Science.gov

Sample records for analogue study sites

  1. The Rio Tinto Mars Analogue site: An extremophilic Raman spectroscopic study

    NASA Astrophysics Data System (ADS)

    Edwards, Howell G. M.; Vandenabeele, Peter; Jorge-Villar, Susana E.; Carter, Elizabeth A.; Perez, Fernando Rull; Hargreaves, Michael D.

    2007-12-01

    The Rio Tinto site is recognised as a terrestrial Mars analogue because of the presence of jarosite and related sulfates which have recently been identified by the NASA Mars Exploration Rover "Opportunity" in the El Capitan region of Meridiani Planum on Mars. It has long been known that acidophilic microbial action is responsible for the deep blood-red colour of the water in Rio Tinto, where the pH varies from about 1.5 to 3.0 and the water is rich in iron and sulfur. Following recent Raman spectroscopic characterisation of the mineral phases of the Rio Tinto system, we report here a study of the biological components found in several specimens of deposited minerals and near the waterside that were collected during a GeoRaman VI Conference organized field trip in 2006. Key biosignatures were found for carotenoids, scytonemin and mycosporine-like amino acids, which are indicative of the biological colonisation of exposed mineral substrates; information from this study will be useful for targeting Martian sites using a miniaturized Raman instrument where the biosignatures of relict or extant life could remain in the geological record.

  2. The Rio Tinto Mars analogue site: an extremophilic Raman spectroscopic study.

    PubMed

    Edwards, Howell G M; Vandenabeele, Peter; Jorge-Villar, Susana E; Carter, Elizabeth A; Perez, Fernando Rull; Hargreaves, Michael D

    2007-12-15

    The Rio Tinto site is recognised as a terrestrial Mars analogue because of the presence of jarosite and related sulfates which have recently been identified by the NASA Mars Exploration Rover "Opportunity" in the El Capitan region of Meridiani Planum on Mars. It has long been known that acidophilic microbial action is responsible for the deep blood-red colour of the water in Rio Tinto, where the pH varies from about 1.5 to 3.0 and the water is rich in iron and sulfur. Following recent Raman spectroscopic characterisation of the mineral phases of the Rio Tinto system, we report here a study of the biological components found in several specimens of deposited minerals and near the waterside that were collected during a GeoRaman VI Conference organized field trip in 2006. Key biosignatures were found for carotenoids, scytonemin and mycosporine-like amino acids, which are indicative of the biological colonisation of exposed mineral substrates; information from this study will be useful for targeting Martian sites using a miniaturized Raman instrument where the biosignatures of relict or extant life could remain in the geological record. PMID:17600759

  3. Theoretical study on the reactive sites and intramolecular interactions in taxol and its four analogues

    NASA Astrophysics Data System (ADS)

    Zhou, Hongwei; Zhang, Zhiqiang; Cheung, Hon-Yeung

    A density-functional study of the paclitaxel (Taxol) molecule and its four analogues has been performed. The theory of Bader's atoms in molecules (AIM) was applied to examine the electronic structure of these molecules at their ground state. Topological analysis reveals that the esterification of hydroxyl group attached to the oxetane ring results in great change of conformation of the taxane ring, and thus is responsible for bioactivity of the oxetane oxygen atom. It was found that there exists some intramolecular interactions in the molecule, including normal hydrogen bonds (HBs) and double HBs. Visualization of the molecule shows that the central bodies (the four fused rings) of the molecules are wrapped by the intramolecular interactions. It is supposed that these intramolecular interactions lower the aqueous solubility and protect the flexible oxetane ring, which is regarded as the dominating bioactivity site of the drug, from being opened. Our results provide an extended and consistent set of data to gauge classical force fields in view of the atomistic investigations of the interaction of the bioactive molecules.

  4. Combined Quantum Chemistry and Photoelectron Spectroscopy Study of the Electronic Structure and Reduction Potentials of Rubredoxin Redox Site Analogues

    SciTech Connect

    Niu, Shuqiang; Wang, Xue B.; Nichols, J. A.; Wang, Lai S.; Ichiye, Toshiko

    2003-04-24

    Iron-sulfur proteins are an important class of electron carriers in a wide variety of biological reactions. Determining the intrinsic contribution of the metal site to the redox potential is crucial in understanding how the protein environment influences the overall redox properties of the Fe-S proteins. Here we combine density functional theory and coupled cluster methods with photodetachment spectroscopy to study the electronic structures and gas-phase redox potentials of the [Fe(SCH3)(4)](2-/-/0) and [Fe(SCH3)(3)](-/0) analogues of the rubredoxin redox site. The calculations show that oxidations of [Fe(SCH3)(4)](2-) and [Fe(SCH3)(4)](-) involve mainly the Fe 3d and S 3p orbitals, respectively. The calculated adiabatic and vertical detachment energies are in good agreement with the experiment for [Fe(SCH3)(3)](-) and [Fe(SCH3)(4)](-). The current results further confirm the "inverted level scheme" for the high-spin [1Fe] systems. The redox couple, [Fe(SCH3)(4)](- /2), which is the one found in rubredoxin, but cannot be accessed experimentally in the gas phase, was investigated using a thermodynamic cycle that relates it to the [Fe(SCH3)(3)](-/0) couple and the ligand association reaction, [Fe(SCH3)(3)](0/-) + SCH3- --> [Fe(SCH3)(4)](-/2-). The calculated reduction energy of [Fe(SCH3)(4)](-) (1.7 eV) compares well with the value (1.6 eV) estimated from the calculated bond energies and the experimental detachment energy of [Fe(SCH3)(3)](-). Thus, this thermodynamic cycle method can be used to estimate metal-ligand bonding energies and determine intrinsic reduction potentials from photodetachment experiments when the reduced forms are not stable in the gas phase.

  5. Lessons from Natural CO2 Leakage Analogue Site Studies and their Application to Secure CO2 Storage and Monitoring

    NASA Astrophysics Data System (ADS)

    Han, W.; McPherson, B. J.; Kim, K.; Chae, G.; Yum, B.

    2011-12-01

    At CO2 injection sites, CO2 leakage from the storage formation could be catastrophic. CO2 is a highly compressible fluid, typically injected at high pressure and temperature conditions. If this compressed CO2 reaches highly permeable conduits such as faults and fractures, CO2 could leak unabated to other formations (e.g. fresh water aquifers) and/or to the surface. Assuming a fast-flow path to the surface, CO2 escaping from the storage formation instantaneously reaches the surface while experiencing adiabatic expansion, which results in Joule-Thomson cooling. The addressed eruptive mechanisms are analogues to natural CO2 eruption mechanisms, which are found in CO2-driven cold-water geysers around the world. A notable example of a CO2-driven cold-water geyser is the Crystal Geyser in central Utah. The fluid mechanics of this regularly erupting geyser was investigated by instrumenting its conduit with pressure, temperature, pH, EC, and dissolved oxygen sensors, measuring every 1 minute during and between eruptions. Results of these measurements suggest that the time-scale of a single-eruption cycle is composed of four successive eruption types with two recharge periods ranging from 30 to 40 hours. Current eruption patterns exhibit a bimodal distribution although previous measurements and anecdotal evidence suggests that this pattern was different prior to recent seismic activity. This cold geyser's eruptions are regular and predictable, and reflect pressure, temperature, EC, pH, and dissolved oxygen changes resulting from Joule-Thomson cooling, endothermic CO2 exsolution, and exothermic CO2 dissolution. Specifically, the perturbation of pressure and temperature data observed at the Crystal Geyser suggested the possibility of using temperature sensing technology within the observation well at the engineered CO2 sequestration site. With the lessons learned from the Crystal Geyser studies, we established the theoretical framework of temperature changes caused by CO2 related chemical reactions in the observation wells and tested with numerical simulation tools, which predicted thermal processes caused by solid NaCl precipitation, buoyancy-driven supercritical CO2 migration, and potential non-isothermal effects. Simulation results suggest that these processes - solid NaCl precipitation, buoyancy effects, Joule-Thomson cooling, water vaporization, and exothermic CO2 reactions - are strongly coupled and dynamic (transient). Overall, a fundamental understanding of potential thermal processes investigated through this research will be beneficial in the collection and analysis of temperature signals collectively measured from monitoring wells.

  6. Chloramphenicol Binding Site with Analogues of Chloramphenicol and Puromycin

    PubMed Central

    Vince, Robert; Almquist, Ronald G.; Ritter, Clare L.; Daluge, Susan

    1975-01-01

    The effect of a series of puromycin analogues and aminoacyl chloramphenicol derivatives on poly(U,C)-directed polyphenylalanine synthesis in an Escherichia coli cell-free system was examined. A comparison between the structures and activities of the puromycin and chloramphenicol analogues was made to examine the proposal that ribosomal binding sites for both antibiotics overlap. Our results suggest that the dichloroacetamido group in the chloramphenicol molecule does not correspond to the role of the aminoacyl moieties of either puromycin or aminoacyl transfer ribonucleic acid. These results comparing the structures and activities of puromycin and chloramphenicol analogues also seem inconsistent with a common binding site for the p-substituted phenyl moieties of the two antibiotics. Previous data have indicated that both sites are mutually affected by the prior binding of either antibiotic. Although it is possible that chloramphenicol and puromycin may have overlapping bindings sites, no common structural features between the two antibiotics are supported by our data. PMID:1103725

  7. Laboratory study of cometary analogues

    NASA Astrophysics Data System (ADS)

    Colangeli, L.; Brucato, J.; Mennella, V.; Palumbo, P.

