animals. In higher eukaryotes, non-homologous integration of targeting vectors occurs several orders of magnitude more frequently than does targeted integration, making the gene-targeting technology highly inefficient. For this reason, negative-selection strategies have been employed to reduce the number of drug-resistant clones associated with non-homologous vector integration, particularly when artificial nucleases to introduce a DNA break at the target site are unavailable or undesirable. As such, an exon-trap strategy using a promoterless drug-resistance marker gene provides an effective way to counterselect non-homologous integrants. However, constructing exon-trapping targeting vectors has been a time-consuming and complicated process. By virtue of highly efficient att-mediated recombination, we successfully developed a simple and rapid method to construct plasmid-based vectors that allow for exon-trapping gene targeting. These exon-trap vectors were useful in obtaining correctly targeted clones in mouse embryonic stem cells and human HT1080 cells. Most importantly, with the use of a conditionally cytotoxic gene, we further developed a novel strategy for negative selection, thereby enhancing the efficiency of counterselection for non-homologous integration of exon-trap vectors. Our methods will greatly facilitate exon-trapping gene-targeting technologies in mammalian cells, particularly when combined with the novel negative selection strategy.

  9. Antibody Selection for Cancer Target Validation of FSH-Receptor in Immunohistochemical Settings

    Directory of Open Access Journals (Sweden)

    Nina Moeker

    2017-10-01

    Full Text Available Background: The follicle-stimulating hormone (FSH-receptor (FSHR has been reported to be an attractive target for antibody therapy in human cancer. However, divergent immunohistochemical (IHC findings have been reported for FSHR expression in tumor tissues, which could be due to the specificity of the antibodies used. Methods: Three frequently used antibodies (sc-7798, sc-13935, and FSHR323 were validated for their suitability in an immunohistochemical study for FSHR expression in different tissues. As quality control, two potential therapeutic anti-hFSHR Ylanthia® antibodies (Y010913, Y010916 were used. The specificity criteria for selection of antibodies were binding to native hFSHR of different sources, and no binding to non-related proteins. The ability of antibodies to stain the paraffin-embedded Flp-In Chinese hamster ovary (CHO/FSHR cells was tested after application of different epitope retrieval methods. Results: From the five tested anti-hFSHR antibodies, only Y010913, Y010916, and FSHR323 showed specific binding to native, cell-presented hFSHR. Since Ylanthia® antibodies were selected to specifically recognize native FSHR, as required for a potential therapeutic antibody candidate, FSHR323 was the only antibody to detect the receptor in IHC/histochemical settings on transfected cells, and at markedly lower, physiological concentrations (ex., in Sertoli cells of human testes. The pattern of FSH323 staining noticed for ovarian, prostatic, and renal adenocarcinomas indicated that FSHR was expressed mainly in the peripheral tumor blood vessels. Conclusion: Of all published IHC antibodies tested, only antibody FSHR323 proved suitable for target validation of hFSHR in an IHC setting for cancer. Our studies could not confirm the previously reported FSHR overexpression in ovarian and prostate cancer cells. Instead, specific overexpression in peripheral tumor blood vessels could be confirmed after thorough validation of the antibodies used.

  10. Visual encoding and fixation target selection in free viewing: presaccadic brain potentials

    Directory of Open Access Journals (Sweden)

    Andrey R Nikolaev

    2013-06-01

    Full Text Available In scrutinizing a scene, the eyes alternate between fixations and saccades. During a fixation, two component processes can be distinguished: visual encoding and selection of the next fixation target. We aimed to distinguish the neural correlates of these processes in the electrical brain activity prior to a saccade onset. Participants viewed color photographs of natural scenes, in preparation for a change detection task. Then, for each participant and each scene we computed an image heat map, with temperature representing the duration and density of fixations. The temperature difference between the start and end points of saccades was taken as a measure of the expected task-relevance of the information concentrated in specific regions of a scene. Visual encoding was evaluated according to whether subsequent change was correctly detected. Saccades with larger temperature difference were more likely to be followed by correct detection than ones with smaller temperature differences. The amplitude of presaccadic activity over anterior brain areas was larger for correct detection than for detection failure. This difference was observed for short scrutinizing but not for long explorative saccades, suggesting that presaccadic activity reflects top-down saccade guidance. Thus, successful encoding requires local scanning of scene regions which are expected to be task-relevant. Next, we evaluated fixation target selection. Saccades moving up in temperature were preceded by presaccadic activity of higher amplitude than those moving down. This finding suggests that presaccadic activity reflects attention deployed to the following fixation location. Our findings illustrate how presaccadic activity can elucidate concurrent brain processes related to the immediate goal of planning the next saccade and the larger-scale goal of constructing a robust representation of the visual scene.

  11. Non-invasive brain stimulation targeting the right fusiform gyrus selectively increases working memory for faces.

    Science.gov (United States)

    Brunyé, Tad T; Moran, Joseph M; Holmes, Amanda; Mahoney, Caroline R; Taylor, Holly A

    2017-04-01

    The human extrastriate cortex contains a region critically involved in face detection and memory, the right fusiform gyrus. The present study evaluated whether transcranial direct current stimulation (tDCS) targeting this anatomical region would selectively influence memory for faces versus non-face objects (houses). Anodal tDCS targeted the right fusiform gyrus (Brodmann's Area 37), with the anode at electrode site PO10, and cathode at FP2. Two stimulation conditions were compared in a repeated-measures design: 0.5mA versus 1.5mA intensity; a separate control group received no stimulation. Participants completed a working memory task for face and house stimuli, varying in memory load from 1 to 4 items. Individual differences measures assessed trait-based differences in facial recognition skills. Results showed 1.5mA intensity stimulation (versus 0.5mA and control) increased performance at high memory loads, but only with faces. Lower overall working memory capacity predicted a positive impact of tDCS. Results provide support for the notion of functional specialization of the right fusiform regions for maintaining face (but not non-face object) stimuli in working memory, and further suggest that low intensity electrical stimulation of this region may enhance demanding face working memory performance particularly in those with relatively poor baseline working memory skills. Published by Elsevier Inc.

  12. Diversity, expression and mRNA targeting abilities of Argonaute-targeting miRNAs among selected vascular plants.

    Science.gov (United States)

    Jagtap, Soham; Shivaprasad, Padubidri V

    2014-12-02

    Micro (mi)RNAs are important regulators of plant development. Across plant lineages, Dicer-like 1 (DCL1) proteins process long ds-like structures to produce micro (mi) RNA duplexes in a stepwise manner. These miRNAs are incorporated into Argonaute (AGO) proteins and influence expression of RNAs that have sequence complementarity with miRNAs. Expression levels of AGOs are greatly regulated by plants in order to minimize unwarranted perturbations using miRNAs to target mRNAs coding for AGOs. AGOs may also have high promoter specificity-sometimes expression of AGO can be limited to just a few cells in a plant. Viral pathogens utilize various means to counter antiviral roles of AGOs including hijacking the host encoded miRNAs to target AGOs. Two host encoded miRNAs namely miR168 and miR403 that target AGOs have been described in the model plant Arabidopsis and such a mechanism is thought to be well conserved across plants because AGO sequences are well conserved. We show that the interaction between AGO mRNAs and miRNAs is species-specific due to the diversity in sequences of two miRNAs that target AGOs, sequence diversity among corresponding target regions in AGO mRNAs and variable expression levels of these miRNAs among vascular plants. We used miRNA sequences from 68 plant species representing 31 plant families for this analysis. Sequences of miR168 and miR403 are not conserved among plant lineages, but surprisingly they differ drastically in their sequence diversity and expression levels even among closely related plants. Variation in miR168 expression among plants correlates well with secondary structures/length of loop sequences of their precursors. Our data indicates a complex AGO targeting interaction among plant lineages due to miRNA sequence diversity and sequences of miRNA targeting regions among AGO mRNAs, thus leading to the assumption that the perturbations by viruses that use host miRNAs to target antiviral AGOs can only be species-specific. We also show

  13. Identification of cytotoxic drugs that selectively target tumor cells with MYC overexpression.

    Directory of Open Access Journals (Sweden)

    Anna Frenzel

    Full Text Available Expression of MYC is deregulated in a wide range of human cancers, and is often associated with aggressive disease and poorly differentiated tumor cells. Identification of compounds with selectivity for cells overexpressing MYC would hence be beneficial for the treatment of these tumors. For this purpose we used cell lines with conditional MYCN or c-MYC expression, to screen a library of 80 conventional cytotoxic compounds for their ability to reduce tumor cell viability and/or growth in a MYC dependent way. We found that 25% of the studied compounds induced apoptosis and/or inhibited proliferation in a MYC-specific manner. The activities of the majority of these were enhanced both by c-MYC or MYCN over-expression. Interestingly, these compounds were acting on distinct cellular targets, including microtubules (paclitaxel, podophyllotoxin, vinblastine and topoisomerases (10-hydroxycamptothecin, camptothecin, daunorubicin, doxorubicin, etoposide as well as DNA, RNA and protein synthesis and turnover (anisomycin, aphidicholin, gliotoxin, MG132, methotrexate, mitomycin C. Our data indicate that MYC overexpression sensitizes cells to disruption of specific pathways and that in most cases c-MYC and MYCN overexpression have similar effects on the responses to cytotoxic compounds. Treatment of the cells with topoisomerase I inhibitors led to down-regulation of MYC protein levels, while doxorubicin and the small molecule MYRA-A was found to disrupt MYC-Max interaction. We conclude that the MYC pathway is only targeted by a subset of conventional cytotoxic drugs currently used in the clinic. Elucidating the mechanisms underlying their specificity towards MYC may be of importance for optimizing treatment of tumors with MYC deregulation. Our data also underscores that MYC is an attractive target for novel therapies and that cellular screenings of chemical libraries can be a powerful tool for identifying compounds with a desired biological activity.

  14. Dipeptidyl peptidase IV as a potential target for selective prodrug activation and chemotherapeutic action in cancers.

    Science.gov (United States)

    Dahan, Arik; Wolk, Omri; Yang, Peihua; Mittal, Sachin; Wu, Zhiqian; Landowski, Christopher P; Amidon, Gordon L

    2014-12-01

    The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r(2) = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r(2) = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI₅₀ = 261 μM) compared to that in SK-MEL-5 cells (GI₅₀ = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

  15. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells

    Science.gov (United States)

    Lagadinou, Eleni D.; Sach, Alexander; Callahan, Kevin; Rossi, Randall M.; Neering, Sarah J.; Minhajuddin, Mohammad; Ashton, John M.; Pei, Shanshan; Grose, Valerie; O’Dwyer, Kristen M.; Liesveld, Jane L.; Brookes, Paul S.; Becker, Michael W.; Jordan, Craig T.

    2013-01-01

    Summary Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally-defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly over-express BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation. PMID:23333149

  16. Identification of genomic variants putatively targeted by selection during dog domestication.

    Science.gov (United States)

    Cagan, Alex; Blass, Torsten

    2016-01-12

    Dogs [Canis lupus familiaris] were the first animal species to be domesticated and continue to occupy an important place in human societies. Recent studies have begun to reveal when and where dog domestication occurred. While much progress has been made in identifying the genetic basis of phenotypic differences between dog breeds we still know relatively little about the genetic changes underlying the phenotypes that differentiate all dogs from their wild progenitors, wolves [Canis lupus]. In particular, dogs generally show reduced aggression and fear towards humans compared to wolves. Therefore, selection for tameness was likely a necessary prerequisite for dog domestication. With the increasing availability of whole-genome sequence data it is possible to try and directly identify the genetic variants contributing to the phenotypic differences between dogs and wolves. We analyse the largest available database of genome-wide polymorphism data in a global sample of dogs 69 and wolves 7. We perform a scan to identify regions of the genome that are highly differentiated between dogs and wolves. We identify putatively functional genomic variants that are segregating or at high frequency [> = 0.75 Fst] for alternative alleles between dogs and wolves. A biological pathways analysis of the genes containing these variants suggests that there has been selection on the 'adrenaline and noradrenaline biosynthesis pathway', well known for its involvement in the fight-or-flight response. We identify 11 genes with putatively functional variants fixed for alternative alleles between dogs and wolves. The segregating variants in these genes are strong candidates for having been targets of selection during early dog domestication. We present the first genome-wide analysis of the different categories of putatively functional variants that are fixed or segregating at high frequency between a global sampling of dogs and wolves. We find evidence that selection has been strongest

  17. ProSelection: A Novel Algorithm to Select Proper Protein Structure Subsets for in Silico Target Identification and Drug Discovery Research.

    Science.gov (United States)

    Wang, Nanyi; Wang, Lirong; Xie, Xiang-Qun

    2017-11-27

    Molecular docking is widely applied to computer-aided drug design and has become relatively mature in the recent decades. Application of docking in modeling varies from single lead compound optimization to large-scale virtual screening. The performance of molecular docking is highly dependent on the protein structures selected. It is especially challenging for large-scale target prediction research when multiple structures are available for a single target. Therefore, we have established ProSelection, a docking preferred-protein selection algorithm, in order to generate the proper structure subset(s). By the ProSelection algorithm, protein structures of "weak selectors" are filtered out whereas structures of "strong selectors" are kept. Specifically, the structure which has a good statistical performance of distinguishing active ligands from inactive ligands is defined as a strong selector. In this study, 249 protein structures of 14 autophagy-related targets are investigated. Surflex-dock was used as the docking engine to distinguish active and inactive compounds against these protein structures. Both t test and Mann-Whitney U test were used to distinguish the strong from the weak selectors based on the normality of the docking score distribution. The suggested docking score threshold for active ligands (SDA) was generated for each strong selector structure according to the receiver operating characteristic (ROC) curve. The performance of ProSelection was further validated by predicting the potential off-targets of 43 U.S. Federal Drug Administration approved small molecule antineoplastic drugs. Overall, ProSelection will accelerate the computational work in protein structure selection and could be a useful tool for molecular docking, target prediction, and protein-chemical database establishment research.

  18. Cancer cell-selective promoter recognition accompanies antitumor effect by glucocorticoid receptor-targeted gold nanoparticle

    Science.gov (United States)

    Sau, Samaresh; Agarwalla, Pritha; Mukherjee, Sudip; Bag, Indira; Sreedhar, Bojja; Pal-Bhadra, Manika; Patra, Chitta Ranjan; Banerjee, Rajkumar

    2014-05-01

    Nanoparticles, such as gold nanoparticles (GNP), upon convenient modifications perform multi tasks catering to many biomedical applications. However, GNP or any other type of nanoparticles is yet to achieve the feat of intracellular regulation of endogenous genes of choice such as through manipulation of a gene-promoter in a chromosome. As for gene modulation and delivery, GNP (or other nanoparticles) showed only limited gene therapy potential, which relied on the delivery of `exogenous' genes invoking gene knockdown or replacement. Practically, there are no instances for the nanoparticle-mediated promoter regulation of `endogenous' genes, more so, as a cancer selective phenomenon. In this regard, we report the development of a simple, easily modifiable GNP-formulation, which promoted/up-regulated the expression of a specific category of `endogenous' genes, the glucocorticoid responsive genes. This genetic up-regulation was induced in only cancer cells by modified GNP-mediated transcriptional activation of its cytoplasmic receptor, glucocorticoid receptor (GR). Normal cells and their GR remained primarily unperturbed by this GNP-formulation. The most potent gene up-regulating GNP-formulation down-regulated a cancer-specific proliferative signal, phospho-Akt in cancer cells, which accompanied retardation of tumor growth in the murine melanoma model. We show that GR-targeted GNPs may find potential use in the targeting and modulation of genetic information in cancer towards developing novel anticancer therapeutics.Nanoparticles, such as gold nanoparticles (GNP), upon convenient modifications perform multi tasks catering to many biomedical applications. However, GNP or any other type of nanoparticles is yet to achieve the feat of intracellular regulation of endogenous genes of choice such as through manipulation of a gene-promoter in a chromosome. As for gene modulation and delivery, GNP (or other nanoparticles) showed only limited gene therapy potential, which relied

  19. Uranium exploration target selection for proterozoic iron oxide/breccia complex type deposits in India

    International Nuclear Information System (INIS)

    Dwivedy, K.K.; Sinha, K.K.

    1997-01-01

    Multimetal iron oxide/breccia complex (IOBC) type deposits exemplified by Olympic Dam in Australia, fall under low grade, large tonnage deposits. A multidisciplinary integrated exploration programme consisting of airborne surveys, ground geological surveys, geophysical and geochemical investigations and exploratory drilling, supported adequately by the state of the art analytical facilities, data processing using various software and digital image processing has shown moderate success in the identification of target areas for this type of deposits in the Proterozoic terrains of India. Intracratonic, anorogenic, continental rift to continental margin environment have been identified in a very wide spectrum of rock associations. The genesis and evolution of such associations during the Middle Proterozoic period have been reviewed and applied for target selection in the (i) Son-Narmada rift valley zone; (ii) areas covered by Dongargarh Supergroup of rocks in Madhya Pradesh; (iii) areas exposing ferruginous breccia in the western part of the Singhbhum Shear Zone (SSZ) around Lotapahar; (iv) Siang Group of rocks in Arunachal Pradesh; (v) Crystalline rocks of Garo Hills around Anek; and (vi) Chhotanagpur Gneissic complex in the Bahia-Ulatutoli tract of Ranchi Plateau. Of theses six areas, the Son-Narmada rift area appears to be the most promising area for IOBC type deposits. Considering occurrences of the uranium anomalies near Meraraich, Kundabhati, Naktu and Kudar and positive favourability criteria observed in a wide variety of rocks spatially related to the rifts and shears, certain sectors in Son-Narmada rift zone have been identified as promising for intense subsurface exploration. 20 refs, 4 figs, 1 tab

  20. GLUT1-mediated selective tumor targeting with fluorine containing platinum(II) glycoconjugates.

    Science.gov (United States)

    Liu, Ran; Fu, Zheng; Zhao, Meng; Gao, Xiangqian; Li, Hong; Mi, Qian; Liu, Pengxing; Yang, Jinna; Yao, Zhi; Gao, Qingzhi

    2017-06-13

    Increased glycolysis and overexpression of glucose transporters (GLUTs) are physiological characteristics of human malignancies. Based on the so-called Warburg effect, 18flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, we focus on the fluorine substituted series of glucose, mannose and galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-flouromalonato-platinum(II) complexes for a comprehensive evaluation on their selective tumor targeting. Besides highly improved water solubility, these sugar-conjugates presented improved cytotoxicity than oxaliplatin in glucose tranporters (GLUTs) overexpressing cancer cell lines and exhibited no cross-resistance to cisplatin. For the highly water soluble glucose-conjugated complex (5a), two novel in vivo assessments were conducted and the results revealed that 5a was more efficacious at a lower equitoxic dose (70% MTD) than oxaliplatin (100% MTD) in HT29 xenograft model, and it was significantly more potent than oxaliplatin in leukemia-bearing DBA/2 mice as well even at equimolar dose levels (18% vs 90% MTD). GLUT inhibitor mediated cell viability analysis, GLUT1 knockdown cell line-based cytotoxicity evaluation, and platinum accumulation study demonstrated that the cellular uptake of the sugar-conjugates was regulated by GLUT1. The higher intrinsic DNA reactivity of the sugar-conjugates was confirmed by kinetic study of platinum(II)-guanosine adduct formation. The mechanistic origin of the antitumor effect of the fluorine complexes was found to be forming the bifunctional Pt-guanine-guanine (Pt-GG) intrastrand cross-links with DNA. The results provide a rationale for Warburg effect targeted anticancer drug design.

  1. Automated selected reaction monitoring data analysis workflow for large-scale targeted proteomic studies.

    Science.gov (United States)

    Surinova, Silvia; Hüttenhain, Ruth; Chang, Ching-Yun; Espona, Lucia; Vitek, Olga; Aebersold, Ruedi

    2013-08-01

    Targeted proteomics based on selected reaction monitoring (SRM) mass spectrometry is commonly used for accurate and reproducible quantification of protein analytes in complex biological mixtures. Strictly hypothesis-driven, SRM assays quantify each targeted protein by collecting measurements on its peptide fragment ions, called transitions. To achieve sensitive and accurate quantitative results, experimental design and data analysis must consistently account for the variability of the quantified transitions. This consistency is especially important in large experiments, which increasingly require profiling up to hundreds of proteins over hundreds of samples. Here we describe a robust and automated workflow for the analysis of large quantitative SRM data sets that integrates data processing, statistical protein identification and quantification, and dissemination of the results. The integrated workflow combines three software tools: mProphet for peptide identification via probabilistic scoring; SRMstats for protein significance analysis with linear mixed-effect models; and PASSEL, a public repository for storage, retrieval and query of SRM data. The input requirements for the protocol are files with SRM traces in mzXML format, and a file with a list of transitions in a text tab-separated format. The protocol is especially suited for data with heavy isotope-labeled peptide internal standards. We demonstrate the protocol on a clinical data set in which the abundances of 35 biomarker candidates were profiled in 83 blood plasma samples of subjects with ovarian cancer or benign ovarian tumors. The time frame to realize the protocol is 1-2 weeks, depending on the number of replicates used in the experiment.

  2. A Novel Sensor Selection and Power Allocation Algorithm for Multiple-Target Tracking in an LPI Radar Network

    Directory of Open Access Journals (Sweden)

    Ji She

    2016-12-01

    Full Text Available Radar networks are proven to have numerous advantages over traditional monostatic and bistatic radar. With recent developments, radar networks have become an attractive platform due to their low probability of intercept (LPI performance for target tracking. In this paper, a joint sensor selection and power allocation algorithm for multiple-target tracking in a radar network based on LPI is proposed. It is found that this algorithm can minimize the total transmitted power of a radar network on the basis of a predetermined mutual information (MI threshold between the target impulse response and the reflected signal. The MI is required by the radar network system to estimate target parameters, and it can be calculated predictively with the estimation of target state. The optimization problem of sensor selection and power allocation, which contains two variables, is non-convex and it can be solved by separating power allocation problem from sensor selection problem. To be specific, the optimization problem of power allocation can be solved by using the bisection method for each sensor selection scheme. Also, the optimization problem of sensor selection can be solved by a lower complexity algorithm based on the allocated powers. According to the simulation results, it can be found that the proposed algorithm can effectively reduce the total transmitted power of a radar network, which can be conducive to improving LPI performance.

  3. Pharmacological targeting of valosin containing protein (VCP) induces DNA damage and selectively kills canine lymphoma cells

    International Nuclear Information System (INIS)

    Nadeau, Marie-Ève; Rico, Charlène; Tsoi, Mayra; Vivancos, Mélanie; Filimon, Sabin; Paquet, Marilène; Boerboom, Derek

    2015-01-01

    lymphoma. The selective activity of EER-1 against lymphoma cells suggests that VCP will represent a clinically useful therapeutic target for the treatment of lymphoma. We further suggest a mechanism of EER-1 action centered on the DNA repair response that may be of central importance for the design and characterization of VCP inhibitory compounds for therapeutic use. The online version of this article (doi:10.1186/s12885-015-1489-1) contains supplementary material, which is available to authorized users

  4. Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

    Science.gov (United States)

    Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

    2012-02-01

    Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Using Deep Learning for Targeted Data Selection, Improving Satellite Observation Utilization for Model Initialization

    Science.gov (United States)

    Lee, Y. J.; Bonfanti, C. E.; Trailovic, L.; Etherton, B.; Govett, M.; Stewart, J.

    2017-12-01

    At present, a fraction of all satellite observations are ultimately used for model assimilation. The satellite data assimilation process is computationally expensive and data are often reduced in resolution to allow timely incorporation into the forecast. This problem is only exacerbated by the recent launch of Geostationary Operational Environmental Satellite (GOES)-16 satellite and future satellites providing several order of magnitude increase in data volume. At the NOAA Earth System Research Laboratory (ESRL) we are researching the use of machine learning the improve the initial selection of satellite data to be used in the model assimilation process. In particular, we are investigating the use of deep learning. Deep learning is being applied to many image processing and computer vision problems with great success. Through our research, we are using convolutional neural network to find and mark regions of interest (ROI) to lead to intelligent extraction of observations from satellite observation systems. These targeted observations will be used to improve the quality of data selected for model assimilation and ultimately improve the impact of satellite data on weather forecasts. Our preliminary efforts to identify the ROI's are focused in two areas: applying and comparing state-of-art convolutional neural network models using the analysis data from the National Center for Environmental Prediction (NCEP) Global Forecast System (GFS) weather model, and using these results as a starting point to optimize convolution neural network model for pattern recognition on the higher resolution water vapor data from GOES-WEST and other satellite. This presentation will provide an introduction to our convolutional neural network model to identify and process these ROI's, along with the challenges of data preparation, training the model, and parameter optimization.

  6. Interval MULTIMOORA method with target values of attributes based on interval distance and preference degree: biomaterials selection

    Science.gov (United States)

    Hafezalkotob, Arian; Hafezalkotob, Ashkan

    2017-06-01

    A target-based MADM method covers beneficial and non-beneficial attributes besides target values for some attributes. Such techniques are considered as the comprehensive forms of MADM approaches. Target-based MADM methods can also be used in traditional decision-making problems in which beneficial and non-beneficial attributes only exist. In many practical selection problems, some attributes have given target values. The values of decision matrix and target-based attributes can be provided as intervals in some of such problems. Some target-based decision-making methods have recently been developed; however, a research gap exists in the area of MADM techniques with target-based attributes under uncertainty of information. We extend the MULTIMOORA method for solving practical material selection problems in which material properties and their target values are given as interval numbers. We employ various concepts of interval computations to reduce degeneration of uncertain data. In this regard, we use interval arithmetic and introduce innovative formula for interval distance of interval numbers to create interval target-based normalization technique. Furthermore, we use a pairwise preference matrix based on the concept of degree of preference of interval numbers to calculate the maximum, minimum, and ranking of these numbers. Two decision-making problems regarding biomaterials selection of hip and knee prostheses are discussed. Preference degree-based ranking lists for subordinate parts of the extended MULTIMOORA method are generated by calculating the relative degrees of preference for the arranged assessment values of the biomaterials. The resultant rankings for the problem are compared with the outcomes of other target-based models in the literature.

  7. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH.

    Science.gov (United States)

    Yun, Jihye; Mullarky, Edouard; Lu, Changyuan; Bosch, Kaitlyn N; Kavalier, Adam; Rivera, Keith; Roper, Jatin; Chio, Iok In Christine; Giannopoulou, Eugenia G; Rago, Carlo; Muley, Ashlesha; Asara, John M; Paik, Jihye; Elemento, Olivier; Chen, Zhengming; Pappin, Darryl J; Dow, Lukas E; Papadopoulos, Nickolas; Gross, Steven S; Cantley, Lewis C

    2015-12-11

    More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an energetic crisis and cell death not seen in KRAS and BRAF wild-type cells. High-dose vitamin C impairs tumor growth in Apc/Kras(G12D) mutant mice. These results provide a mechanistic rationale for exploring the therapeutic use of vitamin C for CRCs with KRAS or BRAF mutations. Copyright © 2015, American Association for the Advancement of Science.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Green tea extract selectively targets nanomechanics of live metastatic cancer cells

    International Nuclear Information System (INIS)

    Cross, Sarah E; Gimzewski, James K; Jin Yusheng; Lu Qingyi; Rao Jianyu

    2011-01-01

    Green tea extract (GTE) is known to be a potential anticancer agent (Yang et al 2009 Nat. Rev. Cancer 9 429-39) with various biological activities (Lu et al 2005 Clin. Cancer Res. 11 1675-83; Yang et al 1998 Carcinogenesis 19 611-6) yet the precise mechanism of action is still unclear. The biomechanical response of GTE treated cells taken directly from patient's body samples was measured using atomic force microscopy (AFM) (Binnig et al 1986 Phys. Rev. Lett. 56 930). We found significant increase in stiffness of GTE treated metastatic tumor cells, with a resulting value similar to untreated normal mesothelial cells, whereas mesothelial cell stiffness after GTE treatment is unchanged. Immunofluorescence analysis showed an increase in cytoskeletal-F-actin in GTE treated tumor cells, suggesting GTE treated tumor cells display mechanical, structural and morphological features similar to normal cells, which appears to be mediated by annexin-I expression, as determined by siRNA analysis of an in vitro cell line model. Our data indicates that GTE selectively targets human metastatic cancer cells but not normal mesothelial cells, a finding that is significantly advantageous compared to conventional chemotherapy agents.

  10. [Targeted pharmacist-led medication order review in hospital: Assessment of a selection method for drug prescriptions].

    Science.gov (United States)

    Jarre, C; Bouchet, J; Hellot-Guersing, M; Leromain, A-S; Derharoutunian, C; Gadot, A; Roubille, R

    2017-11-01

    The aim of this study was to assess a selection method for drug prescriptions developed at the hospital level that allows to target pharmacist-led medication order review for at-risk patients and drugs. A one-month study has been conducted on all targeted medication orders in 19 care units. Selection criteria have been identified: biological criteria, alert medications and drug interactions. Pharmacists' interventions proposed during medication order review were listed and the possible links to the selection criteria were determined. A total of 1612 prescriptions were analysed and 236 pharmacists' interventions were performed (14.6 interventions per 100 prescriptions). Physicians' acceptance rate was 60.6%. The percentage of pharmacists' interventions linked to the selection criteria was 35.6%. The relevance of the biological criteria was identified, particularly the one identifying patients with creatinine clearance below 30ml/min. Six alert medications were also relevant selection criteria: dabigatran, morphine, gentamicin, methotrexate, potassium chloride and trimethoprim sulfamethoxazole. Drug interactions criteria was irrelevant. This study allowed a first assessment of the selection criteria used. A largest study seems necessary to continue the analysis of this selection method for prescriptions, especially the assessment of the alert medications list, in order to refine the prescriptions targeting. Copyright © 2017 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

  11. Attention Blinks for Selection, Not Perception or Memory: Reading Sentences and Reporting Targets

    Science.gov (United States)

    Potter, Mary C.; Wyble, Brad; Olejarczyk, Jennifer

    2011-01-01

    In whole report, a sentence presented sequentially at the rate of about 10 words/s can be recalled accurately, whereas if the task is to report only two target words (e.g., red words), the second target suffers an attentional blink if it appears shortly after the first target. If these two tasks are carried out simultaneously, is there an…

  12. Deciding Where to Attend: Priming of Pop-Out Drives Target Selection

    Science.gov (United States)

    Brascamp, Jan W.; Blake, Randolph; Kristjansson, Arni

    2011-01-01

    With attention and eye-movements humans orient to targets of interest. This orienting occurs faster when the same target repeats: priming of pop-out (PoP). While reaction times (RTs) can be important, PoP's real function could be to steer "where" to orient, a possibility underexposed in many current paradigms, as these predesignate a target to…

  13. Microbial metabolomics: Replacing trial-and-error by the unbiased selection and ranking of targets

    NARCIS (Netherlands)

    Werf, M.J. van der; Jellema, R.H.; Hankemeier, T.

    2005-01-01

    Microbial production strains are currently improved using a combination of random and targeted approaches. In the case of a targeted approach, potential bottlenecks, feed-back inhibition, and side-routes are removed, and other processes of interest are targeted by overexpressing or knocking-out the

  14. Chemical biology based on target-selective degradation of proteins and carbohydrates using light-activatable organic molecules.

    Science.gov (United States)

    Toshima, Kazunobu

    2013-05-01

    Proteins and carbohydrates play crucial roles in a wide range of biological processes, including serious diseases. The development of novel and innovative methods for selective control of specific proteins and carbohydrates functions has attracted much attention in the field of chemical biology. In this account article, the development of novel chemical tools, which can degrade target proteins and carbohydrates by irradiation with a specific wavelength of light under mild conditions without any additives, is introduced. This novel class of photochemical agents promise bright prospects for finding not only molecular-targeted bioprobes for understanding of the structure-activity relationships of proteins and carbohydrates but also novel therapeutic drugs targeting proteins and carbohydrates.

  15. Effectiveness of a selective alcohol prevention program targeting personality risk factors: Results of interaction analyses.

    Science.gov (United States)

    Lammers, Jeroen; Goossens, Ferry; Conrod, Patricia; Engels, Rutger; Wiers, Reinout W; Kleinjan, Marloes

    2017-08-01

    To explore whether specific groups of adolescents (i.e., scoring high on personality risk traits, having a lower education level, or being male) benefit more from the Preventure intervention with regard to curbing their drinking behaviour. A clustered randomized controlled trial, with participants randomly assigned to a 2-session coping skills intervention or a control no-intervention condition. Fifteen secondary schools throughout The Netherlands; 7 schools in the intervention and 8 schools in the control condition. 699 adolescents aged 13-15; 343 allocated to the intervention and 356 to the control condition; with drinking experience and elevated scores in either negative thinking, anxiety sensitivity, impulsivity or sensation seeking. Differential effectiveness of the Preventure program was examined for the personality traits group, education level and gender on past-month binge drinking (main outcome), binge frequency, alcohol use, alcohol frequency and problem drinking, at 12months post-intervention. Preventure is a selective school-based alcohol prevention programme targeting personality risk factors. The comparator was a no-intervention control. Intervention effects were moderated by the personality traits group and by education level. More specifically, significant intervention effects were found on reducing alcohol use within the anxiety sensitivity group (OR=2.14, CI=1.40, 3.29) and reducing binge drinking (OR=1.76, CI=1.38, 2.24) and binge drinking frequency (β=0.24, p=0.04) within the sensation seeking group at 12months post-intervention. Also, lower educated young adolescents reduced binge drinking (OR=1.47, CI=1.14, 1.88), binge drinking frequency (β=0.25, p=0.04), alcohol use (OR=1.32, CI=1.06, 1.65) and alcohol use frequency (β=0.47, p=0.01), but not those in the higher education group. Post hoc latent-growth analyses revealed significant effects on the development of binge drinking (β=-0.19, p=0.02) and binge drinking frequency (β=-0.10, p=0

  16. From Target Selection to Post-Stimulation Analysis: Example of an Unconventional Faulted Reservoir

    Science.gov (United States)

    LeCalvez, J. H.; Williams, M.; Xu, W.; Stokes, J.; Moros, H.; Maxwell, S. C.; Conners, S.

    2011-12-01

    As the global balance of supply and demand forces the hydrocarbon industry toward unconventional resources, technology- and economics-driven shale oil and gas production is gaining momentum throughout many basins worldwide. Production from such unconventional plays is facilitated by massive hydraulic fracturing treatments aimed at increasing permeability and reactivating natural fractures. Large-scale faulting and fracturing partly control stress distribution, hence stimulation-derived hydraulically-induced fracture systems development. Therefore, careful integrated approaches to target selection, treatment staging, and stimulation methods need to be used to economically maximize ultimate hydrocarbon recovery. We present a case study of a multistage, multilateral stimulation project in the Fort Worth Basin, Texas. Wells had to be drilled within city limits in a commercially developing building area. Well locations and trajectories were determined in and around large-scale faults using 3D surface seismic with throws varying from seven to thirty meters. As a result, three horizontal wells were drilled in the Lower Barnett Shale section, 150 m apart with the central well landed about 25 m shallower than the outside laterals. Surface seismic indicates that the surface locations are on top of a major fault complex with the lateral sections drilling away from the major fault system and through a smaller fault. Modeling of the borehole-based microseismic monitoring options led to the selection of an optimum set of configurations given the operational restrictions faced: monitoring would mainly take place using a horizontal array to be tractored downhole and moved according to the well and stage to be monitored. Wells were completed using a perf-and-plug approach allowing for each stimulation stage to obtain a precise orientation of the various three-component accelerometers of the monitoring array as well as the calibration of the velocity model used to process the

  17. Selecting aesthetic gynecologic procedures for plastic surgeons: a review of target methodology.

    Science.gov (United States)

    Ostrzenski, Adam

    2013-04-01

    The objective of this article was to assist cosmetic-plastic surgeons in selecting aesthetic cosmetic gynecologic-plastic surgical interventions. Target methodological analyses of pertinent evidence-based scientific papers and anecdotal information linked to surgical techniques for cosmetic-plastic female external genitalia were examined. A search of the existing literature from 1900 through June 2011 was performed by utilizing electronic and manual databases. A total of 87 articles related to cosmetic-plastic gynecologic surgeries were identified in peer-review journals. Anecdotal information was identified in three sources (Barwijuk, Obstet Gynecol J 9(3):2178-2179, 2011; Benson, 5th annual congress on aesthetic vaginal surgery, Tucson, AZ, USA, November 14-15, 2010; Scheinberg, Obstet Gynecol J 9(3):2191, 2011). Among those articles on cosmetic-plastic gynecologic surgical technique that were reviewed, three articles met the criteria for evidence-based medicine level II, one article was level II-1 and two papers were level II-2. The remaining papers were classified as level III. The pertinent 25 papers met the inclusion criteria and were analyzed. There was no documentation on the safety and effectiveness of cosmetic-plastic gynecologic procedures in the scientific literature. All published surgical interventions are not suitable for a cosmetic-plastic practice. The absence of documentation on safety and effectiveness related to cosmetic-plastic gynecologic procedures prevents the establishment of a standard of practice. Traditional gynecologic surgical procedures cannot be labeled and used as cosmetic-plastic procedures, it is a deceptive practice. Obtaining legal trademarks on traditional gynecologic procedures and creating a business model that tries to control clinical-scientific knowledge dissemination is unethical. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings

  18. Nicotine facilitates nicotinic acetylcholine receptor targeting to mitochondria but makes them less susceptible to selective ligands.

    Science.gov (United States)

    Uspenska, Kateryna; Lykhmus, Olena; Gergalova, Galyna; Chernyshov, Volodymyr; Arias, Hugo R; Komisarenko, Sergiy; Skok, Maryna

    2017-08-24

    Several nicotinic acetylcholine receptor (nAChR) subtypes are expressed in mitochondria to regulate the internal pathway of apoptosis in ion channel-independent manner. However, the mechanisms of nAChR activation in mitochondria and targeting to mitochondria are still unknown. Nicotine has been shown to favor nAChR pentamer assembly, folding, and maturation on the way of biosynthesis. The idea of the present work was to determine whether nicotine affects the content, glycosylation, and function of mitochondrial nAChRs. Experiments were performed in isolated liver mitochondria from mice, that either consumed or not nicotine with the drinking water (200μL/L) for 7days. Mitochondria detergent lysates were studied by sandwich or lectin ELISA for the presence and carbohydrate composition of different nAChR subunits. Intact mitochondria were examined by flow cytometry for the binding of fluorescently labeled α-cobratoxin and were tested in functional assay of cytochrome c release under the effect of either Ca 2+ or wortmannin in the presence or absence of nAChR-selective ligands, including PNU-282987 (1nM), dihydro-β-erythroidine (DhβE, 1μM), PNU-120596 (0.3, 3, or 10μM) and desformylflustrabromine hydrochloride (dFBr, 0.001, 0.3, or 1μM). It was found that nicotine consumption increased the ratio of mitochondrial vs non-mitochondrial nAChRs in the liver, enhanced fucosylation of mitochondrial nAChRs, but prevented the binding of α-cobratoxin and the cytochrome c release-attenuating effects of nAChR-specific agonists, antagonists, or positive allosteric modulators. It is concluded that nicotine consumption in vivo favors nAChR glycosylation and trafficking to mitochondria but makes them less susceptible to the effects of specific ligands. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Thioredoxin Selectivity for Thiol-based Redox Regulation of Target Proteins in Chloroplasts*

    Science.gov (United States)

    Yoshida, Keisuke; Hara, Satoshi; Hisabori, Toru

    2015-01-01

    Redox regulation based on the thioredoxin (Trx) system is believed to ensure light-responsive control of various functions in chloroplasts. Five Trx subtypes have been reported to reside in chloroplasts, but their functional diversity in the redox regulation of Trx target proteins remains poorly clarified. To directly address this issue, we studied the Trx-dependent redox shifts of several chloroplast thiol-modulated enzymes in vitro and in vivo. In vitro assays using a series of Arabidopsis recombinant proteins provided new insights into Trx selectivity for the redox regulation as well as the underpinning for previous suggestions. Most notably, by combining the discrimination of thiol status with mass spectrometry and activity measurement, we identified an uncharacterized aspect of the reductive activation of NADP-malate dehydrogenase; two redox-active Cys pairs harbored in this enzyme were reduced via distinct utilization of Trxs even within a single polypeptide. In our in vitro assays, Trx-f was effective in reducing all thiol-modulated enzymes analyzed here. We then investigated the in vivo physiological relevance of these in vitro findings, using Arabidopsis wild-type and Trx-f-deficient plants. Photoreduction of fructose-1,6-bisphosphatase was partially impaired in Trx-f-deficient plants, but the global impact of Trx-f deficiency on the redox behaviors of thiol-modulated enzymes was not as striking as expected from the in vitro data. Our results provide support for the in vivo functionality of the Trx system and also highlight the complexity and plasticity of the chloroplast redox network. PMID:25878252

  20. Cell Density Affects the Detection of Chk1 Target Engagement by the Selective Inhibitor V158411.

    Science.gov (United States)

    Geneste, Clara C; Massey, Andrew J

    2018-02-01

    Understanding drug target engagement and the relationship to downstream pharmacology is critical for drug discovery. Here we have evaluated target engagement of Chk1 by the small-molecule inhibitor V158411 using two different target engagement methods (autophosphorylation and cellular thermal shift assay [CETSA]). Target engagement measured by these methods was subsequently related to Chk1 inhibitor-dependent pharmacology. Inhibition of autophosphorylation was a robust method for measuring V158411 Chk1 target engagement. In comparison, while target engagement determined using CETSA appeared robust, the V158411 CETSA target engagement EC 50 values were 43- and 19-fold greater than the autophosphorylation IC 50 values. This difference was attributed to the higher cell density in the CETSA assay configuration. pChk1 (S296) IC 50 values determined using the CETSA assay conditions were 54- and 33-fold greater than those determined under standard conditions and were equivalent to the CETSA EC 50 values. Cellular conditions, especially cell density, influenced the target engagement of V158411 for Chk1. The effects of high cell density on apparent compound target engagement potency should be evaluated when using target engagement assays that necessitate high cell densities (such as the CETSA conditions used in this study). In such cases, the subsequent relation of these data to downstream pharmacological changes should therefore be interpreted with care.

  1. Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorder Symptoms and Unhealthy Weight Gain among Female College Students

    Science.gov (United States)

    Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

    2012-01-01

    Objective: Evaluate a selective prevention program targeting both eating disorder symptoms and unhealthy weight gain in young women. Method: Female college students at high-risk for these outcomes by virtue of body image concerns (N = 398; M age = 18.4 years, SD = 0.6) were randomized to the Healthy Weight group-based 4-hr prevention program,…

  2. Optimal management of radial artery grafts in CABG: Patient and target vessel selection and anti-spasm therapy.

    Science.gov (United States)

    Schwann, Thomas A; Gaudino, Mario; Baldawi, Mustafa; Tranbaugh, Robert; Schwann, Alexandra N; Habib, Robert H

    2018-05-01

    The current literature on radial artery grafting is reviewed focusing on the optimal deployment of radial artery grafts in coronary artery bypass surgery with specific attention to the selection of patients and target vessels for radial artery grafting. © 2018 Wiley Periodicals, Inc.

  3. Trial-to-trial dynamics of selective long-term-memory retrieval with continuously changing retrieval targets.

    Science.gov (United States)

    Kizilirmak, Jasmin M; Rösler, Frank; Khader, Patrick H

    2014-10-01

    How do we control the successive retrieval of behaviorally relevant information from long-term memory (LTM) without being distracted by other potential retrieval targets associated to the same retrieval cues? Here, we approach this question by investigating the nature of trial-by-trial dynamics of selective LTM retrieval, i.e., in how far retrieval in one trial has detrimental or facilitatory effects on selective retrieval in the following trial. Participants first learned associations between retrieval cues and targets, with one cue always being linked to three targets, forming small associative networks. In successive trials, participants had to access either the same or a different target belonging to either the same or a different cue. We found that retrieval times were faster for targets that had already been relevant in the previous trial, with this facilitatory effect being substantially weaker when the associative network changed in which the targets were embedded. Moreover, staying within the same network still had a facilitatory effect even if the target changed, which became evident in a relatively higher memory performance in comparison to a network change. Furthermore, event-related brain potentials (ERPs) showed topographically and temporally dissociable correlates of these effects, suggesting that they result from combined influences of distinct processes that aid memory retrieval when relevant and irrelevant targets change their status from trial to trial. Taken together, the present study provides insight into the different processing stages of memory retrieval when fast switches between retrieval targets are required. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. State-selective electron capture into He-like U90+ ions in collisions with gaseous targets

    International Nuclear Information System (INIS)

    Ma, X.; Stoehlker, T.; Brinzanescu, O.; Fritzsche, S.; Ludziejewski, T.; Stachura, Z.; Warczak, A.

    2000-11-01

    For He-like uranium, a state-selective electron capture study was carried out for relativistic collisions with gaseous targets. In the experiment, the projectile X-ray emission produced by electron capture in collisions of 223 MeV/u U 90+ ions on N 2 , Ar, Kr, and Xe targets was measured in coincidence with down-charged U 89+ projectiles. Due to the large fine structure splitting in heavy ions, the well resolved Balmer transitions observed were used to deduce subshell sensitive cross-sections for electron capture. For this purpose a theoretical spectrum analysis and simulation was performed by taking into account electron cascades from states up to n = 40. The state-selective data are compared with theoretical calculations as a function of target atomic number. An overall agreement is found between the experimental data and the theoretical approaches applied except for the j-sensitive part. (orig.)

  5. Selective Detection of Target Volatile Organic Compounds in Contaminated Humid Air Using a Sensor Array with Principal Component Analysis

    Science.gov (United States)

    Itoh, Toshio; Akamatsu, Takafumi; Tsuruta, Akihiro; Shin, Woosuck

    2017-01-01

    We investigated selective detection of the target volatile organic compounds (VOCs) nonanal, n-decane, and acetoin for lung cancer-related VOCs, and acetone and methyl i-butyl ketone for diabetes-related VOCs, in humid air with simulated VOC contamination (total concentration: 300 μg/m3). We used six “grain boundary-response type” sensors, including four commercially available sensors (TGS 2600, 2610, 2610, and 2620) and two Pt, Pd, and Au-loaded SnO2 sensors (Pt, Pd, Au/SnO2), and two “bulk-response type” sensors, including Zr-doped CeO2 (CeZr10), i.e., eight sensors in total. We then analyzed their sensor signals using principal component analysis (PCA). Although the six “grain boundary-response type” sensors were found to be insufficient for selective detection of the target gases in humid air, the addition of two “bulk-response type” sensors improved the selectivity, even with simulated VOC contamination. To further improve the discrimination, we selected appropriate sensors from the eight sensors based on the PCA results. The selectivity to each target gas was maintained and was not affected by contamination. PMID:28753948

  6. Acquisitions as lotteries? : The selection of target-firm risk and its impact on merger outcomes

    NARCIS (Netherlands)

    Schneider, C.A.R.; Spalt, Oliver

    2017-01-01

    From 1987 to 2008, riskier firms were more likely to be taken over. Yet, on average, the acquirer declined in value by 2.8% when it bought a "risky target" (the third tercile, having an annualized idiosyncratic volatility of 61% or more), but only by 0.6% when it bought a "safe target" (the first

  7. Restoration for the future: Setting endpoints and targets and selecting indicators of progress and success

    Science.gov (United States)

    Daniel C. Dey; Callie Jo Schweitzer; John M. Kabrick

    2014-01-01

    Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly written and quantitative endpoints and intermediary targets need to be...