    In situ exploration (e.g., GIOTTO mission) and astronomical observations (e.g., ISO) of comets have provided fundamental information about the structure, chemistry and physical properties of materials present in such primordial bodies of the Solar System. Moreover, it is known that cosmic materials evolve, depending on the efficiency of active processes (e.g., thermal annealing, UV irradiation, ion bombardment, gassolid interactions) in different space environments. Thus, the properties of cometary constituents must be considered in a wider perspective, including cosmic dust formation around cold stars and evolution in the interstellar medium until the formation of proto-planetary nebulae. In this scenario, laboratory experiments provide important hints to clarify the status of cometary compounds. The laboratory work is aimed at both reproducing material properties and at simulating their evolution based on the most effective mechanisms active in space. Several techniques are used to synthesise "analogues" of cometary compounds with controlled chemical and physical characteristics. The study of optical properties, complemented by other analytical techniques, is applied to investigate the products of synthesis in the experiments. The monitoring of the effects produced by processing methods, similar to those active in space, provides information both on the reactivity of materials and on the efficiency of treatments. Such an approach is able to provide quantitative information on chemical and structural modifications produced on organic and refractory materials. The comparison of laboratory results with data coming from space observations and in situ measurements provides a powerful tool to understand the real nature of comets and to place constraints on formation and evolution pathways. The laboratory experiments on analogues gain even more relevance as a sort of training in the future perspective of analysing cometary samples returned to Earth by space missions (e.g., Stardust).

  8. Multiple techniques for mineral identification on Mars:. a study of hydrothermal rocks as potential analogues for astrobiology sites on Mars

    NASA Astrophysics Data System (ADS)

    Bishop, Janice L.; Murad, Enver; Lane, Melissa D.; Mancinelli, Rocco L.

    2004-06-01

    Spectroscopic studies of Mars analog materials combining multiple spectral ranges and techniques are necessary in order to obtain ground truth information for interpretation of rocks and soils on Mars. Two hydrothermal rocks from Yellowstone National Park, Wyoming, were characterized here because they contain minerals requiring water for formation and they provide a possible niche for some of the earliest organisms on Earth. If related rocks formed in hydrothermal sites on Mars, identification of these would be important for understanding the geology of the planet and potential habitability for life. XRD, thermal properties, VNIR, mid-IR, and Raman spectroscopy were employed to identify the mineralogy of the samples in this study. The rocks studied here include a travertine from Mammoth Formation that contains primarily calcite with some aragonite and gypsum and a siliceous sinter from Octopus Spring that contains a variety of poorly crystalline to amorphous silicate minerals. Calcite was detected readily in the travertine rock using any one of the techniques studied. The small amount of gypsum was uniquely identified using XRD, VNIR, and mid-IR, while the aragonite was uniquely identified using XRD and Raman. The siliceous sinter sample was more difficult to characterize using each of these techniques and a combination of all techniques was more useful than any single technique. Although XRD is the historical standard for mineral identification, it presents some challenges for remote investigations. Thermal properties are most useful for minerals with discrete thermal transitions. Raman spectroscopy is most effective for detecting polarized species such as CO 3, OH, and CH, and exhibits sharp bands for most highly crystalline minerals when abundant. Mid-IR spectroscopy is most useful in characterizing Si-O (and metal-O) bonds and also has the advantage that remote information about sample texture (e.g., particle size) can be determined. Mid-IR spectroscopy is also sensitive to structural OH, CO 3, and SO 4 bonds when abundant. VNIR spectroscopy is best for characterizing metal excitational bands and water, and is also a good technique for identification of structural OH, CO 3, SO 4, or CH bonds. Combining multiple techniques provides the most comprehensive information about mineralogy because of the different selection rules and particle size sensitivities, in addition to maximum coverage of excitational and vibrational bands at all wavelengths. This study of hydrothermal rocks from Yellowstone provides insights on how to combine information from multiple instruments to identify mineralogy and hence evidence of water on Mars.

  9. Analogue Sites for Mars Missions - A report from two workshops

    NASA Astrophysics Data System (ADS)

    Hipkin, V.; Voytek, M. A.; Glamoclija, M.

    2014-12-01

    Fieldwork, at terrestrial sites that are analogous in some way to Mars, has a key role in defining questions addressed by Mars missions. For MSL, the question is whether its landing site was habitable, and for Mars 2020, the question is how do we search for and what are signs of life in ancient habitable environments. Implementing these investigations by means of a rover mission on a distant planetary surface has challenges due to a limited set of tools and period of operations. Using this context of planetary missions is important in shaping how analog research can be used to advance planetary science. Following a successful 2010 AGU fall meeting session entitled "Analogue Sites for Mars Missions", two community workshops were held at The Woodlands, TX March 2011 and the Carnegie Institute of Washington in July 2013. These activities represent an ongoing dialogue with the analogue and mission communities. The AGU session solicited presentations of current analogue research relevant to MSL, at which time the landing site selection process was still considering four final sites. The 2011 Woodlands workshop solicited details on representative science questions and analogue sites by means of an abstract template. The output from The Woodlands workshop was an initial metric to assess the utility of analogue sites against specific science questions, as well as recommendations for future activities. The 2013 Carnegie workshop, followed up on some of the recommendations from 2011. Both on-line interactive dialogue and in person discussions targeted broad topics, including 'the advantages and problems of using a great terrestrial analog for field testing', and 'knowing what we currently do about Mars, what would be the best place on the planet to collect the first suite of samples to be returned to Earth? What would be appropriate analog sites on Earth?'. The results and recommendations from both workshops are summarized to publicize and stimulate this ongoing discussion.

  10. Space analogue studies in Antarctica

    NASA Technical Reports Server (NTRS)

    Lugg, D.; Shepanek, M.

    1999-01-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mitogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  11. Space analogue studies in Antarctica

    NASA Astrophysics Data System (ADS)

    Lugg, D.; Shepanek, M.

    1999-09-01

    Medical research has been carried out on the Australian National Antarctic Research Expeditions (ANARE) for 50 years. As an extension of this program collaborative Australian/United States research on immunology, microbiology, psychology and remote medicine has produced important data and insight on how humans adapt to the stress of extreme isolation, confinement and the harsh environment of Antarctica. An outstanding analogue for the isolation and confinement of space missions (especially planetary outposts), ANARE has been used as an international research platform by Australia and the United States since 1993. Collaborative research has demonstrated a lowered responsiveness of the immune system under the isolation and confinement of Antarctic winter-over; a reduction of almost 50% in T cell proliferation to mltogen phytohaemogglutinin, as well as changes in latent herpesvirus states and the expansion of the polyclonal latent Epstein-Barr virus infected B cell populations. Although no clinically significant disease has been found to result from these immune changes, research is currently assessing the effects of psychological factors on the immune system. This and associated research performed to date and its relevance to both organisations is discussed, and comment made on possible extensions to the program in both medical and other fields.

  12. Using fuzzy sets for data interpretation in natural analogue studies

    SciTech Connect

    De Lemos, F.L.; Sullivan, T.; Hellmuth, K.H.

    2008-07-01

    Natural analogue studies can play a key role in deep geological radioactive disposal systems safety assessment. These studies can help develop a better understanding of complex natural processes and, therefore, provide valuable means of confidence building in the safety assessment. In evaluation of natural analogues, there are, however, several sources of uncertainties that stem from factors such as complexity; lack of data; and ignorance. Often, analysts have to simplify the mathematical models in order to cope with the various sources of complexity and this ads uncertainty to the model results. The uncertainties reflected in model predictions must be addressed to understand their impact on safety assessment and therefore, the utility of natural analogues. Fuzzy sets can be used to represent the information regarding the natural processes and their mutual connections. With this methodology we are able to quantify and propagate the epistemic uncertainties in both processes and, thereby, assign degrees of truth to the similarities between them. An example calculation with literature data is provided. In conclusion: Fuzzy sets are an effective way of quantifying semi-quantitative information such as natural analogues data. Epistemic uncertainty that stems from complexity and lack of knowledge regarding natural processes are represented by the degrees of membership. It also facilitates the propagation of this uncertainty throughout the performance assessment by the extension principle. This principle allows calculation with fuzzy numbers, where fuzzy input results in fuzzy output. This may be one of the main applications of fuzzy sets theory to radioactive waste disposal facility performance assessment. Through the translation of natural data into fuzzy numbers, the effect of parameters in important processes in one site can be quantified and compared to processes in other sites with different conditions. The approach presented in this paper can be extended to facilitate a comparison between sites. For example, the degrees of membership can be a measure of similarities between sites and, consequently, confidence in validation tests of models can be enhanced. (authors)

  13. Upheaval Dome, An Analogue Site for Gale Center

    NASA Technical Reports Server (NTRS)

    Conrad, P. G.; Eignebrode, J. L.

    2011-01-01

    We propose Upheaval Dome in southeastern Utah as an impact analogue site on Earth to Mars Science Laboratory candidate landing site Gale Crater. The genesis of Upheaval Dome was a mystery for some time--originally thought to be a salt dome. The 5 km crater was discovered to possess shocked quartz and other shock metamorphic features just a few years ago, compelling evidence that the crater was formed by impact, although the structural geology caused Shoemaker and Herkenhoff to speculate an impact origin some 25 years earlier. The lithology of the crater is sedimentary. The oldest rocks are exposed in the center of the dome, upper Permian sandstones, and progressively younger units are well exposed moving outward from the center. These are Triassic sandstones, siltstones and shales, which are intruded by clastic dikes. There are also other clay-rich strata down section, as is the case with Gale Crater. There is significant deformation in the center of the crater, with folding and steeply tilted beds, unlike the surrounding Canyonlands area, which is relatively undeformed. The rock units are well exposed at Upheaval Dome, and there are shatter cones, impactite fragments, shocked quartz grains and melt rocks present. The mineral shock features suggest that the grains were subjected to dynamic pressures> 10 GPa.