  8. Selection of Novel Peptides Homing the 4T1 CELL Line: Exploring Alternative Targets for Triple Negative Breast Cancer.

    Directory of Open Access Journals (Sweden)

    Vera L Silva

    Full Text Available The use of bacteriophages to select novel ligands has been widely explored for cancer therapy. Their application is most warranted in cancer subtypes lacking knowledge on how to target the cancer cells in question, such as the triple negative breast cancer, eventually leading to the development of alternative nanomedicines for cancer therapeutics. Therefore, the following study aimed to select and characterize novel peptides for a triple negative breast cancer murine mammary carcinoma cell line- 4T1. Using phage display, 7 and 12 amino acid random peptide libraries were screened against the 4T1 cell line. A total of four rounds, plus a counter-selection round using the 3T3 murine fibroblast cell line, was performed. The enriched selective peptides were characterized and their binding capacity towards 4T1 tissue samples was confirmed by immunofluorescence and flow cytometry analysis. The selected peptides (4T1pep1 -CPTASNTSC and 4T1pep2-EVQSSKFPAHVS were enriched over few rounds of selection and exhibited specific binding to the 4T1 cell line. Interestingly, affinity to the human MDA-MB-231 cell line was also observed for both peptides, promoting the translational application of these novel ligands between species. Additionally, bioinformatics analysis suggested that both peptides target human Mucin-16. This protein has been implicated in different types of cancer, as it is involved in many important cellular functions. This study strongly supports the need of finding alternative targeting systems for TNBC and the peptides herein selected exhibit promising future application as novel homing peptides for breast cancer therapy.

  9. Comparing the Selection and Placement of Best Management Practices in Improving Water Quality Using a Multiobjective Optimization and Targeting Method

    Directory of Open Access Journals (Sweden)

    Li-Chi Chiang

    2014-03-01

    Full Text Available Suites of Best Management Practices (BMPs are usually selected to be economically and environmentally efficient in reducing nonpoint source (NPS pollutants from agricultural areas in a watershed. The objective of this research was to compare the selection and placement of BMPs in a pasture-dominated watershed using multiobjective optimization and targeting methods. Two objective functions were used in the optimization process, which minimize pollutant losses and the BMP placement areas. The optimization tool was an integration of a multi-objective genetic algorithm (GA and a watershed model (Soil and Water Assessment Tool—SWAT. For the targeting method, an optimum BMP option was implemented in critical areas in the watershed that contribute the greatest pollutant losses. A total of 171 BMP combinations, which consist of grazing management, vegetated filter strips (VFS, and poultry litter applications were considered. The results showed that the optimization is less effective when vegetated filter strips (VFS are not considered, and it requires much longer computation times than the targeting method to search for optimum BMPs. Although the targeting method is effective in selecting and placing an optimum BMP, larger areas are needed for BMP implementation to achieve the same pollutant reductions as the optimization method.

  10. Targeting MED1 LxxLL Motifs for Tissue-Selective Treatment of Human Breast Cancer

    Science.gov (United States)

    2014-09-01

    microRNA, antisense oligonucleotides, and RNA aptamers, has long been extensively studied (Guo 2010; Keefe et al. 2010; Levy-Nissenbaum et al. 2008; Que...targeted drug delivery when compared with DNA aptamers, protein aptamers, and antibodies (Guo 2010; Keefe et al. 2010; Que-Gewirth and Sullenger...or even organisms (Dua et al. 2011; Keefe et al. 2010; Levy-Nissenbaum et al. 2008; Thiel and Giangrande 2010). Those that do not bind to the target

  11. Split and Splice Approach for Highly Selective Targeting of Human NSCLC Tumors

    Science.gov (United States)

    2014-10-01

    development and implementation of the “split-and- spice ” approach required optimization of many independent parameters, which were addressed in parallel...verify the feasibility of the “split and splice” approach for targeting human NSCLC tumor cell lines in culture and prepare the optimized toxins for...for cultured cells (months 2- 8). 2B. To test the efficiency of cell targeting by the toxin variants reconstituted in vitro (months 3-6). 2C. To

  12. Selecting target populations for ROPS retrofit programs in Pennsylvania and Vermont.

    Science.gov (United States)

    Yoder, A M; Sorensen, J A; Foster, F; Myers, M; Murphy, D; Cook, G; May, J; Jenkins, P

    2013-07-01

    Agriculture has the highest injury and fatality rates when compared with other U.S. industries, and tractor overturns remain the leading cause of agricultural fatalities. Rollover protection structures (ROPS) are the only proven devices to protect a tractor operator in the event of an overturn. These devices are 99% effective when used with a seatbelt. Nearly 49% of tractors in the U.S. are not equipped with a ROPS. Interventions such as social marketing, community awareness campaigns, and financial incentives have been directed at encouraging farmers to install ROPS on their unprotected tractors. The purpose of this study was to conduct similar comparisons of ROPS protection and readiness to retrofit in different segments of the Vermont and Pennsylvania farm communities. A telephone survey was used to collect data on ROPS prevalence, farm demographic characteristics, and farmer's stage of change relative to installing ROPS on farm tractors. Our data provide new and unique information on the prevalence of ROPS-equipped tractors relative to commodity, farm size, and a variety of other demographic variables. Extrapolating from these data, the commodities studied account for roughly 162,072 tractors across the two states. Of these, 85,927 (53%) do not have ROPS. Of these unprotected tractors, 77,203 are in Pennsylvania and 8,724 are in Vermont. Our other two research questions dealt with the farmer's stage of change and possible ways to segment this population. The stage of change portion of our work demonstrates that most Pennsylvania and Vermont farmers are not contemplating ROPS retrofitting in the near future. Since no major differences were found in the stage of change, the number of unprotected tractors was examined for each of the commodity groups. In Pennsylvania, 29% of all unprotected tractors were found on cash crop farms. This trend was even more apparent on smaller farms than large farms. This led to the selection of smaller cash crop farms as the target

  13. SPIDERS: selection of spectroscopic targets using AGN candidates detected in all-sky X-ray surveys

    Science.gov (United States)

    Dwelly, T.; Salvato, M.; Merloni, A.; Brusa, M.; Buchner, J.; Anderson, S. F.; Boller, Th.; Brandt, W. N.; Budavári, T.; Clerc, N.; Coffey, D.; Del Moro, A.; Georgakakis, A.; Green, P. J.; Jin, C.; Menzel, M.-L.; Myers, A. D.; Nandra, K.; Nichol, R. C.; Ridl, J.; Schwope, A. D.; Simm, T.

    2017-07-01

    SPIDERS (SPectroscopic IDentification of eROSITA Sources) is a Sloan Digital Sky Survey IV (SDSS-IV) survey running in parallel to the Extended Baryon Oscillation Spectroscopic Survey (eBOSS) cosmology project. SPIDERS will obtain optical spectroscopy for large numbers of X-ray-selected active galactic nuclei (AGN) and galaxy cluster members detected in wide-area eROSITA, XMM-Newton and ROSAT surveys. We describe the methods used to choose spectroscopic targets for two sub-programmes of SPIDERS X-ray selected AGN candidates detected in the ROSAT All Sky and the XMM-Newton Slew surveys. We have exploited a Bayesian cross-matching algorithm, guided by priors based on mid-IR colour-magnitude information from the Wide-field Infrared Survey Explorer survey, to select the most probable optical counterpart to each X-ray detection. We empirically demonstrate the high fidelity of our counterpart selection method using a reference sample of bright well-localized X-ray sources collated from XMM-Newton, Chandra and Swift-XRT serendipitous catalogues, and also by examining blank-sky locations. We describe the down-selection steps which resulted in the final set of SPIDERS-AGN targets put forward for spectroscopy within the eBOSS/TDSS/SPIDERS survey, and present catalogues of these targets. We also present catalogues of ˜12 000 ROSAT and ˜1500 XMM-Newton Slew survey sources that have existing optical spectroscopy from SDSS-DR12, including the results of our visual inspections. On completion of the SPIDERS programme, we expect to have collected homogeneous spectroscopic redshift information over a footprint of ˜7500 deg2 for >85 per cent of the ROSAT and XMM-Newton Slew survey sources having optical counterparts in the magnitude range 17 < r < 22.5, producing a large and highly complete sample of bright X-ray-selected AGN suitable for statistical studies of AGN evolution and clustering.

  14. ERP markers of target selection discriminate children with high vs. low working memory capacity

    Directory of Open Access Journals (Sweden)

    Andria eShimi

    2015-11-01

    Full Text Available Selective attention enables enhancing a subset out of multiple competing items to maximize the capacity of our limited visual working memory (VWM system. Multiple behavioral and electrophysiological studies have revealed the cognitive and neural mechanisms supporting adults’ selective attention of visual percepts for encoding in VWM. However, research on children is more limited. What are the neural mechanisms involved in children’s selection of incoming percepts in service of VWM? Do these differ from the ones subserving adults’ selection? Ten-year-olds and adults used a spatial arrow cue to select a colored item for later recognition from an array of four colored items. The temporal dynamics of selection were investigated through EEG signals locked to the onset of the memory array. Both children and adults elicited significantly more negative activity over posterior scalp locations contralateral to the item to-be-selected for encoding (N2pc. However, this activity was elicited later and for longer in children compared to adults. Furthermore, although children as a group did not elicit a significant N2pc during the time-window in which N2pc was elicited in adults, the magnitude of N2pc during the adult time-window related to their behavioral performance during the later recognition phase of the task. This in turn highlights how children’s neural activity subserving attention during encoding relates to better subsequent VWM performance. Significant differences were observed when children were divided into groups of high vs. low VWM capacity as a function of cueing benefit. Children with large cue benefits in VWM capacity elicited an adult-like contralateral negativity following attentional selection of the to-be-encoded item, whereas children with low VWM capacity did not. These results corroborate the close coupling between selective attention and VWM from childhood and elucidate further the attentional mechanisms constraining VWM

  15. ERP markers of target selection discriminate children with high vs. low working memory capacity.

    Science.gov (United States)

    Shimi, Andria; Nobre, Anna Christina; Scerif, Gaia

    2015-01-01

    Selective attention enables enhancing a subset out of multiple competing items to maximize the capacity of our limited visual working memory (VWM) system. Multiple behavioral and electrophysiological studies have revealed the cognitive and neural mechanisms supporting adults' selective attention of visual percepts for encoding in VWM. However, research on children is more limited. What are the neural mechanisms involved in children's selection of incoming percepts in service of VWM? Do these differ from the ones subserving adults' selection? Ten-year-olds and adults used a spatial arrow cue to select a colored item for later recognition from an array of four colored items. The temporal dynamics of selection were investigated through EEG signals locked to the onset of the memory array. Both children and adults elicited significantly more negative activity over posterior scalp locations contralateral to the item to-be-selected for encoding (N2pc). However, this activity was elicited later and for longer in children compared to adults. Furthermore, although children as a group did not elicit a significant N2pc during the time-window in which N2pc was elicited in adults, the magnitude of N2pc during the "adult time-window" related to their behavioral performance during the later recognition phase of the task. This in turn highlights how children's neural activity subserving attention during encoding relates to better subsequent VWM performance. Significant differences were observed when children were divided into groups of high vs. low VWM capacity as a function of cueing benefit. Children with large cue benefits in VWM capacity elicited an adult-like contralateral negativity following attentional selection of the to-be-encoded item, whereas children with low VWM capacity did not. These results corroborate the close coupling between selective attention and VWM from childhood and elucidate further the attentional mechanisms constraining VWM performance in children.

  16. Use of mathematics to guide target selection in systems pharmacology; application to receptor tyrosine kinase (RTK) pathways.

    Science.gov (United States)

    Benson, Neil; van der Graaf, Piet H; Peletier, Lambertus A

    2017-11-15

    A key element of the drug discovery process is target selection. Although the topic is subject to much discussion and experimental effort, there are no defined quantitative rules around optimal selection. Often 'rules of thumb', that have not been subject to rigorous exploration, are used. In this paper we explore the 'rule of thumb' notion that the molecule that initiates a pathway signal is the optimal target. Given the multi-factorial and complex nature of this question, we have simplified an example pathway to its logical minimum of two steps and used a mathematical model of this to explore the different options in the context of typical small and large molecule drugs. In this paper, we report the conclusions of our analysis and describe the analysis tool and methods used. These provide a platform to enable a more extensive enquiry into this important topic. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Method for selecting hollow microspheres for use in laser fusion targets

    Science.gov (United States)

    Farnum, Eugene H.; Fries, R. Jay; Havenhill, Jerry W.; Smith, Maurice Lee; Stoltz, Daniel L.

    1976-01-01

    Hollow microspheres having thin and very uniform wall thickness are useful as containers for the deuterium and tritium gas mixture used as a fuel in laser fusion targets. Hollow microspheres are commercially available; however, in commercial lots only a very small number meet the rigid requirements for use in laser fusion targets. Those meeting these requirements may be separated from the unsuitable ones by subjecting the commercial lot to size and density separations and then by subjecting those hollow microspheres thus separated to an external pressurization at which those which are aspherical or which have nonuniform walls are broken and separating the sound hollow microspheres from the broken ones.

  18. Targeting hunter distribution based on host resource selection and kill sites to manage disease risk

    DEFF Research Database (Denmark)

    Dugal, Cherie; van Beest, Floris; Vander Wal, Eric

    2013-01-01

    Endemic and emerging diseases are rarely uniform in their spatial distribution or prevalence among cohorts of wildlife. Spatial models that quantify risk-driven differences in resource selection and hunter mortality of animals at fine spatial scales can assist disease management by identifying high-risk...... areas and individuals. We used resource selection functions (RSFs) and selection ratios (SRs) to quantify sex- and age-specific resource selection patterns of collared (n = 67) and hunter-killed (n = 796) nonmigratory elk (Cervus canadensis manitobensis) during the hunting season between 2002 and 2012...... juvenile males and hunter-killed adult females. In instances where disease infects a metapopulation and eradication is infeasible, a principle goal of management is to limit the spread of disease among infected animals. We map high-risk areas that are regularly used by potentially infectious hosts...

  19. A target recognition method for maritime surveillance radars based on hybrid ensemble selection

    Science.gov (United States)

    Fan, Xueman; Hu, Shengliang; He, Jingbo

    2017-11-01

    In order to improve the generalisation ability of the maritime surveillance radar, a novel ensemble selection technique, termed Optimisation and Dynamic Selection (ODS), is proposed. During the optimisation phase, the non-dominated sorting genetic algorithm II for multi-objective optimisation is used to find the Pareto front, i.e. a set of ensembles of classifiers representing different tradeoffs between the classification error and diversity. During the dynamic selection phase, the meta-learning method is used to predict whether a candidate ensemble is competent enough to classify a query instance based on three different aspects, namely, feature space, decision space and the extent of consensus. The classification performance and time complexity of ODS are compared against nine other ensemble methods using a self-built full polarimetric high resolution range profile data-set. The experimental results clearly show the effectiveness of ODS. In addition, the influence of the selection of diversity measures is studied concurrently.

  20. Quantitative PET Imaging with Novel HER3 Targeted Peptides Selected by Phage Display to Predict Androgen Independent Prostate Cancer Progression

    Science.gov (United States)

    2017-08-01

    Independent Prostate Cancer Progression PRINCIPAL INVESTIGATOR: Benjamin Larimer, PhD CONTRACTING ORGANIZATION: Massachusetts General Hospital Boston...3. DATES COVERED 1 Aug 2016 – 31 July 2017 4. TITLE AND SUBTITLE Cancer Progression 5a. CONTRACT NUMBER Quantitative PET Imaging with Novel HER3...Targeted Peptides Selected by Phage Display to Predict Androgen-Independent Prostate Cancer Progression 5b. GRANT NUMBER W81XWH-16-1-0447 5c

  1. Highly Stable Aptamers Selected from a 2′-Fully Modified fGmH RNA Library for Targeting Biomaterials

    Science.gov (United States)

    Friedman, Adam D.; Kim, Dongwook; Liu, Rihe

    2014-01-01

    When developed as targeting ligands for the in vivo delivery of biomaterials to biological systems, RNA aptamers immediately face numerous obstacles, in particular nuclease degradation and post-selection 2′ modification. This study aims to develop a novel class of highly stable, 2′-fully modified RNA aptamers that are ideal for the targeted delivery of biomaterials. We demonstrated the facile transcription of a fGmH (2′-F-dG, 2′-OMe-dA/dC/dU) RNA library with unexpected hydrophobicity, the direct selection of aptamers from a fGmH RNA library that bind Staphylococcus aureus Protein A (SpA) as a model target, and the superior nuclease and serum stability of these aptamers compared to 2′-partially modified RNA variants. Characterizations of fGmH RNA aptamers binding to purified SpA and to endogenous SpA present on the surface of S. aureus cells demonstrate fGmH RNA aptamer selectivity and stability. Significantly, fGmH RNA aptamers were able to functionalize, stabilize, and further deliver aggregation-prone silver nanoparticles (AgNPs) to S. aureus with SpA-dependent antimicrobial effects. This study describes a novel aptamer class with considerable potential to improve the in vivo applicability of nucleic acid-based affinity molecules to biomaterials. PMID:25443790

  2. Highly stable aptamers selected from a 2'-fully modified fGmH RNA library for targeting biomaterials.

    Science.gov (United States)

    Friedman, Adam D; Kim, Dongwook; Liu, Rihe

    2015-01-01

    When developed as targeting ligands for the in vivo delivery of biomaterials to biological systems, RNA aptamers immediately face numerous obstacles, in particular nuclease degradation and post-selection 2' modification. This study aims to develop a novel class of highly stable, 2'-fully modified RNA aptamers that are ideal for the targeted delivery of biomaterials. We demonstrated the facile transcription of a fGmH (2'-F-dG, 2'-OMe-dA/dC/dU) RNA library with unexpected hydrophobicity, the direct selection of aptamers from a fGmH RNA library that bind Staphylococcus aureus Protein A (SpA) as a model target, and the superior nuclease and serum stability of these aptamers compared to 2'-partially modified RNA variants. Characterizations of fGmH RNA aptamers binding to purified SpA and to endogenous SpA present on the surface of S. aureus cells demonstrate fGmH RNA aptamer selectivity and stability. Significantly, fGmH RNA aptamers were able to functionalize, stabilize, and specifically deliver aggregation-prone silver nanoparticles (AgNPs) to S. aureus with SpA-dependent antimicrobial effects. This study describes a novel aptamer class with considerable potential to improve the in vivo applicability of nucleic acid-based affinity molecules to biomaterials.

  3. Food pantry selection solutions: a randomized controlled trial in client-choice food pantries to nudge clients to targeted foods.

    Science.gov (United States)

    Wilson, Norbert L W; Just, David R; Swigert, Jeffery; Wansink, Brian

    2017-06-01

    Food pantries and food banks are interested in cost-effective methods to encourage the selection of targeted foods without restricting choices. Thus, this study evaluates the effectiveness of nudges toward targeted foods. In October/November 2014, we manipulated the display of a targeted product in a New York State food pantry. We evaluated the binary choice of the targeted good when we placed it in the front or the back of the category line (placement order) and when we presented the product in its original box or unboxed (packaging). The average uptake proportion for the back treatment was 0.231, 95% CI = 0.179, 0.29, n = 205, and for the front treatment, the proportion was 0.337, 95% CI = 0.272, 0.406, n = 238 with an odds ratio of 1.688, 95% CI = 1.088, 2.523. The average uptake for the unboxed treatment was 0.224, 95% CI = 0.174, 0.280, n = 255, and for the boxed intervention, the proportion was 0.356, 95% CI = 0.288, 0.429, n = 188 with an odds ratio of 1.923, 95% CI = 1.237, 2.991. Nudges increased uptake of the targeted food. The findings also hold when we control for a potential confounder. Low cost and unobtrusive nudges can be effective tools for food pantry organizers to encourage the selection of targeted foods. NCT02403882. © The Author 2016. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. Selection and Characterization of Single Chain Antibody Fragments Specific for Hsp90 as a Potential Cancer Targeting Molecule

    Directory of Open Access Journals (Sweden)

    Edyta Petters

    2015-08-01

    Full Text Available Heat shock proteins play an essential role in facilitating malignant transformation and they have been recognized as important factors in human cancers. One of the key elements of the molecular chaperones machinery is Hsp90 and it has recently become a target for anticancer therapeutic approaches. The potential and importance of Hsp90-directed agents becomes apparent when one realizes that disruption of Hsp90 function may influence over 200 oncogenic client proteins. Here, we described the selection and characterization of Hsp90-specific antibody fragments from commercially available Tomlinson I and J phage display libraries. The affinities of Hsp90-binding scFv variants were measured using SPR method. Then, based on the best clone selected, we performed the affinity maturation procedure and obtained valuable Hsp90-specific clones. The selected binders were expressed and applied for immunostaining, ELISA and SPR analysis using model cancer cell lines. All performed experiments confirmed the ability of selected antibodies to interact with the Hsp90. Therefore, the presented Hsp90-specific scFv, might be a starting point for the development of a novel antibody-based strategy targeting cancer.

  5. Radioiodinated methylene blue for melanoma targeting: Chemical characterisation and tumour selectivity of labelled components

    International Nuclear Information System (INIS)

    Blower, Philip J.; Clark, Katherine; Link, Eva M.

    1997-01-01

    Radioiodinated methylene blue contains a mixture of components showing selective uptake in human pigmented melanoma, and it has potential for imaging and therapy. Nuclear magnetic resonance and mass spectroscopic studies show that the majority of the radioactivity (85%) is in the form of monoiodinated methylene blue, 4-iodo-3-methylamino-7-dimethylaminophenaza thionium chloride. The amino group ortho-to iodine has become demethylated to a mono-methylamino group. The remainder (15%) of the mixture is the doubly labelled 4,5-diiodo-3,7-bis(methylamino) phenazathionium chloride. The separated components show similar tumour selectivity in athymic mice bearing human pigmented melanomas

  6. GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation

    Directory of Open Access Journals (Sweden)

    Li Wang

    2018-01-01

    Full Text Available Precise control of gene expression during development is orchestrated by transcription factors and co-regulators including chromatin modifiers. How particular chromatin-modifying enzymes affect specific developmental processes is not well defined. Here, we report that GCN5, a histone acetyltransferase essential for embryonic development, is required for proper expression of multiple genes encoding components of the fibroblast growth factor (FGF signaling pathway in early embryoid bodies (EBs. Gcn5−/− EBs display deficient activation of ERK and p38, mislocalization of cytoskeletal components, and compromised capacity to differentiate toward mesodermal lineage. Genomic analyses identified seven genes as putative direct targets of GCN5 during early differentiation, four of which are cMYC targets. These findings established a link between GCN5 and the FGF signaling pathway and highlighted specific GCN5-MYC partnerships in gene regulation during early differentiation.

  7. Pathway-selective sensitization of Mycobacterium tuberculosis for target-based whole-cell screening

    Science.gov (United States)

    Abrahams, Garth L.; Kumar, Anuradha; Savvi, Suzana; Hung, Alvin W.; Wen, Shijun; Abell, Chris; Barry, Clifton E.; Sherman, David R.; Boshoff, Helena I.M.; Mizrahi, Valerie

    2012-01-01

    SUMMARY Whole-cell screening of Mycobacterium tuberculosis (Mtb) remains a mainstay of drug discovery but subsequent target elucidation often proves difficult. Conditional mutants that under-express essential genes have been used to identify compounds with known mechanism of action by target-based whole-cell screening (TB-WCS). Here, the feasibility of TB-WCS in Mtb was assessed by generating mutants that conditionally express pantothenate synthetase (panC), diaminopimelate decarboxylase (lysA) and isocitrate lyase (icl1). The essentiality of panC and lysA, and conditional essentiality of icl1 for growth on fatty acids, was confirmed. Depletion of PanC and Icl1 rendered the mutants hypersensitive to target-specific inhibitors. Stable reporter strains were generated for use in high-throughput screening, and their utility demonstrated by identifying compounds that display greater potency against a PanC-depleted strain. These findings illustrate the power of TB-WCS as a tool for tuberculosis drug discovery. PMID:22840772

  8. Variable selection for confounder control, flexible modeling and Collaborative Targeted Minimum Loss-based Estimation in causal inference

    Science.gov (United States)

    Schnitzer, Mireille E.; Lok, Judith J.; Gruber, Susan

    2015-01-01

    This paper investigates the appropriateness of the integration of flexible propensity score modeling (nonparametric or machine learning approaches) in semiparametric models for the estimation of a causal quantity, such as the mean outcome under treatment. We begin with an overview of some of the issues involved in knowledge-based and statistical variable selection in causal inference and the potential pitfalls of automated selection based on the fit of the propensity score. Using a simple example, we directly show the consequences of adjusting for pure causes of the exposure when using inverse probability of treatment weighting (IPTW). Such variables are likely to be selected when using a naive approach to model selection for the propensity score. We describe how the method of Collaborative Targeted minimum loss-based estimation (C-TMLE; van der Laan and Gruber, 2010) capitalizes on the collaborative double robustness property of semiparametric efficient estimators to select covariates for the propensity score based on the error in the conditional outcome model. Finally, we compare several approaches to automated variable selection in low-and high-dimensional settings through a simulation study. From this simulation study, we conclude that using IPTW with flexible prediction for the propensity score can result in inferior estimation, while Targeted minimum loss-based estimation and C-TMLE may benefit from flexible prediction and remain robust to the presence of variables that are highly correlated with treatment. However, in our study, standard influence function-based methods for the variance underestimated the standard errors, resulting in poor coverage under certain data-generating scenarios. PMID:26226129

  9. Right hemisphere dominance during spatial selective attention and target detection occurs outside the dorsal fronto-parietal network

    Science.gov (United States)

    Shulman, Gordon L.; Pope, Daniel L. W.; Astafiev, Serguei V.; McAvoy, Mark P.; Snyder, Abraham Z.; Corbetta, Maurizio

    2010-01-01

    Spatial selective attention is widely considered to be right hemisphere dominant. Previous functional magnetic resonance imaging (fMRI) studies, however, have reported bilateral blood-oxygenation-level-dependent (BOLD) responses in dorsal fronto-parietal regions during anticipatory shifts of attention to a location (Kastner et al., 1999; Corbetta et al., 2000; Hopfinger et al., 2000). Right-lateralized activity has mainly been reported in ventral fronto-parietal regions for shifts of attention to an unattended target stimulus (Arrington et al., 2000; Corbetta et al., 2000). However, clear conclusions cannot be drawn from these studies because hemispheric asymmetries were not assessed using direct voxel-wise comparisons of activity in left and right hemispheres. Here, we used this technique to measure hemispheric asymmetries during shifts of spatial attention evoked by a peripheral cue stimulus and during target detection at the cued location. Stimulus-driven shifts of spatial attention in both visual fields evoked right-hemisphere dominant activity in temporo-parietal junction (TPJ). Target detection at the attended location produced a more widespread right hemisphere dominance in frontal, parietal, and temporal cortex, including the TPJ region asymmetrically activated during shifts of spatial attention. However, hemispheric asymmetries were not observed during either shifts of attention or target detection in the dorsal fronto-parietal regions (anterior precuneus, medial intraparietal sulcus, frontal eye fields) that showed the most robust activations for shifts of attention. Therefore, right hemisphere dominance during stimulus-driven shifts of spatial attention and target detection reflects asymmetries in cortical regions that are largely distinct from the dorsal fronto-parietal network involved in the control of selective attention. PMID:20219998

  10. A New Capability for Automated Target Selection and Sampling for use with Remote Sensing Instruments on the MER Rovers

    Science.gov (United States)

    Castano, R.; Estlin, T.; Anderson, R. C.; Gaines, D.; Bornstein, B.; de Granville, C.; Tang, B.; Thompson, D.; Judd, M.

    2008-12-01

    The Onboard Autonomous Science Investigation System (OASIS) evaluates geologic data gathered by a planetary rover. The system is designed to operate onboard a rover identifying and reacting to serendipitous science opportunities, such as rocks with novel properties. OASIS operates by analyzing data the rover gathers, and then using machine learning techniques, prioritizing the data based on criteria set by the science team. This prioritization can be used to organize data for transmission back to Earth and it can be used to search for specific targets it has been told to find by the science team. If one of these targets is found, it is identified as a new science opportunity and a "science alert" is sent to a planning and scheduling system. After reviewing the rover's current operational status to ensure that it has enough resources to complete its traverse and act on the new science opportunity, OASIS can change the command sequence of the rover in order to obtain additional science measurements. Currently, OASIS is being applied on a new front. OASIS is providing a new rover mission technology that enables targeted remote-sensing science in an automated fashion during or after rover traverses. Currently, targets for remote sensing instruments, especially narrow field-of-view instruments (such as the MER Mini- TES spectrometer or the 2009 MSL ChemCam spectrometer) must be selected manually based on imagery already on the ground with the operations team. OASIS will enable the rover flight software to analyze imagery onboard in order to autonomously select and sequence targeted remote-sensing observations in an opportunistic fashion. We are in the process of scheduling an onboard MER experiment to demonstrate the OASIS capability in early 2009.

  11. Drugability of extracellular targets: discovery of small molecule drugs targeting allosteric, functional, and subunit-selective sites on GPCRs and ion channels.

    Science.gov (United States)

    Grigoriadis, Dimitri E; Hoare, Samuel R J; Lechner, Sandra M; Slee, Deborah H; Williams, John A

    2009-01-01

    Beginning with the discovery of the structure of deoxyribose nucleic acid in 1953, by James Watson and Francis Crick, the sequencing of the entire human genome some 50 years later, has begun to quantify the classes and types of proteins that may have relevance to human disease with the promise of rapidly identifying compounds that can modulate these proteins so as to have a beneficial and therapeutic outcome. This so called 'drugable space' involves a variety of membrane-bound proteins including the superfamily of G-protein-coupled receptors (GPCRs), ion channels, and transporters among others. The recent number of novel therapeutics targeting membrane-bound extracellular proteins that have reached the market in the past 20 years however pales in magnitude when compared, during the same timeframe, to the advancements made in the technologies available to aid in the discovery of these novel therapeutics. This review will consider select examples of extracellular drugable targets and focus on the GPCRs and ion channels highlighting the corticotropin releasing factor (CRF) type 1 and gamma-aminobutyric acid receptors, and the Ca(V)2.2 voltage-gated ion channel. These examples will elaborate current technological advancements in drug discovery and provide a prospective framework for future drug development.

  12. Targeted Fluoro Positioning for the Discovery of a Potent and Highly Selective Matrix Metalloproteinase Inhibitor.

    Science.gov (United States)

    Fischer, Thomas; Riedl, Rainer

    2017-04-01

    Invited for this month's cover picture is the group of Professor Rainer Riedl from the Institute of Chemistry and Biotechnology at the Zurich University of Applied Sciences (ZHAW), Switzerland. The cover picture depicts the structure-based design of a drug-like small molecule inhibitor of matrix metalloproteinase-13 (MMP-13) with a combined dual binding motif. The targeted introduction of a single fluoro atom was of vital importance for the optimization of the inhibitor. For more details, read the full text of the Communication at 10.1002/open.201600158.

  13. Targeting MED1 LxxLL Motifs for Tissue-Selective Treatment of Human Breast Cancer

    Science.gov (United States)

    2013-09-01

    AU U UG AU AU CG UA GC au gc gc AA AA AU CG UA GC UA CG UA AU UA UA CG CG UA UA GC GC AU CG GC GU 5́ 3́ U U MG aptamer Survivin siRNA Folate ...DNA/RNA sequence FIGURE 19.5 Diagram of RNA nanoparticle harboring malachite green aptamer, survivin siRNA and folate -DNA/RNA sequence for targeting...modifications were extensively exam- ined to increase its stability in serum by fluori- nation, methylation , and addition of a 3’-3’-linked

  14. The selective processing of emotional visual stimuli while detecting auditory targets : An ERP analysis

    OpenAIRE

    Schupp, Harald Thomas; Stockburger, Jessica; Bublatzky, Florian; Junghöfer, Markus; Weike, Almut I.; Hamm, Alfons O.

    2008-01-01

    Event-related potential studies revealed an early posterior negativity (EPN) for emotional compared to neutral pictures. Exploring the emotion-attention relationship, a previous study observed that a primary visual discrimination task interfered with the emotional modulation of the EPN component. To specify the locus of interference, the present study assessed the fate of selective visual emotion processing while attention is directed towards the auditory modality. While simply viewing a rapi...

  15. Modelling the consequences of targeted selective treatment strategies on performance and emergence of anthelmintic resistance amongst grazing calves

    Directory of Open Access Journals (Sweden)

    Zoe Berk

    2016-12-01

    Full Text Available The development of anthelmintic resistance by helminths can be slowed by maintaining refugia on pasture or in untreated hosts. Targeted selective treatments (TST may achieve this through the treatment only of individuals that would benefit most from anthelmintic, according to certain criteria. However TST consequences on cattle are uncertain, mainly due to difficulties of comparison between alternative strategies. We developed a mathematical model to compare: 1 the most ‘beneficial’ indicator for treatment selection and 2 the method of selection of calves exposed to Ostertagia ostertagi, i.e. treating a fixed percentage of the population with the lowest (or highest indicator values versus treating individuals who exceed (or are below a given indicator threshold. The indicators evaluated were average daily gain (ADG, faecal egg counts (FEC, plasma pepsinogen, combined FEC and plasma pepsinogen, versus random selection of individuals. Treatment success was assessed in terms of benefit per R (BPR, the ratio of average benefit in weight gain to change in frequency of resistance alleles R (relative to an untreated population. The optimal indicator in terms of BPR for fixed percentages of calves treated was plasma pepsinogen and the worst ADG; in the latter case treatment was applied to some individuals who were not in need of treatment. The reverse was found when calves were treated according to threshold criteria, with ADG being the best target indicator for treatment. This was also the most beneficial strategy overall, with a significantly higher BPR value than any other strategy, but its degree of success depended on the chosen threshold of the indicator. The study shows strong support for TST, with all strategies showing improvements on calves treated selectively, compared with whole-herd treatment at 3, 8, 13 weeks post-turnout. The developed model appeared capable of assessing the consequences of other TST strategies on calf populations.

  16. Oxamate, but Not Selective Targeting of LDH-A, Inhibits Medulloblastoma Cell Glycolysis, Growth and Motility

    Directory of Open Access Journals (Sweden)

    Cara J. Valvona

    2018-03-01

    Full Text Available Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4, which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis. Studies indicate MBs have a glycolytic phenotype; however, LDHA has not yet been explored as a therapeutic target for medulloblastoma. LDHA expression was examined in medulloblastoma subgroups and cell lines. The effects of LDHA inhibition by oxamate or LDHA siRNA on medulloblastoma cell line metabolism, migration and proliferation were examined. LDHA was significantly overexpressed in Group 3 and Wnt MBs compared to non-neoplastic cerebellum. Furthermore, we found that oxamate significantly attenuated glycolysis, proliferation and motility in medulloblastoma cell lines, but LDHA siRNA did not. We established that aerobic glycolysis is a potential therapeutic target for medulloblastoma, but broader LDH inhibition (LDHA, B, and C may be more appropriate than LDHA inhibition alone.

  17. Selective targeting of brain tumors with gold nanoparticle-induced radiosensitization.

    Directory of Open Access Journals (Sweden)

    Daniel Y Joh

    Full Text Available Successful treatment of brain tumors such as glioblastoma multiforme (GBM is limited in large part by the cumulative dose of Radiation Therapy (RT that can be safely given and the blood-brain barrier (BBB, which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs. GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ~1.3. Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

  18. A targeted ferritin-microplasmin based thrombolytic nanocage selectively dissolves blood clots.

    Science.gov (United States)

    Seo, Junyoung; Al-Hilal, Taslim A; Jee, Jun-Goo; Kim, Yong-Lim; Kim, Ha-Jeong; Lee, Byung-Heon; Kim, Soyoun; Kim, In-San

    2018-04-01

    The use of thrombolytic therapies is limited by an increased risk of systemic hemorrhage due to lysis of hemostatic clots. We sought to develop a plasmin-based thrombolytic nanocage that efficiently dissolves the clot without causing systemic fibrinolysis or disrupting hemostatic clots. Here, we generated a double chambered short-length ferritin (sFt) construct that has an N-terminal region fused to multivalent clot targeting peptides (CLT: CNAGESSKNC) and a C-terminal end fused to a microplasmin (μPn); CLT recognizes fibrin-fibronectin complexes in clots, μPn efficiently dissolves clots, and the assembly of double chambered sFt (CLT-sFt-μPn) into nanocage structure protects the activated-μPn from its circulating inhibitors. Importantly, activated CLT-sFt-μPn thrombolytic nanocage showed a prolonged circulatory life over activated-μPn and efficiently lysed the preexisting clots in both arterial and venous thromboses models. Thus, CLT-sFt-μPn thrombolytic nanocage platform represents the prototype of a targeted clot-busting agent with high efficacy and safety over existing thrombolytic therapies. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Application of Ultrasound to Selectively Localize Nanodroplets for Targeted Imaging and Therapy

    Directory of Open Access Journals (Sweden)

    Paul A. Dayton

    2006-07-01

    Full Text Available Lipid-coated perfluorocarbon nanodroplets are submicrometer-diameter liquid-filled droplets with proposed applications in molecularly targeted therapeutics and ultrasound (US imaging. Ultrasonic molecular imaging is unique in that the optimal application of these agents depends not only on the surface chemistry, but also on the applied US field, which can increase receptor-ligand binding and membrane fusion. Theory and experiments are combined to demonstrate the displacement of perfluorocarbon nanoparticles in the direction of US propagation, where a traveling US wave with a peak pressure on the order of megapascals and frequency in the megahertz range produces a particle translational velocity that is proportional to acoustic intensity and increases with increasing center frequency. Within a vessel with a diameter on the order of hundreds of micrometers or larger, particle velocity on the order of hundreds of micrometers per second is produced and the dominant mechanism for droplet displacement is shown to be bulk fluid streaming. A model for radiation force displacement of particles is developed and demonstrates that effective particle displacement should be feasible in the microvasculature. In a flowing system, acoustic manipulation of targeted droplets increases droplet retention. Additionally, we demonstrate the feasibility of US-enhanced particle internalization and therapeutic delivery.

  20. PLS-based and regularization-based methods for the selection of relevant variables in non-targeted metabolomics data

    Directory of Open Access Journals (Sweden)

    Renata Bujak

    2016-07-01

    Full Text Available Non-targeted metabolomics constitutes a part of systems biology and aims to determine many metabolites in complex biological samples. Datasets obtained in non-targeted metabolomics studies are multivariate and high-dimensional due to the sensitivity of mass spectrometry-based detection methods as well as complexity of biological matrices. Proper selection of variables which contribute into group classification is a crucial step, especially in metabolomics studies which are focused on searching for disease biomarker candidates. In the present study, three different statistical approaches were tested using two metabolomics datasets (RH and PH study. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA without and with multiple testing correction as well as least absolute shrinkage and selection operator (LASSO were tested and compared. For the RH study, OPLS-DA model built without multiple testing correction, selected 46 and 218 variables based on VIP criteria using Pareto and UV scaling, respectively. In the case of the PH study, 217 and 320 variables were selected based on VIP criteria using Pareto and UV scaling, respectively. In the RH study, OPLS-DA model built with multiple testing correction, selected 4 and 19 variables as statistically significant in terms of Pareto and UV scaling, respectively. For PH study, 14 and 18 variables were selected based on VIP criteria in terms of Pareto and UV scaling, respectively. Additionally, the concept and fundaments of the least absolute shrinkage and selection operator (LASSO with bootstrap procedure evaluating reproducibility of results, was demonstrated. In the RH and PH study, the LASSO selected 14 and 4 variables with reproducibility between 99.3% and 100%. However, apart from the popularity of PLS-DA and OPLS-DA methods in metabolomics, it should be highlighted that they do not control type I or type II error, but only arbitrarily establish a cut-off value for PLS-DA loadings

  1. Application effect of TEM sounding survey on prospecting and target area selection of sandstone-type uranium deposits

    International Nuclear Information System (INIS)

    He Jianguo; Liang Shanming; Zhao Cuiping

    2006-01-01

    Based on the results of transient electromagnetic (TEM) sounding survey during recent years regional geological reconnaissance with drilling (1:250000), the application effect of TEM sounding survey during regional reconnaissance is summarized in this paper. It is suggested that the data of TEM sounding are useful in judging hydrodynamic conditions of groundwater and determining favorable areas for uranium ore-formation; TEM sounding in large areas may be proper for prospecting in gobi-desert areas and be beneficial for regional reconnaissance and target area selection, and may reduce the target area and provide basis for further drilling program. It is of popularized significance in the prospecting for sandstone-type uranium deposits. (authors)

  2. LuIII parvovirus selectively and efficiently targets, replicates in, and kills human glioma cells.

    Science.gov (United States)

    Paglino, Justin C; Ozduman, Koray; van den Pol, Anthony N

    2012-07-01

    Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro. In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

  3. Extending Data Worth Analyses to Select Multiple Observations Targeting Multiple Forecasts

    DEFF Research Database (Denmark)

    Vilhelmsen, Troels Norvin; Ferre, Ty Paul

    2017-01-01

    . In the present study, we extend previous data worth analyses to include: simultaneous selection of multiple new measurements and consideration of multiple forecasts of interest. We show how the suggested approach can be used to optimize data collection. This can be used in a manner that suggests specific...... measurement sets or that produces probability maps indicating areas likely to be informative for specific forecasts. Moreover, we provide examples documenting that sequential measurement election approaches often lead to suboptimal designs and that estimates of data covariance should be included when...

  4. Increasing selective exposure to health messages by targeting person versus behavior schemas.

    Science.gov (United States)

    Pease, Meridith E; Brannon, Laura A; Pilling, Valerie K

    2006-01-01

    Schema correspondence theory (Brannon and Brock, 1994) was applied to the topic of selective exposure to health information. The following question was asked: When do people prefer to expose themselves to health-relevant information tailored to match their own needs and values (i.e., recipient self-schema matching) versus the values and goals that the healthy behavior brings to mind (i.e., behavior schema matching)? In general, recipient self-schema matched messages tended to be preferred over behavior schema matched messages. However, this tendency was attenuated to the extent that the behavior had a very well defined (prototypical) schema.

  5. A recombinant fusion toxin based on enzymatic inactive C3bot1 selectively targets macrophages.

    Directory of Open Access Journals (Sweden)

    Lydia Dmochewitz

    Full Text Available BACKGROUND: The C3bot1 protein (~23 kDa from Clostridium botulinum ADP-ribosylates and thereby inactivates Rho. C3bot1 is selectively taken up into the cytosol of monocytes/macrophages but not of other cell types such as epithelial cells or fibroblasts. Most likely, the internalization occurs by a specific endocytotic pathway via acidified endosomes. METHODOLOGY/PRINCIPAL FINDINGS: Here, we tested whether enzymatic inactive C3bot1E174Q serves as a macrophage-selective transport system for delivery of enzymatic active proteins into the cytosol of such cells. Having confirmed that C3bot1E174Q does not induce macrophage activation, we used the actin ADP-ribosylating C2I (∼50 kDa from Clostridium botulinum as a reporter enzyme for C3bot1E174Q-mediated delivery into macrophages. The recombinant C3bot1E174Q-C2I fusion toxin was cloned and expressed as GST-protein in Escherichia coli. Purified C3bot1E174Q-C2I was recognized by antibodies against C2I and C3bot and showed C2I-specific enzyme activity in vitro. When applied to cultured cells C3bot1E174Q-C2I ADP-ribosylated actin in the cytosol of macrophages including J774A.1 and RAW264.7 cell lines as well as primary cultured human macrophages but not of epithelial cells. Together with confocal fluorescence microscopy experiments, the biochemical data indicate the selective uptake of a recombinant C3-fusion toxin into the cytosol of macrophages. CONCLUSIONS/SIGNIFICANCE: In summary, we demonstrated that C3bot1E174Q can be used as a delivery system for fast, selective and specific transport of enzymes into the cytosol of living macrophages. Therefore, C3-based fusion toxins can represent valuable molecular tools in experimental macrophage pharmacology and cell biology as well as attractive candidates to develop new therapeutic approaches against macrophage-associated diseases.

  6. Model-specific selection of molecular targets for heart failure gene therapy

    Science.gov (United States)

    Katz, Michael G.; Fargnoli, Anthony S.; Tomasulo, Catherine E.; Pritchette, Louella A.; Bridges, Charles R.

    2013-01-01

    Heart failure (HF) is a complex multifaceted problem of abnormal ventricular function and structure. In recent years, new information has been accumulated allowing for a more detailed understanding of the cellular and molecular alterations that are the underpinnings of diverse causes of HF, including myocardial ischemia, pressure-overload, volume-overload or intrinsic cardiomyopathy. Modern pharmacological approaches to treat HF have had a significant impact on the course of the disease, although they do not reverse the underlying pathological state of the heart. Therefore gene-based therapy holds a great potential as a targeted treatment for cardiovascular diseases. Here, we survey the relative therapeutic efficacy of genetic modulation of β-adrenergic receptor signaling, Ca2+ handling proteins and angiogenesis in the most common extrinsic models of HF. PMID:21954055

  7. Selection and identification of a DNA aptamer targeted to Vibrio parahemolyticus.

    Science.gov (United States)

    Duan, Nuo; Wu, Shijia; Chen, Xiujuan; Huang, Yukun; Wang, Zhouping

    2012-04-25

    A whole-bacterium systemic evolution of ligands by exponential enrichment (SELEX) method was applied to a combinatorial library of FAM-labeled single-stranded DNA molecules to identify DNA aptamers demonstrating specific binding to Vibrio parahemolyticus . FAM-labeled aptamer sequences with high binding affinity to V. parahemolyticus were identified by flow cytometric analysis. Aptamer A3P, which showed a particularly high binding affinity in preliminary studies, was chosen for further characterization. This aptamer displayed a dissociation constant (K(d)) of 16.88 ± 1.92 nM. Binding assays to assess the specificity of aptamer A3P showed a high binding affinity (76%) for V. parahemolyticus and a low apparent binding affinity (4%) for other bacteria. Whole-bacterium SELEX is a promising technique for the design of aptamer-based molecular probes for microbial pathogens that does not require the labor-intensive steps of isolating and purifying complex markers or targets.