  14. Spectroscopic study of solar twins and analogues

    NASA Astrophysics Data System (ADS)

    Datson, Juliet; Flynn, Chris; Portinari, Laura

    2015-02-01

    Context. Many large stellar surveys have been and are still being carried out, providing huge amounts of data, for which stellar physical parameters will be derived. Solar twins and analogues provide a means to test the calibration of these stellar catalogues because the Sun is the best-studied star and provides precise fundamental parameters. Solar twins should be centred on the solar values. Aims: This spectroscopic study of solar analogues selected from the Geneva-Copenhagen Survey (GCS) at a resolution of 48 000 provides effective temperatures and metallicities for these stars. We test whether our spectroscopic parameters, as well as the previous photometric calibrations, are properly centred on the Sun. In addition, we search for more solar twins in our sample. Methods: The methods used in this work are based on literature methods for solar twin searches and on methods we developed in previous work to distinguish the metallicity-temperature degeneracies in the differential comparison of spectra of solar analogues versus a reference solar reflection spectrum. Results: We derive spectroscopic parameters for 148 solar analogues (about 70 are new entries to the literature) and verify with a-posteriori differential tests that our values are well-centred on the solar values. We use our dataset to assess the two alternative calibrations of the GCS parameters; our methods favour the latest revision. We show that the choice of spectral line list or the choice of asteroid or time of observation does not affect the results. We also identify seven solar twins in our sample, three of which are published here for the first time. Conclusions: Our methods provide an independent means to differentially test the calibration of stellar catalogues around the values of a well-known benchmark star, which makes our work interesting for calibration tests of upcoming Galactic surveys. Based on observations made with ESO Telescopes at the La Silla Observatory under programme ID 077.D-0525 and 090.D-0133.Table 1 is also available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/574/A124Full Table 5 is only available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (ftp://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/574/A124

  15. Novel benzopsoralen analogues: synthesis, biological activity and molecular docking studies.

    PubMed

    Francisco, Carla S; Rodrigues, Lgia R; Cerqueira, Nuno M F S A; Oliveira-Campos, Ana M F; Esteves, Ana P

    2014-11-24

    New benzopsoralen analogues were synthesized and their inhibitory effect on the growth of tumourtumour cell lines (MDA MB231 and TCC-SUP) was evaluated. The in vitro antitumour activity of the new benzopsoralen analogues was discussed in terms of structure-activity relationship. Molecular docking studies with human-CYP2A6 enzymes were also carried out with the synthesized compounds to evaluate the potential of these molecules to interact with the haem group of the enzymes. The results demonstrated that the compounds that are able to interact with the iron ion of the haem cofactor and at the same time with active site Asn297 are those that have better anti-proliferative activity. PMID:25262050

  16. Irradiation studies of astrophysical ice analogues

    NASA Astrophysics Data System (ADS)

    Holton, Philip D.

    In this thesis the formation of molecular species in cold icy mantles, typical of those in the interstellar medium (ISM) has been studied. The construction of an ultra high vacuum system for the formation and containment of these astrophysical ice analogues is described. The method of preparation of these ices is detailed and analysis methodologies are discussed. VUV spectra of molecular ices (e.g. SO2, CH3NH2, OCS) measured on the UV1 beam line of the Astrid Synchrotron facility at the University of Aarhus in Denmark, are presented. Molecular synthesis (e.g. CO3, CO, H2CO3) induced by ion irradiated CO2/H 2O ices using facilities at Queens University Belfast are also reported. In particular this thesis focuses on the irradiation studies of the binary ice mixture of Methylamine (CH3NH2) and Carbon Dioxide (CO2). The results of irradiation of CH3NH2 and CO2 binary ice mixtures by ultraviolet photons, and electrons are presented. The apparent production of the amino acid - glycine - in our irradiated samples is discussed together with possible production processes.

  17. NASA/ESMD Analogue Mission Plans

    NASA Technical Reports Server (NTRS)

    Hoffman, Stephen J.

    2007-01-01

    A viewgraph presentation exploring Earth and its analogues is shown. The topics include: 1) ESMD Goals for the Use of Earth Analogues; 2) Stakeholders Summary; 3) Issues with Current Analogue Situation; 4) Current state of Analogues; 5) External Implementation Plan (Second Step); 6) Recent Progress in Utilizing Analogues; 7) Website Layout Example-Home Page; 8) Website Layout Example-Analogue Site; 9) Website Layout Example-Analogue Mission; 10) Objectives of ARDIG Analog Initiatives; 11) Future Plans; 12) Example: Cold-Trap Sample Return; 13) Example: Site Characterization Matrix; 14) Integrated Analogue Studies-Prerequisites for Human Exploration; and 15) Rating Scale Definitions.

  18. The role of Asn-212 in the catalytic mechanism of human endonuclease APE1: stopped-flow kinetic study of incision activity on a natural AP site and a tetrahydrofuran analogue.

    PubMed

    Kanazhevskaya, Lyubov Yu; Koval, Vladimir V; Lomzov, Alexander A; Fedorova, Olga S

    2014-09-01

    Mammalian AP endonuclease 1 is a pivotal enzyme of the base excision repair pathway acting on apurinic/apyrimidinic sites. Previous structural and biochemical studies showed that the conserved Asn-212 residue is important for the enzymatic activity of APE1. Here, we report a comprehensive pre-steady-state kinetic analysis of two APE1 mutants, each containing amino acid substitutions at position 212, to ascertain the role of Asn-212 in individual steps of the APE1 catalytic mechanism. We applied the stopped-flow technique for detection of conformational transitions in the mutant proteins and DNA substrates during the catalytic cycle, using fluorophores that are sensitive to the micro-environment. Our data indicate that Asn-212 substitution by Asp reduces the rate of the incision step by ?550-fold, while Ala substitution results in ?70,000-fold decrease. Analysis of the binding steps revealed that both mutants continued to rapidly and efficiently bind to abasic DNA containing the natural AP site or its tetrahydrofuran analogue (F). Moreover, transient kinetic analysis showed that N212A APE1 possessed a higher binding rate and a higher affinity for specific substrates compared to N212D APE1. Molecular dynamics (MD) simulation revealed a significant dislocation of the key catalytic residues of both mutant proteins relative to wild-type APE1. The analysis of the model structure of N212D APE1 provides evidence for alternate hydrogen bonding between Asn-212 and Asp-210 residues, whereas N212A possesses an extended active site pocket due to Asn removal. Taken together, these biochemical and MD simulation results indicate that Asn-212 is essential for abasic DNA incision, but is not crucial for effective recognition/binding. PMID:25038572

  19. Preparing to return to the Moon: Lessons from science-driven analogue missions to the Mistastin Lake impact structure, Canada, a unique lunar analogue site

    NASA Astrophysics Data System (ADS)

    Osinski, G. R.; Barfoot, T.; Chanou, A.; Daly, M. G.; Francis, R.; Hodges, K. V.; Jolliff, B. L.; Mader, M. M.; McCullough, E. M.; Moores, J. E.; Pickersgill, A.; Pontefract, A.; Preston, L.; Shankar, B.; Singleton, A.; Sylvester, P.; Tornabene, L. L.; Young, K. E.

    2013-12-01

    Impact cratering is the dominant geological process on the Moon, Near Earth Asteroids (NEAs) and the moons of Mars - the objectives for the new Solar System Exploration Research Virtual Institute (SSERVI). Led by members of the Canadian Lunar Research Network (CLRN), funded by the Canadian Space Agency, and with participants from the U.S., we carried out a series of analogue missions on Earth in order to prepare and train for future potential robotic and human sample return missions. Critically, these analogue missions were driven by the paradigm that operational and technical objectives are conducted while conducting new science and addressing real overarching scientific objectives. An overarching operational goal was to assess the utility of a robotic field reconnaissance mission as a precursor to a human sortie sample return mission. Here, we focus on the results and lessons learned from a robotic precursor mission and follow on human-robotic mission to the Mistastin Lake impact structure in Labrador, northern Canada (5553'N; 6318'W). The Mistastin structure was chosen because it represents an exceptional analogue for lunar craters. This site includes both an anorthositic target, a central uplift, well-preserved impact melt rocks - mostly derived from melting anorthosite - and is (or was) relatively unexplored. This crater formed ~36 million years ago and has a diameter of ~28 km. The scientific goals for these analogue missions were to further our understanding of impact chronology, shock processes, impact ejecta and potential resources within impact craters. By combining these goals in an analogue mission campaign key scientific requirements for a robotic precursor were determined. From the outset, these analogue missions were formulated and executed like an actual space mission. Sites of interest were chosen using remote sensing imagery without a priori knowledge of the site through a rigorous site selection process. The first deployment occurred in August and September 2010 and involved simulated robotic surveying of selected 'landing sites' at the Mistastin structure. The second deployment took place at the same location in 2011, which included simulated astronaut surface operations with, and without, the aid of a robotic assistant. A mission control team, based at the University of Western Ontario, London, Ontario, 1,900 km from the field site, oversaw operations. Our study showed the value of precursor reconnaissance missions in providing surface geology visualization at resolutions and from viewpoints not achievable from orbit, including high-resolution surface imagery on the scale of 10s of metres to kilometres. Indeed, data collected during the robotic precursor mission led to the formulation of a hypothesis that a large impact melt outcrop - named Discovery Hill - represents an impact melt pond in the terraced region of the crater, analogous to similar ponds of melt documented around the rim of well-preserved lunar craters such as Tycho. Further discoveries, that will be highlight here, include documentation of ejecta deposits for the first time at Mistastin, quantification of shock in anorthosites, and refined age estimates for the Mistastin impact event.

  20. FIGIFIGO as a tool to characterize and identify planetary analogue sites

    NASA Astrophysics Data System (ADS)

    Gritsevich, M.; Peltoniemi, J.; Hakala, T.; Muinonen, K.

    2014-07-01

    We present an overview of the Finnish Geodetic Institute's field goniospectrometer (FIGIFIGO) and highlight its usability to study extraterrestrial analogues on the Earth. The design concept of this custom-made instrument has been proved to have a number of advantages, such as a well-adopted user-friendly interface, a high level of automation, and excellent suitability for field measurements within a wide range of weather conditions. It is perfect for collection of reference data on a given target in natural undisturbed (and well-recorded for further data interpretation) conditions. The instrument communicates via a controlled computer with an implemented simple and user-friendly interface. This allows users to easily set up optional parameters at the beginning of the measurement series. Thus a number of details may be modified, such as the initial position of the sensor, the range and speed of further automated zenith turns, and length of the turnable arm holding the selected optics (including an option for a computer-turned linear polarizer) above the target. The assembly and operation of the instrument are fast and efficient in both laboratory and field conditions. It is battery powered and easily portable, including possible transportation by plane, car, boat, or sledge. The system includes a sky camera to detect the goniometer orientation and a pyranometer to monitor the actual illumination conditions. A fine-tune mirror is used for spatial correction of the optics footprint. Recent calibration of the system has significantly increased the measurement robustness and data reliability, and has provided the operators with information on how to operate the instrument in the most efficient and accurate way. Measurement campaigns are organized frequently and significant amount of reference data has been already collected. The identification of new planetary analogue sites and characterization of known ones using FIGIFIGO could offer new possibilities and provide great insights for the planetary research community.