  8. Site selection and directional models of deserts used for ERBE validation targets

    Science.gov (United States)

    Staylor, W. F.

    1986-01-01

    Broadband shortwave and longwave radiance measurements obtained from the Nimbus 7 Earth Radiation Budget scanner were used to develop reflectance and emittance models for the Sahara, Gibson, and Saudi Deserts. These deserts will serve as in-flight validation targets for the Earth Radiation Budget Experiment being flown on the Earth Radiation Budget Satellite and two National Oceanic and Atmospheric Administration polar satellites. The directional reflectance model derived for the deserts was a function of the sum and product of the cosines of the solar and viewing zenith angles, and thus reciprocity existed between these zenith angles. The emittance model was related by a power law of the cosine of the viewing zenith angle.

  9. Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression

    DEFF Research Database (Denmark)

    Ravnskjær, Kim; Kester, Henri; Liu, Yi

    2007-01-01

    A number of hormones and growth factors stimulate gene expression by promoting the phosphorylation of CREB (P-CREB), thereby enhancing its association with the histone acetylase paralogs p300 and CBP (CBP/p300). Relative to cAMP, stress signals trigger comparable amounts of CREB phosphorylation...... to stress signals, however; and in its absence, P-CREB is unable to stimulate CRE-dependent transcription, due to a block in CBP recruitment. The effect of TORC2 on CBP/p300 promoter occupancy appears pivotal because a gain of function mutant CREB polypeptide with increased affinity for CBP restored CRE......-mediated transcription in cells exposed to stress signals. Taken together, these results indicate that TORC2 is one of the long sought after cofactors that mediates the differential effects of cAMP and stress pathways on CREB target gene expression....

  10. Selectivity and Efficiency of Late Transgene Expression by Transcriptionally Targeted Oncolytic Adenoviruses Are Dependent on the Transgene Insertion Strategy

    Science.gov (United States)

    Quirin, Christina; Rohmer, Stanimira; Fernández-Ulibarri, Inés; Behr, Michael; Hesse, Andrea; Engelhardt, Sarah; Erbs, Philippe; Enk, Alexander H.

    2011-01-01

    Abstract Key challenges facing cancer therapy are the development of tumor-specific drugs and potent multimodal regimens. Oncolytic adenoviruses possess the potential to realize both aims by restricting virus replication to tumors and inserting therapeutic genes into the virus genome, respectively. A major effort in this regard is to express transgenes in a tumor-specific manner without affecting virus replication. Using both luciferase as a sensitive reporter and genetic prodrug activation, we show that promoter control of E1A facilitates highly selective expression of transgenes inserted into the late transcription unit. This, however, required multistep optimization of late transgene expression. Transgene insertion via internal ribosome entry site (IRES), splice acceptor (SA), or viral 2A sequences resulted in replication-dependent expression. Unexpectedly, analyses in appropriate substrates and with matching control viruses revealed that IRES and SA, but not 2A, facilitated indirect transgene targeting via tyrosinase promoter control of E1A. Transgene expression via SA was more selective (up to 1,500-fold) but less effective than via IRES. Notably, we also revealed transgene-dependent interference with splicing. Hence, the prodrug convertase FCU1 (a cytosine deaminase–uracil phosphoribosyltransferase fusion protein) was expressed only after optimizing the sequence surrounding the SA site and mutating a cryptic splice site within the transgene. The resulting tyrosinase promoter-regulated and FCU1-encoding adenovirus combined effective oncolysis with targeted prodrug activation therapy of melanoma. Thus, prodrug activation showed potent bystander killing and increased cytotoxicity of the virus up to 10-fold. We conclude that armed oncolytic viruses can be improved substantially by comparing and optimizing strategies for targeted transgene expression, thereby implementing selective and multimodal cancer therapies. PMID:20939692

  11. Extending Data Worth Analyses to Select Multiple Observations Targeting Multiple Forecasts.

    Science.gov (United States)

    Vilhelmsen, Troels N; Ferré, Ty P A

    2017-09-15

    Hydrological models are often set up to provide specific forecasts of interest. Owing to the inherent uncertainty in data used to derive model structure and used to constrain parameter variations, the model forecasts will be uncertain. Additional data collection is often performed to minimize this forecast uncertainty. Given our common financial restrictions, it is critical that we identify data with maximal information content with respect to forecast of interest. In practice, this often devolves to qualitative decisions based on expert opinion. However, there is no assurance that this will lead to optimal design, especially for complex hydrogeological problems. Specifically, these complexities include considerations of multiple forecasts, shared information among potential observations, information content of existing data, and the assumptions and simplifications underlying model construction. In the present study, we extend previous data worth analyses to include: simultaneous selection of multiple new measurements and consideration of multiple forecasts of interest. We show how the suggested approach can be used to optimize data collection. This can be used in a manner that suggests specific measurement sets or that produces probability maps indicating areas likely to be informative for specific forecasts. Moreover, we provide examples documenting that sequential measurement election approaches often lead to suboptimal designs and that estimates of data covariance should be included when selecting future measurement sets. © 2017, National Ground Water Association.

  12. Molecular basis of cannabinoid CB1 receptor coupling to the G protein heterotrimer Gαiβγ: identification of key CB1 contacts with the C-terminal helix α5 of Gαi.

    Science.gov (United States)

    Shim, Joong-Youn; Ahn, Kwang H; Kendall, Debra A

    2013-11-08

    The cannabinoid (CB1) receptor is a member of the rhodopsin-like G protein-coupled receptor superfamily. The human CB1 receptor, which is among the most expressed receptors in the brain, has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. Different classes of CB1 agonists evoke signaling pathways through the activation of specific subtypes of G proteins. The molecular basis of CB1 receptor coupling to its cognate G protein is unknown. As a first step toward understanding CB1 receptor-mediated G protein signaling, we have constructed a ternary complex structural model of the CB1 receptor and Gi heterotrimer (CB1-Gi), guided by the x-ray structure of β2-adrenergic receptor (β2AR) in complex with Gs (β2AR-Gs), through 824-ns duration molecular dynamics simulations in a fully hydrated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer environment. We identified a group of residues at the juxtamembrane regions of the intracellular loops 2 and 3 (IC2 and IC3) of the CB1 receptor, including Ile-218(3.54), Tyr-224(IC2), Asp-338(6.30), Arg-340(6.32), Leu-341(6.33), and Thr-344(6.36), as potential key contacts with the extreme C-terminal helix α5 of Gαi. Ala mutations of these residues at the receptor-Gi interface resulted in little G protein coupling activity, consistent with the present model of the CB1-Gi complex, which suggests tight interactions between CB1 and the extreme C-terminal helix α5 of Gαi. The model also suggests that unique conformational changes in the extreme C-terminal helix α5 of Gα play a crucial role in the receptor-mediated G protein activation.

  13. Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours

    DEFF Research Database (Denmark)

    Lasko, Loren M; Jakob, Clarissa G; Edalji, Rohinton P

    2017-01-01

    -specific tumour types, including several haematological malignancies and androgen receptor-positive prostate cancer. A-485 inhibited the androgen receptor transcriptional program in both androgen-sensitive and castration-resistant prostate cancer and inhibited tumour growth in a castration-resistant xenograft...... to treat certain cancers, but progress on the development of drug-like histone actyltransferase inhibitors has lagged behind. The histone acetyltransferase paralogues p300 and CREB-binding protein (CBP) are key transcriptional co-activators that are essential for a multitude of cellular processes, and have...... also been implicated in human pathological conditions (including cancer). Current inhibitors of the p300 and CBP histone acetyltransferase domains, including natural products, bi-substrate analogues and the widely used small molecule C646, lack potency or selectivity. Here, we describe A-485, a potent...

  14. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

    Science.gov (United States)

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam; Ardell, Jeffrey L

    2016-11-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. Copyright © 2016 the American Physiological Society.

  15. A novel gene therapy-based approach that selectively targets hypoxic regions within solid tumors

    International Nuclear Information System (INIS)

    Dougherty, S.T.; Dougherty, G.J.; Davis, P.D.

    2003-01-01

    There is compelling evidence that malignant cells present within the hypoxic regions that are commonly found within solid tumors contribute significantly to local recurrence following radiation therapy. We describe now a novel strategy designed to target such cells that exploits the differential production within hypoxic regions of the pro-angiogenic cytokine vascular endothelial cell growth factor (VEGF). Specifically, we have generated cDNA constructs that encode two distinct chimeric cell surface proteins that incorporate, respectively, the extracellular domains of the VEGF receptors Flk-1 or Flt-1, fused in frame to the membrane spanning and cytoplasmic domains of the pro-apoptotic protein Fas. Both chimeric proteins (Flk/Fas and Flt/Fas) appear stable and can be readily detected on the surface of transfected cells by Western blot and/or FACS analysis. Importantly, tumor cells expressing the chimeric proteins were rapidly killed in a dose-dependent fashion upon the addition of exogenous recombinant VEGF. Adenoviral vectors encoding Flk/Fas have been generated and shown to induce tumor cells to undergo apoptosis upon transfer to hypoxic conditions in vitro. This activity is dependent upon the endogenous production of VEGF. Studies are currently underway to test the ability of adenoviral Flk/Fas (Ad.Flk/Fas) to reduce tumor recurrence in vivo when used as an adjuvant therapy in conjunction with clinically relevant doses of ionizing radiation

  16. Selective imaging of cancer cells with a pH-activatable lysosome-targeting fluorescent probe.

    Science.gov (United States)

    Shi, Rongguang; Huang, Lu; Duan, Xiaoxue; Sun, Guohao; Yin, Gui; Wang, Ruiyong; Zhu, Jun-Jie

    2017-10-02

    Fluorescence imaging with tumor-specific fluorescent probe has emerged as a tool to aid surgeons in the identification and removal of tumor tissue. We report here a new lysosome-targeting fluorescent probe (NBOH) with BODIPY fluorephore to distinguish tumor tissue out of normal tissue based on different pH environment. The probe exhibited remarkable pH-dependent fluorescence behavior in a wide pH range from 3.0 to 11.0, especially a sensitive pH-dependent fluorescence change at pH range between 3.5 and 5.5, corresponding well to the acidic microenvironment of tumor cells, in aqueous solution. The response time of NBOH was extremely short and the photostability was proved to be good. Toxicity test and fluorescence cell imaging together with a sub-cellular localization study were carried out revealing its low biotoxicity and good cell membrane permeability. And NBOH was successfully applied to the imaging of tumor tissue in tumor-bearing mice suggesting potential application to surgery as a tumor-specific probe. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.

    Science.gov (United States)

    King, Harry O; Brend, Tim; Payne, Helen L; Wright, Alexander; Ward, Thomas A; Patel, Karan; Egnuni, Teklu; Stead, Lucy F; Patel, Anjana; Wurdak, Heiko; Short, Susan C

    2017-01-10

    Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  18. Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells.

    Science.gov (United States)

    Díaz-Carballo, David; Acikelli, Ali Haydar; Bardenheuer, Walter; Gustmann, Sebastian; Malak, Sascha; Stoll, Raphael; Kedziorski, Thorsten; Nazif, Mhd Ali; Jastrow, Holger; Wennemuth, Gunter; Dammann, Philip; Feigel, Martin; Strumberg, Dirk

    2014-09-01

    Relapse of cancer months or years after an apparently successful therapy is probably caused by cancer stem cells (CSCs) due to their intrinsic features like dormant periods, radiorefraction, and acquired multidrug resistance (MDR) phenotypes, among other mechanisms of cellular drug evasiveness. Thus, the lack of currently efficacious interventions remains a major problem in the treatment of malignancies, together with the inability of existing drugs to destroy specifically CSCs. Neuroblastomas per se are highly chemotherapy-refractory extracranial tumors in infants with very low survival rates. So far, no effective cytostatics against this kind of tumors are clinically available. Therefore, we have put much effort into the development of agents to efficiently combat this malignancy. For this purpose, we tested several compounds isolated from Cuban propolis on induced CSCs (iCSC) derived from LAN-1 neuroblastoma cells which expressed several characteristics of tumor-initiating cells both in in-vitro and in-vivo models. Some small molecules such as flavonoids and polycyclic polyprenylated acylphloroglucinols (PPAP) were isolated using successive RT-HPLC cycles and identified employing mass spectrometry and NMR spectroscopic techniques. Their cytotoxicity was first screened in sensitive cell systems by MTT proliferation assays and afterwards studied in less sensitive neuroblastoma iCSC models. We found several compounds with considerable anti-iCSC activity, most of them belonging to the PPAP class. The majority of the compounds act in a pleiotropic manner on the molecular biology of tumors although their specific targets remain unclear. Nevertheless, two substances, one of them a flavonoid, induced a strong disruption of tubulin polymerization. In addition, an unknown compound strongly inhibited replicative enzymes like toposimerases I/II and DNA polymerase. Here, we report for the first time cytotoxic activities of small molecules isolated from Caribbean propolis

  19. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation

    Science.gov (United States)

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J. Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam

    2016-01-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. PMID:27591222

  20. The Endosymbiotic Bacterium Wolbachia Selectively Kills Male Hosts by Targeting the Masculinizing Gene.

    Directory of Open Access Journals (Sweden)

    Takahiro Fukui

    2015-07-01

    Full Text Available Pathogens are known to manipulate the reproduction and development of their hosts for their own benefit. Wolbachia is an endosymbiotic bacterium that infects a wide range of insect species. Wolbachia is known as an example of a parasite that manipulates the sex of its host's progeny. Infection of Ostrinia moths by Wolbachia causes the production of all-female progeny, however, the mechanism of how Wolbachia accomplishes this male-specific killing is unknown. Here we show for the first time that Wolbachia targets the host masculinizing gene of Ostrinia to accomplish male-killing. We found that Wolbachia-infected O. furnacalis embryos do not express the male-specific splice variant of doublesex, a gene which acts at the downstream end of the sex differentiation cascade, throughout embryonic development. Transcriptome analysis revealed that Wolbachia infection markedly reduces the mRNA level of Masc, a gene that encodes a protein required for both masculinization and dosage compensation in the silkworm Bombyx mori. Detailed bioinformatic analysis also elucidated that dosage compensation of Z-linked genes fails in Wolbachia-infected O. furnacalis embryos, a phenomenon that is extremely similar to that observed in Masc mRNA-depleted male embryos of B. mori. Finally, injection of in vitro transcribed Masc cRNA into Wolbachia-infected embryos rescued male progeny. Our results show that Wolbachia-induced male-killing is caused by a failure of dosage compensation via repression of the host masculinizing gene. Our study also shows a novel strategy by which a pathogen hijacks the host sex determination cascade.

  1. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

    Science.gov (United States)

    Lehmann, Brian D.; Bauer, Joshua A.; Chen, Xi; Sanders, Melinda E.; Chakravarthy, A. Bapsi; Shyr, Yu; Pietenpol, Jennifer A.

    2011-01-01

    Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies. PMID:21633166

  2. Cost-effectiveness analysis of FET PET-guided target selection for the diagnosis of gliomas

    International Nuclear Information System (INIS)

    Heinzel, Alexander; Stock, Stephanie; Mueller, Dirk; Langen, Karl-Josef

    2012-01-01

    Several diagnostic trials have indicated that the combined use of 18 F-fluoroethyl-l-tyrosine (FET) PET and MRI may be superior to MRI alone in selecting the biopsy site for the diagnosis of gliomas. We estimated the cost-effectiveness of the use of amino acid PET compared to MRI alone from the perspective of the German statutory health insurance. To evaluate the incremental cost-effectiveness of the use of amino acid PET, a decision tree model was built. The effectiveness of FET PET was determined by the probability of a correct diagnosis. Costs were estimated for a baseline scenario and for a more expensive scenario in which disease severity was considered. The robustness of the results was tested using deterministic and probabilistic sensitivity analyses. The combined use of PET and MRI resulted in an increase of 18.5% in the likelihood of a correct diagnosis. The incremental cost-effectiveness ratio for one additional correct diagnosis using FET PET was EUR6,405 for the baseline scenario and EUR9,114 for the scenario based on higher disease severity. The probabilistic sensitivity analysis confirmed the robustness of the results. The model indicates that the use of amino acid PET may be cost-effective in patients with glioma. As a result of several limitations in the data used for the model, further studies are needed to confirm the results. (orig.)

  3. Targeted selected reaction monitoring mass spectrometric immunoassay for insulin-like growth factor 1.

    Directory of Open Access Journals (Sweden)

    Eric E Niederkofler

    Full Text Available Insulin-like growth factor 1 (IGF1 is an important biomarker of human growth disorders that is routinely analyzed in clinical laboratories. Mass spectrometry-based workflows offer a viable alternative to standard IGF1 immunoassays, which utilize various pre-analytical preparation strategies. In this work we developed an assay that incorporates a novel sample preparation method for dissociating IGF1 from its binding proteins. The workflow also includes an immunoaffinity step using antibody-derivatized pipette tips, followed by elution, trypsin digestion, and LC-MS/MS separation and detection of the signature peptides in a selected reaction monitoring (SRM mode. The resulting quantitative mass spectrometric immunoassay (MSIA exhibited good linearity in the range of 1 to 1,500 ng/mL IGF1, intra- and inter-assay precision with CVs of less than 10%, and lowest limits of detection of 1 ng/mL. The linearity and recovery characteristics of the assay were also established, and the new method compared to a commercially available immunoassay using a large cohort of human serum samples. The IGF1 SRM MSIA is well suited for use in clinical laboratories.

  4. DUPA conjugation of a cytotoxic indenoisoquinoline topoisomerase I inhibitor for selective prostate cancer cell targeting.

    Science.gov (United States)

    Roy, Jyoti; Nguyen, Trung Xuan; Kanduluru, Ananda Kumar; Venkatesh, Chelvam; Lv, Wei; Reddy, P V Narasimha; Low, Philip S; Cushman, Mark

    2015-04-09

    Prostate-specific membrane antigen (PSMA) is overexpressed in most prostate cancer cells while being present at low or undetectable levels in normal cells. This difference provides an opportunity to selectively deliver cytotoxic drugs to prostate cancer cells while sparing normal cells that lack PSMA, thus improving potencies and reducing toxicities. PSMA has high affinity for 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA) (Ki = 8 nM). After binding to a DUPA-drug conjugate, PSMA internalizes, unloads the conjugate, and returns to the surface. In the present studies, an indenoisoquinoline topoisomerase I inhibitor was conjugated to DUPA via a peptide linker and a drug-release segment that facilitates intracellular cleavage to liberate the drug cargo. The DUPA-indenoisoquinoline conjugate exhibited an IC50 in the low nanomolar range in 22RV1 cell cultures and induced a complete cessation of tumor growth with no toxicity, as determined by loss of body weight and death of treated mice.

  5. Cost-effectiveness analysis of FET PET-guided target selection for the diagnosis of gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Heinzel, Alexander [Research Centre Juelich, Department of Nuclear Medicine of the Heinrich-Heine University of Duesseldorf, Juelich (Germany); Stock, Stephanie; Mueller, Dirk [University Hospital of Cologne, Institute for Health Economics and Clinical Epidemiology, Cologne (Germany); Langen, Karl-Josef [Research Centre Juelich, Institute for Neuroscience and Medicine 4, Juelich (Germany)

    2012-07-15

    Several diagnostic trials have indicated that the combined use of {sup 18}F-fluoroethyl-l-tyrosine (FET) PET and MRI may be superior to MRI alone in selecting the biopsy site for the diagnosis of gliomas. We estimated the cost-effectiveness of the use of amino acid PET compared to MRI alone from the perspective of the German statutory health insurance. To evaluate the incremental cost-effectiveness of the use of amino acid PET, a decision tree model was built. The effectiveness of FET PET was determined by the probability of a correct diagnosis. Costs were estimated for a baseline scenario and for a more expensive scenario in which disease severity was considered. The robustness of the results was tested using deterministic and probabilistic sensitivity analyses. The combined use of PET and MRI resulted in an increase of 18.5% in the likelihood of a correct diagnosis. The incremental cost-effectiveness ratio for one additional correct diagnosis using FET PET was EUR6,405 for the baseline scenario and EUR9,114 for the scenario based on higher disease severity. The probabilistic sensitivity analysis confirmed the robustness of the results. The model indicates that the use of amino acid PET may be cost-effective in patients with glioma. As a result of several limitations in the data used for the model, further studies are needed to confirm the results. (orig.)

  6. Targeting of breast metastases using a viral gene vector with tumour-selective transcription.

    LENUS (Irish Health Repository)

    Rajendran, Simon

    2012-01-31

    BACKGROUND: Adeno-associated virus (AAV) vectors have significant potential as gene delivery vectors for cancer gene therapy. However, broad AAV2 tissue tropism results in nonspecific gene expression. MATERIALS AND METHODS: We investigated use of the C-X-C chemokine receptor type 4 (CXCR4) promoter to restrict AAV expression to tumour cells, in subcutaneous MCF-7 xenograft mouse models of breast cancer and in patient samples, using bioluminescent imaging and flow cytometric analysis. RESULTS: Higher transgene expression levels were observed in subcutaneous MCF-7 tumours relative to normal tissue (muscle) using the CXCR4 promoter, unlike a ubiquitously expressing Cytomegalovirus promoter construct, with preferential AAVCXCR4 expression in epithelial tumour and CXCR4-positive cells. Transgene expression following intravenously administered AAVCXCR4 in a model of liver metastasis was detected specifically in livers of tumour bearing mice. Ex vivo analysis using patient samples also demonstrated higher AAVCXCR4 expression in tumour compared with normal liver tissue. CONCLUSION: This study demonstrates for the first time, the potential for systemic administration of AAV2 vector for tumour-selective gene therapy.

  7. 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

  8. 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.

  9. Impact of sleep inertia on visual selective attention for rare targets and the influence of chronotype.

    Science.gov (United States)

    Ritchie, Hannah K; Burke, Tina M; Dear, Tristan B; Mchill, Andrew W; Axelsson, John; Wright, Kenneth P

    2017-10-01

    Sleep inertia is affected by circadian phase, with worse performance upon awakening from sleep during the biological night than biological day. Visual search/selective visual attention performance is known to be sensitive to sleep inertia and circadian phase. Individual differences exist in the circadian timing of habitual wake time, which may contribute to individual differences in sleep inertia. Because later chronotypes awaken at an earlier circadian phase, we hypothesized that later chronotypes would have worse visual search performance during sleep inertia than earlier chronotypes if awakened at habitual wake time. We analysed performance from 18 healthy participants [five females (22.1 ± 3.7 years; mean ± SD)] at ~1, 10, 20, 30, 40 and 60 min following electroencephalogram-verified awakening from an 8 h in-laboratory sleep opportunity. Cognitive throughput and reaction times of correct responses were impaired by sleep inertia and took ~10-30 min to improve after awakening. Regardless whether chronotype was defined by dim light melatonin onset or mid-sleep clock hour on free days, derived from the Munich ChronoType Questionnaire, the duration of sleep inertia for cognitive throughput and reaction times was longer for later chronotypes (n = 7) compared with earlier chronotypes (n = 7). Specifically, performance for earlier chronotypes showed significant improvement within ~10-20 min after awakening, whereas performance for later chronotypes took ~30 min or longer to show significant improvement (P inertia contributes to longer-lasting impairments in morning performance in later chronotypes. © 2017 European Sleep Research Society.

  10. Speech-language pathologists' practices regarding assessment, analysis, target selection, intervention, and service delivery for children with speech sound disorders.

    Science.gov (United States)

    Mcleod, Sharynne; Baker, Elise

    2014-01-01

    A survey of 231 Australian speech-language pathologists (SLPs) was undertaken to describe practices regarding assessment, analysis, target selection, intervention, and service delivery for children with speech sound disorders (SSD). The participants typically worked in private practice, education, or community health settings and 67.6% had a waiting list for services. For each child, most of the SLPs spent 10-40 min in pre-assessment activities, 30-60 min undertaking face-to-face assessments, and 30-60 min completing paperwork after assessments. During an assessment SLPs typically conducted a parent interview, single-word speech sampling, collected a connected speech sample, and used informal tests. They also determined children's stimulability and estimated intelligibility. With multilingual children, informal assessment procedures and English-only tests were commonly used and SLPs relied on family members or interpreters to assist. Common analysis techniques included determination of phonological processes, substitutions-omissions-distortions-additions (SODA), and phonetic inventory. Participants placed high priority on selecting target sounds that were stimulable, early developing, and in error across all word positions and 60.3% felt very confident or confident selecting an appropriate intervention approach. Eight intervention approaches were frequently used: auditory discrimination, minimal pairs, cued articulation, phonological awareness, traditional articulation therapy, auditory bombardment, Nuffield Centre Dyspraxia Programme, and core vocabulary. Children typically received individual therapy with an SLP in a clinic setting. Parents often observed and participated in sessions and SLPs typically included siblings and grandparents in intervention sessions. Parent training and home programs were more frequently used than the group therapy. Two-thirds kept up-to-date by reading journal articles monthly or every 6 months. There were many similarities with

  11. Selection of focal earthworm species as non-target soil organisms for environmental risk assessment of genetically modified plants.

    Science.gov (United States)

    van Capelle, Christine; Schrader, Stefan; Arpaia, Salvatore

    2016-04-01

    By means of a literature survey, earthworm species of significant relevance for soil functions in different biogeographical regions of Europe (Atlantic, Boreal, Mediterranean) were identified. These focal earthworm species, defined here according to the EFSA Guidance Document on the environmental risk assessment (ERA) of genetically modified plants, are typical for arable soils under crop rotations with maize and/or potatoes within the three regions represented by Ireland, Sweden and Spain, respectively. Focal earthworm species were selected following a matrix of four steps: Identification of functional groups, categorization of non-target species, ranking species on ecological criteria, and final selection of focal species. They are recommended as appropriate non-target organisms to assess environmental risks of genetically modified (GM) crops; in this case maize and potatoes. In total, 44 literature sources on earthworms in arable cropping systems including maize or potato from Ireland, Sweden and Spain were collected, which present information on species diversity, individual density and specific relevance for soil functions. By means of condensed literature data, those species were identified which (i) play an important functional role in respective soil systems, (ii) are well adapted to the biogeographical regions, (iii) are expected to occur in high abundances under cultivation of maize or potato and (iv) fulfill the requirements for an ERA test system based on life-history traits. First, primary and secondary decomposers were identified as functional groups being exposed to the GM crops. In a second step, anecic and endogeic species were categorized as potential species. In step three, eight anecic and endogeic earthworm species belonging to the family Lumbricidae were ranked as relevant species: Aporrectodea caliginosa, Aporrectodea rosea, Aporrectodea longa, Allolobophora chlorotica, Lumbricus terrestris, Lumbricus friendi, Octodrilus complanatus and

  12. Selective Targeting of CTNBB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs.

    Directory of Open Access Journals (Sweden)

    Joost C M Uitdehaag

    Full Text Available The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin, KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines

  13. Selective Targeting of CTNNB1-, KRAS- or MYC-Driven Cell Growth by Combinations of Existing Drugs

    Science.gov (United States)

    Uitdehaag, Joost C. M.; de Roos, Jeroen A. D. M.; van Doornmalen, Antoon M.; Prinsen, Martine B. W.; Spijkers-Hagelstein, Jill A. P.; de Vetter, Judith R. F.; de Man, Jos; Buijsman, Rogier C.; Zaman, Guido J. R.

    2015-01-01

    The aim of combination drug treatment in cancer therapy is to improve response rate and to decrease the probability of the development of drug resistance. Preferably, drug combinations are synergistic rather than additive, and, ideally, drug combinations work synergistically only in cancer cells and not in non-malignant cells. We have developed a workflow to identify such targeted synergies, and applied this approach to selectively inhibit the proliferation of cell lines with mutations in genes that are difficult to modulate with small molecules. The approach is based on curve shift analysis, which we demonstrate is a more robust method of determining synergy than combination matrix screening with Bliss-scoring. We show that the MEK inhibitor trametinib is more synergistic in combination with the BRAF inhibitor dabrafenib than with vemurafenib, another BRAF inhibitor. In addition, we show that the combination of MEK and BRAF inhibitors is synergistic in BRAF-mutant melanoma cells, and additive or antagonistic in, respectively, BRAF-wild type melanoma cells and non-malignant fibroblasts. This combination exemplifies that synergistic action of drugs can depend on cancer genotype. Next, we used curve shift analysis to identify new drug combinations that specifically inhibit cancer cell proliferation driven by difficult-to-drug cancer genes. Combination studies were performed with compounds that as single agents showed preference for inhibition of cancer cells with mutations in either the CTNNB1 gene (coding for β-catenin), KRAS, or cancer cells expressing increased copy numbers of MYC. We demonstrate that the Wnt-pathway inhibitor ICG-001 and trametinib acted synergistically in Wnt-pathway-mutant cell lines. The ERBB2 inhibitor TAK-165 was synergistic with trametinib in KRAS-mutant cell lines. The EGFR/ERBB2 inhibitor neratinib acted synergistically with the spindle poison docetaxel and with the Aurora kinase inhibitor GSK-1070916 in cell lines with MYC amplification

  14. Mixed methods evaluation of targeted selective anthelmintic treatment by resource-poor smallholder goat farmers in Botswana

    Science.gov (United States)

    Walker, Josephine G.; Ofithile, Mphoeng; Tavolaro, F. Marina; van Wyk, Jan A.; Evans, Kate; Morgan, Eric R.

    2015-01-01

    Due to the threat of anthelmintic resistance, livestock farmers worldwide are encouraged to selectively apply treatments against gastrointestinal nematodes (GINs). Targeted selective treatment (TST) of individual animals would be especially useful for smallholder farmers in low-income economies, where cost-effective and sustainable intervention strategies will improve livestock productivity and food security. Supporting research has focused mainly on refining technical indicators for treatment, and much less on factors influencing uptake and effectiveness. We used a mixed method approach, whereby qualitative and quantitative approaches are combined, to develop, implement and validate a TST system for GINs in small ruminants, most commonly goats, among smallholder farmers in the Makgadikgadi Pans region of Botswana, and to seek better understanding of system performance within a cultural context. After the first six months of the study, 42 out of 47 enrolled farmers were followed up; 52% had monitored their animals using the taught inspection criteria and 26% applied TST during this phase. Uptake level showed little correlation with farmer characteristics, such as literacy and size of farm. Herd health significantly improved in those herds where anthelmintic treatment was applied: anaemia, as assessed using the five-point FAMACHA© scale, was 0.44–0.69 points better (95% confidence interval) and body condition score was 0.18–0.36 points better (95% C.I., five-point scale) in treated compared with untreated herds. Only targeting individuals in greatest need led to similar health improvements compared to treating the entire herd, leading to dose savings ranging from 36% to 97%. This study demonstrates that TST against nematodes can be implemented effectively by resource-poor farmers using a community-led approach. The use of mixed methods provides a promising system to integrate technical and social aspects of TST programmes for maximum uptake and effect. PMID

  15. Mesoscale Assessment of CO2 Storage Potential and Geological Suitability for Target Area Selection in the Sichuan Basin

    Directory of Open Access Journals (Sweden)

    Yujie Diao

    2017-01-01

    Full Text Available In China, south of the Yangtze River, there are a large number of carbon sources, while the Sichuan Basin is the largest sedimentary basin; it makes sense to select the targets for CO2 geological storage (CGUS early demonstration. For CO2 enhanced oil and gas, coal bed methane recovery (CO2-EOR, EGR, and ECBM, or storage in these depleted fields, the existing oil, gas fields, or coal seams could be the target areas in the mesoscale. This paper proposed a methodology of GIS superimposed multisource information assessment of geological suitability for CO2 enhanced water recovery (CO2-EWR or only storage in deep saline aquifers. The potential per unit area of deep saline aquifers CO2 storage in Central Sichuan is generally greater than 50 × 104 t/km2 at P50 probability level, with Xujiahe group being the main reservoir. CO2 storage potential of depleted gas fields is 53.73 × 108 t, while it is 33.85 × 108 t by using CO2-EGR technology. This paper recommended that early implementation of CGUS could be carried out in the deep saline aquifers and depleted gas fields in the Sichuan Basin, especially that of the latter because of excellent traps, rich geological data, and well-run infrastructures.

  16. Dual targeting of gene delivery by genetic modification of adenovirus serotype 5 fibers and cell-selective transcriptional control.

    Science.gov (United States)

    Work, L M; Ritchie, N; Nicklin, S A; Reynolds, P N; Baker, A H

    2004-08-01

    Adenovirus (Ad)-mediated gene delivery is a promising approach for genetic manipulation of the vasculature and is being used in both preclinical models and clinical trials. However, safety concerns relating to infection of nontarget tissue and the poor infectivity of vascular cells compared to other cell types necessitates Ad vector refinement. Here, we combine a transductional targeting approach to improve vascular cell infectivity through RGD peptide insertion into adenovirus fibers, combined with transcriptional targeting to endothelial cells using a approximately 1 kb fragment of the fms-like tyrosine kinase receptor-1 (FLT-1) promoter. Single- and double-modified vectors were characterized in human cell lines that either support or have silenced FLT-1 expression. In rat hepatocytes and endothelial cells, the double modification substantially shifted transduction profiles toward vascular endothelial cells. Furthermore, in intact aortae derived from spontaneously hypertensive rats that display enhanced alphav integrin expression on dysfunctional endothelium, enhanced levels of transduction were observed using the double-modified vector but not in aortae derived from normotensive control rats. Our data indicate that Ad-mediated transduction can be beneficially modified in vitro and in vivo by combining fiber modification and a cell-selective promoter within a single-component vector system.

  17. Managing anthelmintic resistance-Variability in the dose of drug reaching the target worms influences selection for resistance?

    Science.gov (United States)

    Leathwick, Dave M; Luo, Dongwen

    2017-08-30

    The concentration profile of anthelmintic reaching the target worms in the host can vary between animals even when administered doses are tailored to individual liveweight at the manufacturer's recommended rate. Factors contributing to variation in drug concentration include weather, breed of animal, formulation and the route by which drugs are administered. The implications of this variability for the development of anthelmintic resistance was investigated using Monte-Carlo simulation. A model framework was established where 100 animals each received a single drug treatment. The 'dose' of drug allocated to each animal (i.e. the concentration-time profile of drug reaching the target worms) was sampled at random from a distribution of doses with mean m and standard deviation s. For each animal the dose of drug was used in conjunction with pre-determined dose-response relationships, representing single and poly-genetic inheritance, to calculate efficacy against susceptible and resistant genotypes. These data were then used to calculate the overall change in resistance gene frequency for the worm population as a result of the treatment. Values for m and s were varied to reflect differences in both mean dose and the variability in dose, and for each combination of these 100,000 simulations were run. The resistance gene frequency in the population after treatment increased as m decreased and as s increased. This occurred for both single and poly-gene models and for different levels of dominance (survival under treatment) of the heterozygote genotype(s). The results indicate that factors which result in lower and/or more variable concentrations of active reaching the target worms are more likely to select for resistance. The potential of different routes of anthelmintic administration to play a role in the development of anthelmintic resistance is discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Tetherin Suppresses Type I Interferon Signaling by Targeting MAVS for NDP52-Mediated Selective Autophagic Degradation in Human Cells.

    Science.gov (United States)

    Jin, Shouheng; Tian, Shuo; Luo, Man; Xie, Weihong; Liu, Tao; Duan, Tianhao; Wu, Yaoxing; Cui, Jun

    2017-10-19

    Tetherin (BST2/CD317) is an interferon-inducible antiviral factor known for its ability to block the release of enveloped viruses from infected cells. Yet its role in type I interferon (IFN) signaling remains poorly defined. Here, we demonstrate that Tetherin is a negative regulator of RIG-I like receptor (RLR)-mediated type I IFN signaling by targeting MAVS. The induction of Tetherin by type I IFN accelerates MAVS degradation via ubiquitin-dependent selective autophagy in human cells. Moreover, Tetherin recruits E3 ubiquitin ligase MARCH8 to catalyze K27-linked ubiquitin chains on MAVS at lysine 7, which serves as a recognition signal for NDP52-dependent autophagic degradation. Taken together, our findings reveal a negative feedback loop of RLR signaling generated by Tetherin-MARCH8-MAVS-NDP52 axis and provide insights into a better understanding of the crosstalk between selective autophagy and optimal deactivation of type I IFN signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding.

    Science.gov (United States)

    Fitzgerald, Megan E; Rawling, David C; Potapova, Olga; Ren, Xiaoming; Kohlway, Andrew; Pyle, Anna Marie

    2017-02-17

    RIG-I is an innate immune receptor that detects and responds to infection by deadly RNA viruses such as influenza, and Hepatitis C. In the cytoplasm, RIG-I is faced with a difficult challenge: it must sensitively detect viral RNA while ignoring the abundance of host RNA. It has been suggested that RIG-I has a ‘proof-reading’ mechanism for rejecting host RNA targets, and that disruptions of this selectivity filter give rise to autoimmune diseases. Here, we directly monitor RNA proof-reading by RIG-I and we show that it is controlled by a set of conserved amino acids that couple RNA and ATP binding to the protein (Motif III). Mutations of this motif directly modulate proof-reading by eliminating or enhancing selectivity for viral RNA, with major implications for autoimmune disease and cancer. More broadly, the results provide a physical explanation for the ATP-gated behavior of SF2 RNA helicases and receptor proteins.

  20. Behavior-Dependent Activity and Synaptic Organization of Septo-hippocampal GABAergic Neurons Selectively Targeting the Hippocampal CA3 Area.

    Science.gov (United States)

    Joshi, Abhilasha; Salib, Minas; Viney, Tim James; Dupret, David; Somogyi, Peter

    2017-12-20

    Rhythmic medial septal (MS) GABAergic input coordinates cortical theta oscillations. However, the rules of innervation of cortical cells and regions by diverse septal neurons are unknown. We report a specialized population of septal GABAergic neurons, the Teevra cells, selectively innervating the hippocampal CA3 area bypassing CA1, CA2, and the dentate gyrus. Parvalbumin-immunopositive Teevra cells show the highest rhythmicity among MS neurons and fire with short burst duration (median, 38 ms) preferentially at the trough of both CA1 theta and slow irregular oscillations, coincident with highest hippocampal excitability. Teevra cells synaptically target GABAergic axo-axonic and some CCK interneurons in restricted septo-temporal CA3 segments. The rhythmicity of their firing decreases from septal to temporal termination of individual axons. We hypothesize that Teevra neurons coordinate oscillatory activity across the septo-temporal axis, phasing the firing of specific CA3 interneurons, thereby contributing to the selection of pyramidal cell assemblies at the theta trough via disinhibition. VIDEO ABSTRACT. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Design of hypoxia-targeting radiopharmaceuticals: selective uptake of copper-64 complexes in hypoxic cells in vitro

    International Nuclear Information System (INIS)

    Dearling, J.L.J.; Lewis, J.S.; Mullen, G.E.D.; Rae, M.T.; Zweit, J.; Blower, P.J.

    1998-01-01

    The well-known perfusion tracer CuPTSM, labelled with 62 Cu or 64 Cu, is believed to be trapped in cells non-selectively by a bioreductive mechanism. It is proposed that by modifying the ligand to increase its electron donor strength (for example by adding alkyl functionality or replacing sulphur ligands with oxygen ligands), the copper complexes will become less easily reduced and tracers with selectivity for hypoxic tissues could thus be developed. The aim of this work was to prepare 64 Cu-labelled complexes of two series of ligands, based on the bis(thiosemicarbazone) (13 ligands) and bis(salicylaldimine) (3 ligands) skeletons, and to evaluate the hypoxia dependence of their uptake in cells. The complexes were incubated with Chinese hamster ovary cells under normoxic and hypoxic conditions, and the cells isolated by centrifugation to determine radioactivity uptake at various time points up to 90 min. Several members of both series demonstrated significant (P 60 Cu, 61 Cu, 62 Cu, 64 Cu) and targeted radiotherapy ( 64 Cu, 67 Cu). (orig.)

  2. Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin

    International Nuclear Information System (INIS)

    Demartis, S.; Tarli, L.; Neri, D.; Borsi, L.; Zardi, L.

    2001-01-01

    Angiogenesis is a characteristic feature of many aggressive tumours and other disorders. Antibodies capable of binding to new blood vessels, but not to mature vessels, could be used as selective targeting agents for immunoscintigraphic and radioimmunotherapeutic applications. Here we show that scFv(L19), a recombinant human antibody fragment with sub-nanomolar affinity for the ED-B domain of fibronectin, a marker of angiogenesis, can be stably labelled with iodine-125 and astatine-211 with full retention of immunoreactivity, using a trimethyl-stannyl benzoate bifunctional derivative. Biodistribution studies in mice bearing two different types of tumour grafted subcutaneously, followed by ex vivo micro-autoradiographic analysis, revealed that scFv(L19) rapidly localises around tumour blood vessels, but not around normal vessels. Four hours after intravenous injection of the stably radioiodinated scFv(L19), tumour to blood ratios were 6:1 in mice bearing the F9 murine teratocarcinoma and 9:1 in mice bearing an FE8 rat sarcoma. As expected, all other organs (including kidney) contained significantly less radioactivity than the tumour. Since the ED-B domain of fibronectin has an identical sequence in mouse and man, scFv(L19) is a pan-species antibody and the results presented here suggest clinical utility of radiolabelled scFv(L19) for the scintigraphic detection of angiogenesis in vivo. Furthermore, it should now be possible to investigate scFv(L19) for the selective delivery of 211 At to the tumour neovasculature, causing the selective death of tumour endothelial cells and tumour collapse. (orig.)

  3. Selective Photothermolysis to target Sebaceous Glands: Theoretical Estimation of Parameters and Preliminary Results Using a Free Electron Laser

    Energy Technology Data Exchange (ETDEWEB)

    Fernanda Sakamoto, Apostolos Doukas, William Farinelli, Zeina Tannous, Michelle D. Shinn, Stephen Benson, Gwyn P. Williams, H. Dylla, Richard Anderson

    2011-12-01

    The success of permanent laser hair removal suggests that selective photothermolysis (SP) of sebaceous glands, another part of hair follicles, may also have merit. About 30% of sebum consists of fats with copious CH2 bond content. SP was studied in vitro, using free electron laser (FEL) pulses at an infrared CH2 vibrational absorption wavelength band. Absorption spectra of natural and artificially prepared sebum were measured from 200 nm to 3000 nm, to determine wavelengths potentially able to target sebaceous glands. The Jefferson National Accelerator superconducting FEL was used to measure photothermal excitation of aqueous gels, artificial sebum, pig skin, human scalp and forehead skin (sebaceous sites). In vitro skin samples were exposed to FEL pulses from 1620 to 1720 nm, spot diameter 7-9.5 mm with exposure through a cold 4C sapphire window in contact with the skin. Exposed and control tissue samples were stained using H and E, and nitroblue tetrazolium chloride staining (NBTC) was used to detect thermal denaturation. Natural and artificial sebum both had absorption peaks near 1210, 1728, 1760, 2306 and 2346 nm. Laser-induced heating of artificial sebum was approximately twice that of water at 1710 and 1720 nm, and about 1.5x higher in human sebaceous glands than in water. Thermal camera imaging showed transient focal heating near sebaceous hair follicles. Histologically, skin samples exposed to {approx}1700 nm, {approx}100-125 ms pulses showed evidence of selective thermal damage to sebaceous glands. Sebaceous glands were positive for NBTC staining, without evidence of selective loss in samples exposed to the laser. Epidermis was undamaged in all samples. Conclusions: SP of sebaceous glands appears to be feasible. Potentially, optical pulses at {approx}1720 nm or {approx}1210 nm delivered with large beam diameter and appropriate skin cooling in approximately 0.1 s may provide an alternative treatment for acne.

  4. An approach to the construction of tailor-made amphiphilic peptides that strongly and selectively bind to hairpin RNA targets.

    Science.gov (United States)

    Lee, Su Jin; Hyun, Soonsil; Kieft, Jeffrey S; Yu, Jaehoon

    2009-02-18

    strategies that can be used to prepare peptides that both strongly and selectively target hairpin RNAs. Specifically, the findings indicate that tailor-made amphiphilic peptide ligands against certain hairpin RNAs can be obtained if the RNA target possesses a deep groove in which both the hydrophobic and hydrophilic spheres of the peptide interact.

  5. Optimization of radiotherapy to target volumes with concave outlines: target-dose homogenization and selective sparing of critical structures by constrained matrix inversion

    Energy Technology Data Exchange (ETDEWEB)

    Colle, C; Van den Berge, D; De Wagter, C; Fortan, L; Van Duyse, B; De Neve, W

    1995-12-01

    The design of 3D-conformal dose distributions for targets with concave outlines is a technical challenge in conformal radiotherapy. For these targets, it is impossible to find beam incidences for which the target volume can be isolated from the tissues at risk. Commonly occurring examples are most thyroid cancers and the targets located at the lower neck and upper mediastinal levels related to some head and neck. A solution to this problem was developed, using beam intensity modulation executed with a multileaf collimator by applying a static beam-segmentation technique. The method includes the definition of beam incidences and beam segments of specific shape as well as the calculation of segment weights. Tests on Sherouse`s GRATISTM planning system allowed to escalate the dose to these targets to 65-70 Gy without exceeding spinal cord tolerance. Further optimization by constrained matrix inversion was investigated to explore the possibility of further dose escalation.

  6. Revealing kinetics and state-dependent binding properties of IKur-targeting drugs that maximize atrial fibrillation selectivity

    Science.gov (United States)

    Ellinwood, Nicholas; Dobrev, Dobromir; Morotti, Stefano; Grandi, Eleonora

    2017-09-01

    The KV1.5 potassium channel, which underlies the ultra-rapid delayed-rectifier current (IKur) and is predominantly expressed in atria vs. ventricles, has emerged as a promising target to treat atrial fibrillation (AF). However, while numerous KV1.5-selective compounds have been screened, characterized, and tested in various animal models of AF, evidence of antiarrhythmic efficacy in humans is still lacking. Moreover, current guidelines for pre-clinical assessment of candidate drugs heavily rely on steady-state concentration-response curves or IC50 values, which can overlook adverse cardiotoxic effects. We sought to investigate the effects of kinetics and state-dependent binding of IKur-targeting drugs on atrial electrophysiology in silico and reveal the ideal properties of IKur blockers that maximize anti-AF efficacy and minimize pro-arrhythmic risk. To this aim, we developed a new Markov model of IKur that describes KV1.5 gating based on experimental voltage-clamp data in atrial myocytes from patient right-atrial samples in normal sinus rhythm. We extended the IKur formulation to account for state-specificity and kinetics of KV1.5-drug interactions and incorporated it into our human atrial cell model. We simulated 1- and 3-Hz pacing protocols in drug-free conditions and with a [drug] equal to the IC50 value. The effects of binding and unbinding kinetics were determined by examining permutations of the forward (kon) and reverse (koff) binding rates to the closed, open, and inactivated states of the KV1.5 channel. We identified a subset of ideal drugs exhibiting anti-AF electrophysiological parameter changes at fast pacing rates (effective refractory period prolongation), while having little effect on normal sinus rhythm (limited action potential prolongation). Our results highlight that accurately accounting for channel interactions with drugs, including kinetics and state-dependent binding, is critical for developing safer and more effective pharmacological anti

  7. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Clinical Practice Guideline Focused Update.