  1. Dynamics of water in prussian blue analogues: Neutron scattering study

    SciTech Connect

    Sharma, V. K.; Mitra, S.; Thakur, N.; Yusuf, S. M.; Mukhopadhyay, R.; Juranyi, Fanni

    2014-07-21

    Dynamics of crystal water in Prussian blue (PB), Fe(III){sub 4}[Fe(II)(CN){sub 6}]{sub 3}.14H{sub 2}O and its analogue Prussian green (PG), ferriferricynaide, Fe(III){sub 4}[Fe(III)(CN){sub 6}]{sub 4}.16H{sub 2}O have been investigated using Quasielastic Neutron Scattering (QENS) technique. PB and its analogue compounds are important materials for their various interesting multifunctional properties. It is known that crystal water plays a crucial role towards the multifunctional properties of Prussian blue analogue compounds. Three structurally distinguishable water molecules: (i) coordinated water molecules at empty nitrogen sites, (ii) non-coordinated water molecules in the spherical cavities, and (iii) at interstitial sites exist in PB. Here spherical cavities are created due to the vacant sites of Fe(CN){sub 6} units. However, PG does not have any such vacant N or Fe(CN){sub 6} units, and only one kind of water molecules, exists only at interstitial sites. QENS experiments have been carried out on both the compounds in the temperature range of 260–360 K to elucidate the dynamical behavior of different kinds of water molecules. Dynamics is found to be much more pronounced in case of PB, compared to PG. A detailed data analysis showed that localized translational diffusion model could describe the observed data for both PB and PG systems. The average diffusion coefficient is found to be much larger in the PB than PG. The obtained domain of dynamics is found to be consistent with the geometry of the structure of the two systems. Combining the data of the two systems, a quantitative estimate of the dynamics, corresponding to the water molecules at different locations is made.

  2. Heterogeneous seepage at the Nopal I natural analogue site, Chihuahua, Mexico

    SciTech Connect

    Dobson, Patrick F.; Cook, Paul J.; Ghezzehei, Teamrat A.; Rodriguez, J. Alfredo; Villalba, Lourdes; de la Garza, Rodrigo

    2008-10-25

    An integrated field, laboratory, and modeling study of the Pena Blanca (Chihuahua, Mexico) natural analogue site is being conducted to evaluate processes that control the mobilization and transport of radionuclides from a uranium ore deposit. One component of this study is an evaluation of the potential for radionuclide transport through the unsaturated zone (UZ) via a seepage study in an adit at the Nopal I uranium mine, excavated 10 m below a mined level surface. Seasonal rainfall on the exposed level surface infiltrates into the fractured rhyolitic ash-flow tuff and seeps into the adit. An instrumented seepage collection system and local automated weather station permit direct correlation between local precipitation events and seepage within the Nopal I +00 adit. Monitoring of seepage within the adit between April 2005 and December 2006 indicates that seepage is highly heterogeneous with respect to time, location, and quantity. Within the back adit area, a few zones where large volumes of water have been collected are linked to fast flow path fractures (0-4 h transit times) presumably associated with focused flow. In most locations, however, there is a 1-6 month time lag between major precipitation events and seepage within the adit, with longer residence times observed for the front adit area. Seepage data obtained from this study will be used to provide input to flow and transport models being developed for the Nopal I hydrogeologic system.

  3. Reactive transport modeling of the clogging process at Maqarin natural analogue site

    NASA Astrophysics Data System (ADS)

    Shao, Haibing; Kosakowski, Georg; Berner, Urs; Kulik, Dmitrii A.; Mder, Urs; Kolditz, Olaf

    The Maqarin site in Jordan has been investigated for three decades as a natural analogue for the long term changes of materials in contact with hyper-alkaline solutions. Similar processes are expected in radioactive waste disposal sites, where cement based materials are in contact with natural rocks or other e.g. clay based materials. In this context, a numerical reactive transport model was used to study local geochemical alterations and induced porosity changes for the Maqarin marl rock in contact with the hyper-alkaline solution. The geochemical setup for the rock mineralogy and the pore water was calibrated to match measurements from the Maqarin site. The setup includes several clay and zeolite minerals, considers cation exchange processes, and a state-of-the-art model for cement phases. Similar to earlier calculations by Steefel and Lichtner (1998) who used a much simpler geochemical model, the pore clogging occurred after several hundred years at a distance of 5-10 mm from the contact to the hyper-alkaline solution. In our calculations, this was caused by a massive precipitation of ettringite and C-S-H minerals. We performed a sensitivity study by varying the intrinsic diffusion coefficient, the Archie's law exponential factor, and the mineral surface area available for dissolution and precipitation. We found that the dissolution of clay minerals controls the availability of Al, which is needed for ettringite and C-S-H phase precipitation. Thus, the amount and kinetically controlled dissolution of clay minerals controls the spatial and temporal evolution of porosity changes. The simulations reveal that neither cation exchange processes nor the formation of zeolite minerals strongly influence the geochemical evolution of the system.

  4. Mode of action of site-directed irreversible folate analogue inhibitors of thymidylate synthase.

    PubMed

    Lobo, A P; Nair, M G; Changchien, L; Weichsel, A; Montfort, W R; Maley, F

    1998-03-31

    5,8-Dideazafolate analogues are tight binding but not irreversible inhibitors of thymidylate synthase (TS). However, when a chloroacetyl (ClAc) group is substituted at the N10-position of 2-desamino-2-methyl-5,8-dideazafolate (DMDDF), the resulting compound, ClAc-DMDDF, although still a reversible inhibitor (KI = 3.4 x 10(-3) M), gradually inactivates thyA-TS irreversibly at a rate of 0.37 min-1. The corresponding iodoacetyl derivative alkylated the enzyme somewhat slower (k3 = 0.15 min-1 ) than ClAc-DMDDF but was bound more tightly (KI = 1.4 x 10(-5) M), resulting in a second-order rate constant (k3/KI) of inactivation that was 100-fold greater than that of ClAc-DMDDF. A tryptic digest of the ClAc-DMDDF-inactivated enzyme yielded a peptide on HPLC, which revealed that cysteine-146, the residue at the active site that is intimately involved in the catalytic process, had reacted with ClAc-DMDDF to form a covalent bond. This derivative was confirmed indirectly by Edman analysis and more directly by mass spectrometry. Deoxyuridine 5'-monophosphate, a substrate in the catalytic reaction, protected against inactivation. Similar to previously described Lactobacillus casei TS inhibition studies with sulfhydryl reagents [Galivan, J., Noonan, J., and Maley, F. (1977) Arch. Biochem. Biophys. 184, 336-345], the kinetics of inhibition suggested that complete inhibition occurs on reaction of only one of the two active site cysteines, although sequence and amino acid analysis revealed that iodoacetate and ClAc-DMDDF had reacted with both active site cysteines. These studies demonstrate that a sulfhydryl reactive compound that is directed to the folate binding site of TS may diffuse to the active site cysteine, and form a covalent bond with this residue. How this inhibition comes about is suggested in a stereoscopic view of the ligand when modeled to the known crystal structure of Escherichia coli TS. PMID:9521774

  5. Natural analogues for CO2 storage sites - analysis of a global dataset

    NASA Astrophysics Data System (ADS)

    Miocic, Johannes; Gilfillan, Stuart; McDermott, Christopher; Haszeldine, R. Stuart

    2013-04-01

    Carbon Capture and Storage is the only industrial scale technology currently available to reduce CO2 emissions from fossil-fuelled power plants and large industrial source to the atmosphere and thus mitigate climate change. CO2 is captured at the source and transported to subsurface storage sites, such as depleted oil and gas fields or saline aquifers. In order to have an effect on emissions and to be considered safe it is crucial that the amount of CO2 leaking from storage sites to shallow aquifers or the surface remains very low (<1% over 1000 years). Some process that influence the safety of a reservoir, such as CO2-rock-brine interactions, can be studied using experiments on both laboratory and field-scale. However, long-term processes such as the development of leakage pathways can only be understood by either predictive modelling or by studying natural CO2 reservoirs as analogues for long term CO2 storage sites. Natural CO2 reservoirs have similar geological trapping mechanisms as anticipated for CO2 storage sites and often have held CO2 for a geological period of time (millions of years) without any indication for leakage. Yet, migration of CO2 from reservoirs to the surface is also common and evidenced by gas seeps such as springs and soil degassing. We have compiled and analysed a dataset comprising of more than 50 natural CO2 reservoirs from different settings all around the globe to provide an overview of the factors that are important for the retention of CO2 in the subsurface and what processes lead to leakage of CO2 from the reservoir. Initial results indicate that if the reservoir is found to be leaking, CO2 migration is along faults and not through caprock layers. This indicates that faults act as fluid pathways and play an important role when characterizing a storage site. Additionally, it appears that overpressure of the overburden and the state of CO2 in the reservoir influence the likelihood of migration and hence the safety of a reservoir.