    Science.gov (United States)

    Denduluri, Neelima; Chavez-MacGregor, Mariana; Telli, Melinda L; Eisen, Andrea; Graff, Stephanie L; Hassett, Michael J; Holloway, Jamie N; Hurria, Arti; King, Tari A; Lyman, Gary H; Partridge, Ann H; Somerfield, Mark R; Trudeau, Maureen E; Wolff, Antonio C; Giordano, Sharon H

    2018-05-22

    Purpose To update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer. Methods An Expert Panel conducted targeted systematic literature reviews guided by a signals approach to identify new, potentially practice-changing data that might translate to revised practice recommendations. Results The Expert Panel reviewed phase III trials that evaluated adjuvant capecitabine after completion of standard preoperative anthracycline- and taxane-based combination chemotherapy by patients with early-stage breast cancer HER2-negative breast cancer with residual invasive disease at surgery; the addition of 1 year of adjuvant pertuzumab to combination chemotherapy and trastuzumab for patients with early-stage, HER2-positive breast cancer; and the use of neratinib as extended adjuvant therapy for patients after combination chemotherapy and trastuzumab-based adjuvant therapy with early-stage, HER2-positive breast cancer. Recommendations Patients with early-stage HER2-negative breast cancer with pathologic, invasive residual disease at surgery following standard anthracycline- and taxane-based preoperative therapy may be offered up to six to eight cycles of adjuvant capecitabine. Clinicians may add 1 year of adjuvant pertuzumab to trastuzumab-based combination chemotherapy in patients with high-risk, early-stage, HER2-positive breast cancer. Clinicians may use extended adjuvant therapy with neratinib to follow trastuzumab in patients with early-stage, HER2-positive breast cancer. Neratinib causes substantial diarrhea, and diarrhea prophylaxis must be used. Additional information can be found at www.asco.org/breast-cancer-guidelines .

  8. Exploring the physicochemical profile and the binding patterns of selected novel anticancer Himalayan plant derived active compounds with macromolecular targets

    Directory of Open Access Journals (Sweden)

    Arun Bahadur Gurung

    Full Text Available Plants are vital source of compounds offering plethora of therapeutic effects against various ailments without much side effects. Due to wide spread prevalence and drug resistance in cancer; there is an urgent need for discovery of new anti-cancer drugs. In the present study, selected novel anti-cancer plants derived compounds (cmpd1 to cmpd15 from Himalayan region were docked with defined molecular targets that regulate cell proliferation and apoptosis. The binding energies of best docked compounds ranged between −8.0 kcal/mol and −11.71 kcal/mol. Further analysis revealed critical hydrogen bonds and hydrophobic interactions between compounds and targets. The best docked compounds viz., cmpd15 against cyclin-dependent kinase-2 (CDK-2, cmpd8 against CDK-6 and cmpd9 against Topoisomerase I and II showed higher binding affinities than the native co-crystal ligands. The root mean square deviation (RMSD and potential energy plot clearly indicates the stability of the complexes during 20 ns molecular dynamics (MD simulation. The Molecular Mechanics/Poisson Boltzmann Surface Area (MM/PBSA binding energy analysis revealed Van der Waals energy component which is the principal stabilizing energy for their interactions except CDK-2/cmpd15 complex. The polar solvation energy did not have favorable contribution to their stabilization. The binding energy decomposition analysis revealed per residue contribution for each docked complexes. Physicochemical profile studies showed that majority of the compounds conform to Lipinski's rule of five (ROF having low to high blood brain barrier (BBB penetration, human intestinal absorption, plasma binding protein inhibition and P glycoprotein inhibition. Keywords: ADMET, Anticancer, MM/PBSA, Molecular docking, Molecular dynamics simulation and plant derived compounds

  9. Algal bioremediation of waste waters from land-based aquaculture using ulva: selecting target species and strains.

    Directory of Open Access Journals (Sweden)

    Rebecca J Lawton

    Full Text Available The optimised reduction of dissolved nutrient loads in aquaculture effluents through bioremediation requires selection of appropriate algal species and strains. The objective of the current study was to identify target species and strains from the macroalgal genus Ulva for bioremediation of land-based aquaculture facilities in Eastern Australia. We surveyed land-based aquaculture facilities and natural coastal environments across three geographic locations in Eastern Australia to determine which species of Ulva occur naturally in this region and conducted growth trials at three temperature treatments on a subset of samples from each location to determine whether local strains had superior performance under local environmental conditions. DNA barcoding using the markers ITS and tufA identified six species of Ulva, with U. ohnoi being the most common blade species and U. sp. 3 the most common filamentous species. Both species occurred at multiple land-based aquaculture facilities in Townsville and Brisbane and multiple strains of each species grew well in culture. Specific growth rates of U. ohnoi and U. sp. 3 were high (over 9% and 15% day(-1 respectively across temperature treatments. Within species, strains of U. ohnoi had higher growth in temperatures corresponding to local conditions, suggesting that strains may be locally adapted. However, across all temperature treatments Townsville strains had the highest growth rates (11.2-20.4% day(-1 and Sydney strains had the lowest growth rates (2.5-8.3% day(-1. We also found significant differences in growth between strains of U. ohnoi collected from the same geographic location, highlighting the potential to isolate and cultivate fast growing strains. In contrast, there was no clearly identifiable competitive strain of filamentous Ulva, with multiple species and strains having variable performance. The fast growth rates and broad geographical distribution of U. ohnoi make this an ideal species to

  10. Developing a multi-pollutant conceptual framework for the selection and targeting of interventions in water industry catchment management schemes.

    Science.gov (United States)

    Bloodworth, J W; Holman, I P; Burgess, P J; Gillman, S; Frogbrook, Z; Brown, P

    2015-09-15

    In recent years water companies have started to adopt catchment management to reduce diffuse pollution in drinking water supply areas. The heterogeneity of catchments and the range of pollutants that must be removed to meet the EU Drinking Water Directive (98/83/EC) limits make it difficult to prioritise areas of a catchment for intervention. Thus conceptual frameworks are required that can disaggregate the components of pollutant risk and help water companies make decisions about where to target interventions in their catchments to maximum effect. This paper demonstrates the concept of generalising pollutants in the same framework by reviewing key pollutant processes within a source-mobilisation-delivery context. From this, criteria are developed (with input from water industry professionals involved in catchment management) which highlights the need for a new water industry specific conceptual framework. The new CaRPoW (Catchment Risk to Potable Water) framework uses the Source-Mobilisation-Delivery concept as modular components of risk that work at two scales, source and mobilisation at the field scale and delivery at the catchment scale. Disaggregating pollutant processes permits the main components of risk to be ascertained so that appropriate interventions can be selected. The generic structure also allows for the outputs from different pollutants to be compared so that potential multiple benefits can be identified. CaRPow provides a transferable framework that can be used by water companies to cost-effectively target interventions under current conditions or under scenarios of land use or climate change. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. A BAND SELECTION METHOD FOR SUB-PIXEL TARGET DETECTION IN HYPERSPECTRAL IMAGES BASED ON LABORATORY AND FIELD REFLECTANCE SPECTRAL COMPARISON

    Directory of Open Access Journals (Sweden)

    S. Sharifi hashjin

    2016-06-01

    Full Text Available In recent years, developing target detection algorithms has received growing interest in hyperspectral images. In comparison to the classification field, few studies have been done on dimension reduction or band selection for target detection in hyperspectral images. This study presents a simple method to remove bad bands from the images in a supervised manner for sub-pixel target detection. The proposed method is based on comparing field and laboratory spectra of the target of interest for detecting bad bands. For evaluation, the target detection blind test dataset is used in this study. Experimental results show that the proposed method can improve efficiency of the two well-known target detection methods, ACE and CEM.

  12. Suppress orthotopic colon cancer and its metastasis through exact targeting and highly selective drug release by a smart nanomicelle.

    Science.gov (United States)

    Zhu, Chunqi; Zhang, Hanbo; Li, Wei; Luo, Lihua; Guo, Xiaomeng; Wang, Zuhua; Kong, Fenfen; Li, Qingpo; Yang, Jie; Du, Yongzhong; You, Jian

    2018-04-01

    The treatment of metastatic cancer is a huge challenge at the moment. Highly precise targeting delivery and drug release in tumor have always been our pursuit in cancer therapy, especially to advance cancer with metastasis, for increasing the efficacy and biosafety. We established a smart nanosized micelle, formed by tocopherol succinate (TOS) conjugated hyaluronic acid (HA) using a disulfide bond linker. The micelle (HA-SS-TOS, HSST) can highly specifically bind with CD44 receptor over-expressed tumor, and response selectively to high GSH level in the cells, inducing disulfide bond breakage and the release of the payload (paclitaxel, PTX). To predict the antitumor efficacy of the micelles more clinically, we established an orthotopic colon cancer model with high metastasis rate, which could be visualized by the luciferase bioluminescence. Our data confirmed CD44 high expression in the colon cancer cells. Highly matching between the micellar fluorescence and bioluminescence of cancer cells in intestines demonstrated an exact recognition of our micelles to orthotopic colon tumor and its metastatic cells, attributing to the mediation of CD44 receptors. Furthermore, the fluorescence of the released Nile Red from the micelles was found only in the tumor and its metastatic cells, and almost completely overlapped with the bioluminescence of the cancer cells, indicating a highly selective drug release. Our micelles presented an excellent therapeutic effect against metastatic colon cancer, and induced significantly prolonged survival time for the mice, which might become a promising nanomedicine platform for the future clinical application against advanced cancers with high CD44 receptor expression. Copyright © 2018 Elsevier Ltd. All rights reserved.

  13. Non-targeted detection of chemical contamination in carbonated soft drinks using NMR spectroscopy, variable selection and chemometrics

    Energy Technology Data Exchange (ETDEWEB)

    Charlton, Adrian J. [Department for Environment, Food and Rural Affairs, Central Science Laboratory, Sand Hutton, York YO41 1LZ (United Kingdom)], E-mail: adrian.charlton@csl.gov.uk; Robb, Paul; Donarski, James A.; Godward, John [Department for Environment, Food and Rural Affairs, Central Science Laboratory, Sand Hutton, York YO41 1LZ (United Kingdom)

    2008-06-23

    An efficient method for detecting malicious and accidental contamination of foods has been developed using a combined {sup 1}H nuclear magnetic resonance (NMR) and chemometrics approach. The method has been demonstrated using a commercially available carbonated soft drink, as being capable of identifying atypical products and to identify contaminant resonances. Soft-independent modelling of class analogy (SIMCA) was used to compare {sup 1}H NMR profiles of genuine products (obtained from the manufacturer) against retail products spiked in the laboratory with impurities. The benefits of using feature selection for extracting contaminant NMR frequencies were also assessed. Using example impurities (paraquat, p-cresol and glyphosate) NMR spectra were analysed using multivariate methods resulting in detection limits of approximately 0.075, 0.2, and 0.06 mM for p-cresol, paraquat and glyphosate, respectively. These detection limits are shown to be approximately 100-fold lower than the minimum lethal dose for paraquat. The methodology presented here is used to assess the composition of complex matrices for the presence of contaminating molecules without a priori knowledge of the nature of potential contaminants. The ability to detect if a sample does not fit into the expected profile without recourse to multiple targeted analyses is a valuable tool for incident detection and forensic applications.

  14. Non-targeted detection of chemical contamination in carbonated soft drinks using NMR spectroscopy, variable selection and chemometrics

    International Nuclear Information System (INIS)

    Charlton, Adrian J.; Robb, Paul; Donarski, James A.; Godward, John

    2008-01-01

    An efficient method for detecting malicious and accidental contamination of foods has been developed using a combined 1 H nuclear magnetic resonance (NMR) and chemometrics approach. The method has been demonstrated using a commercially available carbonated soft drink, as being capable of identifying atypical products and to identify contaminant resonances. Soft-independent modelling of class analogy (SIMCA) was used to compare 1 H NMR profiles of genuine products (obtained from the manufacturer) against retail products spiked in the laboratory with impurities. The benefits of using feature selection for extracting contaminant NMR frequencies were also assessed. Using example impurities (paraquat, p-cresol and glyphosate) NMR spectra were analysed using multivariate methods resulting in detection limits of approximately 0.075, 0.2, and 0.06 mM for p-cresol, paraquat and glyphosate, respectively. These detection limits are shown to be approximately 100-fold lower than the minimum lethal dose for paraquat. The methodology presented here is used to assess the composition of complex matrices for the presence of contaminating molecules without a priori knowledge of the nature of potential contaminants. The ability to detect if a sample does not fit into the expected profile without recourse to multiple targeted analyses is a valuable tool for incident detection and forensic applications

  15. First- and Second-Line Targeted Systemic Therapy in Hepatocellular Carcinoma—An Update on Patient Selection and Response Evaluation

    Directory of Open Access Journals (Sweden)

    Johann von Felden

    2016-11-01

    Full Text Available Advanced hepatocellular carcinoma (HCC with vascular invasion and/or extrahepatic spread and preserved liver function, according to stage C of the Barcelona Clinic Liver Cancer (BCLC classification, has a dismal prognosis. The multi-targeted tyrosine-kinase receptor inhibitor (TKI sorafenib is the only proven active substance in systemic HCC therapy for first-line treatment. In this review, we summarize current aspects in patient selection and management of side effects, and provide an update on response evaluation during first-line sorafenib therapy. Since second-line treatment options have been improved with the successful completion of the RESORCE trial, demonstrating a survival benefit for second-line treatment with the TKI regorafenib, response monitoring during first-line therapy will be critical to deliver optimal systemic therapy in HCC. To this regard, specific side effects, in particular worsening of arterial hypertension and diarrhea, might suggest treatment response during first-line sorafenib therapy; however, clear predictive clinical markers, as well as laboratory test or serum markers, are not established. Assessment of radiologic response according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST is helpful to identify patients who do not benefit from sorafenib treatment.

  16. Targeting of liver tumour in rats by selective delivery of holmium-166 loaded microspheres: a biodistribution study

    Energy Technology Data Exchange (ETDEWEB)

    Nijsen, F.; Rook, D.; Zonnenberg, B.; Klerk, J. de; Rijk, P. van; Schip, F. van het [Dept. of Nuclear Medicine, University Medical Center, Utrecht (Netherlands); Brandt, C. [Animal Inst., Utrecht Univ. (Netherlands); Meijer, R. [Dept. of Radiology, Univ. Medical Center, Utrecht (Netherlands); Dullens, H. [Dept. of Pathology, Univ. Medical Center, Utrecht (Netherlands); Hennink, W. [Dept. of Pharmaceutics, Utrecht Univ. (Netherlands)

    2001-06-01

    Intra-arterial administration of beta-emitting particles that become trapped in the vascular bed of a tumour and remain there while delivering high doses, represents a unique approach in the treatment of both primary and metastatic liver tumours. Studies on selective internal radiation therapy of colorectal liver metastases using yttrium-90 glass microspheres have shown encouraging results. This study describes the biodistribution of 40-{mu}m poly lactic acid microspheres loaded with radioactive holmium-166, after intra-arterial administration into the hepatic artery of rats with implanted liver tumours. Radioactivity measurements showed >95% retention of injected activity in the liver and its resident tumour. The average activity detected in other tissues was {<=}0.1%ID/g, with incidental exceptions in the lungs and stomach. Very little {sup 166}Ho activity was detected in kidneys (<0.1%ID/g), thereby indicating the stability of the microspheres in vivo. Tumour targeting was very effective, with a mean tumour to liver ratio of 6.1{+-}2.9 for rats with tumour (n=15) versus 0.7{+-}0.5 for control rats (n=6; P<0.001). These ratios were not significantly affected by the use of adrenaline. Histological analysis showed that five times as many large (>10) and medium-sized (4-9) clusters of microspheres were present within tumour and peritumoural tissue, compared with normal liver. Single microspheres were equally dispersed throughout the tumour, as well as normal liver parenchyma. (orig.)

  17. Activated platelets in carotid artery thrombosis in mice can be selectively targeted with a radiolabeled single-chain antibody.

    Directory of Open Access Journals (Sweden)

    Timo Heidt

    Full Text Available BACKGROUND: Activated platelets can be found on the surface of inflamed, rupture-prone and ruptured plaques as well as in intravascular thrombosis. They are key players in thrombosis and atherosclerosis. In this study we describe the construction of a radiolabeled single-chain antibody targeting the LIBS-epitope of activated platelets to selectively depict platelet activation and wall-adherent non-occlusive thrombosis in a mouse model with nuclear imaging using in vitro and ex vivo autoradiography as well as small animal SPECT-CT for in vivo analysis. METHODOLOGY/PRINCIPAL FINDINGS: LIBS as well as an unspecific control single-chain antibody were labeled with (111Indium ((111In via bifunctional DTPA ( = (111In-LIBS/(111In-control. Autoradiography after incubation with (111In-LIBS on activated platelets in vitro (mean 3866 ± 28 DLU/mm(2, 4010 ± 630 DLU/mm(2 and 4520 ± 293 DLU/mm(2 produced a significantly higher ligand uptake compared to (111In-control (2101 ± 76 DLU/mm(2, 1181 ± 96 DLU/mm(2 and 1866 ± 246 DLU/mm(2 indicating a specific binding to activated platelets; P<0.05. Applying these findings to an ex vivo mouse model of carotid artery thrombosis revealed a significant increase in ligand uptake after injection of (111In-LIBS in the presence of small thrombi compared to the non-injured side, as confirmed by histology (49630 ± 10650 DLU/mm(2 vs. 17390 ± 7470 DLU/mm(2; P<0.05. These findings could also be reproduced in vivo. SPECT-CT analysis of the injured carotid artery with (111In-LIBS resulted in a significant increase of the target-to-background ratio compared to (111In-control (1.99 ± 0.36 vs. 1.1 ± 0.24; P < 0.01. CONCLUSIONS/SIGNIFICANCE: Nuclear imaging with (111In-LIBS allows the detection of platelet activation in vitro and ex vivo with high sensitivity. Using SPECT-CT, wall-adherent activated platelets in carotid arteries could be depicted in vivo. These results encourage further studies elucidating the role of

  18. Defining the Role of BTLA in Breast Cancer Immunosurveillance and Selective Targeting of the BTLA-HVEM-LIGHT Constimulatory System

    Science.gov (United States)

    2011-05-01

    noted below. Briefly, allogeneic P815 (H-2Kd) or syngeneic EL4 (H-2Kb) target cells were labeled with 1 M CFSE. Target cells were suspended in...not observed toward syngeneic (H-2Kb) EL4 cell targets (data not shown). The mean SEM of three mice per group is shown. Table I. Global gene...noted below. Briefly, allogeneic P815 (H-2Kd) or syngeneic EL4 (H-2Kb) target cells were labeled with 1 M CFSE. Target cells were suspended in medium at

  19. A Novel, Highly Selective Inhibitor of Pestivirus Replication That Targets the Viral RNA-Dependent RNA Polymerase

    Science.gov (United States)

    Paeshuyse, Jan; Leyssen, Pieter; Mabery, Eric; Boddeker, Nina; Vrancken, Robert; Froeyen, Matheus; Ansari, Israrul H.; Dutartre, Hélène; Rozenski, Jef; Gil, Laura H. V. G.; Letellier, Carine; Lanford, Robert; Canard, Bruno; Koenen, Frank; Kerkhofs, Pierre; Donis, Ruben O.; Herdewijn, Piet; Watson, Julia; De Clercq, Erik; Puerstinger, Gerhard; Neyts, Johan

    2006-01-01

    We report on the highly potent and selective antipestivirus activity of 5-[(4-bromophenyl)methyl]-2-phenyl-5H-imidazo[4,5-c]pyridine (BPIP). The 50% effective concentration (EC50) for inhibition of bovine viral diarrhea virus (BVDV)-induced cytopathic effect formation was 0.04 ± 0.01 μM. Comparable reduction of viral RNA synthesis (EC50 = 0.12 ± 0.02 μM) and production of infectious virus (EC50 = 0.074 ± 0.003 μM) were observed. The selectivity index (ratio of 50% cytostatic concentration/EC50) of BPIP was ∼2,000. BPIP was inactive against the hepatitis C virus subgenomic replicon and yellow fever virus but demonstrated weak activity against GB virus. Drug-resistant mutants were at least 300-fold less susceptible to BPIP than wild-type virus; showed cross-resistance to N-propyl-N-[2-(2H-1,2,4-triazino[5,6-b]indol-3-ylthio)ethyl]-1-propanamine (VP32947), and carried the F224S mutation in the viral RNA-dependent RNA polymerase (RdRp). When the F224S mutation was introduced into an infectious clone, the drug-resistant phenotype was obtained. BPIP did not inhibit the in vitro activity of recombinant BVDV RdRp, but did inhibit the activity of replication complexes (RCs). Computational docking revealed that F224 is located at the top of the finger domain of the polymerase. Docking of BPIP in the crystal structure of the BVDV RdRp revealed aromatic ring stacking, some hydrophobic contacts, and a hydrogen bond. Since two structurally unrelated compounds, i.e., BPIP and VP32947, target the same region of the BVDV RdRp, this position may be expected to be critical in the functioning of the polymerase or assembly of the RC. The potential of BPIP for the treatment of pestivirus and hepacivirus infections is discussed. PMID:16352539

  20. Target Selection Recommendations Based on Impact of Deep Brain Stimulation Surgeries on Nonmotor Symptoms of Parkinson′s Disease

    Directory of Open Access Journals (Sweden)

    Xiao-Hong Wang

    2015-01-01

    Full Text Available Objective: This review examines the evidence that deep brain stimulation (DBS has extensive impact on nonmotor symptoms (NMSs of patients with Parkinson′s disease (PD. Data Sources: We retrieved information from the PubMed database up to September, 2015, using various search terms and their combinations including PD, NMSs, DBS, globus pallidus internus (GPi, subthalamic nucleus (STN, and ventral intermediate thalamic nucleus. Study Selection: We included data from peer-reviewed journals on impacts of DBS on neuropsychological profiles, sensory function, autonomic symptoms, weight changes, and sleep disturbances. For psychological symptoms and cognitive impairment, we tried to use more reliable proofs: Random, control, multicenter, large sample sizes, and long period follow-up clinical studies. We categorized the NMSs into four groups: those that would improve definitively following DBS; those that are not significantly affected by DBS; those that remain controversial on their surgical benefit; and those that can be worsened by DBS. Results: In general, it seems to be an overall beneficial effect of DBS on NMSs, such as sensory, sleep, gastrointestinal, sweating, cardiovascular, odor, urological symptoms, and sexual dysfunction, GPi-DBS may produce similar results; Both STN and Gpi-DBS are safe with regard to cognition and psychology over long-term follow-up, though verbal fluency decline is related to DBS; The impact of DBS on behavioral addictions and dysphagia is still uncertain. Conclusions: As the motor effects of STN-DBS and GPi-DBS are similar, NMSs may determine the target choice in surgery of future patients.

  1. Selection of binding targets in parasites using phage-display and aptamer libraries in vivo and in vitro

    Directory of Open Access Journals (Sweden)

    Renata Rosito Tonelli

    2013-01-01

    Full Text Available Parasite infections are largely dependent on interactions between pathogen and different host cell populations to guarantee a successful infectious process. This is particularly true for obligatory intracellular parasites as Plasmodium, Toxoplasma, Leishmania, to name a few. Adhesion to and entry into the cell are essential steps requiring specific parasite and host cell molecules. The large amount of possible involved molecules poses additional difficulties for their identification by the classical biochemical approaches. In this respect, the search for alternative techniques should be pursued. Among them two powerful methodologies can be employed, both relying upon the construction of highly diverse combinatorial libraries of peptides or oligonucleotides that randomly bind with high affinity to targets on the cell surface and are selectively displaced by putative ligands. These are, respectively, the peptide-based phage display and the oligonucleotide-based aptamer techniques.The phage display technique has been extensively employed for the identification of novel ligands in vitro and in vivo in different areas such as cancer, vaccine development and epitope mapping. Particularly, phage display has been employed in the investigation of pathogen-host interactions. Although this methodology has been used for some parasites with encouraging results, in trypanosomatids its use is, as yet, scanty. RNA and DNA aptamers, developed by the SELEX process (Systematic Evolution of Ligands by Exponential Enrichment, were described over two decades ago and since then contributed to a large number of structured nucleic acids for diagnostic or therapeutic purposes or for the understanding of the cell biology. Similarly to the phage display technique scarce use of the SELEX process has been used in the probing of parasite-host interaction.In this review, an overall survey on the use of both phage display and aptamer technologies in different pathogenic

  2. Selection of binding targets in parasites using phage-display and aptamer libraries in vivo and in vitro.

    Science.gov (United States)

    Tonelli, R R; Colli, W; Alves, M J M

    2012-01-01

    Parasite infections are largely dependent on interactions between pathogen and different host cell populations to guarantee a successful infectious process. This is particularly true for obligatory intracellular parasites as Plasmodium, Toxoplasma, and Leishmania, to name a few. Adhesion to and entry into the cell are essential steps requiring specific parasite and host cell molecules. The large amount of possible involved molecules poses additional difficulties for their identification by the classical biochemical approaches. In this respect, the search for alternative techniques should be pursued. Among them two powerful methodologies can be employed, both relying upon the construction of highly diverse combinatorial libraries of peptides or oligonucleotides that randomly bind with high affinity to targets on the cell surface and are selectively displaced by putative ligands. These are, respectively, the peptide-based phage display and the oligonucleotide-based aptamer techniques. The phage display technique has been extensively employed for the identification of novel ligands in vitro and in vivo in different areas such as cancer, vaccine development, and epitope mapping. Particularly, phage display has been employed in the investigation of pathogen-host interactions. Although this methodology has been used for some parasites with encouraging results, in trypanosomatids its use is, as yet, scanty. RNA and DNA aptamers, developed by the SELEX process (Systematic Evolution of Ligands by Exponential Enrichment), were described over two decades ago and since then contributed to a large number of structured nucleic acids for diagnostic or therapeutic purposes or for the understanding of the cell biology. Similarly to the phage display technique scarce use of the SELEX process has been used in the probing of parasite-host interaction. In this review, an overall survey on the use of both phage display and aptamer technologies in different pathogenic organisms will be

  3. Using an in Silico Approach to Teach 3D Pharmacodynamics of the Drug-Target Interaction Process Focusing on Selective COX2 Inhibition by Celecoxib

    Science.gov (United States)

    Tavares, Maurício T.; Primi, Marina C.; Silva, Nuno A. T. F.; Carvalho, Camila F.; Cunha, Micael R.; Parise-Filho, Roberto

    2017-01-01

    Teaching the molecular aspects of drug-target interactions and selectivity is not always an easy task. In this context, the use of alternative and engaging approaches could help pharmacy and chemistry students better understand this important topic of medicinal chemistry. Herein a 4 h practical exercise that uses freely available software as a…

  4. The Long-Term Effectiveness of a Selective, Personality-Targeted Prevention Program in Reducing Alcohol Use and Related Harms: A Cluster Randomized Controlled Trial

    Science.gov (United States)

    Newton, Nicola C.; Conrod, Patricia J.; Slade, Tim; Carragher, Natacha; Champion, Katrina E.; Barrett, Emma L.; Kelly, Erin V.; Nair, Natasha K.; Stapinski, Lexine; Teesson, Maree

    2016-01-01

    Background: This study investigated the long-term effectiveness of Preventure, a selective personality-targeted prevention program, in reducing the uptake of alcohol, harmful use of alcohol, and alcohol-related harms over a 3-year period. Methods: A cluster randomized controlled trial was conducted to assess the effectiveness of Preventure.…

  5. The effect of spatial organization of targets and distractors on the capacity to selectively memorize objects in visual short-term memory.

    Science.gov (United States)

    Abbes, Aymen Ben; Gavault, Emmanuelle; Ripoll, Thierry

    2014-01-01

    We conducted a series of experiments to explore how the spatial configuration of objects influences the selection and the processing of these objects in a visual short-term memory task. We designed a new experiment in which participants had to memorize 4 targets presented among 4 distractors. Targets were cued during the presentation of distractor objects. Their locations varied according to 4 spatial configurations. From the first to the last configuration, the distance between targets' locations was progressively increased. The results revealed a high capacity to select and memorize targets embedded among distractors even when targets were extremely distant from each other. This capacity is discussed in relation to the unitary conception of attention, models of split attention, and the competitive interaction model. Finally, we propose that the spatial dispersion of objects has different effects on attentional allocation and processing stages. Thus, when targets are extremely distant from each other, attentional allocation becomes more difficult while processing becomes easier. This finding implicates that these 2 aspects of attention need to be more clearly distinguished in future research.

  6. Broad target cell selectivity of Kaposi's sarcoma-associated herpesvirus glycoprotein-mediated cell fusion and virion entry

    International Nuclear Information System (INIS)

    Kaleeba, Johnan A.R.; Berger, Edward A.

    2006-01-01

    The molecular mechanism of Kaposi's sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) entry is poorly understood. We tested a broad variety of cell types of diverse species and tissue origin for their ability to function as targets in a quantitative reporter gene assay for KSHV-glycoprotein-mediated cell fusion. Several human, non-human primate, and rabbit cell lines were efficient targets, whereas rodent and all human lymphoblastoid cell lines were weak targets. Parallel findings were obtained with a virion entry assay using a recombinant KSHV encoding a reporter gene. No correlation was observed between target cell activity and surface expression of α3β1 integrin, a proposed KSHV receptor. We hypothesize that target cell permissiveness in both the cell fusion and virion entry assays reflects the presence of a putative KSHV fusion-entry receptor

  7. Recent advances in hopanoids analysis: Quantification protocols overview, main research targets and selected problems of complex data exploration.

    Science.gov (United States)

    Zarzycki, Paweł K; Portka, Joanna K

    2015-09-01

    Pentacyclic triterpenoids, particularly hopanoids, are organism-specific compounds and are generally considered as useful biomarkers that allow fingerprinting and classification of biological, environmental and geological samples. Simultaneous quantification of various hopanoids together with battery of related non-polar and low-molecular mass compounds may provide principal information for geochemical and environmental research focusing on both modern and ancient investigations. Target compounds can be derived from microbial biomass, water columns, sediments, coals, crude fossils or rocks. This create number of analytical problems due to different composition of the analytical matrix and interfering compounds and therefore, proper optimization of quantification protocols for such biomarkers is still the challenge. In this work we summarizing typical analytical protocols that were recently applied for quantification of hopanoids like compounds from different samples. Main steps including components of interest extraction, pre-purification, fractionation, derivatization and quantification involving gas (1D and 2D) as well as liquid separation techniques (liquid-liquid extraction, solid-phase extraction, planar and low resolution column chromatography, high-performance liquid chromatography) are described and discussed from practical point of view, mainly based on the experimental papers that were published within last two years, where significant increase in hopanoids research was noticed. The second aim of this review is to describe the latest research trends concerning determination of hopanoids and related low-molecular mass lipids analyzed in various samples including sediments, rocks, coals, crude oils and plant fossils as well as stromatolites and microbial biomass cultivated under different conditions. It has been found that majority of the most recent papers are based on uni- or bivariate approach for complex data analysis. Data interpretation involves

  8. Target-specific NMR detection of protein–ligand interactions with antibody-relayed {sup 15}N-group selective STD

    Energy Technology Data Exchange (ETDEWEB)

    Hetényi, Anasztázia [University of Szeged, Department of Medical Chemistry (Hungary); Hegedűs, Zsófia [University of Szeged, SZTE-MTA Lendület Foldamer Research Group, Institute of Pharmaceutical Analysis Department (Hungary); Fajka-Boja, Roberta; Monostori, Éva [Biological Research Center of the Hungarian Academy of Sciences, Lymphocyte Signal Transduction Laboratory, Institute of Genetics (Hungary); Kövér, Katalin E. [University of Debrecen, Department of Inorganic and Analytical Chemistry (Hungary); Martinek, Tamás A., E-mail: martinek@pharm.u-szeged.hu [University of Szeged, SZTE-MTA Lendület Foldamer Research Group, Institute of Pharmaceutical Analysis Department (Hungary)

    2016-12-15

    Fragment-based drug design has been successfully applied to challenging targets where the detection of the weak protein–ligand interactions is a key element. {sup 1}H saturation transfer difference (STD) NMR spectroscopy is a powerful technique for this work but it requires pure homogeneous proteins as targets. Monoclonal antibody (mAb)-relayed {sup 15}N-GS STD spectroscopy has been developed to resolve the problem of protein mixtures and impure proteins. A {sup 15}N-labelled target-specific mAb is selectively irradiated and the saturation is relayed through the target to the ligand. Tests on the anti-Gal-1 mAb/Gal-1/lactose system showed that the approach is experimentally feasible in a reasonable time frame. This method allows detection and identification of binding molecules directly from a protein mixture in a multicomponent system.

  9. Receptor-Targeted Nipah Virus Glycoproteins Improve Cell-Type Selective Gene Delivery and Reveal a Preference for Membrane-Proximal Cell Attachment.

    Directory of Open Access Journals (Sweden)

    Ruben R Bender

    2016-06-01

    Full Text Available Receptor-targeted lentiviral vectors (LVs can be an effective tool for selective transfer of genes into distinct cell types of choice. Moreover, they can be used to determine the molecular properties that cell surface proteins must fulfill to act as receptors for viral glycoproteins. Here we show that LVs pseudotyped with receptor-targeted Nipah virus (NiV glycoproteins effectively enter into cells when they use cell surface proteins as receptors that bring them closely enough to the cell membrane (less than 100 Å distance. Then, they were flexible in receptor usage as demonstrated by successful targeting of EpCAM, CD20, and CD8, and as selective as LVs pseudotyped with receptor-targeted measles virus (MV glycoproteins, the current standard for cell-type specific gene delivery. Remarkably, NiV-LVs could be produced at up to two orders of magnitude higher titers compared to their MV-based counterparts and were at least 10,000-fold less effectively neutralized than MV glycoprotein pseudotyped LVs by pooled human intravenous immunoglobulin. An important finding for NiV-LVs targeted to Her2/neu was an about 100-fold higher gene transfer activity when particles were targeted to membrane-proximal regions as compared to particles binding to a more membrane-distal epitope. Likewise, the low gene transfer activity mediated by NiV-LV particles bound to the membrane distal domains of CD117 or the glutamate receptor subunit 4 (GluA4 was substantially enhanced by reducing receptor size to below 100 Å. Overall, the data suggest that the NiV glycoproteins are optimally suited for cell-type specific gene delivery with LVs and, in addition, for the first time define which parts of a cell surface protein should be targeted to achieve optimal gene transfer rates with receptor-targeted LVs.

  10. Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma

    Science.gov (United States)

    Staquicini, Fernanda I.; Ozawa, Michael G.; Moya, Catherine A.; Driessen, Wouter H.P.; Barbu, E. Magda; Nishimori, Hiroyuki; Soghomonyan, Suren; Flores, Leo G.; Liang, Xiaowen; Paolillo, Vincenzo; Alauddin, Mian M.; Basilion, James P.; Furnari, Frank B.; Bogler, Oliver; Lang, Frederick F.; Aldape, Kenneth D.; Fuller, Gregory N.; Höök, Magnus; Gelovani, Juri G.; Sidman, Richard L.; Cavenee, Webster K.; Pasqualini, Renata; Arap, Wadih

    2010-01-01

    The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an iron-mimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors. PMID:21183793

  11. Empirical Evidence of Target Leverage, Adjustment Costs and Adjustment Speed of Non-Financial Firms in Selected African Countries

    OpenAIRE

    Oyebola Fatima Etudaiye-Muhtar; Oyebola Fatima Etudaiye-Muhtar; Rubi Ahmad

    2015-01-01

    The issue of target leverage for corporate firms in developing countries has received little attention in extant literature, especially countries in Africa. Given the imperfection that exists in African financial markets that may limit firms access to external capital, this study investigates dynamic adjustment towards a target debt ratio. In addition, the study used a dynamic panel data estimation technique to determine adjustment costs and speed of adjustment in non-financial firms in selec...

  12. Defining the Role of BTLA in Breast Cancer Immunosurveillance and Selective Targeting of the BTLA-HVEM-LIGHT Costimulatory System

    Science.gov (United States)

    2010-05-01

    assay was conducted as reported by Jedema et al. (41), with alterations noted below. Briefly, allogeneic P815 (H-2Kd) or syngeneic EL4 (H-2Kb) target...cells lysed (CFSE7- AAD) was determined by FACS. CTL activity was not observed toward syngeneic (H-2Kb) EL4 cell targets (data not shown). The mean...could induce BTLA phosphor- ylation (Fig. 4c,d). We analyzed BTLA phosphorylation in EL4 cells using immunoprecipitation immunoblot analysis as

  13. Validation, optimisation, and application data in support of the development of a targeted selected ion monitoring assay for degraded cardiac troponin T

    Directory of Open Access Journals (Sweden)

    Alexander S. Streng

    2016-06-01

    Full Text Available Cardiac troponin T (cTnT fragmentation in human serum was investigated using a newly developed targeted selected ion monitoring assay, as described in the accompanying article: “Development of a targeted selected ion monitoring assay for the elucidation of protease induced structural changes in cardiac troponin T” [1]. This article presents data describing aspects of the validation and optimisation of this assay. The data consists of several figures, an excel file containing the results of a sequence identity search, and a description of the raw mass spectrometry (MS data files, deposited in the ProteomeXchange repository with id PRIDE: http://www.ebi.ac.uk/pride/archive/projects/PXD003187.

  14. A protein-targeting strategy used to develop a selective inhibitor of the E17K point mutation in the PH domain of Akt1

    Science.gov (United States)

    Deyle, Kaycie M.; Farrow, Blake; Qiao Hee, Ying; Work, Jeremy; Wong, Michelle; Lai, Bert; Umeda, Aiko; Millward, Steven W.; Nag, Arundhati; Das, Samir; Heath, James R.

    2015-05-01

    Ligands that can bind selectively to proteins with single amino-acid point mutations offer the potential to detect or treat an abnormal protein in the presence of the wild type (WT). However, it is difficult to develop a selective ligand if the point mutation is not associated with an addressable location, such as a binding pocket. Here we report an all-chemical synthetic epitope-targeting strategy that we used to discover a 5-mer peptide with selectivity for the E17K-transforming point mutation in the pleckstrin homology domain of the Akt1 oncoprotein. A fragment of Akt1 that contained the E17K mutation and an I19[propargylglycine] substitution was synthesized to form an addressable synthetic epitope. Azide-presenting peptides that clicked covalently onto this alkyne-presenting epitope were selected from a library using in situ screening. One peptide exhibits a 10:1 in vitro selectivity for the oncoprotein relative to the WT, with a similar selectivity in cells. This 5-mer peptide was expanded into a larger ligand that selectively blocks the E17K Akt1 interaction with its PIP3 (phosphatidylinositol (3,4,5)-trisphosphate) substrate.

  15. Quantitative PET Imaging with Novel HER3-Targeted Peptides Selected by Phage Display to Predict Androgen-Independent Prostate Cancer Progression

    Science.gov (United States)

    2017-12-01

    Independent Prostate Cancer Progression PRINCIPAL INVESTIGATOR: Benjamin Larimer, PhD CONTRACTING ORGANIZATION: Massachusetts General Hospital Boston...TYPE Final 3. DATES COVERED 1 Aug 2016 – 19 August 2017 Selected by Phage Display to Predict Androgen-Independent Prostate Cancer Progression 5a...highly specific peptide that targets HER3 for prostate cancer imaging. The peptide was labeled with a PET imaging radionuclide and injected into mice

  16. Modelling the impacts of pasture contamination and stocking rate for the development of targeted selective treatment strategies for Ostertagia ostertagi infection in calves

    OpenAIRE

    Berk, Zoe; Laurenson, Yan C.S.M.; Forbes, Andrew B.; Kyriazakis, Ilias

    2017-01-01

    A simulation study was carried out to assess whether variation in pasture contamination or stocking rate impact upon the optimal design of targeted selective treatment (TST) strategies. Two methods of TST implementation were considered: 1) treatment of a fixed percentage of a herd according to a given phenotypic trait, or 2) treatment of individuals that exceeded a threshold value for a given phenotypic trait. Four phenotypic traits, on which to base treatment were considered: 1) average dail...

  17. Molecular evolution of pentatricopeptide repeat genes reveals truncation in species lacking an editing target and structural domains under distinct selective pressures

    Directory of Open Access Journals (Sweden)

    Hayes Michael L

    2012-05-01

    Full Text Available Abstract Background Pentatricopeptide repeat (PPR proteins are required for numerous RNA processing events in plant organelles including C-to-U editing, splicing, stabilization, and cleavage. Fifteen PPR proteins are known to be required for RNA editing at 21 sites in Arabidopsis chloroplasts, and belong to the PLS class of PPR proteins. In this study, we investigate the co-evolution of four PPR genes (CRR4, CRR21, CLB19, and OTP82 and their six editing targets in Brassicaceae species. PPR genes are composed of approximately 10 to 20 tandem repeats and each repeat has two α-helical regions, helix A and helix B, that are separated by short coil regions. Each repeat and structural feature was examined to determine the selective pressures on these regions. Results All of the PPR genes examined are under strong negative selection. Multiple independent losses of editing site targets are observed for both CRR21 and OTP82. In several species lacking the known editing target for CRR21, PPR genes are truncated near the 17th PPR repeat. The coding sequences of the truncated CRR21 genes are maintained under strong negative selection; however, the 3’ UTR sequences beyond the truncation site have substantially diverged. Phylogenetic analyses of four PPR genes show that sequences corresponding to helix A are high compared to helix B sequences. Differential evolutionary selection of helix A versus helix B is observed in both plant and mammalian PPR genes. Conclusion PPR genes and their cognate editing sites are mutually constrained in evolution. Editing sites are frequently lost by replacement of an edited C with a genomic T. After the loss of an editing site, the PPR genes are observed with three outcomes: first, few changes are detected in some cases; second, the PPR gene is present as a pseudogene; and third, the PPR gene is present but truncated in the C-terminal region. The retention of truncated forms of CRR21 that are maintained under strong negative

  18. Molecular evolution of pentatricopeptide repeat genes reveals truncation in species lacking an editing target and structural domains under distinct selective pressures.

    Science.gov (United States)

    Hayes, Michael L; Giang, Karolyn; Mulligan, R Michael

    2012-05-14

    Pentatricopeptide repeat (PPR) proteins are required for numerous RNA processing events in plant organelles including C-to-U editing, splicing, stabilization, and cleavage. Fifteen PPR proteins are known to be required for RNA editing at 21 sites in Arabidopsis chloroplasts, and belong to the PLS class of PPR proteins. In this study, we investigate the co-evolution of four PPR genes (CRR4, CRR21, CLB19, and OTP82) and their six editing targets in Brassicaceae species. PPR genes are composed of approximately 10 to 20 tandem repeats and each repeat has two α-helical regions, helix A and helix B, that are separated by short coil regions. Each repeat and structural feature was examined to determine the selective pressures on these regions. All of the PPR genes examined are under strong negative selection. Multiple independent losses of editing site targets are observed for both CRR21 and OTP82. In several species lacking the known editing target for CRR21, PPR genes are truncated near the 17th PPR repeat. The coding sequences of the truncated CRR21 genes are maintained under strong negative selection; however, the 3' UTR sequences beyond the truncation site have substantially diverged. Phylogenetic analyses of four PPR genes show that sequences corresponding to helix A are high compared to helix B sequences. Differential evolutionary selection of helix A versus helix B is observed in both plant and mammalian PPR genes. PPR genes and their cognate editing sites are mutually constrained in evolution. Editing sites are frequently lost by replacement of an edited C with a genomic T. After the loss of an editing site, the PPR genes are observed with three outcomes: first, few changes are detected in some cases; second, the PPR gene is present as a pseudogene; and third, the PPR gene is present but truncated in the C-terminal region. The retention of truncated forms of CRR21 that are maintained under strong negative selection even in the absence of an editing site target

  19. The SET1 Complex Selects Actively Transcribed Target Genes via Multivalent Interaction with CpG Island Chromatin.

    Science.gov (United States)

    Brown, David A; Di Cerbo, Vincenzo; Feldmann, Angelika; Ahn, Jaewoo; Ito, Shinsuke; Blackledge, Neil P; Nakayama, Manabu; McClellan, Michael; Dimitrova, Emilia; Turberfield, Anne H; Long, Hannah K; King, Hamish W; Kriaucionis, Skirmantas; Schermelleh, Lothar; Kutateladze, Tatiana G; Koseki, Haruhiko; Klose, Robert J

    2017-09-05

    Chromatin modifications and the promoter-associated epigenome are important for the regulation of gene expression. However, the mechanisms by which chromatin-modifying complexes are targeted to the appropriate gene promoters in vertebrates and how they influence gene expression have remained poorly defined. Here, using a combination of live-cell imaging and functional genomics, we discover that the vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in a form of multivalent chromatin reading that involves recognition of non-methylated DNA and histone H3 lysine 4 trimethylation (H3K4me3). CFP1 defines SET1 complex occupancy on chromatin, and its multivalent interactions are required for the SET1 complex to place H3K4me3. In the absence of CFP1, gene expression is perturbed, suggesting that normal targeting and function of the SET1 complex are central to creating an appropriately functioning vertebrate promoter-associated epigenome. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. The SET1 Complex Selects Actively Transcribed Target Genes via Multivalent Interaction with CpG Island Chromatin

    Directory of Open Access Journals (Sweden)

    David A. Brown

    2017-09-01

    Full Text Available Chromatin modifications and the promoter-associated epigenome are important for the regulation of gene expression. However, the mechanisms by which chromatin-modifying complexes are targeted to the appropriate gene promoters in vertebrates and how they influence gene expression have remained poorly defined. Here, using a combination of live-cell imaging and functional genomics, we discover that the vertebrate SET1 complex is targeted to actively transcribed gene promoters through CFP1, which engages in a form of multivalent chromatin reading that involves recognition of non-methylated DNA and histone H3 lysine 4 trimethylation (H3K4me3. CFP1 defines SET1 complex occupancy on chromatin, and its multivalent interactions are required for the SET1 complex to place H3K4me3. In the absence of CFP1, gene expression is perturbed, suggesting that normal targeting and function of the SET1 complex are central to creating an appropriately functioning vertebrate promoter-associated epigenome.

  1. The role of natural selection in shaping genetic variation in a promising Chagas disease drug target: Trypanosoma cruzi trans-sialidase.

    Science.gov (United States)

    Gallant, Joseph P; Lima-Cordón, Raquel Asunción; Justi, Silvia A; Monroy, Maria Carlota; Viola, Toni; Stevens, Lori

    2018-04-21

    Rational drug design creates innovative therapeutics based on knowledge of the biological target to provide more effective and responsible therapeutics. Chagas disease, endemic throughout Latin America, is caused by Trypanosoma cruzi, a protozoan parasite. Current therapeutics are problematic with widespread calls for new approaches. Researchers are using rational drug design for Chagas disease and one target receiving considerable attention is the T. cruzi trans-sialidase protein (TcTS). In T. cruzi, trans-sialidase catalyzes the transfer of sialic acid from a mammalian host to coat the parasite surface membrane and avoid immuno-detection. However, the role of TcTS in pathology variance among and within genetic variants of the parasite is not well understood despite numerous studies. Previous studies reported the crystalline structure of TcTS and the TS protein structure in other trypanosomes where the enzyme is often inactive. However, no study has examined the role of natural selection in genetic variation in TcTS. To understand the role of natural selection in TcTS DNA sequence and protein variation, we examined a 471 bp portion of the TcTS gene from 48 T. cruzi samples isolated from insect vectors. Because there may be multiple parasite genotypes infecting one insect and there are multiple copies of TcTS per parasite genome, all 48 sequences had multiple polymorphic bases. To resolve these polymorphisms, we examined cloned sequences from two insect vectors. The data are analyzed to understand the role of natural selection in shaping genetic variation in TcTS and interpreted in light of the possible role of TcTS as a drug target. The analysis highlights negative or purifying selection on three amino acids previously shown to be important in TcTS transfer activity. One amino acid in particular, Tyr342, is a strong candidate for a drug target because it is under negative selection and amino acid substitutions inactivate TcTS transfer activity. Chagas disease

  2. Phylogenetic selection of target species in Amaryllidaceae tribe Haemantheae for acetylcholinesterase inhibition and affinity to the serotonin reuptake transport protein

    Science.gov (United States)

    We present phylogenetic analyses of 37 taxa of Amaryllidaceae, tribe Haemantheae and Amaryllis belladonna L. as an outgroup, in order to provide a phylogenetic framework for the selection of candidate plants for lead discoveries in relation to Alzheimer´s disease and depression. DNA sequences from t...

  3. Selected Arterial Infusion Chemotherapy Combined with Target Drugs 
for Non-small Cell Lung Cancer with Multiple Brain Metastase

    Directory of Open Access Journals (Sweden)

    Jinduo LI

    2012-05-01

    Full Text Available Background and objective The aim of this study is to evaluate the efficacy of selected arterial infusion chemotherapy in treating non-small cell lung cancer (NSCLC with multiple brain metastases and corresponding factors to influencing prognosis. Methods From September 2008 to October 2011, a total of 31 patients of NSCLC with multiple brain metastases (≥3 received selected incranial, bronchial and corresponding target arterial infusion chemotherapy combined with EGFR-TKIs. Interventional treatment was performed every four weeks, two-six cycles with synchronized or sequential targeted drugs (erlotinib, gefitinib or icotinib. Follow-up CT and MRI were regularly finished at interval of four weeks after two cycles of interventional treatment were finished or during taking targeted drugs in order to evaluate efficacy of the therapy. The procedure was stopped for the tumor disease was worse or the patient could not tolerate the toxity of drugs any longer. Results 31 patients was performed two to six cycles of interventional therapy, 3cycles at average. Response assessment showed that 5 (16.1% patients got a complete response (CR, 7 (22.6% had a partial response (PR, 11 (35.5% had a stable disease (SD and 8 (25.8% had a progressive disease (PD. The objective response rate (ORR was 38.7%, and the disease control rate was 74.2%. The median progression free survival (PFS and overall survival (OS were 13.1 months and 15.1 months. The 6-month survival rate, one-year survival rate and two-year survival rate were 79%, 61.1%, and 31.1%, respectively. The patients’ OS and PFS were influenced by smoking state, tumor pathology, extracranial metastases, period of targeted drug taking and performance status, not by sex, age, before therapy and the total of brain metastases. Conclusion Selected arterial infusion chemotherapy with targeted drugs is one of the most effective and safe treatment to NSCLC with multiple brain metastases. Smoking status, tumor

  4. Design and evaluation of multi-indicator profiles for targeted-selective treatment against gastrointestinal nematodes at housing in adult dairy cows.

    Science.gov (United States)

    Ravinet, Nadine; Lehebel, Anne; Bareille, Nathalie; Lopez, Carlos; Chartier, Christophe; Chauvin, Alain; Madouasse, Aurélien

    2017-04-15

    Targeted-selective treatments against gastrointestinal nematode (GIN) in adult dairy cows require the identification of "cows to treat", i.e. cows whose milk production (MP) would increase after treatment. This study aimed at quantifying the ability of multi-indicator profiles to identify such cows. A randomized controlled clinical trial was conducted at housing in 25 French pasturing dairy herds. In each herd, treated cows received fenbendazole orally, control cows remained untreated. Daily MP was recorded and the MP variation between the pre- and post-visit periods was calculated (ΔMP) for each cow. ΔMP was modelled with control cows data (n=412) (piecewise linear mixed model). Estimated parameters were applied to treated cows data (n=414) to predict the expected ΔMP in treated cows if they had not been treated. Treated cows with an observed ΔMP (with treatment) higher than the expected ΔMP (without treatment) were labelled as "cows to treat". Herds where at least 50% of the young cows were "cows to treat" were qualified as "herds to target". To characterize such cows and herds, the available candidate indicators were (i) at the cow-level: parity, stage of lactation and production level, faecal egg count (FEC), serum pepsinogen level and anti-Ostertagia antibody level (expressed as ODR); (ii) at the herd-level: bulk tank milk (BTM) Ostertagia ODR, Time of Effective Contact (TEC, in months) with GIN infective larvae before the first calving, and percentage of positive FEC. These indicators were tested one-by-one or in combination to assess their ability to characterize "herds to target" and "cows to treat" (Chi-square tests). 115 out of 414 treated cows (27.8%) were considered as "cows to treat", and 9 out of 22 herds were qualified as "herds to target". The indicators retained to profile such cows and herds were the parity, the production level, the BTM Ostertagia ODR and the TEC. Multi-indicator profiles were much more specific than single indicator

  5. Metallogenic geologic prerequisites of sandstone-type uranium deposits and target area selection. Taking Erlian and Ordos basins as examples

    International Nuclear Information System (INIS)

    Chen Fazheng

    2002-01-01

    Sandstone-type uranium deposit is the main target of recent uranium prospecting and exploration. According to the metallogenic characteristics, sandstone-type uranium deposits are divided into three groups: paleo-channel type, interlayer oxidation zone type and phreatic interlayer oxidation type. The author makes an analysis on the geologic prerequisites of the three types of uranium deposits, the similarities and difference, and preliminarily summarizes genetic models of different types of uranium deposits. Finally, taking Erlian and Ordos basins as examples, the author makes an evaluation and a strategic analysis on the uranium metallogenic prospect of the above two basins

  6. Asteroseismology of OB stars with hundreds of single snapshot spectra (and a few time-series of selected targets)

    Science.gov (United States)

    Simón-Díaz, S.

    2015-01-01

    Imagine we could do asteroseismology of large samples of OB-type stars by using just one spectrum per target. That would be great! But this is probably a crazy and stupid idea. Or maybe not. Maybe we have the possibility to open a new window to investigate stellar oscillations in massive stars that has been in front of us for many years, but has not attracted very much our attention: the characterization and understanding of the so-called macroturbulent broadening in OB-type stars.

  7. Optimizing the Targeting of Mouse Parvovirus 1 to Murine Melanoma Selects for Recombinant Genomes and Novel Mutations in the Viral Capsid Gene

    Directory of Open Access Journals (Sweden)

    Matthew Marr

    2018-01-01

    Full Text Available Combining virus-enhanced immunogenicity with direct delivery of immunomodulatory molecules would represent a novel treatment modality for melanoma, and would require development of new viral vectors capable of targeting melanoma cells preferentially. Here we explore the use of rodent protoparvoviruses targeting cells of the murine melanoma model B16F10. An uncloned stock of mouse parvovirus 1 (MPV1 showed some efficacy, which was substantially enhanced following serial passage in the target cell. Molecular cloning of the genes of both starter and selected virus pools revealed considerable sequence diversity. Chimera analysis mapped the majority of the improved infectivity to the product of the major coat protein gene, VP2, in which linked blocks of amino acid changes and one or other of two apparently spontaneous mutations were selected. Intragenic chimeras showed that these represented separable components, both contributing to enhanced infection. Comparison of biochemical parameters of infection by clonal viruses indicated that the enhancement due to changes in VP2 operates after the virus has bound to the cell surface and penetrated into the cell. Construction of an in silico homology model for MPV1 allowed placement of these changes within the capsid shell, and revealed aspects of the capsid involved in infection initiation that had not been previously recognized.

  8. Lorazepam induces multiple disturbances in selective attention: attentional overload, decrement in target processing efficiency, and shifts in perceptual discrimination and response bias.

    Science.gov (United States)

    Michael, George Andrew; Bacon, Elisabeth; Offerlin-Meyer, Isabelle

    2007-09-01

    There is a general consensus that benzodiazepines affect attentional processes, yet only few studies have tried to investigate these impairments in detail. The purpose of the present study was to investigate the effects of a single dose of Lorazepam on performance in a target cancellation task with important time constraints. We measured correct target detections and correct distractor rejections, misses and false positives. The results show that Lorazepam produces multiple kinds of shifts in performance, which suggests that it impairs multipLe processes: (a) the evolution of performance over time was not the same between the placebo and the Lorazepam groups, with the Lorazepam affecting performance quite early after the beginning of the test. This is suggestive of a depletion of attentional resources during sequential attentional processing; (b) Lorazepam affected differently target and distractor processing, with target detection being the most impaired; (c) misses were more frequent under Lorazepam than under placebo, but no such difference was observed as far as false positives were concerned. Signal detection analyses showed that Lorazepam (d) decreased perceptual discrimination, and (e) reliably increased response bias. Our results bring new insights on the multiple effects of Lorazepam on selective attention which, when combined, may have deleterious effects on human performance.

  9. An engineered genetic selection for ternary protein complexes inspired by a natural three-component hitchhiker mechanism.

    Science.gov (United States)

    Lee, Hyeon-Cheol; Portnoff, Alyse D; Rocco, Mark A; DeLisa, Matthew P

    2014-12-22

    The bacterial twin-arginine translocation (Tat) pathway is well known to translocate correctly folded monomeric and dimeric proteins across the tightly sealed cytoplasmic membrane. We identified a naturally occurring heterotrimer, the Escherichia coli aldehyde oxidoreductase PaoABC, that is co-translocated by the Tat translocase according to a ternary "hitchhiker" mechanism. Specifically, the PaoB and PaoC subunits, each devoid of export signals, are escorted to the periplasm in a piggyback fashion by the Tat signal peptide-containing subunit PaoA. Moreover, export of PaoA was blocked when either PaoB or PaoC was absent, revealing a surprising interdependence for export that is not seen for classical secretory proteins. Inspired by this observation, we created a bacterial three-hybrid selection system that links the formation of ternary protein complexes with antibiotic resistance. As proof-of-concept, a bispecific antibody was employed as an adaptor that physically crosslinked one antigen fused to a Tat export signal with a second antigen fused to TEM-1 β-lactamase (Bla). The resulting non-covalent heterotrimer was exported in a Tat-dependent manner, delivering Bla to the periplasm where it hydrolyzed β-lactam antibiotics. Collectively, these results highlight the remarkable flexibility of the Tat system and its potential for studying and engineering ternary protein interactions in living bacteria.

  10. Deep Brain Stimulation Target Selection in an Advanced Parkinson's Disease Patient with Significant Tremor and Comorbid Depression

    Directory of Open Access Journals (Sweden)

    Amar S. Patel

    2017-04-01

    Full Text Available Clinical Vignette: A 67-year-old female with advanced Parkinson's disease (PD, medically refractory tremor, and a history of significant depression presents for evaluation of deep brain stimulation (DBS candidacy.  Clinical Dilemma: Traditionally, stimulation of the subthalamic nucleus (STN has been the preferred target for patients with significant PD tremor. However, STN stimulation is avoided in patients with a significant pre-surgical history of mood disorder.  Clinical Solution: Bilateral DBS of the globus pallidus interna led to significant short term improvement in PD motor symptoms, including significant tremor reduction.  Gap in Knowledge: There is insufficient evidence to support or refute clinicians' traditional preference for STN stimulation in treating refractory PD tremor. Similarly, the available evidence for risk of worsening depression and/or suicidality after STN DBS is mixed. Both questions require further clarification to guide patient and clinician decision-making.

  11. Practical consideration in the selection of X-ray fluorescence tube targets for analysis of geological materials

    International Nuclear Information System (INIS)

    Attawiya, M.Y.; El-Behay, A.Z.; Khattab, F.M.

    1985-01-01

    Four X-ray fluorescence tubes with different targets (Cr, W, Mo and Rh) were compared for their suitability to analyze twelve of the most common major and trace elements in some geological samples. The major elements and Si, Al, Ca, K, Ti, and S. All elements having wavelengths higher than that of the iron K-absorption edge, gave significantly higher intensities of their characteristic fluorescence radiations when using a Cr-anode tube compared to W, Mo and Rh anode tubes. However, for the light elements (Si and Al) the Rh-anode tube of equal efficiency as the Cr-anode tube. The highest Ka-line intensity of Fe was obtained by the W-anode tube. The lowest detection limits (highest sensitivity) for the trace elements Rb, Sr, Zr, and Nb are obtained using both the Mo and Rh tubes. (author)

  12. Differential Expression of FosB Proteins and Potential Target Genes in Select Brain Regions of Addiction and Depression Patients.

    Directory of Open Access Journals (Sweden)

    Paula A Gajewski

    Full Text Available Chronic exposure to stress or drugs of abuse has been linked to altered gene expression throughout the body, and changes in gene expression in discrete brain regions are thought to underlie many psychiatric diseases, including major depressive disorder and drug addiction. Preclinical models of these disorders have provided evidence for mechanisms of this altered gene expression, including transcription factors, but evidence supporting a role for these factors in human patients has been slow to emerge. The transcription factor ΔFosB is induced in the prefrontal cortex (PFC and hippocampus (HPC of rodents in response to stress or cocaine, and its expression in these regions is thought to regulate their "top down" control of reward circuitry, including the nucleus accumbens (NAc. Here, we use biochemistry to examine the expression of the FosB family of transcription factors and their potential gene targets in PFC and HPC postmortem samples from depressed patients and cocaine addicts. We demonstrate that ΔFosB and other FosB isoforms are downregulated in the HPC but not the PFC in the brains of both depressed and addicted individuals. Further, we show that potential ΔFosB transcriptional targets, including GluA2, are also downregulated in the HPC but not PFC of cocaine addicts. Thus, we provide the first evidence of FosB gene expression in human HPC and PFC in these psychiatric disorders, and in light of recent findings demonstrating the critical role of HPC ΔFosB in rodent models of learning and memory, these data suggest that reduced ΔFosB in HPC could potentially underlie cognitive deficits accompanying chronic cocaine abuse or depression.

  13. In silico molecular docking studies of new potential 4-phthalazinyl-hydrazones on selected Trypanosoma cruzi and Leishmania enzyme targets.

    Science.gov (United States)

    Romero, Angel H; López, Simón E

    2017-09-01

    Recently, a series of 4-phthalazinyl-hydrazones under its E-configuration have exhibited excellent in vitro antichagasic and antileishmanial profiles. Preliminary assays on both parasites suggested that the most active derivatives act through oxidative and nitrosative stress mechanisms; however, their exact mode of actions as anti-trypanosomal and anti-leishmanial agents have not been completely elucidated. This motivated to perform a molecular docking study on essential trypanosomatid enzymes such as superoxide dismutase (SOD), trypanothione reductase (TryR), cysteine-protease (CP) and pteridine reductase 1 (PTR1). In addition, to understand the experimental results of nitric oxide production obtained for infected macrophages with Leishmania parasite, a molecular docking was evaluated on nitric oxide synthase (iNOS) enzyme of Rattus norvegicus. Both diastereomers (E and Z) of the 4-phthalazinyl-hydrazones were docked on the mentioned targets. In general, molecular docking on T. cruzi enzymes revealed that the E-diastereomers exhibited lower binding energies than Z-diastereomers on the Fe-SOD and CP enzymes, while Z-diastereomers showed lower docking energies than E-isomers on TryR enzyme. For the Leishmania docking studies, the Z-isomers exhibited the best binding affinities on the PTR1 and iNOS enzymes, while the TryR enzyme showed a minor dependence with the stereoselectivity of the tested phthalazines. However, either the structural information of the ligand-enzyme complexes or the experimental data suggest that the significant antitrypanosomatid activity of the most active derivatives is not associated to the inhibition of the SOD, CP and PTR1 enzymes, while the TryR inhibition and nitric oxide generation in host cells emerge as interesting antitrypanosomatid therapeutic targets. Copyright © 2017 Elsevier Inc. All rights reserved.

  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. Assessing the impact of a targeted plyometric training on changes in selected kinematic parameters of the swimming start.

    Science.gov (United States)

    Rejman, Marek; Bilewski, Marek; Szczepan, Stefan; Klarowicz, Andrzej; Rudnik, Daria; Maćkała, Krzysztof

    2017-01-01

    The aim of this study was to analyse changes taking place within selected kinematic parameters of the swimming start, after completing a six-week plyometric training, assuming that the take-off power training improves its effectiveness. The experiment included nine male swimmers. In the pre-test the swimmers performed three starts focusing on the best performance. Next, a plyometric training programme, adapted from sprint running, was introduced in order to increase a power of the lower extremities. The programme entailed 75 minute sessions conducted twice a week. Afterwards, a post-test was performed, analogous to the pre-test. Spatio-temporal structure data of the swimming start were gathered from video recordings of the swimmer above and under water. Impulses triggered by the plyometric training contributed to a shorter start time (the main measure of start effectiveness) and glide time as well as increasing average take-off, flight and glide velocities including take-off, entry and glide instantaneous velocities. The glide angle decreased. The changes in selected parameters of the swimming start and its confirmed diagnostic values, showed the areas to be susceptible to plyometric training and suggested that applied plyometric training programme aimed at increasing take-off power enhances the effectiveness of the swimming start.

  16. 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.

  17. Selection of Bacillus species for targeted in situ release of prebiotic galacto-rhamnogalacturonan from potato pulp in piglets

    DEFF Research Database (Denmark)

    Jers, Carsten; Strube, Mikael Lenz; Cantor, Mette D

    2017-01-01

    We have previously shown that galacto-rhamnogalacturonan fibers can be enzymatically extracted from potato pulp and that these fibers have potential for exerting a prebiotic effect in piglets. The spore-forming Bacillus species are widely used as probiotics in feed supplements for pigs. In this s......We have previously shown that galacto-rhamnogalacturonan fibers can be enzymatically extracted from potato pulp and that these fibers have potential for exerting a prebiotic effect in piglets. The spore-forming Bacillus species are widely used as probiotics in feed supplements for pigs....... In this study, we evaluated the option for further functionalizing Bacillus feed supplements by selecting strains possessing the enzymes required for extraction of the potentially prebiotic fibers. We established that it would require production and secretion of pectin lyase and/or polygalacturonase...... of producing prebiotic fibers via a feed containing Bacillus spores and potato pulp and identified candidates for future in vivo evaluation in piglets....

  18. PeptideManager: A Peptide Selection Tool for Targeted Proteomic Studies Involving Mixed Samples from Different Species

    Directory of Open Access Journals (Sweden)

    Kevin eDemeure

    2014-09-01

    Full Text Available The search for clinically useful protein biomarkers using advanced mass spectrometry approaches represents a major focus in cancer research. However, the direct analysis of human samples may be challenging due to limited availability, the absence of appropriate control samples, or the large background variability observed in patient material. As an alternative approach, human tumors orthotopically implanted into a different species (xenografts are clinically relevant models that have proven their utility in pre-clinical research. Patient derived xenografts for glioblastoma have been extensively characterized in our laboratory and have been shown to retain the characteristics of the parental tumor at the phenotypic and genetic level. Such models were also found to adequately mimic the behavior and treatment response of human tumors. The reproducibility of such xenograft models, the possibility to identify their host background and perform tumor-host interaction studies, are major advantages over the direct analysis of human samples.At the proteome level, the analysis of xenograft samples is challenged by the presence of proteins from two different species which, depending on tumor size, type or location, often appear at variable ratios. Any proteomics approach aimed at quantifying proteins within such samples must consider the identification of species specific peptides in order to avoid biases introduced by the host proteome. Here, we present an in-house methodology and tool developed to select peptides used as surrogates for protein candidates from a defined proteome (e.g., human in a host proteome background (e.g., mouse, rat suited for a mass spectrometry analysis. The tools presented here are applicable to any species specific proteome, provided a protein database is available. By linking the information from both proteomes, PeptideManager significantly facilitates and expedites the selection of peptides used as surrogates to analyze

  19. The regional metallogenesis and optimum selection of prospecting target for superlarge uranium deposit in metallogenic area of erguna

    International Nuclear Information System (INIS)

    Luo Yi; Wang Zhengbang; Hou Huiqun; Zhou Dean; Qi Fucheng; Xiao Xiangping

    1995-06-01

    The study area, an activation zone of the median Massif in Xingmeng geosynclinal area, geologically underwent the multiple tectono-magmatic reworking of granitizations during Shinagan, Caledonia and Hercynian periods and of continental rift volcanism in the Mesozoic-Cenozoic era. It is an important potential area for uranium metallogenesis in volcanic basin in North China. The study identifies that four stages of uranium preconcentration and three phases of hydrothermal superimposed-reworking uranium metallogenesis occurred along with the regional geological elevation process. Studies on the U-Pb isotope and induced fission track of various kinds of basement rocks from the area indicate that the basement composed of crustal source remelting type Caledonian and Hercynian granites is favourable for uranium metallogenesis in volcanic basin, and that the late Jurassic intermediate-acid volcano-rock directly act as the source of uranium and that Cretaceous-Tertiary extension-rift basalt magmatic activation supply an important hydrothermal reworking condition for the uranium metallogenesis in volcanic basin. Based on comparative study on the metallogenetic conditions of typical large-scale volcanic uranium deposits at home and abroad, nine prospecting criteria are summarized, the polygenetic mixing hydrothermal uranium metallogenetic model for penetrable volcano-collapse basin is presented, and the main prospecting targets of uranium deposits are pointed out. (2 figs.)

  20. Selected issues relating to target companies and their boards in the context of merger and acquisition transactions

    International Nuclear Information System (INIS)

    Allen, F.R.

    1998-01-01

    Some of the practical, legal and regulatory issues which the board of directors of a target company should bear in mind in their deliberations concerning a take-over bid are reviewed. Directors of such companies will require compliance with and adherence to standard legal and regulatory rules of conduct. Developing a team to deal with the myriad details of a take-over, acquisition or merger, preparing and compiling and maintaining a manual of relevant information are highly recommended. Fiduciary duties of directors and its relevance to mergers and acquisitions are illustrated by reference to a number of recent actual court cases involving these issues. Relevant Canadian and U.S. Case Law is reviewed. It is emphasized throughout the paper that take-over transactions, mergers and acquisitions are complex and time consuming processes. It is essential and customary for senior management to be active participants in most merger and acquisition matters to provide the strategic input which drives the efforts of all involved. Equally important is to establish appropriate governance practices and to prepare and equip the corporation's mergers and acquisitions team in advance, should such events arise on short notice by design or otherwise. 38 refs

  1. The Importance of Target Market Selection for More Profitable Olive Oil Exports by Turkey: A Case Study

    Directory of Open Access Journals (Sweden)

    Mustafa METE

    2015-12-01

    Full Text Available In this study, the quotas and taxes implemented by EU to Turkey were examined and it was observed that these policies have negative effects on Turkey’s olive oil exports. Due to the restrictive policies and low profitability in the entry to the EU market, it was determined that Turkey should be directed to the markets that have higher profitability compared with the exports to EU countries. These detections were carried out in accordance with the information obtained from International Trade Center (ITC and Market Access Database (MAD. As a result of the detections it has been found that exports to the EU countries are more profitable and the entry to the market is easier than to the US. As a result of the researches in ITC and MAD databases, actual companies in oil imports in the US market have been determined and it has shown by examining a bill of loading sample that the firms that make olive oils exports in Turkey easily enter new target markets if they know the usage of the databases

  2. Multiple insecticide resistance mechanisms involving metabolic changes and insensitive target sites selected in anopheline vectors of malaria in Sri Lanka

    Directory of Open Access Journals (Sweden)

    Karunaratne SHP Parakrama

    2008-08-01

    Full Text Available Abstract Background The current status of insecticide resistance and the underlying resistance mechanisms were studied in the major vector of malaria, Anopheles culicifacies, and the secondary vector, Anopheles subpictus in five districts (Anuradhapura, Kurunegala, Moneragala, Puttalam and Trincomalee of Sri Lanka. Eight other anophelines, Anopheles annularis, Anopheles barbirostris, Anopheles jamesii, Anopheles nigerrimus, Anopheles peditaeniatus, Anopheles tessellatus, Anopheles vagus and Anopheles varuna from Anuradhapura district were also tested. Methods Adult females were exposed to the WHO discriminating dosages of DDT, malathion, fenitrothion, propoxur, λ-cyhalothrin, cyfluthrin, cypermethrin, deltamethrin, permethrin and etofenprox. The presence of metabolic resistance by esterase, glutathione S-transferase (GST and monooxygenase-based mechanisms, and the sensitivity of the acetylcholinesterase target site were assessed using synergists, and biochemical, and metabolic techniques. Results All the anopheline species had high DDT resistance. All An. culicifacies and An. subpictus populations were resistant to malathion, except An. culicifacies from Kurunegala, where there was no malathion carboxylesterase activity. Kurunegala and Puttalam populations of An. culicifacies were susceptible to fenitrothion. All the An. culicifacies populations were susceptible to carbamates. Both species were susceptible to the discriminating dosages of cypermethrin and cyfluthrin, but had different levels of resistance to other pyrethroids. Of the 8 other anophelines, only An. nigerrimus and An. peditaeniatus were resistant to all the insecticides tested, probably due to their high exposure to the insecticides used in agriculture. An. vagus showed some resistance to permethrin. Esterases, GSTs and monooxygenases were elevated in both An. culicifacies and An. subpictus. AChE was most sensitive to insecticides in Kurunegala and Trincomalee An. culicifacies

  3. Evaluation of a developmental hierarchy for breast cancer cells to assess risk-based patient selection for targeted treatment.

    Science.gov (United States)

    Bliss, Sarah A; Paul, Sunirmal; Pobiarzyn, Piotr W; Ayer, Seda; Sinha, Garima; Pant, Saumya; Hilton, Holly; Sharma, Neha; Cunha, Maria F; Engelberth, Daniel J; Greco, Steven J; Bryan, Margarette; Kucia, Magdalena J; Kakar, Sham S; Ratajczak, Mariusz Z; Rameshwar, Pranela

    2018-01-10

    This study proposes that a novel developmental hierarchy of breast cancer (BC) cells (BCCs) could predict treatment response and outcome. The continued challenge to treat BC requires stratification of BCCs into distinct subsets. This would provide insights on how BCCs evade treatment and adapt dormancy for decades. We selected three subsets, based on the relative expression of octamer-binding transcription factor 4 A (Oct4A) and then analysed each with Affymetrix gene chip. Oct4A is a stem cell gene and would separate subsets based on maturation. Data analyses and gene validation identified three membrane proteins, TMEM98, GPR64 and FAT4. BCCs from cell lines and blood from BC patients were analysed for these three membrane proteins by flow cytometry, along with known markers of cancer stem cells (CSCs), CD44, CD24 and Oct4, aldehyde dehydrogenase 1 (ALDH1) activity and telomere length. A novel working hierarchy of BCCs was established with the most immature subset as CSCs. This group was further subdivided into long- and short-term CSCs. Analyses of 20 post-treatment blood indicated that circulating CSCs and early BC progenitors may be associated with recurrence or early death. These results suggest that the novel hierarchy may predict treatment response and prognosis.

  4. Selective Radiofrequency Stimulation of the Dorsal Root Ganglion (DRG) as a Method for Predicting Targets for Neuromodulation in Patients With Post Amputation Pain: A Case Series.

    Science.gov (United States)

    Hunter, Corey W; Yang, Ajax; Davis, Tim

    2017-10-01

    While spinal cord stimulation (SCS) has established itself as an accepted and validated treatment for neuropathic pain, there are a number of conditions where it has experienced less, long-term success: post amputee pain (PAP) being one of them. Dorsal root ganglion (DRG) stimulation has shown great promise, particularly in conditions where traditional SCS has fallen short. One major difference between DRG stimulation and traditional SCS is the ability to provide focal stimulation over targeted areas. While this may be a contributing factor to its superiority, it can also be a limitation insofar stimulating the wrong DRG(s) can lead to failure. This is particularly relevant in conditions like PAP where neuroplastic maladaptation occurs causing the pain to deviate from expected patterns, thus creating uncertainty and variability in predicting targets for stimulation. We propose selective radiofrequency (RF) stimulation of the DRG as a method for preoperatively predicting targets for neuromodulation in patients with PAP. We present four patients with PAP of the lower extremities. RF stimulation was used to selectively stimulate individual DRG's, creating areas of paresthesias to see which most closely correlated/overlapped with the painful area(s). RF stimulation to the DRG's that resulted in the desirable paresthesia coverage in the residual or the missing limb(s) was recorded as "positive." Trial DRG leads were placed based on the positive RF stimulation findings. In each patient, stimulating one or more DRG(s) produced paresthesias patterns that were contradictory to know dermatomal patterns. Upon completion of a one-week trial all four patients reported 60-90% pain relief, with coverage over the painful areas, and opted for permanent implant. Mapping the DRG via RF stimulation appears to provide improved accuracy for determining lead placement in the setting of PAP where pain patterns are known to deviate from conventional dermatomal mapping. © 2017

  5. Targeting of VX2 Rabbit Liver Tumor by Selective Delivery of 3-Bromopyruvate: A Biodistribution and Survival Study

    Science.gov (United States)

    Vali, Mustafa; Vossen, Josephina A.; Buijs, Manon; Engles, James M.; Liapi, Eleni; Ventura, Veronica Prieto; Khwaja, Afsheen; Acha-Ngwodo, Obele; Shanmugasundaram, Ganapathy; Syed, Labiq; Wahl, Richard L.; Geschwind, Jean-Francois H.

    2009-01-01

    The aim of this study was to determine the biodistribution and tumor targeting ability of 14C-labeled 3-bromopyruvate ([14C]3-BrPA) after i.a. and i.v. delivery in the VX2 rabbit model. In addition, we evaluated the effects of [14C]3-BrPA on tumor and healthy tissue glucose metabolism by determining 18F-deoxyglucose (FDG) uptake. Last, we determined the survival benefit of i.a. administered 3-BrPA. In total, 60 rabbits with VX2 liver tumor received either 1.75 mM [14C]3-BrPA i.a., 1.75 mM [14C]3-BrPA i.v., 20 mM [14C]3-BrPA i.v., or 25 ml of phosphate-buffered saline (PBS). All rabbits (with the exception of the 20 mM i.v. group) received FDG 1 h before sacrifice. Next, we compared survival of animals treated with i.a. administered 1.75 mM [14C]3-BrPA in 25 ml of PBS (n = 22) with controls (n = 10). After i.a. infusion, tumor uptake of [14C]3-BrPA was 1.8 ± 0.2% percentage of injected dose per gram of tissue (%ID/g), whereas other tissues showed minimal uptake. After i.v. infusion (1.75 mM), tumor uptake of [14C]3-BrPA was 0.03 ± 0.01% ID/g. After i.a. administration of [14C]3-BrPA, tumor uptake of FDG was 26 times lower than in controls. After i.v. administration of [14C]3-BrPA, there was no significant difference in tumor FDG uptake. Survival analysis showed that rabbits treated with 1.75 mM 3-BrPA survived longer (55 days) than controls (18.6 days). Intra-arterially delivered 3-BrPA has a favorable biodistribution profile, combining a high tumor uptake resulting in blockage of FDG uptake with no effects on healthy tissue. The local control of the liver tumor by 3-BrPA resulted in a significant survival benefit. PMID:18591216

  6. Nanosized As2O3/Fe2O3 complexes combined with magnetic fluid hyperthermia selectively target liver cancer cells.

    Science.gov (United States)

    Wang, Zi-Yu; Song, Jian; Zhang, Dong-Sheng

    2009-06-28

    To study the methods of preparing the magnetic nano-microspheres of Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complexes and their therapeutic effects with magnetic fluid hyperthermia (MFH). Nanospheres were prepared by chemical co-precipitation and their shape and diameter were observed. Hemolysis, micronucleus, cell viability, and LD(50) along with other in vivo tests were performed to evaluate the Fe(2)O(3) microsphere biocompatibility. The inhibition ratio of tumors after Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) injections combined with induced hyperthermia in xenograft human hepatocarcinoma was calculated. Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) particles were round with an average diameter of 20 nm and 100 nm as observed under transmission electron microscope. Upon exposure to an alternating magnetic field (AMF), the temperature of the suspension of magnetic particles increased to 41-51 degrees C, depending on different particle concentrations, and remained stable thereafter. Nanosized Fe(2)O(3) microspheres are a new kind of biomaterial without cytotoxic effects. The LD(50) of both Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) in mice was higher than 5 g/kg. One to four weeks after Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complex injections into healthy pig livers, no significant differences were found in serum AST, ALT, BUN and Cr levels among the pigs of all groups (P > 0.05), and no obvious pathological alterations were observed. After exposure to alternating magnetic fields, the inhibition ratio of the tumors was significantly different from controls in the Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) groups (68.74% and 82.79%, respectively; P < 0.01). Tumors of mice in treatment groups showed obvious necrosis, while normal tissues adjoining the tumor and internal organs did not. Fe(2)O(3) and As(2)O(3)/Fe(2)O(3) complexes exerted radiofrequency-induced hyperthermia and drug toxicity on tumors without any liver or kidney damage. Therefore, nanospheres are ideal carriers for tumor-targeted therapy.

  7. Selective toxicity of persian gulf sea cucumber holothuria parva on human chronic lymphocytic leukemia b lymphocytes by direct mitochondrial targeting.

    Science.gov (United States)

    Salimi, Ahmad; Motallebi, Abbasali; Ayatollahi, Maryam; Seydi, Enayatollah; Mohseni, Ali Reza; Nazemi, Melika; Pourahmad, Jalal

    2017-04-01

    Natural products isolated from marine environment are well known for their pharmacodynamic potential in diversity of disease treatments such as cancer or inflammatory conditions. Sea cucumbers are one of the marine animals of the phylum Echinoderm. Many studies have shown that the sea cucumber contains antioxidants and anti-cancer compounds. Chronic lymphocytic leukemia (CLL) is a disease characterized by the relentless accumulation of CD5 + B lymphocytes. CLL is the most common leukemia in adults, about 25-30% of all leukemias. In this study B lymphocytes and their mitochondria (cancerous and non-cancerous) were obtained from peripheral blood of human subjects and B lymphocyte cytotoxicity assay, and caspase 3 activation along with mitochondrial upstream events of apoptosis signaling including reactive oxygen species (ROS) production, collapse of mitochondrial membrane potential (MMP) and mitochondrial swelling were determined following the addition of Holothuria parva extract to both cancerous and non-cancerous B lymphocytes and their mitochondria. Our in vitro finding showed that mitochondrial ROS formation, MMP collapse, and mitochondrial swelling and cytochrome c release were significantly (P < 0.05) increased after addition of different concentrations of H. parva only in cancerous BUT NOT normal non-cancerous mitochondria. Consistently, different concentrations of H. parva significantly (P < 0.05) increased cytotoxicity and caspase 3 activation only in cancerous BUT NOT normal non-cancerous B lymphocytes. These results showed that H. parva methanolic extract has a selective mitochondria mediated apoptotic effect on chronic lymphocytic leukemia B lymphocytes hence may be promising in the future anticancer drug development for treatment of CLL. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1158-1169, 2017. © 2016 Wiley Periodicals, Inc.

  8. In vitro efficacy, resistance selection, and structural modeling studies implicate the malarial parasite apicoplast as the target of azithromycin.

    Science.gov (United States)

    Sidhu, Amar Bir Singh; Sun, Qingan; Nkrumah, Louis J; Dunne, Michael W; Sacchettini, James C; Fidock, David A

    2007-01-26

    Azithromycin (AZ), a broad-spectrum antibacterial macrolide that inhibits protein synthesis, also manifests reasonable efficacy as an antimalarial. Its mode of action against malarial parasites, however, has remained undefined. Our in vitro investigations with the human malarial parasite Plasmodium falciparum document a remarkable increase in AZ potency when exposure is prolonged from one to two generations of intraerythrocytic growth, with AZ producing 50% inhibition of parasite growth at concentrations in the mid to low nanomolar range. In our culture-adapted lines, AZ displayed no synergy with chloroquine (CQ), amodiaquine, or artesunate. AZ activity was also unaffected by mutations in the pfcrt (P. falciparum chloroquine resistance transporter) or pfmdr1 (P. falciparum multidrug resistance-1) drug resistance loci, as determined using transgenic lines. We have selected mutant, AZ-resistant 7G8 and Dd2 parasite lines. In the AZ-resistant 7G8 line, the bacterial-like apicoplast large subunit ribosomal RNA harbored a U438C mutation in domain I. Both AZ-resistant lines revealed a G76V mutation in a conserved region of the apicoplast-encoded P. falciparum ribosomal protein L4 (PfRpl4). This protein is predicted to associate with the nuclear genome-encoded P. falciparum ribosomal protein L22 (PfRpl22) and the large subunit rRNA to form the 50 S ribosome polypeptide exit tunnel that can be occupied by AZ. The PfRpl22 sequence remained unchanged. Molecular modeling of mutant PfRpl4 with AZ suggests an altered orientation of the L75 side chain that could preclude AZ binding. These data imply that AZ acts on the apicoplast bacterial-like translation machinery and identify Pfrpl4 as a potential marker of resistance.

  9. Quality changes of pasteurised mango juice during storage. Part I: Selecting shelf-life markers by integration of a targeted and untargeted multivariate approach.

    Science.gov (United States)

    Wibowo, Scheling; Grauwet, Tara; Gedefa, Getnet Belete; Hendrickx, Marc; Van Loey, Ann

    2015-12-01

    For the first time, a multivariate approach combining targeted and untargeted data was used to obtain insight into quality changes in pasteurised mango juice (cv. 'Totapuri') as a function of storage (42°C for 8weeks). Mango juice samples were formulated with addition of different potential precursors for different quality-related chemical reactions: ascorbic acid, citric acid and sugars. Control (diluted mango puree with water), ascorbic acid-enriched (AA 250 and AA 500 ), citric acid-enriched (CA, CA+AA 250 and CA+AA 500 ) and sugar-enriched (S) samples were characterised for a range of targeted quality parameters as well as for a volatile fingerprint (untargeted). Selection of shelf-life markers or quality parameters significantly changing during shelf-life was performed over all formulations as well as per mango juice formulation. Our study showed that a common trend over all formulations was observed for colour values (VID>│0.90│), while specific shelf-life markers were selected for each formulation. In acidified mango juice samples (CA, CA+AA 250 , CA+AA 500 ), more terpene oxides were selected compared to other formulations. In ascorbic acid-enriched samples (AA 250 , AA 500 , CA+AA 250 , CA+AA 500 ), furfural and ascorbic acid were significantly changing during shelf-life. It seems that the reaction pathways for compounds being formed or degraded upon shelf-life are clearly affected by the acidity level. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    Science.gov (United States)

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

    2014-01-01

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

  11. Impact of target area selection in 125 Iodine seed brachytherapy on locoregional recurrence in patients with non-small cell lung cancer.

    Science.gov (United States)

    Yan, Wei-Liang; Lv, Jin-Shuang; Guan, Zhi-Yu; Wang, Li-Yang; Yang, Jing-Kui; Liang, Ji-Xiang

    2017-05-01

    Computed tomography (CT)-guided percutaneous implantation of 125 Iodine radioactive seeds requires the precise arrangement of seeds by tumor shape. We tested whether selecting target areas, including subclinical areas around tumors, can influence locoregional recurrence in patients with non-small cell lung cancer (NSCLC). We divided 82 patients with NSCLC into two groups. Target areas in group 1 (n = 40) were defined along tumor margins based on lung-window CT. Target areas in group 2 (n = 42) were extended by 0.5 cm in all dimensions outside tumor margins. Preoperative plans for both groups were based on a treatment plan system, which guided 125 I seed implantation. Six months later, patients underwent chest CT to evaluate treatment efficacy (per Response Evaluation Criteria in Solid Tumors version 1). We compared locoregional recurrences between the groups after a year of follow-up. We then used the treatment plan system to extend target areas for group 1 patients by 0.5 cm (defined as group 3 data) and compared these hypothetical group 3 planned seeds with the actual seed numbers used in group 1 patients. All patients successfully underwent implantation; none died during the follow-up period. Recurrence was significantly lower in group 2 than in group 1 ( P  area for 125 I seeds can decrease recurrence risk by eradicating cancerous lymph-duct blockades within the extended areas. © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.

  12. Selection, Identification, and Binding Mechanism Studies of an ssDNA Aptamer Targeted to Different Stages of E. coli O157:H7.

    Science.gov (United States)

    Zou, Ying; Duan, Nuo; Wu, Shijia; Shen, Mofei; Wang, Zhouping

    2018-06-06

    Enterohemorrhagic Escherichia coli O157:H7 ( E. coli O157:H7) is known as an important food-borne pathogen related to public health. In this study, aptamers which could bind to different stages of E. coli O157:H7 (adjustment phase, log phase, and stationary phase) with high affinity and specificity were obtained by the whole cell-SELEX method through 14 selection rounds including three counter-selection rounds. Altogether, 32 sequences were obtained, and nine families were classified to select the optimal aptamer. To analyze affinity and specificity by flow cytometer, an ssDNA aptamer named Apt-5 was picked out as the optimal aptamer that recognizes different stages of E. coli O157:H7 specifically with the K d value of 9.04 ± 2.80 nM. In addition, in order to study the binding mechanism, target bacteria were treated by proteinase K and trypsin, indicating that the specific binding site is not protein on the cell membrane. Furthermore, when we treated E. coli O157:H7 with EDTA, the result showed that the binding site might be lipopolysaccharide (LPS) on the outer membrane of E. coli O157:H7.

  13. Targeting the PDGF-B/PDGFR-β Interface with Destruxin A5 to Selectively Block PDGF-BB/PDGFR-ββ Signaling and Attenuate Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Xingqi Wang

    2016-05-01

    Full Text Available PDGF-BB/PDGFR-ββ signaling plays very crucial roles in the process of many diseases such as liver fibrosis. However, drug candidates with selective affinities for PDGF-B/PDGFR-β remain deficient. Here, we identified a natural cyclopeptide termed destruxin A5 that effectively inhibits PDGF-BB-induced PDGFR-β signaling. Interestingly and importantly, the inhibitory mechanism is distinct from the mechanism of tyrosine kinase inhibitors because destruxin A5 does not have the ability to bind to the ATP-binding pocket of PDGFR-β. Using Biacore T200 technology, thermal shift technology, microscale thermophoresis technology and computational analysis, we confirmed that destruxin A5 selectively targets the PDGF-B/PDGFR-β interaction interface to block this signaling. Additionally, the inhibitory effect of destruxin A5 on PDGF-BB/PDGFR-ββ signaling was verified using in vitro, ex vivo and in vivo models, in which the extent of liver fibrosis was effectively alleviated by destruxin A5. In summary, destruxin A5 may represent an efficacious and more selective inhibitor of PDGF-BB/PDGFR-ββ signaling.

  14. Targeting Medication Non-Adherence Behavior in Selected Autoimmune Diseases: A Systematic Approach to Digital Health Program Development.

    Directory of Open Access Journals (Sweden)

    Trevor van Mierlo

    discovered. Over one third of articles identified the following risk factors as common contributors to medication non-adherence (percent of studies reporting: patients not understanding treatment (44%, side effects (41%, age (37%, dose regimen (33%, and perceived medication ineffectiveness (33%. An unanticipated finding that emerged was the need for risk stratification tools (81% with patient-centric approaches (67%.This study systematically identifies and categorizes medication non-adherence risk factors in select autoimmune diseases. Findings indicate that patients understanding of their disease and the role of medication are paramount. An unexpected finding was that the majority of research articles called for the creation of tailored, patient-centric interventions that dispel personal misconceptions about disease, pharmacotherapy, and how the body responds to treatment. To our knowledge, these interventions do not yet exist in digital format. Rather than adopting a systems level approach, digital health programs should focus on cohorts with heterogeneous needs, and develop tailored interventions based on individual non-adherence patterns.

  15. Selective splenic targeting of In-114m by heat-treated red blood cells for the treatment of lymphoid cell malignancy

    International Nuclear Information System (INIS)

    Sharma, H.L.; Jackson, N.C.; Jackson, H.; Smith, A.M.; Shukla, S.K.

    1998-01-01

    Spleen targeted In-114m, using labelled autologous lymphocytes, has produced a significant antitumour effect in patients with chronic lymphocytic leukaemia and Non-Hodgkins lymphoma (Sharma et al, Anti-Cancer Research 17, 1815-1822,1997). Heat treated red blood cells could be used as alternative vectors for splenic targeting of In-114m, making the technique easier, more universally applicable and furthermore, may reduce the myelosuppression seen with labelled lymphocytes. Red blood cells from HO3T rats were labelled with In-114m-oxine, incubated at 49.5 deg. C for 15 minutes and their distribution investigated in the spleen, liver and blood or recipient animals. The splenic uptake in the spleen at 24h was 64.08%, remained unchanged at 7 days, cleared slowly after that, clearly demonstrating the specificity of HTRBC to target In-114m to the spleen. The depletion of peripheral blood lymphocytes was measured in two groups of HO3T rats following the administration of 1.6 and 3.2 MBq of In-114m-HTRBC respectively. Compared to the controls, ∼ 70% of lymphocytes were depleted in the treated animals within one week and remained unchanged for 6 weeks. Using a rat T-cell lymphocytic leukaemia model, with resemblance to the clinical disease, an anti-leukaemic effect of his method of treatment, was monitored. An average life span of the treated group (1.85 MBq of In-114m-HTRBC) was 17.1 days, compared to the 13.5 days for the untreated group. These results are similar to the ones reported by targeting In-114m with labelled lymphocytes. In summary, the project has shown that In-114m-HTRBC can be used to deposit the radioactivity, selectively in the spleen, which in turn, depletes the peripheral blood lymphocytes and produces an anti-leukaemic effect in terms of enhanced life span. The bone marrow toxicity from In-114m therapy is under investigation and a pharmacokinetic study in selected cancer patients is planned following which, a clinical trial will be considered. (author)

  16. Selective targeted delivery of the TNF-alpha receptor p75 and uteroglobin to the vasculature of inflamed tissues: a preliminary report

    Directory of Open Access Journals (Sweden)

    Ventura Elisa

    2011-11-01

    Full Text Available Abstract Background Ligand-targeted approaches have proven successful in improving the therapeutic index of a number of drugs. We hypothesized that the specific targeting of TNF-alpha antagonists to inflamed tissues could increase drug efficacy and reduce side effects. Results Using uteroglobin (UG, a potent anti-inflammatory protein, as a scaffold, we prepared a bispecific tetravalent molecule consisting of the extracellular ligand-binding portion of the human TNF-alpha receptor P75 (TNFRII and the scFv L19. L19 binds to the ED-B containing fibronectin isoform (B-FN, which is expressed only during angiogenesis processes and during tissue remodeling. B-FN has also been demonstrated in the pannus in rheumatoid arthritis. L19-UG-TNFRII is a stable, soluble homodimeric protein that maintains the activities of both moieties: the immuno-reactivity of L19 and the capability of TNFRII to inhibit TNF-alpha. In vivo bio-distribution studies demonstrated that the molecule selectively accumulated on B-FN containing tissues, showing a very fast clearance from the blood but a very long residence time on B-FN containing tissues. Despite the very fast clearance from the blood, this fusion protein was able to significantly improve the severe symptomatology of arthritis in collagen antibody-induced arthritis (CAIA mouse model. Conclusions The recombinant protein described here, able to selectively deliver the TNF-alpha antagonist TNFRII to inflamed tissues, could yield important contributions for the therapy of degenerative inflammatory diseases.