  6. Confocal {mu}-XRF, {mu}-XAFS, and {mu}-XRD Studies of Sediment from a Nuclear Waste Disposal Natural Analogue Site and Fractured Granite Following a Radiotracer Migration Experiment

    SciTech Connect

    Denecke, Melissa A.; Brendebach, Boris; Rothe, Joerg; Simon, Rolf; Janssens, Koen; Nolf, Wout de; Vekemans, Bart; Falkenberg, Gerald; Somogyi, Andrea; Noseck, Ulrich

    2007-02-02

    Combined {mu}-XRF, {mu}-XAFS, and {mu}-XRD investigations of a uranium-rich tertiary sediment, from a nuclear repository natural analogue site, and a fractured granite bore core section after a column tracer experiment using a Np(V) containing cocktail have been performed. Most {mu}-XRF/{mu}-XAFS measurements are recorded in a confocal geometry to provide added depth information. The U-rich sediment results show uranium to be present as a tetravalent phosphate and that U(IV) is associated with As(V). Arsenic present is either As(V) or As(0). The As(0) forms thin coatings on the surface of pyrite nodules. A hypothesis for the mechanism of uranium immobilization is proposed, where arsenopyrite acted as reductant of ground water dissolved U(VI) leading to precipitation of less soluble U(IV) and thereby forming As(V). Results for the granite sample show the immobilized Np to be tetravalent and associated with facture material.

  7. Millimeter and Submillimeter Studies of Interstellar Ice Analogues

    NASA Astrophysics Data System (ADS)

    Mesko, AJ; Wagner, Ian C.; Smith, Houston Hartwell; Milam, Stefanie N.; Widicus Weaver, Susanna L.

    2015-06-01

    The chemistry of interstellar ice analogues has been a topic of great interest to astrochemists over the last 20 years. Currently, the models of interstellar chemistry feature icy-grain reactions as a primary mechanism for the formation of many astrochemical species as well as potentially astrobiologically-relevant complex organic molecules. This talk presents new spectral results collected by a millimeter and submillimeter spectrometer coupled to a vacuum chamber designed to study the sublimation or sputtered products of icy-grain reactions initiated by thermal-processing or photo-processing of interstellar ice analogues. Initial results from thermal desorption and UV photoprocessing experiments of pure water ice and water + methanol ice mixtures will be presented.

  8. Scientific results and lessons learned from an integrated crewed Mars exploration simulation at the Rio Tinto Mars analogue site

    NASA Astrophysics Data System (ADS)

    Orgel, Csilla; Kereszturi, kos; Vczi, Tams; Groemer, Gernot; Sattler, Birgit

    2014-02-01

    Between 15 and 25 April 2011 in the framework of the PolAres programme of the Austrian Space Forum, a five-day field test of the Aouda.X spacesuit simulator was conducted at the Rio Tinto Mars-analogue site in southern Spain. The field crew was supported by a full-scale Mission Control Center (MCC) in Innsbruck, Austria. The field telemetry data were relayed to the MCC, enabling a Remote Science Support (RSS) team to study field data in near-real-time and adjust the flight planning in a flexible manner. We report on the experiences in the field of robotics, geophysics (Ground Penetrating Radar) and geology as well as life sciences in a simulated spaceflight operational environment. Extravehicular Activity (EVA) maps had been prepared using Google Earth and aerial images. The Rio Tinto mining area offers an excellent location for Mars analogue simulations. It is recognised as a terrestrial Mars analogue site because of the presence of jarosite and related sulphates, which have been identified by the NASA Mars Exploration Rover "Opportunity" in the El Capitan region of Meridiani Planum on Mars. The acidic, high ferric-sulphate content water of Rio Tinto is also considered as a possible analogue in astrobiology regarding the analysis of ferric sulphate related biochemical pathways and produced biomarkers. During our Mars simulation, 18 different types of soil and rock samples were collected by the spacesuit tester. The Raman results confirm the presence of minerals expected, such as jarosite, different Fe oxides and oxi-hydroxides, pyrite and complex Mg and Ca sulphates. Eight science experiments were conducted in the field. In this contribution first we list the important findings during the management and realisation of tests, and also a first summary of the scientific results. Based on these experiences suggestions for future analogue work are also summarised. We finish with recommendations for future field missions, including the preparation of the experiments, communication and data transfer - as an aid to the planning of future simulations.

  9. Studies on radiolabeled somatostatin analogues in rats and in patients.

    PubMed

    Breeman, W A; Bakker, W H; De Jong, M; Hofland, L J; Kwekkeboom, D J; Kooij, P P; Visser, T J; Krenning, E P

    1996-09-01

    We present the pharmacokinetical aspects of somatostatin receptor scintigraphy in rats with the radioiodinated [Tyr3]octreotide and 111In-labeled [DTPA-D-Phe1]octreotide. The residence time of both radionuclides in somatostatin receptor-positive tissues and tumors is completely different, indicating the difference in metabolism of the two radiopharmaceuticals. The effects of the injected radioactive dose and mass of the radioligand and its injection rate on the biodistribution is intensively studied. We found in rat that the uptake of radioactivity in somatostatin receptor-positive tissues is a bell-shaped function of the injected mass depending on the tissue under study, being optimal between 0.5-5 micrograms. This indicates that the sensitivity of the detection of somatostatin receptor-positive tumor by receptor scintigraphy may be improved by varying the mass of the radiopharmaceutical, which has also been confirmed in patient studies. Priming with somatostatin analogues at various time points relative to the radioligand was studied as well. In all the somatostatin receptor-positive tissues we found a significant change in % injected dose uptake of radioactivity, depending on the ligand, its mass and the tissue under study. This might also be a means to increase the target to background ratio in somatostatin receptor scintigraphy. The possible role of the radiopharmaceutical [111In-DTPA-D-Phe1]RC-160 in somatostatin scintigraphy in visualizing somatostatin receptor-positive tumors that do not bind octreotide, for instance somatostatin receptor subtype 4, is discussed. Internalization of the receptor-ligand and metabolism of the radioiodinated and 111In-labeled somatostatin analogues were studied in vitro and in vivo to get insight into metabolism of the radioligand. Internalization of the radioligand is of special importance when radiotherapy of certain somatostatin receptor-positive human tumors with alpha- or beta-emitting radiolabeled somatostatin analogues is considered. Further, peptide receptor radionuclide therapy with several radionuclides is reviewed. PMID:8961800

  10. Simulation and preparation of surface EVA in reduced gravity at the Marseilles Bay subsea analogue sites

    NASA Astrophysics Data System (ADS)

    Weiss, P.; Gardette, B.; Chiri, B.; Collina-Girard, J.; Delauze, H. G.

    2012-12-01

    Extravehicular activity (EVA) of astronauts during space missions is simulated nowadays underwater in neutral buoyancy facilities. Certain aspects of weightlessness can be reproduced underwater by adding buoyancy to a diver-astronaut, therefore exposing the subject to the difficulties of working without gravity. Such tests were done at the COMEX' test pool in Marseilles in the 1980s to train for a French-Russian mission to the MIR station, for the development of the European HERMES shuttle and the COLUMBUS laboratory. However, space agencies are currently studying missions to other destinations than the International Space Station in orbit, such as the return to the Moon, NEO (near-Earth objects) or Mars. All these objects expose different gravities: Moon has one sixth of Earth's gravity, Mars has a third of Earth's gravity and asteroids have virtually no surface gravity; the astronaut "floats" above the ground. The preparation of such missions calls for a new concept in neutral buoyancy training, not on man-made structures, but on natural terrain, underwater, to simulate EVA operations such as sampling, locomotion or even anchoring in low gravity. Underwater sites can be used not only to simulate the reduced gravity that astronauts will experience during their field trips, also human factors like stress are more realistically reproduced in such environment. The Bay of Marseille hosts several underwater sites that can be used to simulate various geologic morphologies, such as sink-holes which can be used to simulate astronaut descends into craters, caves where explorations of lava tubes can be trained or monolithic rock structures that can be used to test anchoring devices (e.g., near Earth objects). Marseilles with its aerospace and maritime/offshore heritage hosts the necessary logistics and expertise that is needed to perform such simulations underwater in a safe manner (training of astronaut-divers in local test pools, research vessels, subsea robots and submarines). COMEX is currently preparing a space mission simulation in the Marseilles Bay (foreseen in June 2012), and the paper will give an overview of the different underwater analogue sites that are available to the scientific community for the simulation of surface EVA or the test of scientific instruments and devices.

  11. Two Active Site Divalent Ions in the Crystal Structure of the Hammerhead Ribozyme Bound to a Transition State Analogue.

    PubMed

    Mir, Aamir; Golden, Barbara L

    2016-02-01

    The crystal structure of the hammerhead ribozyme bound to the pentavalent transition state analogue vanadate reveals significant rearrangements relative to the previously determined structures. The active site contracts, bringing G10.1 closer to the cleavage site and repositioning a divalent metal ion such that it could, ultimately, interact directly with the scissile phosphate. This ion could also position a water molecule to serve as a general acid in the cleavage reaction. A second divalent ion is observed coordinated to O6 of G12. This metal ion is well-placed to help tune the pKA of G12. On the basis of this crystal structure as well as a wealth of biochemical studies, we propose a mechanism in which G12 serves as the general base and a magnesium-bound water serves as a general acid. PMID:26551631

  12. Rapid on-site detection of ephedrine and its analogues used as adulterants in slimming dietary supplements by TLC-SERS.

    PubMed

    Lv, Diya; Cao, Yan; Lou, Ziyang; Li, Shujin; Chen, Xiaofei; Chai, Yifeng; Lu, Feng

    2015-02-01

    Ephedrine and its analogues are in the list of prohibited substance in adulteration to botanical dietary supplements (BDS) for their uncontrollable stimulating side effects. However, they were always adulterated illegally in BDS to promote losing weight. In order to avoid detection, various kinds of ephedrine analogues were added rather than ephedrine itself. This has brought about great difficulties in authentication of BDS. In this study, we put forward for the first time a method which combined thin-layer chromatography (TLC) and surface-enhanced Raman scattering (SERS) to directly identify trace adulterant. Ephedrine, pseudoephedrine, methylephedrine, and norephedrine were mixed and used in this method to develop ananalytical model. As a result, the four analogues were separated efficiently in TLC analysis, and trace-components and low-background SERS detection was realized. The limit of detection (LOD) of the four analogues was 0.01mg/mL. Eight common Raman peaks (???=?620, 1003, 1030, 1159, 1181, 1205, 1454, 1603cm(-1)) were extracted experimentally and statistically to characterize the common feature of ephedrine analogues. ATLC-SERS method coupled with common-peak model was adopted to examine nine practical samples, two of which were found to be adulterated with ephedrine analogues. Identification results were then confirmed by UPLC-QTOF/MS analysis. The proposed method was simple, rapid, and accurate andcan also be employed to trace adulterant identification even when there are no available reference derivatives on-site or unknown types of ephedrine analogues are adulterated. PMID:25542571

  13. Geochemistry of a continental site of serpentinization, the Tablelands Ophiolite, Gros Morne National Park: A Mars analogue

    NASA Astrophysics Data System (ADS)

    Szponar, Natalie; Brazelton, William J.; Schrenk, Matthew O.; Bower, Dina M.; Steele, Andrew; Morrill, Penny L.

    2013-06-01

    The presence of aqueously altered, olivine-rich rocks along with carbonate on Mars suggest that serpentinization may have occurred in the past and may be occurring presently in the subsurface, and possibly contributing methane (CH4) to the martian atmosphere. Serpentinization, the hydration of olivine in ultramafic rocks, yields ultra-basic fluids (pH ⩾ 10) with unique chemistry (i.e. Ca2+-OH- waters) and hydrogen gas, which can support abiogenic production of hydrocarbons (i.e. Fischer-Tropsch Type synthesis) and subsurface chemosynthetic metabolisms. Mars analogue sites of present-day serpentinization can be used to determine what geochemical measurements are required for determining the source methane at sites of serpentinization on Earth and possibly on Mars. The Tablelands Ophiolite is a continental site of present-day serpentinization and a Mars analogue due to the presence of altered olivine-rich ultramafic rocks with both carbonate and serpentine signatures. This study describes the geochemical indicators of present-day serpentinization as evidenced by meteoric ultra-basic reducing groundwater discharging from ultramafic rocks, and travertine and calcium carbonate sediment, which form at the discharge points of the springs. Dissolved hydrogen concentrations (0.06-1.20 mg/L) and methane (0.04-0.30 mg/L) with δ13CCH4 values (-28.5‰ to -15.6‰) were measured in the spring fluids. Molecular and isotopic analyses of CH4, ethane, propane, butane, pentane and hexane suggest a non-microbial source of methane, and attribute the origin of methane and higher hydrocarbon gases to either thermogenic or abiogenic pathways.

  14. Capsaicin and its analogues: structure-activity relationship study.

    PubMed

    Huang, X-F; Xue, J-Y; Jiang, A-Q; Zhu, H-L

    2013-01-01

    Capsaicin, the main ingredient responsible for the hot pungent taste of chilli peppers, is an alkaloid found in the Capsicum family. Capsaicin was traditionally used for muscular pain, headaches, to improve circulation and for its gastrointestinal protective effects. It was also commonly added to herbal formulations because it acts as a catalyst for other herbs and aids in their absorption. In addition, capsaicin and other capsaicinoid compounds showed strong evidence of having promising potential in the fight against many types of cancer. The mechanism of action of capsaicin has been extensively studied over the past decade. It has been established that capsaicin binds to the transient receptor potential vanilloid 1 receptor which was expressed predominantly by sensory neurons. And many analogues of capsaicin have been synthesized and evaluated for diverse bioactivities. In this review, we will attempt to summarize the biology and structure-activity relationship of capsaicinoids. PMID:23627937

  15. Site-specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity

    PubMed Central

    Gong, Nian; Ma, Ai-Niu; Zhang, Li-Jie; Luo, Xiao-Su; Zhang, Yin-Hui; Xu, Michael; Wang, Yong-Xiang

    2011-01-01

    BACKGROUND AND PURPOSE Exenatide is a 39-amino-acid peptide widely used to manage type 2 diabetes mellitus. However, it has a short plasma half-life and requires a twice daily injection regime. To overcome these drawbacks we used maleimide-polyethylene glycol to induce site-specific PEGylation. EXPERIMENTAL APPROACH The analogue PB-105 (ExC39) was produced by replacing cysteine at position 39 of exenatide to provide a free thiol group. PB-105 showed the same glucoregulatory activity as exenatide in mice. Site-specific PEGylation of PB-105 was performed to produce PB-110 (ExC39PEG5kDa), PB-106 (ExC39PEG20kDa), PB-107 (ExC39PEG30kDa) and PB-108 (ExC39PEG40kDa). Their effects on intracellular cAMP, acute glucoregulatory activity and pharmacokinetic profile were compared in mice and rats. KEY RESULTS PEGylation shifted the concentrationresponse curve of PB-105 to the right in a parallel, polyethylene glycol mass-dependent manner but with an inflexion point of at least 20 kDa. The activities of PB-107 and PB-108 but not PB-106 were reduced by 90% and 99%. PEGylation affected in vivo glucoregulatory activity in the same Inflexion-Shift fashion at least at 20 kDa, but linearly increased plasma duration and systemic exposure without inflexion. PB-106 had a plasma t1/2 approximately 10-fold that of PB-105, and exhibited superior glucoregulatory activity compared with PB-105 in normal and diabetic mice. CONCLUSIONS AND IMPLICATIONS Site-specific PEGylation of exenatide with a permanent amide linkage affects its activity in a new type of Inflexion-Shift fashion. PB-106 is a putative new analogue for treating diabetes; it possesses no loss of in vitro activity, prolonged plasma duration and superior, improved in vivo glucoregulatory activity compared with exenatide. PMID:21244372

  16. Natural analogue studies of the role of colloids, natural organics and microorganisms on radionuclide transport

    SciTech Connect

    McCarthy, J.F.

    1994-10-01

    Colloids may be important as a geochemical transport mechanism for radionuclides at geological repositories if they are (1) present in the groundwater, (2) stable with respect to both colloidal and chemical stabilities, (3) capable of adsorbing radionuclides, especially if the sorption is irreversible, and (4) mobile in the subsurface. The available evidence from natural analogue and other field studies relevant to these issues is reviewed, as is the potential role of mobile microorganisms ({open_quotes}biocolloids{close_quotes}) on radionuclide migration. Studies have demonstrated that colloids are ubiquitous in groundwater, although colloid concentrations in deep, geochemically stable systems may be too low to affect radionuclide transport. However, even low colloid populations cannot be dismissed as a potential concern because colloids appear to be stable, and many radionuclides that adsorb to colloids are not readily desorbed over long periods. Field studies offer somewhat equivocal evidence concerning colloid mobility and cannot prove or disprove the significance of colloid transport in the far-field environment. Additional research is needed at new sites to properly represent a repository far-field. Performance assessment would benefit from natural analogue studies to examine colloid behavior at sites encompassing a suite of probable groundwater chemistries and that mimic the types of formations selected for radioactive waste repositories.

  17. Clearance and early hydrolysis of atrial natriuretic factor in vivo. Structural analysis of cleavage sites and design of an analogue that inhibits hormone cleavage.

    PubMed Central

    Condra, C L; Leidy, E A; Bunting, P; Colton, C D; Nutt, R F; Rosenblatt, M; Jacobs, J W

    1988-01-01

    This study examines the clearance and early hydrolysis of atrial natriuretic factor (ANF) in vivo. Radiolabeled ANF was cleared from the circulation of the rat with biphasic kinetics; the majority (90%) of ANF cleared with a t1/2 of 15 s, the remaining peptide was cleared with a t1/2 of 5 min. Microsequence analysis of ANF peptides recovered from the circulation of rats revealed five major degradation products of the intact hormone. The first cleavage occurred between amino acids 12 and 13 of the hormone and would inactivate ANF. Over time, additional fragments of the hormone were generated, including fragments of 6, 7, 21, and 24 amino acids in length. Whole body radioautography of rats injected with [123I]-ANF revealed the kidney as a predominant organ involved in clearance of ANF. Subsequent amino acid sequence analyses of radiolabeled ANF exposed to the kidney in vivo indicated that this organ generated four of the five major hydrolysis products observed in circulation, namely, the 6, 7, 16, and 21 amino acid fragments of the hormone. In an attempt to stabilize ANF in vivo, a synthetic analogue of the hormone was prepared that contained the amino acid analogue, aminoisobutyric acid, substituted at position 13. This analogue completely abolished the in vivo cleavage of ANF at this site. These studies demonstrate the usefulness of a protein chemistry approach in characterizing hormone metabolism in vivo and designing analogues with enhanced in vivo stability to cleavage. Images PMID:2966813

  18. Bacterial Motility As a Biosignature: Tests at Icy Moon Analogue Sites

    NASA Astrophysics Data System (ADS)

    Nadeau, J. L.; Lindensmith, C.; Deming, J. W.; Stocker, R.; Graff, E.; Serabyn, E.; Wallace, J. K.; Liewer, K.; Kuhn, J.

    2014-12-01

    Extraterrestrial life in our Solar System, if present, is almost certain to be microbial. Methods and technologies for unambiguous detection of living or extinct microorganisms are needed for life-detection missions to the Jovian and Saturnian moons, where liquid water is known to exist. Our research focuses specifically on microbial meaningful motion as a biosignature—"waving crowds" at the micron scale. Digital Holographic Microscopy (DHM) is an excellent tool for unambiguous identification of bacterial and protozoal swimming, even in the presence of turbidity, drift, and currents. The design of a holographic instrument with bacteria scale resolution was described in the previous talk. In this presentation, we will illustrate the design challenges for construction of a field instrument for extreme environments and space, and present plans for scientific investigations at analogue sites for the coming season. The challenges of creating a field instrument involve performance trade-offs, the ability to operate at extreme temperatures, and handling large volumes of data. A fully autonomous instrument without external cables or power is also desirable, and this is something that previous holographic instruments have not achieved. The primary issues for space exploration are identification of a laser and drive electronics that are qualified for the expected radiation environments of the moons around gas giant planets. Tests in Earth analogue environments will establish performance parameters as well as answer scientific questions that traditional microscopic techniques cannot. Specifically, we will visit a Greenland field site to determine whether or not microorganisms are motile within the brine-filled interior network of sea ice, and if they can be autonomously tracked using the instrument. Motility within the liquid phase of a frozen matrix has been hypothesized to explain how bacteria contribute to the biogeochemical signatures detected in ice, but observational evidence of motility in natural samples at subzero temperatures does not exist. Complementing tests for bacterial motility in ice-brines, we will also test for motility in the subzero waters directly beneath the ice, where motility has long been suspected but also never observed.