  17. Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

    Directory of Open Access Journals (Sweden)

    Katrin Hack

    Full Text Available We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787 retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

  18. Investigation of targeted pyrrolizidine alkaloids in traditional Chinese medicines and selected herbal teas sourced in Ireland using LC-ESI-MS/MS.

    Science.gov (United States)

    Griffin, Caroline T; Gosetto, Francesca; Danaher, Martin; Sabatini, Stefano; Furey, Ambrose

    2014-01-01

    Publications linking hepatotoxicity to the use of herbal preparations are escalating. Herbal teas, traditional Chinese medicines (TCMs) and dietary supplements have been shown to contain pyrrolizidine alkaloids (PAs). Acute PA toxicosis of the liver can result in sinusoidal-obstruction syndrome, also known as veno-occlusive disease (VOD). This paper describes a sensitive and robust method for the detection of targeted PAs and their N-oxides (PANOs) in herbal products (selected herbal teas and TCMs) sourced within Ireland. The sample preparation includes a simple acidic extraction with clean-up via solid-phase extraction (SPE). Sample extracts were accurately analysed by using LC-ESI-MS/MS applying for the first time a pentafluorophenyl (PFP) core-shell column to the chromatographic separation of PAs and PANOs. The method was validated for selectivity, taking into consideration matrix effects, specificity, linearity, precision and trueness. Limits of detection (LOD) and limits of quantitation (LOQ) were quantified for all PAs and PANOs ranging from 0.4 to 1.9 µg kg⁻¹ and from 1.3 to 6.3 µg kg⁻¹, respectively. In this study 10 PAs and four PANOs were targeted because they are commercially available as reference standards. Therefore, this study can only report the levels of these PAs and PANOs analysed in the herbal teas and TCMs. The results reported represent the minimum levels of PAs and PANOs present in the samples analysed; commercially available herbal teas (n = 18) and TCMs (n = 54). A total of 50% herbal teas and 78% Chinese medicines tested positive for one or more PAs and/or PANOs included within this study, ranging from 10 to 1733 and from 13 to 3668 µg kg⁻¹, respectively.

  19. The use of Stationary Phase Optimized Selectivity Liquid Chromatography for the development of herbal fingerprints to detect targeted plants in plant food supplements.

    Science.gov (United States)

    Deconinck, E; Djiogo, C A Sokeng; Kamugisha, A; Courselle, P

    2017-08-01

    The consumption of plant food supplements is increasing steadily and more and more, these products are bought through internet. Often the products sold through internet are not registered or declared with a national authority, meaning that no or minimal quality control is performed and that they could contain herbs or plants that are regulated. Stationary Phase Optimized Selectivity Liquid Chromatography (SOS-LC) was evaluated for the development of specific fingerprints, to be used for the detection of targeted plants in plant food supplements. Three commonly used plants in plant food supplements and two regulated plants were used to develop fingerprints with SOS-LC. It was shown that for all plants specific fingerprints could be obtained, allowing the detection of these targeted plants in triturations with different herbal matrices as well as in real samples of suspicious supplements seized by the authorities. For three of the five plants a more specific fingerprint was obtained, compared to the ones developed on traditional columns described in literature. It could therefore be concluded that the combination of segments of different types of stationary phases, as used in SOS-LC, has the potential of becoming a valuable tool in the quality control and the identification of crude herbal or plant material and in the detection of regulated plants in plant food supplements or other herbal preparations. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141.

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    Jye-Lin Hsu

    2015-04-01

    Full Text Available Human cytomegalovirus (HCMV US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I. Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane Profiling revealed US2 was unique in downregulating additional cellular targets, including: five distinct integrin α-chains, CD112, the interleukin-12 receptor, PTPRJ and thrombomodulin. US2 recruited the cellular E3 ligase TRC8 to direct the proteasomal degradation of all its targets, reminiscent of its degradation of MHC-I. Whereas integrin α-chains were selectively degraded, their integrin β1 binding partner accumulated in the ER. Consequently integrin signaling, cell adhesion and migration were strongly suppressed. US2 was necessary and sufficient for degradation of the majority of its substrates, but remarkably, the HCMV NK cell evasion function UL141 requisitioned US2 to enhance downregulation of the NK cell ligand CD112. UL141 retained CD112 in the ER from where US2 promoted its TRC8-dependent retrotranslocation and degradation. These findings redefine US2 as a multifunctional degradation hub which, through recruitment of the cellular E3 ligase TRC8, modulates diverse immune pathways involved in antigen presentation, NK cell activation, migration and coagulation; and highlight US2's impact on HCMV pathogenesis.

  1. Seasonal influenza vaccination coverage rate of target groups in selected cities and provinces in China by season (2009/10 to 2011/12.

    Directory of Open Access Journals (Sweden)

    Lei Zhou

    Full Text Available BACKGROUND: The objectives of the survey were to identify the level of influenza vaccination coverage in China in three influenza seasons 2009/10 to 2011/12, and to find out potential predictors for seasonal influenza vaccination. METHODS: In September and October 2011, representative urban household telephone surveys were conducted in five provinces in China with a response rate of 6%. Four target groups were defined for analysis: 1 children ≤ 5 years old; 2 elderly persons aged ≥ 60 years old; 3 health care workers (persons working in the medical field and 4 chronically ill persons. RESULTS: The overall mean vaccination rate was 9.0%. Among the four target groups, the rate of vaccination of children aged ≤ 5 years old (mean = 26% was highest and the rate of elderly people aged ≥ 60 years old (mean = 7.4% was the lowest, while the rates of persons who suffer from a chronic illness (mean = 9.4% and health care workers (9.5% were similar. A subsidy for influenza vaccination, age group, health care workers, suffering from a chronic illness and living in Eastern China were independent significant predictors for influenza vaccination. CONCLUSIONS: The seasonal influenza vaccination coverage rates among urban populations in selected cities and provinces in China were far below previously reported rates in developed countries. Influenza vaccination coverage rates differed widely between different target groups and provinces in China. Subsidy policy might have a positive effect on influenza vaccination rate, but further cost-effectiveness studies, as well as the vaccination rate associated factors studies are still needed to inform strategies to increase coverage.

  2. Examination of 12-lipoxygenase (12-LOX) as a therapeutic target in non-small cell lung cancer (NSCLC): Mechanisms controlling survival and induction of apoptosis following selective inhibition

    LENUS (Irish Health Repository)

    Cathcart, Mary Clare

    2011-06-01

    Background: Platelet-type 12-LOX is an arachidonic acid metabolising enzyme resulting in the formation of 12(S)-HETE, which stimulates tumour cell adhesion, invasion and metastasis. This study aimed to examine the expression profile and role of this enzyme in NSCLC, and determine if it is a potential target for intervention. Methods: A panel of retrospective resected lung tumours was stained for 12-LOX expression by IHC. Levels of the 12-LOX metabolite, 12(S)-HETE, were examined in 50 NSCLC serum samples, and correlated with serum VEGF. A panel of NSCLC cell lines were treated with baicalein (10 uM), a selective inhibitor of 12-LOX, or 12(S)-HETE (100 ng\\/ml) and cell survival\\/proliferation examined by BrdU. Apoptosis following 12-LOX inhibition was examined by HCS and validated by FACS and DNA laddering. The effect of 12-LOX inhibition on NSCLC tumour growth and survival was examined in-vivo using an athymic nude mouse model. Gene alterations following 12-LOX inhibition in NSCLC cell lines were assessed by qPCR arrays and validated by RT-PCR. Transient transfection methods were used to examine the effects of 12-LOX overexpression in NSCLC cells. Results: 12-LOX expression was observed to a varying degree in human lung cancers of varying histological subtypes. 12(S)-HETE levels were correlated (p<0.05) with those of VEGF. Baicalein inhibited proliferation\\/survival in all cell lines, while 12(S)-HETE increased proliferation. 12-LOX inhibition increased apoptosis, indicated by a reduction in f-actin content and mitochondrial mass potential. Treatment with baicalein significantly reduced the growth of NSCLC tumours and increased overall survival in athymic nude mice. qPCR array data implicated a number of apoptosis\\/angiogenesis genes regulating these effects, including bcl-2, VEGF, integrin A2 and A4. 12-LOX overexpression resulted in an increase in VEGF secretion, confirming qPCR observations. Conclusions: 12-LOX is a survival factor\\/potential target in

  3. Selection and delineation of lymph node target volumes in head and neck conformal radiotherapy. proposal for standardizing terminology and procedure based on the surgical experience

    International Nuclear Information System (INIS)

    Gregoire, V.; Coche, E.; Cosnard, G.; Hamoir, M.; Reychler, H.

    2000-01-01

    The increasing use of 3D treatment planning in head and neck radiation oncology has created an urgent need for new guidelines for the selection and the delineation of the neck node areas to be included in the clinical target volume. Surgical literature has provided us with valuable information on the extent of pathological nodal involvement in the neck as a function of the primary tumor site. In addition, few clinical series have also reported information on radiological nodal involvement in those areas not commonly included in radical neck dissection. Taking all these data together, guidelines for the selection of the node levels to be irradiated for the major head and neck sites could be proposed. To fill the missing link between these Guidelines and the 3D treatment planning, recommendations for the delineation of these node levels (levels I-VI and retropharyngeal) on CT (or MRI) slices have been proposed using the guidelines outlined by the Committee for Head and Neck Surgery and Oncology of the American Academy for Otolarynology-Head and Neck Surgery. These guidelines were adapted to take into account specific radiological landmarks more easily identified on CT or MRI slices than in the operating field. (author)

  4. Novel β-lactamase-random peptide fusion libraries for phage display selection of cancer cell-targeting agents suitable for enzyme prodrug therapy

    Science.gov (United States)

    Shukla, Girja S.; Krag, David N.

    2010-01-01

    Novel phage-displayed random linear dodecapeptide (X12) and cysteine-constrained decapeptide (CX10C) libraries constructed in fusion to the amino-terminus of P99 β-lactamase molecules were used for identifying β-lactamase-linked cancer cell-specific ligands. The size and quality of both libraries were comparable to the standards of other reported phage display systems. Using the single-round panning method based on phage DNA recovery, we identified severalβ-lactamase fusion peptides that specifically bind to live human breast cancer MDA-MB-361 cells. The β-lactamase fusion to the peptides helped in conducting the enzyme activity-based clone normalization and cell-binding screening in a very time- and cost-efficient manner. The methods were suitable for 96-well readout as well as microscopic imaging. The success of the biopanning was indicated by the presence of ~40% cancer cell-specific clones among recovered phages. One of the binding clones appeared multiple times. The cancer cell-binding fusion peptides also shared several significant motifs. This opens a new way of preparing and selecting phage display libraries. The cancer cell-specific β-lactamase-linked affinity reagents selected from these libraries can be used for any application that requires a reporter for tracking the ligand molecules. Furthermore, these affinity reagents have also a potential for their direct use in the targeted enzyme prodrug therapy of cancer. PMID:19751096

  5. Target prioritization and strategy selection for active case-finding of pulmonary tuberculosis: a tool to support country-level project planning.

    Science.gov (United States)

    Nishikiori, Nobuyuki; Van Weezenbeek, Catharina

    2013-02-02

    Despite the progress made in the past decade, tuberculosis (TB) control still faces significant challenges. In many countries with declining TB incidence, the disease tends to concentrate in vulnerable populations that often have limited access to health care. In light of the limitations of the current case-finding approach and the global urgency to improve case detection, active case-finding (ACF) has been suggested as an important complementary strategy to accelerate tuberculosis control especially among high-risk populations. The present exercise aims to develop a model that can be used for county-level project planning. A simple deterministic model was developed to calculate the number of estimated TB cases diagnosed and the associated costs of diagnosis. The model was designed to compare cost-effectiveness parameters, such as the cost per case detected, for different diagnostic algorithms when they are applied to different risk populations. The model was transformed into a web-based tool that can support national TB programmes and civil society partners in designing ACF activities. According to the model output, tuberculosis active case-finding can be a costly endeavor, depending on the target population and the diagnostic strategy. The analysis suggests the following: (1) Active case-finding activities are cost-effective only if the tuberculosis prevalence among the target population is high. (2) Extensive diagnostic methods (e.g. X-ray screening for the entire group, use of sputum culture or molecular diagnostics) can be applied only to very high-risk groups such as TB contacts, prisoners or people living with human immunodeficiency virus (HIV) infection. (3) Basic diagnostic approaches such as TB symptom screening are always applicable although the diagnostic yield is very limited. The cost-effectiveness parameter was sensitive to local diagnostic costs and the tuberculosis prevalence of target populations. The prioritization of appropriate target

  6. Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia—New Developments and Future Perspective

    Directory of Open Access Journals (Sweden)

    Madeleine Monique Uys

    2017-08-01

    Full Text Available α2A- and α2C-adrenoceptors (ARs are the primary α2-AR subtypes involved in central nervous system (CNS function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective α2-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine and atypical antipsychotic (e.g., clozapine drug action. Both α2C- and α2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA release, with α2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine. While the α2A-AR is widely distributed throughout the CNS, α2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α2C-AR plays a more prominent role during states of low endogenous NA activity, while the α2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α2-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α2A- and α2C-ARs on behavioral markers of mood and cognition, implying that non-selective α2-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro-cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer’s disease. This review will emphasize the importance and

  7. Octadecylamine-Mediated Versatile Coating of CoFe2O4 NPs for the Sustained Release of Anti-Inflammatory Drug Naproxen and in Vivo Target Selectivity.

    Science.gov (United States)

    Georgiadou, Violetta; Makris, George; Papagiannopoulou, Dionysia; Vourlias, Georgios; Dendrinou-Samara, Catherine

    2016-04-13

    Magnetic nanoparticles (MNPs) can play a distinct role in magnetic drug delivery via their distribution to the targeted area. The preparation of such MNPs is a challenging multiplex task that requires the optimization of size, magnetic, and surface properties for the achievement of desirable target selectivity, along with the sustained drug release as a prerequisite. In that context, CoFe2O4 MNPs with a small size of ∼7 nm and moderate saturation magnetization of ∼60 emu g(-1) were solvothermally synthesized in the presence of octadecylamine (ODA) with a view to investigate the functionalization route effect on the drug release. Synthetic regulations allowed us to prepare MNPs with aminated (AmMNPs) and amine-free (FAmMNPs) surface. The addition of the nonsteroidal anti-inflammatory drug with a carboxylate donor, Naproxen (NAP), was achieved by direct coupling with the NH2 groups, rendered by ODA, through the formation of an amide bond in the case of AmMNPs. In the case of FAmMNPs, indirect coupling of NAP was performed through an intermediate linker (polyethylenimine) and on PEG-ylated MNPs. FT-IR, (1)H NMR, (13)C NMR, and UV-vis data confirmed the addition of NAP, whereas diverse drug-release behavior was observed for the different functionalization approaches. The biological behavior of the MNPs@NAP was evaluated in vitro in rat serum and in vivo in mice, after radiolabeling with a γ-emitting radionuclide, (99m)Tc. The in vivo fate of MNPs@NAP carriers was in straightforward relation with the direct or indirect coupling of NAP. Furthermore, an inflammation was induced intramuscularly, where the directly coupled (99m)Tc-MNPs@NAP carriers showed increased accumulation at the inflammation site.

  8. 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

  9. Effective identification of Lactobacillus casei group species: genome-based selection of the gene mutL as the target of a novel multiplex PCR assay.

    Science.gov (United States)

    Bottari, Benedetta; Felis, Giovanna E; Salvetti, Elisa; Castioni, Anna; Campedelli, Ilenia; Torriani, Sandra; Bernini, Valentina; Gatti, Monica

    2017-07-01

    Lactobacillus casei,Lactobacillus paracasei and Lactobacillusrhamnosus form a closely related taxonomic group (the L. casei group) within the facultatively heterofermentative lactobacilli. Strains of these species have been used for a long time as probiotics in a wide range of products, and they represent the dominant species of nonstarter lactic acid bacteria in ripened cheeses, where they contribute to flavour development. The close genetic relationship among those species, as well as the similarity of biochemical properties of the strains, hinders the development of an adequate selective method to identify these bacteria. Despite this being a hot topic, as demonstrated by the large amount of literature about it, the results of different proposed identification methods are often ambiguous and unsatisfactory. The aim of this study was to develop a more robust species-specific identification assay for differentiating the species of the L. casei group. A taxonomy-driven comparative genomic analysis was carried out to select the potential target genes whose similarity could better reflect genome-wide diversity. The gene mutL appeared to be the most promising one and, therefore, a novel species-specific multiplex PCR assay was developed to rapidly and effectively distinguish L. casei, L. paracasei and L. rhamnosus strains. The analysis of a collection of 76 wild dairy isolates, previously identified as members of the L. casei group combining the results of multiple approaches, revealed that the novel designed primers, especially in combination with already existing ones, were able to improve the discrimination power at the species level and reveal previously undiscovered intraspecific biodiversity.

  10. Fast, sensitive, and selective gas chromatography tandem mass spectrometry method for the target analysis of chemical secretions from femoral glands in lizards.

    Science.gov (United States)

    Sáiz, Jorge; García-Roa, Roberto; Martín, José; Gómara, Belén

    2017-09-08

    Chemical signaling is a widespread mode of communication among living organisms that is used to establish social organization, territoriality and/or for mate choice. In lizards, femoral and precloacal glands are important sources of chemical signals. These glands protrude chemical secretions used to mark territories and also, to provide valuable information from the bearer to other individuals. Ecologists have studied these chemical secretions for decades in order to increase the knowledge of chemical communication in lizards. Although several studies have focused on the chemical analysis of these secretions, there is a lack of faster, more sensitive and more selective analytical methodologies for their study. In this work a new GC coupled to tandem triple quadrupole MS (GC-QqQ (MS/MS)) methodology is developed and proposed for the target study of 12 relevant compounds often found in lizard secretions (i.e. 1-hexadecanol, palmitic acid, 1-octadecanol, oleic acid, stearic acid, 1-tetracosanol, squalene, cholesta-3,5-diene, α-tocopherol, cholesterol, ergosterol and campesterol). The method baseline-separated the analytes in less than 7min, with instrumental limits of detection ranging from 0.04 to 6.0ng/mL. It was possible to identify differences in the composition of the samples from the lizards analyzed, which depended on the species, the habitat occupied and the diet of the individuals. Moreover, α-tocopherol has been determined for the first time in a lizard species, which was thought to lack its expression in chemical secretions. Globally, the methodology has been proven to be a valuable alternative to other published methods with important improvements in terms of analysis time, sensitivity, and selectivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Identification of effective treatment criteria for use in targeted selective treatment programs to control haemonchosis in periparturient ewes in Ontario, Canada.

    Science.gov (United States)

    Westers, T; Jones-Bitton, A; Menzies, P; VanLeeuwen, J; Poljak, Z; Peregrine, A S

    2016-11-01

    Haemonchosis is often associated with late gestation and parturition in ewes in Canada. Due to widespread concerns about development of anthelmintic resistance (AR), targeted selective treatment (TST), where individual animals are treated with an anthelmintic rather than the entire flock, is a possible strategy to control clinical signs in recently lambed ewes while still maintaining parasite refugia. Performing fecal egg counts (FEC) on individual animals is often cost-prohibitive, so indicators that identify ewes with high FEC are essential for TST programs. The study objectives were to: a) evaluate the ability of four TST indicators to identify periparturient ewes with high Haemonchus sp. FEC and b) determine appropriate treatment thresholds for statistically-significant indicators. A field study was conducted during the 2013 and 2014 lambing seasons (February-May) on three client-owned farms in Ontario with documented AR and problems with haemonchosis in ewes. Ewes were examined within three days of lambing and selected for treatment with oral closantel (10mg/kg body weight), a novel anthelmintic to Canada, if they met at least one of four criteria: a) the last grazing season was their first grazing season; b) body condition score ≤2; c) Faffa Malan Chart (FAMACHA © ) score ≥3; and/or d) three or more nursing lambs. Fecal samples were collected per rectum on the treatment day from each of 20 randomly selected treated and untreated ewes on each farm. Haemonchus sp. percentages on each farm, as determined by coproculture, ranged from 53% to 92% of total fecal trichostrongyle-type egg counts. Mean Haemonchus sp. FECs were significantly higher in treated ewes (n=136) than in untreated ewes (n=103) on the day of treatment in both years (p=0.001), suggesting the indicators were suitable for identifying animals with high Haemonchus sp. FEC. A linear mixed model was fit with logarithmic-transformed Haemonchus sp. FEC as the outcome variable, the four indicators

  12. Targeting the active site of the placental isozyme of alkaline phosphatase by phage-displayed scFv antibodies selected by a specific uncompetitive inhibitor

    Directory of Open Access Journals (Sweden)

    Kala Mrinalini

    2005-12-01

    . Conclusion The results demonstrate the biochemical modulation of scFv binding. Also, the scFvs bound to the active site and denied the access to the substrate. The selection strategy could generate specific anti-enzyme antibodies to PLAP that can potentially be used for targeting, for modulating enzyme activity in in vitro and in vivo and as probes for the active site. This strategy also has a general application in selecting antibodies from combinatorial libraries to closely related molecules and conformations.

  13. Concentrations of Selected Metals In Some Ready-To-Eat-Foods Consumed in Southern Nigeria: Estimation of Dietary Intakes and Target Hazard Quotients

    Directory of Open Access Journals (Sweden)

    Chukwujindu Maxwell Iwegbue

    2013-12-01

    Full Text Available Concentrations of selected metals (Cu, Cd, Ni, Pb, Mn, Fe, Zn, Cr and Co in some ready-to-eat-foods consumed in Nigeria were investigated with a view providing information on the risk associated with the consumption of these products. The concentrations of metals (mg.kg-1 in these ready-to-eat-foods are in the ranges of 2.4 – 5.2 for Cu; 0.1– 0.8 for Cd; 0.7 – 4.0 for Ni; 8.1 – 53.7 for Fe; 8.9 – 20.0 for Zn; 0.1 – 3.8 for Pb; 5.1 – 14.4 for Mn; 0.83 – 21.4 for Cr and 0.20 – 1.32 for Co. The concentrations and estimated intakes of Cd, Ni and Pb in some of these food types exceeded the permissible limits and tolerable daily intake respectively. The target hazard quotients (THQ for the individual metals indicate levels of concern for Ni, Cd, and Co in some of the ready-to-eat-foods. The combined THQ values for the metals in the examined samples ranged from 1.7 to 10 with significant contributions from Cd, Ni and Co.

  14. Occurrence of boscalid and other selected fungicides in surface water and groundwater in three targeted use areas in the United States.

    Science.gov (United States)

    Reilly, Timothy J; Smalling, Kelly L; Orlando, James L; Kuivila, Kathryn M

    2012-09-01

    To provide an assessment of the occurrence of fungicides in water resources, the US Geological Survey used a newly developed analytical method to measure 33 fungicides and an additional 57 current-use pesticides in water samples from streams, ponds, and shallow groundwater in areas of intense fungicide use within three geographic areas across the United States. Sampling sites were selected near or within farms using prophylactic fungicides at rates and types typical of their geographic location. At least one fungicide was detected in 75% of the surface waters and 58% of the groundwater wells sampled. Twelve fungicides were detected including boscalid (72%), azoxystrobin (51%), pyraclostrobin (40%), chlorothalonil (38%) and pyrimethanil (28%). Boscalid, a carboxamide fungicide registered for use in the US in 2003, was detected more frequently than atrazine and metolachlor, two herbicides that are typically the most frequently occurring pesticides in many large-scale water quality studies. Fungicide concentrations ranged from less than the method detection limit to approximately 2000 ngL(-1). Currently, limited toxicological data for non-target species exists and the environmental impacts are largely unknown. The results of this study indicate the importance of including fungicides in pesticide monitoring programs, particularly in areas where crops are grown that require frequent treatments to prevent fungal diseases. Published by Elsevier Ltd.

  15. Imatinib and gastrointestinal stromal tumor (GIST: a selective targeted therapy Imatinib y tumor del estroma gastrointestinal (GIST: un tratamiento selectivo frente a una diana molecular

    Directory of Open Access Journals (Sweden)

    A. Fernández

    2004-10-01

    Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by an anomalous receptor for a growth factor with tyrosine-kinase activity (c-kit. This anomaly causes a permanent activation of the receptor and uncontrolled cell growth. These tumors show a poor response to traditional chemotherapy drugs, and are thus associated with low survival in cases of advanced disease. Imatinib, a tyrosine kinase inhibitor, is an example of selective targeted oncologic therapy that induces improved survival in these patients. We discuss two cases of metastatic gastrointestinal stromal tumors with a good response to imatinib, and also review the pathophysiology and treatment-related outcome of this type of tumors. We include results from clinical phase-III studies.Los tumores del estroma gastrointestinal son los tumores mesenquimales más frecuentes del tracto digestivo y se originan de las células intersticiales de Cajal. Se caracterizan por presentar un receptor para el factor de crecimiento con actividad tirosin kinasa (c-kit anómalo que condiciona su activación permanente y un crecimiento celular incontrolado. Tienen una baja supervivencia en casos de enfermedad avanzada, con escasa respuesta a los agentes quimioterápicos tradicionales. El imatinib es un fármaco inhibidor de la tirosín kinasa y un ejemplo de terapia oncológica selectiva que condiciona un importante aumento en la supervivencia de estos pacientes. Se presentan 2 casos de enfermedad metastásica con buena respuesta a imatinib, así como una revisión sobre la fisiopatología y evolución en el tratamiento de este tipo de tumores, incluyendo resultados de estudios en fase III.

  16. Selective in vitro targeting of GRP and NMB receptors in human tumours with the new bombesin tracer 177Lu-AMBA

    International Nuclear Information System (INIS)

    Waser, Beatrice; Eltschinger, Veronique; Reubi, Jean C.; Linder, Karen; Nunn, Adrian

    2007-01-01

    To investigate the in vitro binding properties of a novel radiolabelled bombesin analogue, 177 Lu-AMBA, in human neoplastic and non-neoplastic tissues selected for their expression of the bombesin receptor subtypes GRP-R, NMB-R and BRS-3. In vitro receptor autoradiography was performed in cancers expressing the various bombesin receptor subtypes. The novel radioligand 177 Lu-AMBA was used and compared with established bombesin radioligands such as 125 I-Tyr 4 -bombesin and 125 I-[D-Tyr 6 ,β-Ala 11 ,Phe 13 ,Nle 14 ]-bombesin(6-14). In vitro incidence of detection of each of the three bombesin receptor subtypes was evaluated in each tumour. 177 Lu-AMBA identified all GRP-R-expressing tumours, such as prostatic, mammary and renal cell carcinomas as well as gastrointestinal stromal tumours. 177 Lu-AMBA also identified all NMB-expressing tumours, but did not detect BRS-3-expressing tumours or BRS-3-expressing pancreatic islets. GRP-R-expressing peritumoural vessels were heavily labelled with 177 Lu-AMBA. In contrast to the strongly GRP-R-positive mouse pancreas, the human pancreas was not labelled with 177 Lu-AMBA unless chronic pancreatitis was diagnosed. In general, the sensitivity was slightly better with 177 Lu-AMBA than with the conventional bombesin radioligands. The present in vitro study suggests that 177 Lu-AMBA may be a very useful in vivo targeting agent for GRP-R-expressing tumours, NMB-R-expressing tumours and GRP-R-expressing neoangiogenic vessels. (orig.)

  17. Selective in vitro targeting of GRP and NMB receptors in human tumours with the new bombesin tracer {sup 177}Lu-AMBA

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Eltschinger, Veronique; Reubi, Jean C. [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Bern (Switzerland); Linder, Karen; Nunn, Adrian [Bracco Research USA Inc, Princeton, NJ (United States)

    2007-01-15

    To investigate the in vitro binding properties of a novel radiolabelled bombesin analogue, {sup 177}Lu-AMBA, in human neoplastic and non-neoplastic tissues selected for their expression of the bombesin receptor subtypes GRP-R, NMB-R and BRS-3. In vitro receptor autoradiography was performed in cancers expressing the various bombesin receptor subtypes. The novel radioligand {sup 177}Lu-AMBA was used and compared with established bombesin radioligands such as {sup 125}I-Tyr{sup 4}-bombesin and {sup 125}I-[D-Tyr{sup 6},{beta}-Ala{sup 11},Phe{sup 13},Nle{sup 14}]-bombesin(6-14). In vitro incidence of detection of each of the three bombesin receptor subtypes was evaluated in each tumour. {sup 177}Lu-AMBA identified all GRP-R-expressing tumours, such as prostatic, mammary and renal cell carcinomas as well as gastrointestinal stromal tumours. {sup 177}Lu-AMBA also identified all NMB-expressing tumours, but did not detect BRS-3-expressing tumours or BRS-3-expressing pancreatic islets. GRP-R-expressing peritumoural vessels were heavily labelled with {sup 177}Lu-AMBA. In contrast to the strongly GRP-R-positive mouse pancreas, the human pancreas was not labelled with {sup 177}Lu-AMBA unless chronic pancreatitis was diagnosed. In general, the sensitivity was slightly better with {sup 177}Lu-AMBA than with the conventional bombesin radioligands. The present in vitro study suggests that {sup 177}Lu-AMBA may be a very useful in vivo targeting agent for GRP-R-expressing tumours, NMB-R-expressing tumours and GRP-R-expressing neoangiogenic vessels. (orig.)

  18. ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters.

    Science.gov (United States)

    Hanukoglu, Israel

    2017-02-01

    The acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) are members of a superfamily of channels that play critical roles in mechanosensation, chemosensation, nociception, and regulation of blood volume and pressure. These channels look and function like a tripartite funnel that directs the flow of Na + ions into the cytoplasm via the channel pore in the membrane. The subunits that form these channels share a common structure with two transmembrane segments (TM1 and TM2) and a large extracellular part. In most vertebrates, there are five paralogous genes that code for ASICs (ASIC1-ASIC5), and four for ENaC subunits alpha, beta, gamma, and delta (α, β, γ, and δ). While ASICs can form functional channels as a homo- or heterotrimer, ENaC functions as an obligate heterotrimer composed of α-β-γ or β-γ-δ subunits. The structure of ASIC has been determined in several conformations, including desensitized and open states. This review presents a comparison of the structures of these states using easy-to-understand molecular models of the full complex, the central tunnel that includes an outer vestibule, the channel pore, and ion selectivity filter. The differences in the secondary, tertiary, and quaternary structures of the states are summarized to pinpoint the conformational changes responsible for channel opening. Results of site-directed mutagenesis studies of ENaC subunits are examined in light of ASIC1 models. Based on these comparisons, a molecular model for the selectivity filter of ENaC is built by in silico mutagenesis of an ASIC1 structure. These models suggest that Na + ions pass through the filter in a hydrated state. © 2016 Federation of European Biochemical Societies.

  19. 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/

  20. Selectivity of Inhibition of N-Succinyl-l,l-Diaminopimelic Acid Desuccinylase in Bacteria: The product of dapE-gene Is Not the Target of l-Captopril Antimicrobial Activity.

    Science.gov (United States)

    Uda, Narasimha Rao; Creus, Marc

    2011-01-01

    The emergence of bacterial strains that are resistant to virtually all currently available antibiotics underscores the importance of developing new antimicrobial compounds. N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE) is a metallohydrolase involved in the meso-diaminopimelate (mDAP)/lysine biosynthetic pathway necessary for lysine biosynthesis and for building the peptidoglycan cell wall. Because DapE is essential for Gram-negative and some Gram-positive bacteria, DapE has been proposed as a good target for antibiotic development. Recently, l-captopril has been suggested as a lead compound for inhibition of DapE, although its selectivity for this enzyme target in bacteria remains unclear (Gillner et al. (2009)). Here, we tested the selectivity of l-captopril against DapE in bacteria. Since DapE knockout strains of gram-negative bacteria are viable upon chemical supplementation with mDAP, we reasoned that the antimicrobial activity of compounds targeting DapE should be abolished in mDAP-containing media. Although l-captopril had modest antimicrobial activity in Escherichia coli and in Salmonella enterica, to our surprise, inhibition of bacterial growth was independent both of mDAP supplementation and DapE over-expression. We conclude that DapE is not the main target of l-captopril inhibition in these bacteria. The methods implemented here will be useful for screening DapE-selective antimicrobial compounds directly in bacterial cultures.

  1. Does a person selectively recall the good or the bad from their personal past? It depends on the recall target and the person's favourability of self-views.

    Science.gov (United States)

    Ritchie, Timothy D; Sedikides, Constantine; Skowronski, John J

    2017-09-01

    In three studies, participants remembered real-life behaviours at Time 1 and attempted to recall them at Time 2. When the recall target was the self, a positivity bias emerged: self-positivity. In Study 3, self-positivity extended to an individual (target) who was liked by the participant, but did it not extend to a disliked target. For this latter target, a negativity bias emerged. For recall targets that were participants' acquaintances, self-positivity in recall was also eliminated in Studies 1 and 3, and a negativity bias in recall emerged in Study 2. Finally, in Study 2 (but not Study 3), the favourability of participants' self-view predicted the magnitude of the self-positivity in self-recall, but it did not predict valence effects in other-recall. Taken together, the results indicate that the link between behaviour valence and recall is moderated by the recall target and the favourability of one's self-view.

  2. Towards a mechanistic understanding of vulnerability to hook-and-line fishing: Boldness as the basic target of angling-induced selection

    DEFF Research Database (Denmark)

    Klefoth, Thomas; Skov, Christian; Kuparinen, Anna

    2017-01-01

    by juvenile growth rate, while morphological traits were only weakly related to angling vulnerability. In addition, we found juvenile growth rate to be moderately correlated with boldness. Hence, direct selection on boldness will also induce indirect selection on juvenile growth and vice versa, but given......In passively operated fishing gear, boldness-related behaviors should fundamentally affect the vulnerability of individual fish and thus be under fisheries selection. To test this hypothesis, we used juvenile common-garden reared carp (Cyprinus carpio) within a narrow size range to investigate...... the mechanistic basis of behavioral selection caused by angling. We focused on one key personality trait (i.e., boldness), measured in groups within ponds, two morphological traits (body shape and head shape), and one life-history trait (juvenile growth capacity) and studied mean standardized selection gradients...

  3. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells.

    Science.gov (United States)

    Rix, U; Remsing Rix, L L; Terker, A S; Fernbach, N V; Hantschel, O; Planyavsky, M; Breitwieser, F P; Herrmann, H; Colinge, J; Bennett, K L; Augustin, M; Till, J H; Heinrich, M C; Valent, P; Superti-Furga, G

    2010-01-01

    Resistance to the BCR-ABL tyrosine kinase inhibitor imatinib poses a pressing challenge in treating chronic myeloid leukemia (CML). This resistance is often caused by point mutations in the ABL kinase domain or by overexpression of LYN. The second-generation BCR-ABL inhibitor INNO-406 is known to inhibit most BCR-ABL mutants and LYN efficiently. Knowledge of its full target spectrum would provide the molecular basis for potential side effects or suggest novel therapeutic applications and possible combination therapies. We have performed an unbiased chemical proteomics native target profile of INNO-406 in CML cells combined with functional assays using 272 recombinant kinases thereby identifying several new INNO-406 targets. These include the kinases ZAK, DDR1/2 and various ephrin receptors. The oxidoreductase NQO2, inhibited by both imatinib and nilotinib, is not a relevant target of INNO-406. Overall, INNO-406 has an improved activity over imatinib but a slightly broader target profile than both imatinib and nilotinib. In contrast to dasatinib and bosutinib, INNO-406 does not inhibit all SRC kinases and most TEC family kinases and is therefore expected to elicit fewer side effects. Altogether, these properties may make INNO-406 a valuable component in the drug arsenal against CML.

  4. Strategy for Extracting DNA from Clay Soil and Detecting a Specific Target Sequence via Selective Enrichment and Real-Time (Quantitative) PCR Amplification ▿

    Science.gov (United States)

    Yankson, Kweku K.; Steck, Todd R.

    2009-01-01

    We present a simple strategy for isolating and accurately enumerating target DNA from high-clay-content soils: desorption with buffers, an optional magnetic capture hybridization step, and quantitation via real-time PCR. With the developed technique, μg quantities of DNA were extracted from mg samples of pure kaolinite and a field clay soil. PMID:19633108

  5. An in vitro and in vivo study of peptide-functionalized nanoparticles for brain targeting : The importance of selective blood–brain barrier uptake

    NARCIS (Netherlands)

    Bode, Gerard H.; Coué, G.M.J.P.C.; Freese, Christian; Pickl, Karin E.; Sanchez-Purrà, Maria; Albaiges, Berta; Borrós, Salvador; van Winden, Ewoud C.; Tziveleka, Leto Aikaterini; Sideratou, Zili; Engbersen, Johan F.J.; Singh, Smriti; Albrecht, Krystyna; Groll, Jürgen; Möller, Martin; Pötgens, Andy J.G.; Schmitz, Christoph; Fröhlich, Eleonore; Grandfils, Christian; Sinner, Frank M.; Kirkpatrick, C. James; Steinbusch, Harry W.M.; Frank, Hans Georg; Unger, Ronald E.; Martinez-Martinez, Pilar

    2017-01-01

    Targeted delivery of drugs across endothelial barriers remains a formidable challenge, especially in the case of the brain, where the blood–brain barrier severely limits entry of drugs into the central nervous system. Nanoparticle-mediated transport of peptide/protein-based drugs across endothelial

  6. Efficacy Trial of a Selective Prevention Program Targeting Both Eating Disorders and Obesity among Female College Students: 1- and 2-Year Follow-Up Effects

    Science.gov (United States)

    Stice, Eric; Rohde, Paul; Shaw, Heather; Marti, C. Nathan

    2013-01-01

    Objective: Evaluate the effects of a prevention program targeting both eating disorders and obesity at 1- and 2-year follow-ups. Method: Female college students at risk for these outcomes because of body image concerns (N = 398) were randomized to the "Healthy Weight 2" group-based 4-hr prevention program, which promotes lasting healthy…

  7. PSA-selective activation of cytotoxic human serine proteases within the tumor microenvironment as a therapeutic strategy to target prostate cancer.

    Science.gov (United States)

    Rogers, Oliver C; Anthony, Lizamma; Rosen, D Marc; Brennen, W Nathaniel; Denmeade, Samuel R

    2018-04-27

    Prostate cancer is the most diagnosed malignancy and the second leading cause of cancer-related death in American men. While localized therapy is highly curative, treatments for metastatic prostate cancer are largely palliative. Thus, new innovative therapies are needed to target metastatic tumors. Prostate-Specific Antigen (PSA) is a chymotrypsin-like protease with a unique substrate specificity that is secreted by both normal and malignant prostate epithelial cells. Previous studies demonstrated the presence of high levels (μM-mM) of enzymatically active PSA is present in the extracellular fluid of the prostate cancer microenvironment. Because of this, PSA is an attractive target for a protease activated pro-toxin therapeutic strategy. Because prostate cancers typically grow very slowly, a strategy employing a proliferation-independent cytotoxic payload is preferred. Recently, it was shown that the human protease Granzyme B (GZMB), at low micromolar concentrations in the extracellular space, can cleave an array of extracellular matrix (ECM) proteins thus perturbing cell growth, signaling, motility, and integrity. It is also well established that other human proteases such as trypsin can induce similar effects. Because both enzymes require N-terminal proteolytic activation, we propose to convert these proteins into PSA-activated cytotoxins. In this study, we examine the enzymatic and cell targeting parameters of these PSA-activated cytotoxic serine proteases. These pro-enzymes were activated robustly by PSA and induced ECM damage that led to the death of prostate cancer cells in vitro thus supporting the potential use of this strategy as means to target metastatic prostate cancers.

  8. Selective targeting of the mTORC1/2 protein kinase complexes leads to antileukemic effects in vitro and in vivo

    International Nuclear Information System (INIS)

    Schuster, K; Zheng, J; Arbini, A A; Zhang, C C; Scaglioni, P P

    2011-01-01

    The BCR/ABL tyrosine kinase promotes leukemogenesis through activation of several targets that include the phosphoinositide 3-kinase (PI3K). Tyrosine kinase inhibitors (TKIs), which target BCR/ABL, induce striking clinical responses. However, therapy with TKIs is associated with limitations such as drug intolerance, inability to universally eradicate the disease and emergence of BCR/ABL drug-resistant mutants. To overcome these limitations, we tested whether inhibition of the PI3K/target of rapamycin (mTOR) signaling pathway has antileukemic effect in primary hematopoietic stem cells and BA/F3 cells expressing the BCR/ABL oncoprotein. We determined that dual inhibition of PI3K/mTOR causes growth arrest and apoptosis leading to profound antileukemic effects both in vitro and in vivo. We also established that pharmacologic inhibition of the mTORC1/mTORC2 complexes is sufficient to cause these antileukemic effects. Our results support the development of inhibitors of the mTORC1/2 complexes for the therapy of leukemias that either express BCR/ABL or display deregulation of the PI3K/mTOR signaling pathway

  9. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized

    OpenAIRE

    van Delft, Mark F.; Wei, Andrew H.; Mason, Kylie D.; Vandenberg, Cassandra J.; Chen, Lin; Czabotar, Peter E.; Willis, Simon N.; Scott, Clare L.; Day, Catherine L.; Cory, Suzanne; Adams, Jerry M.; Roberts, Andrew W.; Huang, David C.S.

    2006-01-01

    Since apoptosis is impaired in malignant cells overexpressing pro-survival Bcl-2 proteins, drugs mimicking their natural antagonists, BH3-only proteins, might overcome chemoresistance. Of seven putative BH3 mimetics tested, only ABT-737 triggered Bax/Bak-mediated apoptosis. Despite its high affinity for Bcl-2, Bcl-xL and Bcl-w, many cell types proved refractory to ABT-737. We show that this resistance reflects its inability to target another pro-survival relative, Mcl-1. Down-regulation of Mc...

  10. 基于区间数灰色关联决策的电力目标选择方法%Selection Method of Power Targets Based on Interval Number Grey Relation Decision-Making

    Institute of Scientific and Technical Information of China (English)

    吴畏; 赵文杰; 刘辉

    2011-01-01

    Aiming at the target selection problems under unpredictable information in the process of battlefield decision-making, which the tradition methods can't solve, the method of interval number grey relation decision-making is applied to propose the model of power targets selection through an analysis of the parameters involved in determining the importance of power targets. In this model, the factors' weights are obtained by combination weighting way. The method is scientific and reasonable based on the illustration of an application example, and plays an important role in assisting wartime command decision-making.%针对传统方法不能很好地解决战场决策信息不确定的目标选择问题,通过对影响电力目标重要程度的评价指标进行分析,应用区间数灰色关联决策方法完成了电力目标选择模型的构建.模型中的指标权重通过组合赋权法获得.经实例验证证明,该方法是科学、合理的,对战时的指挥决策起到了较好的辅助作用.

  11. Magnitude of the benefit of progression-free survival as a potential surrogate marker in phase 3 trials assessing targeted agents in molecularly selected patients with advanced non-small cell lung cancer: systematic review.

    Directory of Open Access Journals (Sweden)

    Katsuyuki Hotta

    Full Text Available BACKGROUND: In evaluation of the clinical benefit of a new targeted agent in a phase 3 trial enrolling molecularly selected patients with advanced non-small cell lung cancer (NSCLC, overall survival (OS as an endpoint seems to be of limited use because of a high level of treatment crossover for ethical reasons. A more efficient and useful indicator for assessing efficacy is needed. METHODS AND FINDINGS: We identified 18 phase 3 trials in the literature investigating EGFR-tyrosine kinase inhibitor (TKIs or ALK-TKIs, now approved for use to treat NSCLC, compared with standard cytotoxic chemotherapy (eight trials were performed in molecularly selected patients and ten using an "all-comer" design. Receiver operating characteristic analysis was used to identify the best threshold by which to divide the groups. Although trials enrolling molecularly selected patients and all-comer trials had similar OS-hazard ratios (OS-HRs (0.99 vs. 1.04, the former exhibited greater progression-free survival-hazard ratios (PFS-HR (mean, 0.40 vs. 1.01; P<0.01. A PFS-HR of 0.60 successfully distinguished between the two types of trials (sensitivity 100%, specificity 100%. The odds ratio for overall response was higher in trials with molecularly selected patients than in all-comer trials (mean: 6.10 vs. 1.64; P<0.01. An odds ratio of 3.40 for response afforded a sensitivity of 88% and a specificity of 90%. CONCLUSION: The notably enhanced PFS benefit was quite specific to trials with molecularly selected patients. A PFS-HR cutoff of ∼0.6 may help detect clinical benefit of molecular targeted agents in which OS is of limited use, although desired threshold might differ in an individual trial.

  12. Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target.