  19. 2009 Arctic Mars Analogue Svalbard Expedition (AMASE) Evolved Gas Studies

    NASA Astrophysics Data System (ADS)

    Mahaffy, P. R.; McAdam, A.; Eigenbrode, J.; Steele, A.

    2009-12-01

    The Arctic Mars Analogue Svalbard Expedition (AMASE) continued its multi-year campaign in August 2009 to study selected sedimentary and igneous environments in this geological diverse archipelago using a variety of measurement techniques and protocols that are candidates for future Mars missions. The X-ray diffraction mineralogical and evolved gas analysis (EGA) employed during the AMASE-2009 campaign closely mimicked similar experiments that are planned for the 2011 Mars Science Laboratory (MSL). Field instruments similar to those under development for the ESA ExoMars or other rover missions provided imaging, spectroscopic, and subsurface sounding data. A variety of microbiology and field life detection techniques rounded out the AMASE-2009 analytical tools. The evolved gas mass spectrometer utilized on AMASE-2009 was designed to model elements of the Sample Analysis at Mars (SAM) suite of instruments on MSL. Powdered rock samples were heated from ambient to 1000 C in a helium stream and evolved gases continuously analyzed by a mass spectrometer. A continued focus of AMASE-2009 was analysis of carbonates from the Spitsbergen Sverrefjell volcano [1]. The similarity of macromolecular carbon (MMC) associated with magnetite in carbonate globules found in an ice cave in Sverrefjell to those studied in the Mars meteorite ALH84001 has been a motivation for their intensive study. The MMC associated with these carbonates appears to have been formed abiotically [2] following the eruption of the Sverrefjell volcano into glacial ice. The AMASE-2008 EGA studies of microsampled carbonate layers are described and the ability and limitations of these in situ tools to distinguish biomarkers. [1] H. Amundsen, Nature 327, 692-695 (1987). [2] A. Steele et al., Meteoritics and Planetary Science 42, 1549-1566 (2007) Acknowledgement: Support of this work is from the NASA ASTEP program with A. Steele AMASE PI and H. Amundsen Expedition lead.

  20. Synthetic isoprenoid analogues for the study of prenylated proteins: Fluorescent imaging and proteomic applications.

    PubMed

    Wang, Yen-Chih; Distefano, Mark D

    2016-02-01

    Protein prenylation is a posttranslational modification catalyzed by prenyltransferases involving the attachment of farnesyl or geranylgeranyl groups to residues near the C-termini of proteins. This irreversible covalent modification is important for membrane localization and proper signal transduction. Here, the use of isoprenoid analogues for studying prenylated proteins is reviewed. First, experiments with analogues containing small fluorophores that are alternative substrates for prenyltransferases are described. Those analogues have been useful for quantifying binding affinity and for the production of fluorescently labeled proteins. Next, the use of analogues that incorporate biotin, bioorthogonal groups or antigenic moieties is described. Such probes have been particularly useful for identifying proteins that are naturally prenylated within mammalian cells. Overall, the use of isoprenoid analogues has contributed significantly to the understanding of protein prenlation. PMID:26709869

  1. Multipurpose ligand, DAKLI (Dynorphin A-analogue Kappa LIgand), with high affinity and selectivity for dynorphin (. kappa. opioid) binding sites

    SciTech Connect

    Goldstein, A.; Nestor, J.J. Jr.; Naidu, A.; Newman, S.R. )

    1988-10-01

    The authors describe a synthetic ligand, DALKI (Dynorphin A-analogue Kappa LIgand), related to the opioid peptide dynorphin A. A single reactive amino group at the extended carboxyl terminus permits various reporter groups to be attached, such as {sup 125}I-labeled Bolton-Hunter reagent, fluorescein isothiocyanate, or biotin. These derivatives have high affinity and selectivity for the dynorphin ({kappa} opioid) receptor. An incidental finding is that untreated guinea pig brain membranes have saturable avidin binding sites.

  2. Emotions and Habitability study in Moon Mars Analogue.

    NASA Astrophysics Data System (ADS)

    Mertens, Alexandre; Lia Schlacht, Irene

    Euro Moon Mars mission have been conducted by students and field researchers in the Mars Desert Research Station (MDRS) a habitat installed by the Mars Society (MS) in the Utah desert. The campaign was supported by ILEWG International Lunar Exploration Working Group, ESTEC, NASA Ames, and partners. It investigated human aspects of isolation in a Mars analogue base. The project is in line with the ILEWG which coordinates several MDRS missions, and contributes to the preparation of future Mars sample return missions. The objective is to study and improve the habitat dynamics in a closed and small environment. Investigation cover different fields as emotional, sociological and psychological aspects and a food study but also habitability aspects. The study has been conducted by asking to the crew members to perform task and fill in questionnaires before, during and after the simulation. Video recovering, pictures and heart rate counting will also be used. One of the main study subject, conducted by Bernard Rimé, concerns the sharing of emotions in an isolated environ-e ment. Another is "Mars Habitability Experiment", which responsible is Irene Schlacht, will try to determine whether humans need variability of stimuli such as it happens in the natural environment -e.g. seasonal changing -to gain efficiency, reliability and well-being. This study have been conducted from February 19 to April 19 on two crews presenting different aspects that could lead to various behaviours. The first crew is made of people from different countries that don't know each other very well. On the opposite, the second crew members have the same cultural background -they come from the same country, university -and they know each other for at least six months. This allow studying how the extreme conditions of the isolation affect the crew efficiency, creativity and sanity according to its homogeneity. Report on the science and technical results, and implications for Earth-Mars comparative stud-ies, will be present. Main co-sponsors (SKOR, ILEWG, ESA ESTEC, COSPAR, DAAD, MARS SOCIETY).

  3. Probing the bacteriochlorophyll binding site by reconstitution of the light-harvesting complex of Rhodospirillum rubrum with bacteriochlorophyll a analogues

    SciTech Connect

    Parkes-Loach, P.S.; Bass, W.J.; Loach, P.A. ); Michalski, T.J.; Smith, U. )

    1990-03-27

    Structural features of bacteriochlorophyll (BChl) a that are required for binding to the light-harvesting proteins of Rhodospirillum rubrum were determined by testing for reconstitution of the B873 or B820 (structural subunit of B873) light-harvesting complexes with BChl a analogues. The results indicate that the binding site is very specific; of the analogues tested, only derivatives of BChl a with ethyl, phytyl, and geranylgeranyl esterifying alcohols and BChl b (phytyl) successfully reconstituted to form B820-and B873-type complexes. BChl analogues lacking magnesium, the C-3 acetyl group, or the C13{sup 2} carbomethoxy group did not reconstitute to form B820 or B873. Also unreactive were 13{sup 2}-hydroxy BChl a and 3-acetylchlorophyll a. Competition experiments showed that several of these nonreconstituting analogues significantly slowed BChl a binding to form B820 and blocked BChl a-B873 formation, indicating that the analogues may competitively bind to the protein even though they do not form red-shifted complexes. With the R. rubrum polypeptides, BChl b formed complexes that were further red-shifted than those of BChl a; however, the energies of the red shifts, binding behavior, and circular dichroism (CD) spectra were similar. B873 complexes reconstituted with the geranylgeranyl BChl a derivative, which contains the native esterifying alcohol for R. rubrum, showed in-vivo-like CD features, but the phytyl and ethyl B873 complexes showed inverted CD features in the near infrared. The B820 complex with the ethyl derivative was about 30-fold less stable than the two longer esterifying alcohol derivatives, but all formed stable B873 complexes.

  4. Natural analogue studies as supplements to biomineralization research

    SciTech Connect

    McNeil, M.B.

    1995-09-01

    Chemical reactions can alter the chemistry and crystal structure of solid objects over archeological or geological times, while preserving external physical shapes. The reactions resulting in these structures offer natural analogues to laboratory experiments in biomineralization and to biologically influenced alteration of nuclear waste packages, and thus, they offer the only available way of validating models that purport waste package behavior over archaeological or geological times. Potential uses of such analogues in the construction and validation of hypothetical mechanisms of microbiological corrosion and biomineralization are reviewed. Evidence from such analogues suggests that biofilms can control materials alteration in ways usually overlooked. The newly hypothesized mechanisms involve control by biofilms of the cation flow near the solid surface and offer plausible mechanisms for the formation of mixed-cation minerals under conditions that would lead to dealloying in abiotic experiments; they also account for the formation of unusual minerals [such as posnjakite, Cu{sub 4}SO{sub 4}(OH){sub 6{center_dot}}H{sub 2}O] and mineral morphologies unusual in corrosion [malachite, Cu{sub 2}CO{sub 3}(OH){sub 2}, rarely forms botryoidally under corrosion conditions and its occasional presence on archaeological objects that appear to have undergone microbiological corrosion may be related to biofilm phenomena].

  5. Martian Feeling: An Analogue Study to Simulate a Round-Trip to Mars using the International Space Station

    NASA Astrophysics Data System (ADS)

    Felix, C. V.; Gini, A.