    Science.gov (United States)

    Watson, Gabrielle M; Lucas, William A H; Gunzburg, Menachem J; Wilce, Jacqueline A

    2017-01-01

    Growth factor receptor bound protein 7 (Grb7) is an adaptor protein with established roles in the progression of both breast and pancreatic cancers. Through its C-terminal SH2 domain, Grb7 binds to phosphorylated tyrosine kinases to promote proliferative and migratory signaling. Here, we investigated the molecular basis for the specificity of a Grb7 SH2-domain targeted peptide inhibitor. We identified that arginine 462 in the BC loop is unique to Grb7 compared to Grb2, another SH2 domain bearing protein that shares the same consensus binding motif as Grb7. Using surface plasmon resonance we demonstrated that Grb7-SH2 binding to G7-18NATE is reduced 3.3-fold when the arginine is mutated to the corresponding Grb2 amino acid. The reverse mutation in Grb2-SH2 (serine to arginine), however, was insufficient to restore binding of G7-18NATE to Grb2-SH2. Further, using a microarray, we confirmed that G7-18NATE is specific for Grb7 over a panel of 79 SH2 domains, and identified that leucine at the βD6 position may also be a requirement for Grb7-SH2 binding. This study provides insight into the specificity defining features of Grb7 for the inhibitor molecule G7-18NATE, that will assist in the development of improved Grb7 targeted inhibitors.

  13. Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target

    Directory of Open Access Journals (Sweden)

    Gabrielle M. Watson

    2017-09-01

    Full Text Available Growth factor receptor bound protein 7 (Grb7 is an adaptor protein with established roles in the progression of both breast and pancreatic cancers. Through its C-terminal SH2 domain, Grb7 binds to phosphorylated tyrosine kinases to promote proliferative and migratory signaling. Here, we investigated the molecular basis for the specificity of a Grb7 SH2-domain targeted peptide inhibitor. We identified that arginine 462 in the BC loop is unique to Grb7 compared to Grb2, another SH2 domain bearing protein that shares the same consensus binding motif as Grb7. Using surface plasmon resonance we demonstrated that Grb7-SH2 binding to G7-18NATE is reduced 3.3-fold when the arginine is mutated to the corresponding Grb2 amino acid. The reverse mutation in Grb2-SH2 (serine to arginine, however, was insufficient to restore binding of G7-18NATE to Grb2-SH2. Further, using a microarray, we confirmed that G7-18NATE is specific for Grb7 over a panel of 79 SH2 domains, and identified that leucine at the βD6 position may also be a requirement for Grb7-SH2 binding. This study provides insight into the specificity defining features of Grb7 for the inhibitor molecule G7-18NATE, that will assist in the development of improved Grb7 targeted inhibitors.

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

    Directory of Open Access Journals (Sweden)

    Jagadeesh Kumar Dasappa

    2013-01-01

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

  15. A Family of Salmonella Type III Secretion Effector Proteins Selectively Targets the NF-κB Signaling Pathway to Preserve Host Homeostasis.

    Science.gov (United States)

    Sun, Hui; Kamanova, Jana; Lara-Tejero, Maria; Galán, Jorge E

    2016-03-01

    Microbial infections usually lead to host innate immune responses and inflammation. These responses most often limit pathogen replication although they can also result in host-tissue damage. The enteropathogenic bacteria Salmonella Typhimurium utilizes a type III secretion system to induce intestinal inflammation by delivering specific effector proteins that stimulate signal transduction pathways resulting in the production of pro-inflammatory cytokines. We show here that a family of related Salmonella Typhimurium effector proteins PipA, GogA and GtgA redundantly target components of the NF-κB signaling pathway to inhibit transcriptional responses leading to inflammation. We show that these effector proteins are proteases that cleave both the RelA (p65) and RelB transcription factors but do not target p100 (NF-κB2) or p105 (NF-κB1). A Salmonella Typhimurium strain lacking these effectors showed increased ability to stimulate NF-κB and increased virulence in an animal model of infection. These results indicate that bacterial pathogens can evolve determinants to preserve host homeostasis and that those determinants can reduce the pathogen's virulence.

  16. Dead end1 is an essential partner of NANOS2 for selective binding of target RNAs in male germ cell development.

    Science.gov (United States)

    Suzuki, Atsushi; Niimi, Yuki; Shinmyozu, Kaori; Zhou, Zhi; Kiso, Makoto; Saga, Yumiko

    2016-01-01

    RNA-binding proteins (RBPs) play important roles for generating various cell types in many developmental processes, including eggs and sperms. Nanos is widely known as an evolutionarily conserved RNA-binding protein implicated in germ cell development. Mouse NANOS2 interacts directly with the CCR4-NOT (CNOT) deadenylase complex, resulting in the suppression of specific RNAs. However, the mechanisms involved in target specificity remain elusive. We show that another RBP, Dead end1 (DND1), directly interacts with NANOS2 to load unique RNAs into the CNOT complex. This interaction is mediated by the zinc finger domain of NANOS2, which is essential for its association with target RNAs. In addition, the conditional deletion of DND1 causes the disruption of male germ cell differentiation similar to that observed in Nanos2-KO mice. Thus, DND1 is an essential partner for NANOS2 that leads to the degradation of specific RNAs. We also present the first evidence that the zinc finger domain of Nanos acts as a protein-interacting domain for another RBP, providing a novel insight into Nanos-mediated germ cell development. © 2015 The Authors.

  17. Insight into the Selectivity of the G7-18NATE Inhibitor Peptide for the Grb7-SH2 Domain Target

    Science.gov (United States)

    Watson, Gabrielle M.; Lucas, William A. H.; Gunzburg, Menachem J.; Wilce, Jacqueline A.

    2017-01-01

    Growth factor receptor bound protein 7 (Grb7) is an adaptor protein with established roles in the progression of both breast and pancreatic cancers. Through its C-terminal SH2 domain, Grb7 binds to phosphorylated tyrosine kinases to promote proliferative and migratory signaling. Here, we investigated the molecular basis for the specificity of a Grb7 SH2-domain targeted peptide inhibitor. We identified that arginine 462 in the BC loop is unique to Grb7 compared to Grb2, another SH2 domain bearing protein that shares the same consensus binding motif as Grb7. Using surface plasmon resonance we demonstrated that Grb7-SH2 binding to G7-18NATE is reduced 3.3-fold when the arginine is mutated to the corresponding Grb2 amino acid. The reverse mutation in Grb2-SH2 (serine to arginine), however, was insufficient to restore binding of G7-18NATE to Grb2-SH2. Further, using a microarray, we confirmed that G7-18NATE is specific for Grb7 over a panel of 79 SH2 domains, and identified that leucine at the βD6 position may also be a requirement for Grb7-SH2 binding. This study provides insight into the specificity defining features of Grb7 for the inhibitor molecule G7-18NATE, that will assist in the development of improved Grb7 targeted inhibitors. PMID:29018805

  18. Planteose as a storage carbohydrate required for early stage of germination of Orobanche minor and its metabolism as a possible target for selective control

    Science.gov (United States)

    Wakabayashi, Takatoshi; Joseph, Benesh; Yasumoto, Shuhei; Akashi, Tomoyoshi; Aoki, Toshio; Harada, Kazuo; Muranaka, Satoru; Bamba, Takeshi; Fukusaki, Eiichiro; Takeuchi, Yasutomo; Yoneyama, Koichi; Muranaka, Toshiya; Sugimoto, Yukihiro; Okazawa, Atsushi

    2015-01-01

    Root parasitic weeds in Orobanchaceae cause serious damage to worldwide agriculture. Germination of the parasites requires host-derived germination stimulants, such as strigolactones, as indicators of host roots within reach of the parasite’s radicles. This unique germination process was focused on to identify metabolic pathways required for germination, and to design a selective control strategy. A metabolomic analysis of germinating seeds of clover broomrape, Orobanche minor, was conducted to identify its distinctive metabolites. Consequently, a galactosyl-sucrose trisaccharide, planteose (α-d-galactopyranosyl-(1→6)-β-d-fructofuranosyl-(2→1)-α-d-glucopyranoside), was identified as a metabolite that decreased promptly after reception of the germination stimulant. To investigate the importance of planteose metabolism, the effects of several glycosidase inhibitors were examined, and nojirimycin bisulfite (NJ) was found to alter the sugar metabolism and to selectively inhibit the germination of O. minor. Planteose consumption was similar in NJ-treated seeds and non-treated germinating seeds; however, NJ-treated seeds showed lower consumption of sucrose, a possible intermediate of planteose metabolism, resulting in significantly less glucose and fructose. This inhibitory effect was recovered by adding glucose. These results suggest that planteose is a storage carbohydrate required for early stage of germination of O. minor, and NJ inhibits germination by blocking the supply of essential glucose from planteose and sucrose. Additionally, NJ selectively inhibited radicle elongation of germinated seeds of Orobanchaceae plants (Striga hermonthica and Phtheirospermum japonicum). Thus, NJ will be a promising tool to develop specific herbicides to the parasites, especially broomrapes, and to improve our understanding of the molecular mechanisms of this unique germination. PMID:25821071

  19. Selective targeting of pro-inflammatory Th1 cells by microRNA-148a-specific antagomirs in vivo.

    Science.gov (United States)

    Maschmeyer, Patrick; Petkau, Georg; Siracusa, Francesco; Zimmermann, Jakob; Zügel, Franziska; Kühl, Anja Andrea; Lehmann, Katrin; Schimmelpfennig, Sarah; Weber, Melanie; Haftmann, Claudia; Riedel, René; Bardua, Markus; Heinz, Gitta Anne; Tran, Cam Loan; Hoyer, Bimba Franziska; Hiepe, Falk; Herzog, Sebastian; Wittmann, Jürgen; Rajewsky, Nikolaus; Melchers, Fritz Georg; Chang, Hyun-Dong; Radbruch, Andreas; Mashreghi, Mir-Farzin

    2018-05-01

    In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Planteose as a storage carbohydrate required for early stage of germination of Orobanche minor and its metabolism as a possible target for selective control.

    Science.gov (United States)

    Wakabayashi, Takatoshi; Joseph, Benesh; Yasumoto, Shuhei; Akashi, Tomoyoshi; Aoki, Toshio; Harada, Kazuo; Muranaka, Satoru; Bamba, Takeshi; Fukusaki, Eiichiro; Takeuchi, Yasutomo; Yoneyama, Koichi; Muranaka, Toshiya; Sugimoto, Yukihiro; Okazawa, Atsushi

    2015-06-01

    Root parasitic weeds in Orobanchaceae cause serious damage to worldwide agriculture. Germination of the parasites requires host-derived germination stimulants, such as strigolactones, as indicators of host roots within reach of the parasite's radicles. This unique germination process was focused on to identify metabolic pathways required for germination, and to design a selective control strategy. A metabolomic analysis of germinating seeds of clover broomrape, Orobanche minor, was conducted to identify its distinctive metabolites. Consequently, a galactosyl-sucrose trisaccharide, planteose (α-d-galactopyranosyl-(1→6)-β-d-fructofuranosyl-(2→1)-α-d-glucopyranoside), was identified as a metabolite that decreased promptly after reception of the germination stimulant. To investigate the importance of planteose metabolism, the effects of several glycosidase inhibitors were examined, and nojirimycin bisulfite (NJ) was found to alter the sugar metabolism and to selectively inhibit the germination of O. minor. Planteose consumption was similar in NJ-treated seeds and non-treated germinating seeds; however, NJ-treated seeds showed lower consumption of sucrose, a possible intermediate of planteose metabolism, resulting in significantly less glucose and fructose. This inhibitory effect was recovered by adding glucose. These results suggest that planteose is a storage carbohydrate required for early stage of germination of O. minor, and NJ inhibits germination by blocking the supply of essential glucose from planteose and sucrose. Additionally, NJ selectively inhibited radicle elongation of germinated seeds of Orobanchaceae plants (Striga hermonthica and Phtheirospermum japonicum). Thus, NJ will be a promising tool to develop specific herbicides to the parasites, especially broomrapes, and to improve our understanding of the molecular mechanisms of this unique germination. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental

  1. MAPK3 at the Autism-Linked Human 16p11.2 Locus Influences Precise Synaptic Target Selection at Drosophila Larval Neuromuscular Junctions.

    Science.gov (United States)

    Park, Sang Mee; Park, Hae Ryoun; Lee, Ji Hye

    2017-02-01

    Proper synaptic function in neural circuits requires precise pairings between correct pre- and post-synaptic partners. Errors in this process may underlie development of neuropsychiatric disorders, such as autism spectrum disorder (ASD). Development of ASD can be influenced by genetic factors, including copy number variations (CNVs). In this study, we focused on a CNV occurring at the 16p11.2 locus in the human genome and investigated potential defects in synaptic connectivity caused by reduced activities of genes located in this region at Drosophila larval neuromuscular junctions, a well-established model synapse with stereotypic synaptic structures. A mutation of rolled , a Drosophila homolog of human mitogen-activated protein kinase 3 ( MAPK3 ) at the 16p11.2 locus, caused ectopic innervation of axonal branches and their abnormal defasciculation. The specificity of these phenotypes was confirmed by expression of wild-type rolled in the mutant background. Albeit to a lesser extent, we also observed ectopic innervation patterns in mutants defective in Cdk2, Gα q , and Gp93, all of which were expected to interact with Rolled MAPK3. A further genetic analysis in double heterozygous combinations revealed a synergistic interaction between rolled and Gp93 . In addition, results from RT-qPCR analyses indicated consistently reduced rolled mRNA levels in Cdk2 , Gα q , and Gp93 mutants. Taken together, these data suggest a central role of MAPK3 in regulating the precise targeting of presynaptic axons to proper postsynaptic targets, a critical step that may be altered significantly in ASD.

  2. Cas9/sgRNA selective targeting of the P23H Rhodopsin mutant allele for treating retinitis pigmentosa by intravitreal AAV9.PHP.B-based delivery.

    Science.gov (United States)

    Giannelli, Serena G; Luoni, Mirko; Castoldi, Valerio; Massimino, Luca; Cabassi, Tommaso; Angeloni, Debora; Demontis, Gian Carlo; Leocani, Letizia; Andreazzoli, Massimiliano; Broccoli, Vania

    2018-03-01

    P23H is the most common mutation in the RHODOPSIN (RHO) gene leading to a dominant form of retinitis pigmentosa (RP), a rod photoreceptor degeneration that invariably causes vision loss. Specific disruption of the disease P23H RHO mutant while preserving the wild-type (WT) functional allele would be an invaluable therapy for this disease. However, various technologies tested in the past failed to achieve effective changes and consequently therapeutic benefits. We validated a CRISPR/Cas9 strategy to specifically inactivate the P23H RHO mutant, while preserving the WT allele in vitro. We, then, translated this approach in vivo by delivering the CRISPR/Cas9 components in murine Rho+/P23H mutant retinae. Targeted retinae presented a high rate of cleavage in the P23H but not WT Rho allele. This gene manipulation was sufficient to slow photoreceptor degeneration and improve retinal functions. To improve the translational potential of our approach, we tested intravitreal delivery of this system by means of adeno-associated viruses (AAVs). To this purpose, the employment of the AAV9-PHP.B resulted the most effective in disrupting the P23H Rho mutant. Finally, this approach was translated successfully in human cells engineered with the homozygous P23H RHO gene mutation. Overall, this is a significant proof-of-concept that gene allele specific targeting by CRISPR/Cas9 technology is specific and efficient and represents an unprecedented tool for treating RP and more broadly dominant genetic human disorders affecting the eye, as well as other tissues.

  3. Human NK cells selective targeting of colon cancer-initiating cells: A role for natural cytotoxicity receptors and MHC class i molecules

    KAUST Repository

    Tallerico, Rossana

    2013-01-23

    Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma- derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved.

  4. Human NK cells selective targeting of colon cancer-initiating cells: A role for natural cytotoxicity receptors and MHC class i molecules

    KAUST Repository

    Tallerico, Rossana; Todaro, Matilde; Di Franco, Simone; MacCalli, Cristina; Garofalo, Cinzia; Sottile, Rosa; Palmieri, Camillo; Tirinato, Luca; Pangigadde, Pradeepa N.; La Rocca, Rosanna; Mandelboim, Ofer; Stassi, Giorgio; Di Fabrizio, Enzo M.; Parmiani, Giorgio; Moretta, Alessandro; Dieli, Francesco; Kã rre, Klas; Carbone, Ennio

    2013-01-01

    Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma- derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors. Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved.

  5. A parallel panning scheme used for selection of a GluA4-specific Fab targeting the ligand-binding domain

    DEFF Research Database (Denmark)

    Clausen, Rasmus P; Mohr, Andreas Ø; Riise, Erik

    2016-01-01

    A method for development of murine Fab fragments towards extracellular domains of a surface receptor is presented. The GluA4 ionotropic glutamate receptor is used as a model system. Recombinant GluA4 ectodomain comprising both the N-terminal domain (NTD) and the ligand-binding domain (LBD) in one...... molecule was used for immunization. A Fab-phage library was constructed and a parallel panning approach enabled selection of murine Fab fragments towards either intact ectodomain or the isolated LBD of the GluA4 receptor. One LBD-Fab (FabL9) showed exclusive selectivity for the GluA4 LBD, over a panel...... of LBDs from GluA2, GluK1, GluK2 and GluD2. Soluble FabL9 was produced in amounts suitable for characterization. Competitive ELISA and rat-brain immunoprecipitation experiments confirmed that the FabL9 epitope is conserved in the LBD and in the intact native receptor. By an alignment of GluA2 and GluA4...

  6. Targeting Type 2 Diabetes with C-Glucosyl Dihydrochalcones as Selective Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: Synthesis and Biological Evaluation.

    Science.gov (United States)

    Jesus, Ana R; Vila-Viçosa, Diogo; Machuqueiro, Miguel; Marques, Ana P; Dore, Timothy M; Rauter, Amélia P

    2017-01-26

    Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC 50 = 9-23 nM) were considerably weaker inhibitors of SGLT1 (IC 50 = 10-19 μM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.

  7. DP97, a DEAD box DNA/RNA helicase, is a target gene-selective co-regulator of the constitutive androstane receptor

    International Nuclear Information System (INIS)

    Kanno, Yuichiro; Serikawa, Takafumi; Inajima, Jun; Inouye, Yoshio

    2012-01-01

    Highlights: ► DP97 interacts with nuclear receptor CAR. ► DP97 enhances CAR-mediated transcriptional activation. ► DP97 synergistically enhances transactivity of CAR by the co-expression of SRC-1 or PGC1α. ► DP97 is a gene-selective co-activator for hCAR. -- Abstract: The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that DP97, a member of the DEAD box DNA/RNA helicase protein family, is a novel CAR-interacting protein. Using HepG2 cells expressing human CAR in the presence of tetracycline, we showed that knockdown of DP97 with small interfering RNAs suppressed tetracycline-inducible mRNA expression of CYP2B6 and UGT1A1 but not CYP3A4. Thus, DP97 was found to be a gene (or promoter)-selective co-activator for hCAR. DP97-mediated CAR transactivation was synergistically enhanced by the co-expression of SRC-1 or PGC1α, therefore it might act as mediator between hCAR and appropriate co-activators.

  8. DP97, a DEAD box DNA/RNA helicase, is a target gene-selective co-regulator of the constitutive androstane receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp [Faculty of Pharmaceutical Sciences, Toho University, Chiba (Japan); Serikawa, Takafumi; Inajima, Jun; Inouye, Yoshio [Faculty of Pharmaceutical Sciences, Toho University, Chiba (Japan)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer DP97 interacts with nuclear receptor CAR. Black-Right-Pointing-Pointer DP97 enhances CAR-mediated transcriptional activation. Black-Right-Pointing-Pointer DP97 synergistically enhances transactivity of CAR by the co-expression of SRC-1 or PGC1{alpha}. Black-Right-Pointing-Pointer DP97 is a gene-selective co-activator for hCAR. -- Abstract: The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that DP97, a member of the DEAD box DNA/RNA helicase protein family, is a novel CAR-interacting protein. Using HepG2 cells expressing human CAR in the presence of tetracycline, we showed that knockdown of DP97 with small interfering RNAs suppressed tetracycline-inducible mRNA expression of CYP2B6 and UGT1A1 but not CYP3A4. Thus, DP97 was found to be a gene (or promoter)-selective co-activator for hCAR. DP97-mediated CAR transactivation was synergistically enhanced by the co-expression of SRC-1 or PGC1{alpha}, therefore it might act as mediator between hCAR and appropriate co-activators.

  9. Key Ingredients-Target Groups, Methods and Messages, and Evaluation-of Local-Level, Public Interventions to Counter Stigma and Discrimination: A Lived Experience Informed Selective Narrative Literature Review.

    Science.gov (United States)

    Ashton, Laura J; Gordon, Sarah E; Reeves, Racheal A

    2018-04-01

    A proliferation of recent literature provides substantial direction as to the key ingredients-target groups, messages and methods, and evaluation-of local-level, public interventions to counter stigma and discrimination. This paper provides a selective narrative review of that literature from the perspective or standpoint of anti-stigma experts with lived experience of mental distress, the key findings of which have been synthesised and presented in diagrammatic overviews (infographics). These are intended to guide providers in planning, delivering and evaluating lived experience-directed local-level, public interventions to counter stigma and discrimination in accord with current best practice.

  10. 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

  11. Gas sensing at the nanoscale: engineering SWCNT-ITO nano-heterojunctions for the selective detection of NH3 and NO2 target molecules

    Science.gov (United States)

    Rigoni, F.; Drera, G.; Pagliara, S.; Perghem, E.; Pintossi, C.; Goldoni, A.; Sangaletti, L.

    2017-01-01

    The gas response of single-wall carbon nanotubes (SWCNT) functionalized with indium tin oxide (ITO) nanoparticles (NP) has been studied at room temperature and an enhanced sensitivity to ammonia and nitrogen dioxide is demonstrated. The higher sensitivity in the functionalized sample is related to the creation of nano-heterojunctions at the interface between SWCNT bundles and ITO NP. Furthermore, the different response of the two devices upon NO2 exposure provides a way to enhance also the selectivity. This behavior is rationalized by considering a gas sensing mechanism based on the build-up of space-charge layers at the junctions. Finally, full recovery of the signal after exposure to NO2 is achieved by UV irradiation for the functionalized sample, where the ITO NP can play a role to hinder the poisoning effects on SWCNT due to NO2 chemisorption.

  12. BDNF/TrkB Signaling as a Potential Novel Target in Pediatric Brain Tumors: Anticancer Activity of Selective TrkB Inhibition in Medulloblastoma Cells.

    Science.gov (United States)

    Thomaz, Amanda; Jaeger, Mariane; Buendia, Marienela; Bambini-Junior, Victorio; Gregianin, Lauro José; Brunetto, Algemir Lunardi; Brunetto, André T; de Farias, Caroline Brunetto; Roesler, Rafael

    2016-07-01

    Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Deregulation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling has been associated with increased proliferative capabilities, invasiveness, and chemoresistance in several types of cancer. However, the relevance of this pathway in MB remains unknown. Here, we show that the selective TrkB inhibitor N-[2-[[(hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl]-benzo[b]thiophene-2-carboxamide (ANA-12) markedly reduced the viability and survival of human cell lines representative of different MB molecular subgroups. These findings provide the first evidence supporting further investigation of TrkB inhibition as a potential novel strategy for MB treatment.

  13. Target-Triggered Switching on and off the Luminescence of Lanthanide Coordination Polymer Nanoparticles for Selective and Sensitive Sensing of Copper Ions in Rat Brain.

    Science.gov (United States)

    Huang, Pengcheng; Wu, Fangying; Mao, Lanqun

    2015-07-07

    Copper ions (Cu(2+)) in the central nervous system play a crucial role in the physiological and pathological events, so simple, selective, and sensitive detection of cerebral Cu(2+) is of great importance. In this work, we report a facile yet effective fluorescent method for sensing of Cu(2+) in rat brain using one kind of lanthanide coordination polymer nanoparticle, adenosine monophosphate (AMP) and terbium ion (Tb(3+)), i.e., AMP-Tb, as the sensing platform. Initially, a cofactor ligand, 5-sulfosalicylic acid (SSA), as the sensitizer, was introduced into the nonluminescent AMP-Tb suspension, resulting in switching on the luminescence of AMP-Tb by the removal of coordinating water molecules and concomitant energy transfer from SSA to Tb(3+). The subsequent addition of Cu(2+) into the resulting SSA/AMP-Tb can strongly quench the fluorescence because the specific coordination interaction between SSA and Cu(2+) rendered energy transfer from SSA to Tb(3+) inefficient. The decrease ratio of the fluorescence intensities of SSA/AMP-Tb at 550 nm show a linear relationship for Cu(2+) within the concentration range from 1.5 to 24 μM with a detection limit of 300 nM. The method demonstrated here is highly selective and is free from the interference of metal ions, amino acids, and the biological species commonly existing in the brain such as dopamine, lactate, and glucose. Eventually, by combining the microdialysis technique, the present method has been successfully applied in the detection of cerebral Cu(2+) in rat brain with the basal dialysate level of 1.91 ± 0.40 μM (n = 3). This method is very promising to be used for investigating the physiological and pathological events that cerebral Cu(2+) participates in.

  14. 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.

  15. 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.

  16. 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

  17. Galaxy And Mass Assembly (GAMA): the G02 field, Herschel-ATLAS target selection and Data Release 3 arXiv

    CERN Document Server

    Baldry, I.K.; Brown, M.J.I.; Robotham, A.S.G.; Driver, S.P.; Dunne, L.; Alpaslan, M.; Brough, S.; Cluver, M.E.; Eardley, E.; Farrow, D.J.; Heymans, C.; Hildebrandt, H.; Hopkins, A.M.; Kelvin, L.S.; Loveday, J.; Moffett, A.J.; Norberg, P.; Owers, M.S.; Taylor, E.N.; Wright, A.H.; Bamford, S.P.; Bland-Hawthorn, J.; Bourne, N.; Bremer, M.N.; Colless, M.; Conselice, C.J.; Croom, S.M.; Davies, L.J.M.; Foster, C.; Grootes, M.W.; Holwerda, B.W.; Jones, D.H.; Kafle, P.R.; Kuijken, K.; Lara-Lopez, M.A.; Lopez-Sanchez, A.R.; Meyer, M.J.; Phillipps, S.; Sutherland, W.J.; van Kampen, E.; Wilkins, S.M.

    We describe data release 3 (DR3) of the Galaxy And Mass Assembly (GAMA) survey. The GAMA survey is a spectroscopic redshift and multi-wavelength photometric survey in three equatorial regions each of 60.0 deg^2 (G09, G12, G15), and two southern regions of 55.7 deg^2 (G02) and 50.6 deg^2 (G23). DR3 consists of: the first release of data covering the G02 region and of data on H-ATLAS sources in the equatorial regions; and updates to data on sources released in DR2. DR3 includes 154809 sources with secure redshifts across four regions. A subset of the G02 region is 95.5% redshift complete to r<19.8 over an area of 19.5 deg^2, with 20086 galaxy redshifts, that overlaps substantially with the XXL survey (X-ray) and VIPERS (redshift survey). In the equatorial regions, the main survey has even higher completeness (98.5%), and spectra for about 75% of H-ATLAS filler targets were also obtained. This filler sample extends spectroscopic redshifts, for probable optical counterparts to H-ATLAS sub-mm sources, to 0.8 ma...

  18. A 1.1-1.9 GHz SETI SURVEY OF THE KEPLER FIELD. I. A SEARCH FOR NARROW-BAND EMISSION FROM SELECT TARGETS

    Energy Technology Data Exchange (ETDEWEB)

    Siemion, Andrew P. V.; Korpela, Eric; Werthimer, Dan; Cobb, Jeff; Lebofsky, Matt; Marcy, Geoffrey W. [University of California, Berkeley, 110 Sproul Hall, Berkeley, CA 94720 (United States); Demorest, Paul; Maddalena, Ron J.; Langston, Glen [National Radio Astronomy Observatory, 520 Edgemont Rd Charlottesville, VA 22903 (United States); Howard, Andrew W. [Institute for Astronomy, University of Hawaii, 640 North A' ohoku Place, 209 Hilo, HI 96720-2700 (United States); Tarter, Jill [SETI Institute, 189 Bernardo Ave 100 Mountain View, CA 94043 (United States)

    2013-04-10

    We present a targeted search for narrow-band (<5 Hz) drifting sinusoidal radio emission from 86 stars in the Kepler field hosting confirmed or candidate exoplanets. Radio emission less than 5 Hz in spectral extent is currently known to only arise from artificial sources. The stars searched were chosen based on the properties of their putative exoplanets, including stars hosting candidates with 380 K > T{sub eq} > 230 K, stars with five or more detected candidates or stars with a super-Earth (R{sub p} < 3 R{sub Circled-Plus }) in a >50 day orbit. Baseband voltage data across the entire band between 1.1 and 1.9 GHz were recorded at the Robert C. Byrd Green Bank Telescope between 2011 February and April and subsequently searched offline. No signals of extraterrestrial origin were found. We estimate that fewer than {approx}1% of transiting exoplanet systems host technological civilizations that are radio loud in narrow-band emission between 1 and 2 GHz at an equivalent isotropically radiated power (EIRP) of {approx}1.5 Multiplication-Sign 10{sup 21} erg s{sup -1}, approximately eight times the peak EIRP of the Arecibo Planetary Radar, and we limit the number of 1-2 GHz narrow-band-radio-loud Kardashev type II civilizations in the Milky Way to be <10{sup -6} M{sub Sun }{sup -1}. Here we describe our observations, data reduction procedures and results.

  19. 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

  20. Tc-labeling of Peptidomimetic Antagonist to Selectively Target alpha(v)beta(3) Receptor-Positive Tumor: Comparison of PDA and EDDA as co-Ligands.

    Science.gov (United States)

    Shin, In Soo; Maeng, Jin Soo; Jang, Beom-Su; You, Eric; Cheng, Kenneth; Li, King C P; Wood, Bradford; Carrasquillo, Jorge A; Danthi, S Narasimhan; Paik, Chang H

    2010-01-01

    OBJECTIVES: The aim of this research was to synthesize radiolabeled peptidomimetic integrin alpha(v)beta(3) antagonist with (99m)Tc for rapid targeting of integrin alpha(v)beta(3) receptors in tumor to produce a high tumor to background ratio. METHODS: The amino terminus of 4-[2-(3,4,5,6-tetra-hydropyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonyl-amino-beta-alanine hydrochloride (IAC) was conjugated with N-hydroxysuccinimide ester of HYNIC and labeled with (99m)Tc using tricine with either 1,5-pyridinedicarboxylic acid (PDA) or ethylenediamine-N,N'-diacetic acid (EDDA) as the co-ligand. The products, (99m)Tc EDDA(2)/HYNIC-IAC (P1) and (99m)Tc PDA (tricin)/HYNIC-IAC (P2) were subjected to in vitro serum stability, receptor-binding, biodistribution and imaging studies. RESULTS: P1 and P2 were synthesized with an overall yield of >80%. P1 was slightly more stable than P2 when incubated in serum at 37 degrees C for 18 hrs (84 vs 77% intact). The In vitro receptor-binding of P1 was higher than that of P2 (78.02 +/- 13.48 vs 51.05 +/- 14.05%) when incubated with alpha(v)beta(3) at a molar excess (0.8 muM). This receptor binding was completely blocked by a molar excess of an unlabeled peptidomimetic antagonist. Their differences shown in serum stability and the receptor-binding appeared to be related to their biological behaviors in tumor uptake and retention; the 1 h tumor uptakes of P1 and P2 were 3.17+/-0.52 and 2.13+/-0.17 % ID/g, respectively. P1 was retained in the tumor longer than P2. P1 was excreted primarily through the renal system whereas P2 complex was excreted equally via both renal and hepatobiliary systems. Thus, P1 was retained in the whole-body with 27.25 +/- 3.67% ID at 4 h whereas 54.04 +/- 3.57% ID of P2 remained in the whole-body at 4 h. This higher whole-body retention of P2 appeared to be resulted from a higher amount of radioactivity retained in liver and intestine. These findings were supported by

  1. 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

  2. A selective inhibition of c-Fos/activator protein-1 as a potential therapeutic target for intervertebral disc degeneration and associated pain.

    Science.gov (United States)

    Makino, Hiroto; Seki, Shoji; Yahara, Yasuhito; Shiozawa, Shunichi; Aikawa, Yukihiko; Motomura, Hiraku; Nogami, Makiko; Watanabe, Kenta; Sainoh, Takeshi; Ito, Hisakatsu; Tsumaki, Noriyuki; Kawaguchi, Yoshiharu; Yamazaki, Mitsuaki; Kimura, Tomoatsu

    2017-12-05

    Intervertebral disc (IVD) degeneration is a major cause of low back pain. The transcription factor c-Fos/Activator Protein-1 (AP-1) controls the expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that contribute to the pathogenesis IVD degeneration. We investigated the effects of inhibition of c-Fos/AP-1 on IVD degeneration and associated pain. A selective inhibitor, T-5224, significantly suppressed the interleukin-1β-induced up-regulation of Mmp-3, Mmp-13 and Adamts-5 transcription in human nucleus pulposus cells and in a mouse explant culture model of IVD degeneration. We used a tail disc percutaneous needle puncture method to further assess the effects of oral administration of T-5224 on IVD degeneration. Analysis of disc height, T2-magnetic resonance imaging (MRI) findings, and histology revealed that IVD degeneration was significantly mitigated by T-5224. Further, oral administration of T-5224 ameliorated pain as indicated by the extended tail-flick latency in response to heat stimulation of rats with needle-puncture-induced IVD degeneration. These findings suggest that the inhibition of c-Fos/AP-1 prevents disc degeneration and its associated pain and that T-5224 may serve as a drug for the prevention of IVD degeneration.

  3. LINEAMENTS MAP OF TURKEY FROM LANDSAT IMAGERY AND SELECTING TARGET AREAS FOR MINERAL EXPLORATION, RELATIONSHIP OF REGIONAL LINEAMENTS TO EARTHQUAKE EPICENTERS, MINERAL WATERS AND HOT SPRINGS

    Directory of Open Access Journals (Sweden)

    İsmail HENDEN

    1984-06-01

    Full Text Available Landsat coverage countrywide have been interpreted and a map of lineaments has been prepared. Circular features which are the surface expressions of deep or near   intrusions have  been  carefully mapped in order to investigate their relationship (if any to known mineralizations. From the outset it was postulated that the miner- alizations  are    located at the intersections of lineaments, especially in the vicinity of circular features.  To  test this hypo- thesis known mineralizations were placed on this map. It is noted that the metallic mineral deposits can be grouped into ten regions,  and out  of these,  two regions need to  be explored more intensively. In  some regions selected, locations of possible mineralizations were determined. Earthquake epicenters, mineral water sources and hot spring locations were placed on the  lineaments map. It is seen  that the hot springs and earthquake epicentres are located on regional fault systems.

  4. Equivalent 5 year bNED in select prostate cancer patients managed with surgery or radiation therapy despite exclusion of the seminal vesicles from the clinical target volume

    International Nuclear Information System (INIS)

    D'Amico, A. V.; Whittington, R.; Kaplan, I.; Beard, C.; Schultz, D.; Malkowicz, S.B.; Tomaszewski, J.E.; Wein, A.; Coleman, C.N.

    1997-01-01

    Purpose: Prostate Specific Antigen (PSA) failure free survival was determined for select prostate cancer patients treated definitively with external beam radiation therapy to the prostate only or a radical retropubic prostatectomy. Materials and Methods: A logistic regression multivariable analysis evaluating the variables of PSA, biopsy Gleason score, and clinical stage was used to evaluate the endpoint of pathologic seminal vesicle invasion (SVI) in 749 consecutive prostate cancer patients treated with a radical retropubic prostatectomy. In a subgroup of 325 surgically and 197 radiation managed patients who did not have the clinical predictors of SVI, PSA failure free survival (bNED) was determined. Comparisons were made using the log rank test. Radiation managed patients in this subgroup were treated to a median dose of 66 Gray (66 - 70 Gray) in 2 Gray fractions to the prostate only. A 95% normalization was used routinely. Results: The pre-treatment PSA (> 10 ng/ml), biopsy Gleason score (≥ 7), and clinical stage (T 2b,2c,3 versus T 1,2a ) were found to be significant independent predictors (p 1,2a , PSA < 10 ng/ml, and biopsy Gleason ≤ 6 prostate cancer

  5. Analysis of phage Mu DNA transposition by whole-genome Escherichia coli tiling arrays reveals a complex relationship to distribution of target selection protein B, transcription and chromosome architectural elements.

    Science.gov (United States)

    Ge, Jun; Lou, Zheng; Cui, Hong; Shang, Lei; Harshey, Rasika M

    2011-09-01

    Of all known transposable elements, phage Mu exhibits the highest transposition efficiency and the lowest target specificity. In vitro, MuB protein is responsible for target choice. In this work, we provide a comprehensive assessment of the genome-wide distribution of MuB and its relationship to Mu target selection using high-resolution Escherichia coli tiling DNA arrays. We have also assessed how MuB binding and Mu transposition are influenced by chromosome-organizing elements such as AT-rich DNA signatures, or the binding of the nucleoid-associated protein Fis, or processes such as transcription. The results confirm and extend previous biochemical and lower resolution in vivo data. Despite the generally random nature of Mu transposition and MuB binding, there were hot and cold insertion sites and MuB binding sites in the genome, and differences between the hottest and coldest sites were large. The new data also suggest that MuB distribution and subsequent Mu integration is responsive to DNA sequences that contribute to the structural organization of the chromosome.

  6. The Role of Public Interaction with the Juno Mission: Contextual Information about the Atmosphere and Target Selection for the JunoCam

    Science.gov (United States)

    Orton, G. S.; Hansen, C. J.; Momary, T.; Bolton, S. J.

    2016-12-01

    Among the many "firsts" of the Juno mission is the open enlistment of the public in the operation of its visible camera, JunoCam. Although the scientific thrust of the Juno mission is largely focused on innovative approaches to understanding the structure and composition of the interior of Jupiter, JunoCam was added to the payload largely to function in the role of education and public outreach (E/PO). For the first time, the public will be able to engage in the discussion and choice of targets for a major NASA mission, other than two images of Jupiter's polar regions that will be made on each orbit. The discussion about which "electable" features to image is enabled by a continuously updated map of Jupiter's cloud system while Jupiter is far enough from the sun to be observable by the amateur community. This map is created bi-weekly from a set of images uploaded by a world-wide network of amateur astronomers, ranging from very devoted astrophotographers to telescope and video `hobbyists'. Juno therefore engages the world-wide amateur-astronomy community as a vast network of co-investigators, whose products stimulate conversation and global public awareness of Jupiter and Juno's investigative role. Contributed images also provide a temporal context to inform the Juno atmospheric investigation team of the state and evolution of the atmosphere. These bi-weekly maps provide the focus for ongoing discussion about various planetary features over a long time frame. Approximately two weeks before Juno's closest approach to Jupiter on each orbit, starting in mid-November of 2016, the atmospheric features that have been under discussion and will be in the field of view of the instrument nominated for voting, and the public will vote on where to point JunoCam's "elective" features (each orbit will otherwise image the north polar region and south polar region from a non-oblique viewpoint for the first time in over 40 years since the passage of Pioneer 11. The Juno mission

  7. Selective effects of acute alcohol intake on the prospective and retrospective components of a prospective-memory task with emotional targets.

    Science.gov (United States)

    Walter, Nora T; Bayen, Ute J

    2016-01-01

    Prospective memory involves remembering to do something in the future and has a prospective component (remembering that something must be done) and a retrospective component (remembering what must be done and when it must be done). Initial studies reported an impairment in prospective-memory performance due to acute alcohol consumption. Retrospective-memory studies demonstrated that alcohol effects vary depending on the emotionality of the information that needs to be learned. The aim of the present study was to investigate possible differential effects of a mild acute alcohol dose (0.4 g/kg) on the prospective and retrospective components of prospective memory depending on cue valence. Seventy-five participants were allocated to an alcohol or placebo group and performed a prospective-memory task in which prospective-memory cue valence was manipulated (negative, neutral, positive). The multinomial model of event-based prospective memory (Smith and Bayen 2004) was used to measure alcohol and valence effects on the two prospective-memory components separately. Overall, no main effect of alcohol or valence on prospective-memory performance occurred. However, model-based analyses demonstrated a significantly higher retrospective component for positive compared with negative cues in the placebo group. In the alcohol group, the prospective component was weaker for negative than for neutral cues and the retrospective component was stronger for positive than for neutral cues. Group comparisons showed that the alcohol group had a significantly lower prospective component for negative cues and a lower retrospective component for neutral cues. This is the first study to demonstrate selective alcohol effects on prospective-memory components depending on prospective-memory cue valence.

  8. A step by step selection method for the location and the size of a waste-to-energy facility targeting the maximum output energy and minimization of gate fee.

    Science.gov (United States)

    Kyriakis, Efstathios; Psomopoulos, Constantinos; Kokkotis, Panagiotis; Bourtsalas, Athanasios; Themelis, Nikolaos

    2017-06-23

    This study attempts the development of an algorithm in order to present a step by step selection method for the location and the size of a waste-to-energy facility targeting the maximum output energy, also considering the basic obstacle which is in many cases, the gate fee. Various parameters identified and evaluated in order to formulate the proposed decision making method in the form of an algorithm. The principle simulation input is the amount of municipal solid wastes (MSW) available for incineration and along with its net calorific value are the most important factors for the feasibility of the plant. Moreover, the research is focused both on the parameters that could increase the energy production and those that affect the R1 energy efficiency factor. Estimation of the final gate fee is achieved through the economic analysis of the entire project by investigating both expenses and revenues which are expected according to the selected site and outputs of the facility. In this point, a number of commonly revenue methods were included in the algorithm. The developed algorithm has been validated using three case studies in Greece-Athens, Thessaloniki, and Central Greece, where the cities of Larisa and Volos have been selected for the application of the proposed decision making tool. These case studies were selected based on a previous publication made by two of the authors, in which these areas where examined. Results reveal that the development of a «solid» methodological approach in selecting the site and the size of waste-to-energy (WtE) facility can be feasible. However, the maximization of the energy efficiency factor R1 requires high utilization factors while the minimization of the final gate fee requires high R1 and high metals recovery from the bottom ash as well as economic exploitation of recovered raw materials if any.

  9. 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

  10. Some problems on target-area selection for searching interstratified infiltration sandstone-type uranium deposits suitable to in-situ leaching

    International Nuclear Information System (INIS)

    Hu Shaokang

    2005-01-01

    its eastern and western parts. These two structure belts are of global significance and have a control to the uranium ore formation. So, it should be paid more attention to their characteristics, processes and the scope of their influences in strategic prospection area selection. (authors)

  11. 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

  12. 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)

  13. 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.

  14. Application of plug-plug technique to ACE experiments for discovery of peptides binding to a larger target protein: a model study of calmodulin-binding fragments selected from a digested mixture of reduced BSA.

    Science.gov (United States)

    Saito, Kazuki; Nakato, Mamiko; Mizuguchi, Takaaki; Wada, Shinji; Uchimura, Hiromasa; Kataoka, Hiroshi; Yokoyama, Shigeyuki; Hirota, Hiroshi; Kiso, Yoshiaki

    2014-03-01

    To discover peptide ligands that bind to a target protein with a higher molecular mass, a concise screening methodology has been established, by applying a "plug-plug" technique to ACE experiments. Exploratory experiments using three mixed peptides, mastoparan-X, β-endorphin, and oxytocin, as candidates for calmodulin-binding ligands, revealed that the technique not only reduces the consumption of the protein sample, but also increases the flexibility of the experimental conditions, by allowing the use of MS detection in the ACE experiments. With the plug-plug technique, the ACE-MS screening methodology successfully selected calmodulin-binding peptides from a random library with diverse constituents, such as protease digests of BSA. Three peptides with Kd values between 8-147 μM for calmodulin were obtained from a Glu-C endoprotease digest of reduced BSA, although the digest showed more than 70 peaks in its ACE-MS electropherogram. The method established here will be quite useful for the screening of peptide ligands, which have only low affinities due to their flexible chain structures but could potentially provide primary information for designing inhibitors against the target protein. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Kaposi sarcoma-associated herpes virus targets the lymphotactin receptor with both a broad spectrum antagonist vCCL2 and a highly selective and potent agonist vCCL3

    DEFF Research Database (Denmark)

    Lüttichau, Hans R; Johnsen, Anders H; Jurlander, Jesper

    2007-01-01

    virus (KSHV) encodes three chemokine-like proteins named vCCL1, vCCL2, and vCCL3. In this study vCCL3 was probed in parallel with vCCL1 and vCCL2 against a panel of the 18 classified human chemokine receptors. In calcium mobilization assays vCCL1 acted as a selective CCR8 agonist, whereas vCCL2......Large DNA viruses such as herpesvirus and poxvirus encode proteins that target and exploit the chemokine system of their host. These proteins have the potential to block or change the orchestrated recruitment of leukocytes to sites of viral infection. The genome of Kaposi sarcoma-associated herpes...... was found to act as a broad spectrum chemokine antagonist of human chemokine receptors, including the lymphotactin receptor. In contrast vCCL3 was found to be a highly selective agonist for the human lymphotactin receptor XCR1. The potency of vCCL3 was found to be 10-fold higher than the endogenous human...

  16. 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...

  17. 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...

  18. A Selective Surface-Enhanced Raman Scattering Sensor for Mercury(II) Based on a Porous Polymer Material and the Target-Mediated Displacement of a T-Rich Strand

    Science.gov (United States)

    Kang, Y.; Zhang, L.; Zhang, H.; Wu, T.; Du, Y.

    2017-05-01

    A sensitive and selective surface-enhanced Raman scattering (SERS) sensor for mercury(II) was fabricated based on the target-mediated displacement of a T-rich oligonucleotide strand. A DNA/aptamer duplex was prepared by the hybridization between a tetramethylrhodamine(TMR)-labeled thymine(T)-rich Hg2+-specific aptamer (denoted as TMR-aptamer) and a thiolated adenine-rich capturing DNA. The duplex can be immobilized onto the SERS substrate of the Ag-moiety modified glycidyl methacrylate-ethylene dimethacrylate (denoted as Ag-GMA-EDMA) via self-assembly by the thiol anchor, in which the TMR-aptamer exists in a double-stranded chain. In this case, the label of the TMR moiety approaches the substrate surface and produces a strong SERS signal. Upon the addition of the target, a pair of TMR-aptamers could cooperatively coordinate with Hg2+ to form a stable duplex-like structure mediated by the T-Hg2+-T complex between two adjacent strands, which triggers the release of the TMR-aptamer from the SERS substrate surface, thus drawing the TMR tags away from the substrate with a significant decrease in the SERS signal. This optical sensor shows a sensitive response to Hg2+ in a concentration from 5 nM to 2.0 μM with a detection limit of 2.5 nM. The prepared sensor is negligibly responsive to other metal ions, can be easily regenerated, and shows good performance in real sample analysis.

  19. 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

  20. Bioinformatics for cancer immunotherapy target discovery

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Campos, Benito; Barnkob, Mike Stein

    2014-01-01

    therapy target discovery in a bioinformatics analysis pipeline. We describe specialized bioinformatics tools and databases for three main bottlenecks in immunotherapy target discovery: the cataloging of potentially antigenic proteins, the identification of potential HLA binders, and the selection epitopes...

  1. Selective Activation of AMPK β1-Containing Isoforms Improves Kidney Function in a Rat Model of Diabetic Nephropathy.

    Science.gov (United States)

    Salatto, Christopher T; Miller, Russell A; Cameron, Kimberly O; Cokorinos, Emily; Reyes, Allan; Ward, Jessica; Calabrese, Matthew F; Kurumbail, Ravi G; Rajamohan, Francis; Kalgutkar, Amit S; Tess, David A; Shavnya, Andre; Genung, Nathan E; Edmonds, David J; Jatkar, Aditi; Maciejewski, Benjamin S; Amaro, Marina; Gandhok, Harmeet; Monetti, Mara; Cialdea, Katherine; Bollinger, Eliza; Kreeger, John M; Coskran, Timothy M; Opsahl, Alan C; Boucher, Germaine G; Birnbaum, Morris J; DaSilva-Jardine, Paul; Rolph, Tim

    2017-05-01

    Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the β 1 subunit. After confirming that human and rodent kidney predominately express AMPK β 1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  2. Vascular targeting with peptide libraries

    Energy Technology Data Exchange (ETDEWEB)

    Pasqualini, R. [La Jolla Cancer Research Center The Burnham Inst., La Jolla CA (United States)

    1999-06-01

    The authors have developed an 'in vivo' selection system in which phage capable of selective homing to different tissues are recovered from a phage display peptide library following intravenous administration. Using this strategy, they have isolate several organ and tumor-homing peptides. They have shown that each of those peptides binds of different receptors that are selectively expressed on the vasculature of the target tissue. The tumor-homing peptides bind to receptors that are up regulated in tumor angiogenic vasculature. Targeted delivery of doxorubicin to angiogenic vasculature using these peptides in animals models decrease toxicity and increased the therapeutic efficacy of the drug. Vascular targeting may facilitate the development of other treatment strategies that rely on inhibition of angio genesis and lead to advances to extend the potential for targeting of drugs, genes and radionuclides in the context of many diseases.

  3. Hypoxia targeting copper complexes

    International Nuclear Information System (INIS)

    Dearling, J.L.

    1998-11-01

    The importance and incidence of tumour hypoxia, its measurement and current treatments available, including pharmacological and radiopharmacological methods of targeting hypoxia, are discussed. A variety of in vitro and in vivo methods for imposing hypoxia have been developed and are reviewed. Copper, its chemistry, biochemistry and radiochemistry, the potential for use of copper radionuclides and its use to date in this field is considered with particular reference to the thiosemicarbazones. Their biological activity, metal chelation, in vitro and in vivo studies of their radiocopper complexes and the potential for their use as hypoxia targeting radiopharmaceuticals is described. The reduction of the copper(II) complex to copper(l), its pivotal importance in their biological behaviour, and the potential for manipulation of this to effect hypoxia selectivity are described. An in vitro method for assessing the hypoxia selectivity of radiopharmaceuticals is reported. The rapid deoxygenation and high viability of a mammalian cell culture in this system is discussed and factors which may affect the cellular uptake of a radiopharmaceutical are described. The design, synthesis and complexation with copper and radiocopper of a range of bis(thiosemicarbazones) is reported. Synthesis of these compounds is simple giving high yields of pure products. The characteristics of the radiocopper complexes ( 64 Cu) including lipophilicity and redox activity are reported (reduction potentials in the range -0.314 - -0.590 V). High cellular uptakes of the radiocopper complexes of the ligands, in hypoxic and normoxic EMT6 and CHO320 cells, were observed. Extremes of selectivity are shown ranging from the hypoxia selective 64 Cu(II)ATSM to normoxic cell selective 64 Cu(II)GTS. The selectivities observed are compared with the physico chemical characteristics of the complexes. A good correlation exists between selectivity of the complex and its Cu(II)/Cu(I) reduction potential, with hypoxia

  4. Repetition priming in selective attention

    DEFF Research Database (Denmark)

    Ásgeirsson, Árni Gunnar; Kristjánsson, Árni; Bundesen, Claus

    2015-01-01

    . Repeating target colors enhanced performance for all 12 observers. As predicted, this was only true under conditions that required selection of a target among distractors, but not when a target was presented alone. Model fits by TVA were obtained with a trial-by-trial maximum likelihood estimation procedure...

  5. Immunotherapy Targets in Pediatric Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Orentas, Rimas J.; Lee, Daniel W.; Mackall, Crystal, E-mail: rimas.orentas@nih.gov, E-mail: mackallc@mail.nih.gov [Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD (United States)

    2012-01-30

    Immunotherapy for cancer has shown increasing success and there is ample evidence to expect that progress gleaned in immune targeting of adult cancers can be translated to pediatric oncology. This manuscript reviews principles that guide selection of targets for immunotherapy of cancer, emphasizing the similarities and distinctions between oncogene-inhibition targets and immune targets. It follows with a detailed review of molecules expressed by pediatric tumors that are already under study as immune targets or are good candidates for future studies of immune targeting. Distinctions are made between cell surface antigens that can be targeted in an MHC independent manner using antibodies, antibody derivatives, or chimeric antigen receptors versus intracellular antigens which must be targeted with MHC restricted T cell therapies. Among the most advanced immune targets for childhood cancer are CD19 and CD22 on hematologic malignancies, GD2 on solid tumors, and NY-ESO-1 expressed by a majority of synovial sarcomas, but several other molecules reviewed here also have properties which suggest that they too could serve as effective targets for immunotherapy of childhood cancer.

  6. Immunotherapy Targets in Pediatric Cancer

    International Nuclear Information System (INIS)

    Orentas, Rimas J.; Lee, Daniel W.; Mackall, Crystal

    2012-01-01

    Immunotherapy for cancer has shown increasing success and there is ample evidence to expect that progress gleaned in immune targeting of adult cancers can be translated to pediatric oncology. This manuscript reviews principles that guide selection of targets for immunotherapy of cancer, emphasizing the similarities and distinctions between oncogene-inhibition targets and immune targets. It follows with a detailed review of molecules expressed by pediatric tumors that are already under study as immune targets or are good candidates for future studies of immune targeting. Distinctions are made between cell surface antigens that can be targeted in an MHC independent manner using antibodies, antibody derivatives, or chimeric antigen receptors versus intracellular antigens which must be targeted with MHC restricted T cell therapies. Among the most advanced immune targets for childhood cancer are CD19 and CD22 on hematologic malignancies, GD2 on solid tumors, and NY-ESO-1 expressed by a majority of synovial sarcomas, but several other molecules reviewed here also have properties which suggest that they too could serve as effective targets for immunotherapy of childhood cancer.

  7. Targeted enzyme prodrug therapies.

    Science.gov (United States)

    Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

    2010-09-01

    The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

  8. EDITORIAL: Nanotechnological selection Nanotechnological selection

    Science.gov (United States)

    Demming, Anna

    2013-01-01

    At the nanoscale measures can move from a mass-scale analogue calibration to counters of discrete units. The shift redefines the possible levels of control that can be achieved in a system if adequate selectivity can be imposed. As an example as ionic substances pass through nanoscale pores, the quantity of ions is low enough that the pore can contain either negative or positive ions. Yet precise control over this selectivity still raises difficulties. In this issue researchers address the challenge of how to regulate the ionic selectivity of negative and positive charges with the use of an external charge. The approach may be useful for controlling the behaviour, properties and chemical composition of liquids and has possible technical applications for nanofluidic field effect transistors [1]. Selectivity is a critical advantage in the administration of drugs. Nanoparticles functionalized with targeting moieties can allow delivery of anti-cancer drugs to tumour cells, whilst avoiding healthy cells and hence reducing some of the debilitating side effects of cancer treatments [2]. Researchers in Belarus and the US developed a new theranostic approach—combining therapy and diagnosis—to support the evident benefits of cellular selectivity that can be achieved when nanoparticles are applied in medicine [3]. Their process uses nanobubbles of photothermal vapour, referred to as plasmonic nanobubbles, generated by plasmonic excitations in gold nanoparticles conjugated to diagnosis-specific antibodies. The intracellular plasmonic nanobubbles are controlled by laser fluence so that the response can be tuned in individual living cells. Lower fluence allows non-invasive high-sensitive imaging for diagnosis and higher fluence can disrupt the cellular membrane for treatments. The selective response of carbon nanotubes to different gases has leant them to be used within various different types of sensors, as summarized in a review by researchers at the University of

  9. VCAM-1-targeted core/shell nanoparticles for selective adhesion and delivery to endothelial cells with lipopolysaccharide-induced inflammation under shear flow and cellular magnetic resonance imaging in vitro.

    Science.gov (United States)

    Yang, Hong; Zhao, Fenglong; Li, Ying; Xu, Mingming; Li, Li; Wu, Chunhui; Miyoshi, Hirokazu; Liu, Yiyao

    2013-01-01

    Multifunctional nanomaterials with unique magnetic and luminescent properties have broad potential in biological applications. Because of the overexpression of vascular cell adhesion molecule-1 (VCAM-1) receptors in inflammatory endothelial cells as compared with normal endothelial cells, an anti-VCAM-1 monoclonal antibody can be used as a targeting ligand. Herein we describe the development of multifunctional core-shell Fe(3)O(4)@SiO2 nanoparticles with the ability to target inflammatory endothelial cells via VCAM-1, magnetism, and fluorescence imaging, with efficient magnetic resonance imaging contrast characteristics. Superparamagnetic iron oxide and fluorescein isothiocyanate (FITC) were loaded successfully inside the nanoparticle core and the silica shell, respectively, creating VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles that were characterized by scanning electron microscopy, transmission electron microscopy, fluorescence spectrometry, zeta potential assay, and fluorescence microscopy. The VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles typically had a diameter of 355 ± 37 nm, showed superparamagnetic behavior at room temperature, and cumulative and targeted adhesion to an inflammatory subline of human umbilical vein endothelial cells (HUVEC-CS) activated by lipopolysaccharide. Further, our data show that adhesion of VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles to inflammatory HUVEC-CS depended on both shear stress and duration of exposure to stress. Analysis of internalization into HUVEC-CS showed that the efficiency of delivery of VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles was also significantly greater than that of nontargeted Fe(3)O(4)@SiO2(FITC)-NH2 nanoparticles. Magnetic resonance images showed that the superparamagnetic iron oxide cores of the VCAM-1-targeted Fe(3)O(4)@SiO2(FITC) nanoparticles could also act as a contrast agent for magnetic resonance imaging. Taken together, the cumulative adhesion and uptake potential of

  10. First-in-human phase I study of ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2, in subjects with open-angle glaucoma undergoing glaucoma filtration surgery.

    Directory of Open Access Journals (Sweden)

    Norbert Pfeiffer

    Full Text Available To evaluate the safety and tolerability of intravitreal ISTH0036, an antisense oligonucleotide selectively targeting transforming growth factor beta 2 (TGF-β2, in patients with primary open angle glaucoma (POAG undergoing trabeculectomy (TE; glaucoma filtration surgery.In this prospective phase I trial glaucoma patients scheduled for TE with mitomycin C (MMC received a single intravitreal injection of ISTH0036 at the end of surgery in escalating total doses of 6.75 μg, 22.5 μg, 67.5 μg or 225 μg, resulting in calculated intraocular ISTH0036 concentrations in the vitreous humor of approximately 0.3 μM, 1 μM, 3 μM or 10 μM after injection, respectively. Outcomes assessed included: type and frequency of adverse events (AEs, intraocular pressure (IOP, numbers of interventions post trabeculectomy, bleb survival, visual acuity, visual field, electroretinogram (ERG, slit lamp biomicroscopy and optic disc assessment.In total, 12 patients were treated in the 4 dose groups. Main ocular AEs observed were corneal erosion, corneal epithelium defect, or too high or too low IOP, among others. No AE was reported to be related to ISTH0036. All other safety-related analyses did not reveal any toxicities of concern, either. The mean medicated preoperative IOP at decision time-point for surgery was 27.3 mmHg +/- 12.6 mmHg (SD. Mean IOP (±SD for dose levels 1, 2, 3, and 4 were at Day 43 9.8 mmHg ± 1.0 mmHg, 11.3 mmHg ± 6.7 mmHg, 5.5 mmHg ± 3.0 mmHg and 7.5 mmHg ± 2.3 mmHg SD; and at Day 85 9.7 mmHg ± 3.3 mmHg, 14.2 mmHg ± 6.5 mmHg, 5.8 mmHg ± 1.8 mmHg and 7.8 mmHg ± 0.6 mmHg, respectively. In contrast to IOP values for dose levels 1 and 2, IOP values for dose levels 3 and 4 persistently remained below 10 mmHg throughout the observation period.This first-in-human trial demonstrates that intravitreal injection of ISTH0036 at the end of TE is safe. Regarding IOP control, single-dose ISTH0036 administration of 67.5 μg or 225 μg at the time of TE

  11. Cooperative tumour cell membrane targeted phototherapy

    Science.gov (United States)

    Kim, Heegon; Lee, Junsung; Oh, Chanhee; Park, Ji-Ho

    2017-06-01

    The targeted delivery of therapeutics using antibodies or nanomaterials has improved the precision and safety of cancer therapy. However, the paucity and heterogeneity of identified molecular targets within tumours have resulted in poor and uneven distribution of targeted agents, thus compromising treatment outcomes. Here, we construct a cooperative targeting system in which synthetic and biological nanocomponents participate together in the tumour cell membrane-selective localization of synthetic receptor-lipid conjugates (SR-lipids) to amplify the subsequent targeting of therapeutics. The SR-lipids are first delivered selectively to tumour cell membranes in the perivascular region using fusogenic liposomes. By hitchhiking with extracellular vesicles secreted by the cells, the SR-lipids are transferred to neighbouring cells and further spread throughout the tumour tissues where the molecular targets are limited. We show that this tumour cell membrane-targeted delivery of SR-lipids leads to uniform distribution and enhanced phototherapeutic efficacy of the targeted photosensitizer.

  12. Development of targeted radiotherapy systems

    International Nuclear Information System (INIS)

    Ferro, Guillermina; Villarreal, Jose E.; Garcia, Laura; Tendilla, Jose I.; Paredes, Lydia; Murphy, Consuelo A.; Pedraza, Martha

    2001-01-01

    Conventional or external beam radiotherapy, has been a viable alternative for cancer treatment. Although this technique is effective, its use is limited if the patient has multiple malignant lesions (metastases). An alternative approach is based on the design of radiopharmaceuticals that, to be administered in the patient, are directed specifically toward the target cell producing a selective radiation delivery. This treatment is known as targeted radiotherapy. We have summarized and discussed some results related to our investigations on the development of targeted radiotherapy systems, including aspects of internal dosimetry

  13. A Cryogenic Infrared Calibration Target

    Science.gov (United States)

    Wollack, E. J.; Kinzer, R. E., Jr.; Rinehart, S. A.

    2014-01-01

    A compact cryogenic calibration target is presented that has a peak diffuse reflectance, R target. The resulting target assembly is lightweight, has a low-geometric profile, and has survived repeated thermal cycling from room temperature to approx.4 K. Basic design considerations, governing equations, and test data for realizing the structure described are provided. The optical properties of selected absorptive materials-Acktar Fractal Black, Aeroglaze Z306, and Stycast 2850 FT epoxy loaded with stainless steel powder-are characterized and presented

  14. Target Choice and Unique Synergies in Global Mobile Telephony

    DEFF Research Database (Denmark)

    Claussen, Jörg; Köhler, Rebecca; Kretschmer, Tobias

    2018-01-01

    their foresight to select specific targets: First, they lower integration costs by selecting geographically close targets. This effect is stronger when buyer and target are in the same country, but only if the market is not so concentrated that it provokes regulatory interventions. Second, they select targets......The success of acquisitions rests on detecting and realizing unique synergies between buyer and target through their dyadic relationships. We study the role of unique dyad-specific synergies in the selection of takeover targets in the global mobile telecommunications industry. Firms use...... that can be acquired at a modest bid premium because they have asymmetric bargaining power. Finally, they select targets which can generate significant synergies due to technological synergies. Our work expands the existing target selection literature by studying dyad-specific factors within a single...

  15. High-efficiency target-ion sources for RIB generation

    International Nuclear Information System (INIS)

    Alton, G.D.

    1993-01-01

    A brief review is given of high-efficiency ion sources which have been developed or are under development at ISOL facilities which show particular promise for use at existing, future, or radioactive ion beam (RIB) facilities now under construction. Emphasis will be placed on those sources which have demonstrated high ionization efficiency, species versatility, and operational reliability and which have been carefully designed for safe handling in the high level radioactivity radiation fields incumbent at such facilities. Brief discussions will also be made of the fundamental processes which affect the realizable beam intensities in target-ion sources. Among the sources which will be reviewed will be selected examples of state-of-the-art electron-beam plasma-type ion sources, thermal-ionization, surface-ionization, ECR, and selectively chosen ion source concepts which show promise for radioactive ion beam generation. A few advanced, chemically selective target-ion sources will be described, such as sources based on the use of laser-resonance ionization, which, in principle, offer a more satisfactory solution to isobaric contamination problems than conventional electromagnetic techniques. Particular attention will be given to the sources which have been selected for initial or future use at the Holifield Radioactive Ion Beam Facility now under construction at the Oak Ridge National Laboratory

  16. Aptamers for Targeted Drug Delivery

    Directory of Open Access Journals (Sweden)

    Partha Ray

    2010-05-01

    Full Text Available Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX. SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery.

  17. Target-to-Target Repetition Cost and Location Negative Priming Are Dissociable: Evidence for Different Mechanisms

    Science.gov (United States)

    Chao, Hsuan-Fu

    2011-01-01

    In a location-selection task, the repetition of a prior distractor location as the target location would slow down the response. This effect is termed the location negative priming (NP) effect. Recently, it has been demonstrated that repetition of a prior target location as the current target location would also slow down response. Because such…

  18. 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

  19. High Potency of Indolyl Aryl Sulfone Nonnucleoside Inhibitors towards Drug-Resistant Human Immunodeficiency Virus Type 1 Reverse Transcriptase Mutants Is Due to Selective Targeting of Different Mechanistic Forms of the Enzyme

    Science.gov (United States)

    Cancio, Reynel; Silvestri, Romano; Ragno, Rino; Artico, Marino; De Martino, Gabriella; La Regina, Giuseppe; Crespan, Emmanuele; Zanoli, Samantha; Hübscher, Ulrich; Spadari, Silvio; Maga, Giovanni

    2005-01-01

    Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation. PMID:16251294

  20. Progress in ISOL target-ion source systems

    Energy Technology Data Exchange (ETDEWEB)

    Koester, U. [Institut Laue Langevin, 6 Rue Jules Horowitz, F-38042 Grenoble Cedex 9 (France); ISOLDE, CERN, CH-1211 Geneve 23 (Switzerland)], E-mail: koester@ill.fr; Arndt, O. [HGF VISTARS and Institut fuer Kernchemie, Johannes-Gutenberg Universitaet Mainz, D-55128 Mainz (Germany); Bouquerel, E.; Fedoseyev, V.N. [ISOLDE, CERN, CH-1211 Geneve 23 (Switzerland); Franberg, H. [ISOLDE, CERN, CH-1211 Geneve 23 (Switzerland); Laboratory for Radio- and Environmental Chemistry, Paul Scherrer Institut, CH-5232 Villigen PSI (Switzerland); Joinet, A. [ISOLDE, CERN, CH-1211 Geneve 23 (Switzerland); Centre d' Etude Spatiale des Rayonnements, 9 Av. du Colonel Roche, F-31028 Toulouse Cedex 4 (France); Jost, C. [HGF VISTARS and Institut fuer Kernchemie, Johannes-Gutenberg Universitaet Mainz, D-55128 Mainz (Germany); Kerkines, I.S.K. [Laboratory of Physical Chemistry, National and Kapodistrian University of Athens, Department of Chemistry, Zografou 157 71, GR (Greece); Cherry L. Emerson Center for Scientific Computation and Department of Chemistry, Emory University, Atlanta, GA 30322 (United States); Kirchner, R. [Gesellschaft fuer Schwerionenforschung, Planckstr. 1, D-64291 Darmstadt (Germany)

    2008-10-15

    The heart of every ISOL (isotope separation on-line) facility is its target and ion source system. Its efficiency, selectivity and rapidity is decisive for the production of intense and pure ion beams of short-lived isotopes. Recent progress in ISOL target and ion source technology is discussed at the examples of radioactive ion beams of exotic zinc and tin isotopes that were purified by isothermal chromatography and molecular sideband separation respectively. An outlook is given to which other elements these purification methods are applicable.

  1. Progress in ISOL target-ion source systems

    International Nuclear Information System (INIS)

    Koester, U.; Arndt, O.; Bouquerel, E.; Fedoseyev, V.N.; Franberg, H.; Joinet, A.; Jost, C.; Kerkines, I.S.K.; Kirchner, R.

    2008-01-01

    The heart of every ISOL (isotope separation on-line) facility is its target and ion source system. Its efficiency, selectivity and rapidity is decisive for the production of intense and pure ion beams of short-lived isotopes. Recent progress in ISOL target and ion source technology is discussed at the examples of radioactive ion beams of exotic zinc and tin isotopes that were purified by isothermal chromatography and molecular sideband separation respectively. An outlook is given to which other elements these purification methods are applicable.

  2. ORION laser target diagnostics

    International Nuclear Information System (INIS)

    Bentley, C. D.; Edwards, R. D.; Andrew, J. E.; James, S. F.; Gardner, M. D.; Comley, A. J.; Vaughan, K.; Horsfield, C. J.; Rubery, M. S.; Rothman, S. D.; Daykin, S.; Masoero, S. J.; Palmer, J. B.; Meadowcroft, A. L.; Williams, B. M.; Gumbrell, E. T.; Fyrth, J. D.; Brown, C. R. D.; Hill, M. P.; Oades, K.

    2012-01-01

    The ORION laser facility is one of the UK's premier laser facilities which became operational at AWE in 2010. Its primary mission is one of stockpile stewardship, ORION will extend the UK's experimental plasma physics capability to the high temperature, high density regime relevant to Atomic Weapons Establishment's (AWE) program. The ORION laser combines ten laser beams operating in the ns regime with two sub ps short pulse chirped pulse amplification beams. This gives the UK a unique combined long pulse/short pulse laser capability which is not only available to AWE personnel but also gives access to our international partners and visiting UK academia. The ORION laser facility is equipped with a comprehensive suite of some 45 diagnostics covering optical, particle, and x-ray diagnostics all able to image the laser target interaction point. This paper focuses on a small selection of these diagnostics.

  3. ORION laser target diagnostics.

    Science.gov (United States)

    Bentley, C D; Edwards, R D; Andrew, J E; James, S F; Gardner, M D; Comley, A J; Vaughan, K; Horsfield, C J; Rubery, M S; Rothman, S D; Daykin, S; Masoero, S J; Palmer, J B; Meadowcroft, A L; Williams, B M; Gumbrell, E T; Fyrth, J D; Brown, C R D; Hill, M P; Oades, K; Wright, M J; Hood, B A; Kemshall, P

    2012-10-01

    The ORION laser facility is one of the UK's premier laser facilities which became operational at AWE in 2010. Its primary mission is one of stockpile stewardship, ORION will extend the UK's experimental plasma physics capability to the high temperature, high density regime relevant to Atomic Weapons Establishment's (AWE) program. The ORION laser combines ten laser beams operating in the ns regime with two sub ps short pulse chirped pulse amplification beams. This gives the UK a unique combined long pulse/short pulse laser capability which is not only available to AWE personnel but also gives access to our international partners and visiting UK academia. The ORION laser facility is equipped with a comprehensive suite of some 45 diagnostics covering optical, particle, and x-ray diagnostics all able to image the laser target interaction point. This paper focuses on a small selection of these diagnostics.

  4. Biochemical characterization of recombinant influenza A polymerase heterotrimer complex: Endonuclease activity and evaluation of inhibitors

    Czech Academy of Sciences Publication Activity Database

    Xing, W.; Barauskas, O.; Kirschberg, T.; Niedziela-Majka, A.; Clarke, M.; Birkuš, Gabriel; Weissburg, P.; Liu, X.; Schultz, B. E.; Sakowicz, R.; Kwon, H. J.; Feng, J. Y.

    2017-01-01

    Roč. 12, č. 8 (2017), č. článku e0181969. E-ISSN 1932-6203 Institutional support: RVO:61388963 Keywords : virus PA endonuclease * respiratory syncytial virus * RNA synthesis Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 2.806, year: 2016 http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181969

  5. A cluster-randomized controlled trial evaluating the effects of delaying onset of adolescent substance abuse on cognitive development and addiction following a selective, personality-targeted intervention programme: the Co-Venture trial.

    Science.gov (United States)

    O'Leary-Barrett, Maeve; Mâsse, Benoit; Pihl, Robert O; Stewart, Sherry H; Séguin, Jean R; Conrod, Patricia J

    2017-10-01

    Substance use and binge drinking during early adolescence are associated with neurocognitive abnormalities, mental health problems and an increased risk for future addiction. The trial aims to evaluate the protective effects of an evidence-based substance use prevention programme on the onset of alcohol and drug use in adolescence, as well as on cognitive, mental health and addiction outcomes over 5 years. Thirty-eight high schools will be recruited, with a final sample of 31 schools assigned to intervention or control conditions (3826 youth). Brief personality-targeted interventions will be delivered to high-risk youth attending intervention schools during the first year of the trial. Control school participants will receive no intervention above what is offered to them in the regular curriculum by their respective schools. Public/private French and English high schools in Montreal (Canada). All grade 7 students (12-13 years old) will be invited to participate. High-risk youth will be identified as those scoring one standard deviation or more above the school mean on one of the four personality subscales of the Substance Use Risk Profile Scale (40-45% youth). Self-reported substance use and mental health symptoms and cognitive functioning measured annually throughout 5 years. Primary outcomes are the onset of substance use disorders at 4 years post-intervention (year 5). Secondary intermediate outcomes are the onset of alcohol and substance use 2 years post-intervention and neuropsychological functions; namely, the protective effects of substance use prevention on cognitive functions generally, and executive functions and reward sensitivity specifically. This longitudinal, cluster-randomized controlled trial will investigate the impact of a brief personality-targeted intervention program on reducing the onset of addiction 4 years-post intervention. Results will tease apart the developmental sequences of uptake and growth in substance use and cognitive

  6. Targets for high power neutral beams

    International Nuclear Information System (INIS)

    Kim, J.

    1980-01-01

    Stopping high-power, long-pulse beams is fast becoming an engineering challenge, particularly in neutral beam injectors for heating magnetically confined plasmas. A brief review of neutral beam target technology is presented along with heat transfer calculations for some selected target designs

  7. [Selective mutism].

    Science.gov (United States)

    Ytzhak, A; Doron, Y; Lahat, E; Livne, A

    2012-10-01

    Selective mutism is an uncommon disorder in young children, in which they selectively don't speak in certain social situations, while being capable of speaking easily in other social situations. Many etiologies were proposed for selective mutism including psychodynamic, behavioral and familial etc. A developmental etiology that includes insights from all the above is gaining support. Accordingly, mild language impairment in a child with an anxiety trait may be at the root of developing selective mutism. The behavior will be reinforced by an avoidant pattern in the family. Early treatment and followup for children with selective mutism is important. The treatment includes non-pharmacological therapy (psychodynamic, behavioral and familial) and pharmacologic therapy--mainly selective serotonin reuptake inhibitors (SSRI).

  8. Voyager 2 Uranus targeting strategy

    Science.gov (United States)

    Cesarone, R. J.; Gray, D. L.; Potts, C. L.; Francis, K.

    1986-01-01

    One of the major challenges involved in the Voyager 2 Uranus flyby is to deliver the spacecraft to an appropriate aimpoint at the optimum time, so as to maximize the science return of the mission, while yet keeping propellant expenditure low. An unusual targeting strategy has been devised to satisfy these requirements. Its complexity arises from the great distance of the planet Uranus and the limited performance capabilities of Voyager. This selected strategy is developed in relation to a set of candidate strategies, mission requirements and shifting science objectives. The analysis of these candidates is conducted via a Monte Carlo simulation, the results of which yield data for the comparative evaluation and eventual and selection of the actual targeting strategy to be employed.

  9. CATAMARAN targeted at innovative radiopharmacy

    International Nuclear Information System (INIS)

    Impens, N.; Aerts, A.

    2010-01-01

    In cancer therapy there is a great need for specific treatments: therapies that kill cancer cells selectively without affecting the healthy cells. In the CATAMARAN project (Cancer Targeting Molecules Attached to Radionuclides) SCK-CEN develops, in a preclinical trial, products that deliver the right radiation doses at the right place in the human body. With the new multidisciplinary expertise that has been built up in the project, SCK-CEN is contributing to new medical applications of radiation.

  10. Malaysia; Selected Issues

    OpenAIRE

    International Monetary Fund

    1998-01-01

    This Selected Issues paper on Malaysia highlights quantitative assessment of additional measures required during the medium term to achieve fiscal targets. The authorities aim to lower the budget deficit to about 3 percent of GDP by 2015, down from 4.0 percent in 2013, and to balance the budget by 2020. It suggests that ranking fiscal instruments under different fiscal policy goals can help policymakers identify the composition of fiscal adjustment based on their preferences. By combining ran...

  11. 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.

  12. Site selection

    CERN Multimedia

    CERN PhotoLab

    1968-01-01

    To help resolve the problem of site selection for the proposed 300 GeV machine, the Council selected "three wise men" (left to right, J H Bannier of the Netherlands, A Chavanne of Switzerland and L K Boggild of Denmark).

  13. Benchmark selection

    DEFF Research Database (Denmark)

    Hougaard, Jens Leth; Tvede, Mich

    2002-01-01

    Within a production theoretic framework, this paper considers an axiomatic approach to benchmark selection. It is shown that two simple and weak axioms; efficiency and comprehensive monotonicity characterize a natural family of benchmarks which typically becomes unique. Further axioms are added...... in order to obtain a unique selection...

  14. 99mTc-labeling of Peptidomimetic Antagonist to Selectively Target αvβ3 Receptor-Positive Tumor: Comparison of PDA and EDDA as co-Ligands

    Science.gov (United States)

    Shin, In Soo; Maeng, Jin Soo; Jang, Beom-Su; You, Eric; Cheng, Kenneth; Li, King C.P; Wood, Bradford; Carrasquillo, Jorge A.; Danthi, S. Narasimhan; Paik, Chang H.

    2010-01-01

    Objectives The aim of this research was to synthesize radiolabeled peptidomimetic integrin αvβ3 antagonist with 99mTc for rapid targeting of integrin αvβ3 receptors in tumor to produce a high tumor to background ratio. Methods The amino terminus of 4-[2-(3,4,5,6-tetra-hydropyrimidin-2-ylamino)-ethyloxy]benzoyl-2-(S)-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonyl-amino-β-alanine hydrochloride (IAC) was conjugated with N-hydroxysuccinimide ester of HYNIC and labeled with 99mTc using tricine with either 1,5-pyridinedicarboxylic acid (PDA) or ethylenediamine-N,N′-diacetic acid (EDDA) as the co-ligand. The products, 99mTc EDDA2/HYNIC-IAC (P1) and 99mTc PDA (tricin)/HYNIC-IAC (P2) were subjected to in vitro serum stability, receptor-binding, biodistribution and imaging studies. Results P1 and P2 were synthesized with an overall yield of >80%. P1 was slightly more stable than P2 when incubated in serum at 37 °C for 18 hrs (84 vs 77% intact). The In vitro receptor-binding of P1 was higher than that of P2 (78.02 ± 13.48 vs 51.05 ± 14.05%) when incubated with αvβ3 at a molar excess (0.8 μM). This receptor binding was completely blocked by a molar excess of an unlabeled peptidomimetic antagonist. Their differences shown in serum stability and the receptor-binding appeared to be related to their biological behaviors in tumor uptake and retention; the 1 h tumor uptakes of P1 and P2 were 3.17±0.52 and 2.13±0.17 % ID/g, respectively. P1 was retained in the tumor longer than P2. P1 was excreted primarily through the renal system whereas P2 complex was excreted equally via both renal and hepatobiliary systems. Thus, P1 was retained in the whole-body with 27.25 ± 3.67% ID at 4 h whereas 54.04 ± 3.57% ID of P2 remained in the whole-body at 4 h. This higher whole-body retention of P2 appeared to be resulted from a higher amount of radioactivity retained in liver and intestine. These findings were supported by imaging studies showing higher tumor

  15. The use of fused PET/CT images for patient selection and radical radiotherapy target volume definition in patients with non-small cell lung cancer: Results of a prospective study with mature survival data

    International Nuclear Information System (INIS)

    Mac Manus, Michael P.; Everitt, Sarah; Bayne, Mike; Ball, David; Plumridge, Nikki; Binns, David; Herschtal, Alan; Cruickshank, Deborah; Bressel, Mathias; Hicks, Rodney J.

    2013-01-01

    Background and purpose: This prospective study investigated the impact of radiotherapy (RT)-planning FDG-PET/CT on management of non-small cell lung cancer (NSCLC). Materials and methods: Patients still eligible for radical RT after conventional staging underwent RT-planning PET/CT and, if disease was still treatable to 60 Gy, they entered our planning study, where visually-contoured tumour volumes derived with and without PET information were compared. If PET/CT detected advanced disease, palliative therapy was given. Overall survival (OS) for palliative and curative patients was compared. Results: Of 76 eligible patients, only 50 (66%) received radical chemoRT after PET/CT while 26 (34%) received palliative therapies because PET/CT detected advanced disease. Without PET, FDG-avid tumour would reside outside the planning target volume (PTV) in 36% of radical cases and in 25% 95% prescribed dose. OS for all patients was 56.8% and 24.9% at 1 and 4 years, respectively. OS for patients given chemoRT was 77.5% and 35.6% at 1 and 4 years, respectively and was 32% for stage IIIA patients at 4 years. OS for patients treated palliatively was inferior (P < 0.001); 16.3% and 4.1% at 1 and 4 years, respectively. Conclusions: Planning PET/CT frequently changed management and was associated with excellent survival. Survival data from this study were presented in part at the 2011 World Lung Cancer Conference, Amsterdam and planning data at the 2010 Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, Chicago

  16. Target assignment for security officers to K targets (TASK)

    International Nuclear Information System (INIS)

    Rowland, J.R.; Shelton, K.W.; Stunkel, C.B.

    1983-02-01

    A probabilistic algorithm is developed to provide an optimal Target Assignment for Security officers to K targets (TASK) using a maximin criterion. Under the assumption of only a limited number (N) of security officers, the TASK computer model determines deployment assignments which maximize the system protection against sabotage by an adversary who may select any link in the system, including the weakest, for the point of attack. Applying the TASK model to a hypothetical nuclear facility containing a nine-level building reveals that aggregate targets covering multiple vital areas should be utilized to reduce the number of possible target assignments to a value equal to or only slightly larger than N. The increased probability that a given aggregate target is covered by one or more security officers offsets the slight decrease in interruption probability due to its occurring earlier in the adversary's path. In brief, the TASK model determines the optimal maximin deployment strategy for limited numbers of security officers and calculates a quantitative measure of the resulting system protection

  17. A resistance locus in the American heirloom rice variety Carolina Gold Select is triggered by TAL effectors with diverse predicted targets and is effective against African strains of Xanthomonas oryzae pv. oryzicola.

    Science.gov (United States)

    Triplett, Lindsay R; Cohen, Stephen P; Heffelfinger, Christopher; Schmidt, Clarice L; Huerta, Alejandra I; Tekete, Cheick; Verdier, Valerie; Bogdanove, Adam J; Leach, Jan E

    2016-09-01

    The rice pathogens Xanthomonas oryzae pathovar (pv.) oryzae and pv. oryzicola produce numerous transcription activator-like (TAL) effectors that increase bacterial virulence by activating expression of host susceptibility genes. Rice resistance mechanisms against TAL effectors include polymorphisms that prevent effector binding to susceptibility gene promoters, or that allow effector activation of resistance genes. This study identifies, in the heirloom variety Carolina Gold Select, a third mechanism of rice resistance involving TAL effectors. This resistance manifests through strong suppression of disease development in response to diverse TAL effectors from both X. oryzae pathovars. The resistance can be triggered by an effector with only 3.5 central repeats, is independent of the composition of the repeat variable di-residues that determine TAL effector binding specificity, and is independent of the transcriptional activation domain. We determined that the resistance is conferred by a single dominant locus, designated Xo1, that maps to a 1.09 Mbp fragment on chromosome 4. The Xo1 interval also confers complete resistance to the strains in the African clade of X. oryzae pv. oryzicola, representing the first dominant resistance locus against bacterial leaf streak in rice. The strong phenotypic similarity between the TAL effector-triggered resistance conferred by Xo1 and that conferred by the tomato resistance gene Bs4 suggests that monocots and dicots share an ancient or convergently evolved mechanism to recognize analogous TAL effector epitopes. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

  18. 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

  19. Aptamer Selection Express: A Novel Method for Rapid Single-Step Selection and Sensing of Aptamers

    National Research Council Canada - National Science Library

    Fan, Maomian; Roper, Shelly; Andrews, Carrie; Allman, Amity; Bruno, John; Kiel, Jonathan

    2008-01-01

    ...). This process has been used to select aptamers against different types of targets (Bacillus anthracis spores, Bacillus thuringiensis spores, MS-2 bacteriophage, ovalbumin, and botulinum neurotoxin...

  20. Comparison of the efficiency of antibody selection from semi-synthetic scFv and non-immune Fab phage display libraries against protein targets for rapid development of diagnostic immunoassays.

    Science.gov (United States)

    Chan, Conrad E Z; Chan, Annie H Y; Lim, Angeline P C; Hanson, Brendon J

    2011-10-28

    Rapid development of diagnostic immunoassays against novel emerging or genetically modified pathogens in an emergency situation is dependent on the timely isolation of specific antibodies. Non-immune antibody phage display libraries are an efficient in vitro method for selecting monoclonal antibodies and hence ideal in these circumstances. Such libraries can be constructed from a variety of sources e.g. B cell cDNA or synthetically generated, and use a variety of antibody formats, typically scFv or Fab. However, antibody source and format can impact on the quality of antibodies generated and hence the effectiveness of this methodology for the timely production of antibodies. We have carried out a comparative screening of two antibody libraries, a semi-synthetic scFv library and a human-derived Fab library against the protective antigen toxin component of Bacillus anthracis and the epsilon toxin of Clostridium botulinum. We have shown that while the synthetic library produced a diverse collection of specific scFv-phage, these contained a high frequency of unnatural amber stops and glycosylation sites which limited their conversion to IgG, and also a high number which lost specificity when expressed as IgG. In contrast, these limitations were overcome by the use of a natural human library. Antibodies from both libraries could be used to develop sandwich ELISA assays with similar sensitivity. However, the ease and speed with which full-length IgG could be generated from the human-derived Fab library makes screening this type of library the preferable method for rapid antibody generation for diagnostic assay development. Copyright © 2011 Elsevier B.V. All rights reserved.

  1. Physical measurements of inertial-fusion targets

    International Nuclear Information System (INIS)

    Weinstein, B.W.

    1981-01-01

    Measurement of inertial-fusion targets has stimulated the development of many new techniques and instruments. This paper reviews the basis for selected target measurement requirements and the development of optical interferometry, optical scattering, microradiography and scanning electron microscopy as applied to target measurement. We summarize the resolution and speed which have been achieved to date, and describe several systems in which these are traded off to fill specific measurement applications. We point out the extent to which present capabilities meet the requirements for target measurement and the key problems which remain to be solved

  2. Selective mutism.

    Science.gov (United States)

    Hua, Alexandra; Major, Nili

    2016-02-01

    Selective mutism is a disorder in which an individual fails to speak in certain social situations though speaks normally in other settings. Most commonly, this disorder initially manifests when children fail to speak in school. Selective mutism results in significant social and academic impairment in those affected by it. This review will summarize the current understanding of selective mutism with regard to diagnosis, epidemiology, cause, prognosis, and treatment. Studies over the past 20 years have consistently demonstrated a strong relationship between selective mutism and anxiety, most notably social phobia. These findings have led to the recent reclassification of selective mutism as an anxiety disorder in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. In addition to anxiety, several other factors have been implicated in the development of selective mutism, including communication delays and immigration/bilingualism, adding to the complexity of the disorder. In the past few years, several randomized studies have supported the efficacy of psychosocial interventions based on a graduated exposure to situations requiring verbal communication. Less data are available regarding the use of pharmacologic treatment, though there are some studies that suggest a potential benefit. Selective mutism is a disorder that typically emerges in early childhood and is currently conceptualized as an anxiety disorder. The development of selective mutism appears to result from the interplay of a variety of genetic, temperamental, environmental, and developmental factors. Although little has been published about selective mutism in the general pediatric literature, pediatric clinicians are in a position to play an important role in the early diagnosis and treatment of this debilitating condition.

  3. 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

  4. 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.

  5. Design and Discovery of N -(2-Methyl-5'-morpholino-6'-((tetrahydro-2 H -pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers

    Energy Technology Data Exchange (ETDEWEB)

    Nishiguchi, Gisele A.; Rico, Alice; Tanner, Huw; Aversa, Robert J.; Taft, Benjamin R.; Subramanian, Sharadha; Setti, Lina; Burger, Matthew T.; Wan, Lifeng; Tamez, Victoriano; Smith, Aaron; Lou, Yan; Barsanti, Paul A.; Appleton, Brent A.; Mamo, Mulugeta; Tandeske, Laura; Dix, Ina; Tellew, John E.; Huang, Shenlin; Griner, Lesley A. Mathews; Cooke, Vesselina G.; Van Abbema, Anne; Merritt, Hanne; Ma, Sylvia; Gampa, Kalyani; Feng, Fei; Yuan, Jing; Wang, Yingyun; Haling, Jacob R.; Vaziri; #8741; , Sepideh; Hekmat-Nejad, Mohammad; Jansen, Johanna M.; Polyakov, Valery; Zang, Richard; Sethuraman, Vijay; Amiri, Payman; Singh, Mallika; Lees, Emma; Shao, Wenlin; Stuart, Darrin D.; Dillon, Michael P.; Ramurthy, Savithri (Novartis)

    2017-06-06

    RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [Aversa, Biaryl amide compounds as kinase inhibitors and their preparation. WO 2014151616, 2014], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.

  6. Tyrosine kinase inhibitors: Multi-targeted or single-targeted?

    Science.gov (United States)

    Broekman, Fleur; Giovannetti, Elisa; Peters, Godefridus J

    2011-02-10

    Since in most tumors multiple signaling pathways are involved, many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases. The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL, SCR, platelet derived growth factor, vascular endothelial growth factor receptor and epidermal growth factor receptor families. Both multi-kinase inhibitors and single-kinase inhibitors have advantages and disadvantages, which are related to potential resistance mechanisms, pharmacokinetics, selectivity and tumor environment. In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist. Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor. Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity, while differences in gene expression exist between tumor and stromal cells. Considering these aspects, one type of inhibitor can generally not be preferred above the other, but will depend on the specific genetic constitution of the patient and the tumor, allowing personalized therapy. The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered (epi)genetics of the tumor. This strategy might result in treatment by a single multi kinase inhibitor for one patient, but in treatment by a couple of single kinase inhibitors for other patients.

  7. Study of target and non-target interplay in spatial attention task.

    Science.gov (United States)

    Sweeti; Joshi, Deepak; Panigrahi, B K; Anand, Sneh; Santhosh, Jayasree

    2018-02-01

    Selective visual attention is the ability to selectively pay attention to the targets while inhibiting the distractors. This paper aims to study the targets and non-targets interplay in spatial attention task while subject attends to the target object present in one visual hemifield and ignores the distractor present in another visual hemifield. This paper performs the averaged evoked response potential (ERP) analysis and time-frequency analysis. ERP analysis agrees to the left hemisphere superiority over late potentials for the targets present in right visual hemifield. Time-frequency analysis performed suggests two parameters i.e. event-related spectral perturbation (ERSP) and inter-trial coherence (ITC). These parameters show the same properties for the target present in either of the visual hemifields but show the difference while comparing the activity corresponding to the targets and non-targets. In this way, this study helps to visualise the difference between targets present in the left and right visual hemifields and, also the targets and non-targets present in the left and right visual hemifields. These results could be utilised to monitor subjects' performance in brain-computer interface (BCI) and neurorehabilitation.

  8. 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

  9. 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

  10. 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)

  11. 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

  12. Capacity Development and Strengthening for Energy Policy formulation and implementation of Sustainable Energy Projects in Indonesia CASINDO. Deliverable No. 7. Report on the selection of SMKs for the project's target provinces and working agreements between SMKs and the project

    Energy Technology Data Exchange (ETDEWEB)

    Kamphuis, E. [ETC Nederland, Leusden (Netherlands); Permana, I. [Technical Education Development Centre TEDC, Bandung (Indonesia)

    2010-05-15

    The overall objective of the CASINDO programme is to establish a self-sustaining and self-developing structure at both the national and regional level to build and strengthen human capacity to enable the provinces of North Sumatra, Yogyakarta, Central Java, West Nusa Tenggara and Papua to formulate sound policies for renewable energy and energy efficiency and to develop and implement sustainable energy projects. This report explains the stepwise approach taken in the selection of SMKs (Sekolah Menengah Kejuruan of the Ministry of Education; SMKs are Vocational and Technical Schools) for CASINDO's target provinces. For this, data of the Indonesian Ministry of Education were used, site visits were made and interviews were conducted. The exercise resulted in ranking the 11 best SMKs observed. Terms for working agreements between the SMKs and CASINDO have been formulated as well as a work planning.

  13. Visuospatial selective attention in chickens.

    Science.gov (United States)

    Sridharan, Devarajan; Ramamurthy, Deepa L; Schwarz, Jason S; Knudsen, Eric I

    2014-05-13

    Voluntary control of attention promotes intelligent, adaptive behaviors by enabling the selective processing of information that is most relevant for making decisions. Despite extensive research on attention in primates, the capacity for selective attention in nonprimate species has never been quantified. Here we demonstrate selective attention in chickens by applying protocols that have been used to characterize visual spatial attention in primates. Chickens were trained to localize and report the vertical position of a target in the presence of task-relevant distracters. A spatial cue, the location of which varied across individual trials, indicated the horizontal, but not vertical, position of the upcoming target. Spatial cueing improved localization performance: accuracy (d') increased and reaction times decreased in a space-specific manner. Distracters severely impaired perceptual performance, and this impairment was greatly reduced by spatial cueing. Signal detection analysis with an "indecision" model demonstrated that spatial cueing significantly increased choice certainty in localizing targets. By contrast, error-aversion certainty (certainty of not making an error) remained essentially constant across cueing protocols, target contrasts, and individuals. The results show that chickens shift spatial attention rapidly and dynamically, following principles of stimulus selection that closely parallel those documented in primates. The findings suggest that the mechanisms that control attention have been conserved through evolution, and establish chickens--a highly visual species that is easily trained and amena