    When talking about human space exploration, Mars missions are always present. It is clear that sooner or later, humanity will take this adventure. Arguably the most important aspect to consider for the success of such an endeavour is the human element. The safety of the crew throughout a Martian mission is a top priority for all space agencies. Therefore, such a mission should not take place until all the risks have been fully understood and mitigated. A mission to Mars presents unique human and technological challenges in terms of isolation, confinement, autonomy, reliance on mission control, communication delays and adaptation to different gravity levels. Analogue environments provide the safest way to simulate these conditions, mitigate the risks and evaluate the effects of long-term space travel on the crew. Martian Feeling is one of nine analogue studies, from the Mars Analogue Path (MAP) report [1], proposed by the TP Analogue group of ISU Masters class 2010. It is an integrated analogue study which simulates the psychological, physiological and operational conditions that an international, six-person, mixed gender crew would experience on a mission to Mars. Set both onboard the International Space Station (ISS) and on Earth, the Martian Feeling study will perform a ``dress rehearsal'' of a mission to Mars. The study proposes to test both human performance and operational procedures in a cost-effective manner. Since Low Earth Orbit (LEO) is more accessible than other space-based locations, an analogue studies in LEO would provide the required level of realism to a simulated transit mission to Mars. The sustained presence of microgravity and other elements of true spaceflight are features of LEO that are neither currently feasible nor possible to study in terrestrial analogue sites. International collaboration, economics, legal and ethical issues were considered when the study was proposed. As an example of international collaboration, the ISS would demonstrate an effective model for an international effort to send humans to Mars. The proposed starting date is the year 2017, before the planned retirement of the ISS, which is currently scheduled for 2020.

  6. 3CAPS – a structural AP–site analogue as a tool to investigate DNA base excision repair

    PubMed Central

    Schuermann, David; Scheidegger, Simon P.; Weber, Alain R.; Bjørås, Magnar; Leumann, Christian J.; Schär, Primo

    2016-01-01

    Abasic sites (AP-sites) are frequent DNA lesions, arising by spontaneous base hydrolysis or as intermediates of base excision repair (BER). The hemiacetal at the anomeric centre renders them chemically reactive, which presents a challenge to biochemical and structural investigation. Chemically more stable AP-site analogues have been used to avoid spontaneous decay, but these do not fully recapitulate the features of natural AP–sites. With its 3′–phosphate replaced by methylene, the abasic site analogue 3CAPS was suggested to circumvent some of these limitations. Here, we evaluated the properties of 3CAPS in biochemical BER assays with mammalian proteins. 3CAPS-containing DNA substrates were processed by APE1, albeit with comparably poor efficiency. APE1-cleaved 3CAPS can be extended by DNA polymerase β but repaired only by strand displacement as the 5′–deoxyribophosphate (dRP) cannot be removed. DNA glycosylases physically and functionally interact with 3CAPS substrates, underlining its structural integrity and biochemical reactivity. The AP lyase activity of bifunctional DNA glycosylases (NTH1, NEIL1, FPG), however, was fully inhibited. Notably, 3CAPS-containing DNA also effectively inhibited the activity of bifunctional glycosylases on authentic substrates. Hence, the chemically stable 3CAPS with its preserved hemiacetal functionality is a potent tool for BER research and a potential inhibitor of bifunctional DNA glycosylases. PMID:26733580

  7. 3CAPS - a structural AP-site analogue as a tool to investigate DNA base excision repair.

    PubMed

    Schuermann, David; Scheidegger, Simon P; Weber, Alain R; Bjørås, Magnar; Leumann, Christian J; Schär, Primo

    2016-03-18

    Abasic sites (AP-sites) are frequent DNA lesions, arising by spontaneous base hydrolysis or as intermediates of base excision repair (BER). The hemiacetal at the anomeric centre renders them chemically reactive, which presents a challenge to biochemical and structural investigation. Chemically more stable AP-site analogues have been used to avoid spontaneous decay, but these do not fully recapitulate the features of natural AP-sites. With its 3'-phosphate replaced by methylene, the abasic site analogue 3CAPS was suggested to circumvent some of these limitations. Here, we evaluated the properties of 3CAPS in biochemical BER assays with mammalian proteins. 3CAPS-containing DNA substrates were processed by APE1, albeit with comparably poor efficiency. APE1-cleaved 3CAPS can be extended by DNA polymerase β but repaired only by strand displacement as the 5'-deoxyribophosphate (dRP) cannot be removed. DNA glycosylases physically and functionally interact with 3CAPS substrates, underlining its structural integrity and biochemical reactivity. The AP lyase activity of bifunctional DNA glycosylases (NTH1, NEIL1, FPG), however, was fully inhibited. Notably, 3CAPS-containing DNA also effectively inhibited the activity of bifunctional glycosylases on authentic substrates. Hence, the chemically stable 3CAPS with its preserved hemiacetal functionality is a potent tool for BER research and a potential inhibitor of bifunctional DNA glycosylases. PMID:26733580

  8. Pharmacokinetic studies of amino acid analogues of 2-nitroimidazole, new hypoxic cell radiosensitizers

    SciTech Connect

    Agrawal, K.C.; Larroquette, C.A.; Garg, P.K.

    1984-08-01

    A series of new analogues of 2-nitroimidazole has been synthesized by inserting various amino acids at 1-position through an amide bond. The ethyl esters were found to be the most effective radiosensitizers in vitro against hypoxic Chinese hamster (V-79) cells. However, the free acid of phenylalanine analogue was less active as a radiosensitizer and required 5 mM concentration to produce SER of 1.9. In contrast, the free acid of tyrosine analogue was inactive in this test system. The pharmacokinetic studies with the esters revealed their rapid hydrolysis in serum to the corresponding acids within 5 minutes as detected by HPLC. The pharmacokinetic parameters were therefore determined by employing the free acid analogues and solubilizing them as their sodium salts. The drugs were administered intraperitoneally at 0.5 mg/g dose level to C-57 mice bearing B16 melanoma. Peak tumor concentration of approximately 217 ug/g was achieved within 15 min with phenylalanine analogue. The tumor to brain ratio was 10:1 suggesting that this agent is excluded from CNS and that the phenylalanine analogue should be considered a potentially less neurotoxic radiosensitizer than misonidazole.

  9. Model Membrane and Cell Studies of Antimicrobial Activity of Melittin Analogues.

    PubMed

    Jamasbi, Elaheh; Mularski, Anna; Separovic, Frances

    2016-01-01

    Melittin is a 26 residue peptide and the major component of bee (Apis mellifera) venom. Although melittin has both anticancer and antimicrobial properties, utilization has been limited due to its high lytic activity against eukaryotic cells. The mechanism of this lytic activity remains unclear but several mechanisms have been proposed, including pore formation or a detergent like mechanism, which result in lysis of cell membranes. Several analogues of melittin have been synthesized to further understand the role of specific residues in its antimicrobial and lytic activity. Melittin analogues that have a proline residue substituted for an alanine, lysine or cysteine have been studied with both model membrane systems and living cells. These studies have revealed that the proline residue plays a critical role in antimicrobial activity and cytotoxicity. Analogues lacking the proline residue and dimers of these analogues displayed decreased cytotoxicity and minimum inhibition concentrations. Several mutant studies have shown that, when key substitutions are made, the resultant peptides have more activity in terms of pore formation than the native melittin. Designing analogues that retain antimicrobial and anticancer activity while minimizing haemolytic activity will be a promising way to utilize melittin as a potential therapeutic agent. PMID:26139117

  10. Characterization and comparison of perezone with some analogues. Experimental and theoretical study

    NASA Astrophysics Data System (ADS)

    Escobedo-González, Rene Gerardo; Bahena, Luis; Arias Tellez, José Luis; Hinojosa Torres, Jaime; Ruvalcaba, Rene Miranda; Aceves-Hernández, Juan Manuel

    2015-10-01

    Perezone had been used for centuries in the traditional Mexican medicine, it is useful and a handful of illness. Perezone and other derivatives also present activity against certain lines of cancer, such as the myeloblastoid leukemia cell line K-562 and carcinoma cell lines (PC-3 and SKLU-1) with IC50 <10 μM. Perezone and isoperezone have shown the major cytotoxic potency. Characterization of perezone was carried out by UV-Visible, IR, DSC, TGA and powder X-ray diffraction, as well as docking studies using caspase-3 structures as receptors. Theoretical studies for optimizing the geometry of perezone were carried out and the results compared with values of single crystal X-ray diffraction. The experimental values of atomic distances, angles and dihedral angles are in good agreement with the theoretical values. Interaction of perezone with the cysteine catalytic site with the caspase-3 was found in the docking studies. A docking study of perezone, with horminone, thymoquinone and isoperezone as ligands and the protein apoptein, caspase-3 as receptor, was carried to demonstrate that the hindrance steric factor, chemical structure and the functional groups are important in the biological activity of these natural products. The docking score energetic values are in good agreement with the experimental cytotoxic results obtained from the experiments when perezone and analogues were studied in different types of cancer.

  11. Natural Analogue Synthesis Report

    SciTech Connect

    A. M. Simmons

    2002-05-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the ''Yucca Mountain Site Description'' (CRWMS M and O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport, impact of radionuclide release on the biosphere, and potentially disruptive events. Results of these studies will be used to corroborate estimates of the magnitude and limitation of operative processes in order to build realism into conceptual and numerical process models used as a foundation for PA in the representative case of postclosure safety.

  12. Optimization of Spin-Unrestricted Density Functional Theory for Redox Properties of Rubredoxin Redox Site Analogues

    SciTech Connect

    Niu, Shuqiang; Nichols, Jeffery A.; Ichiye, Toshiko

    2009-05-01

    Systematic studies of the accuracy of density functional theory (DFT) methods, especially the recently developed hybrid generalized gradient approximation (GGA) functionals, for structural and energetic properties of iron-sulfur redox sites are essential before these methods can be used to answer important biological questions about these systems. Here, the geometries, electronic structures, and reduction potentials of redox site analogs of the iron-sulfur protein rubredoxin are investigated using DFT (B3LYP, B97gga1 and BHandH), the Moller-Plesset perturbation theory series (MP2, MP3, MP4SDQ), and coupled cluster (CCSD, CCSD(T)) methods. For the geometries of [Fe(SCH3)4]2-/1- and [Fe(SCH3)3]1-/0, the DFT optimizations give reasonable values and the inclusion of a core electron basis substantially reduces the errors in the calculated geometries. However, for the vertical detachment energy (VDE) and adiabatic detachment energy (ADE) of [Fe(SCH3)4]1- and [Fe(SCH3)3]1-, the B3LYP functional gives the most accurately computed ADE and VDE using DFT, which are comparable with those at the CCSD level of theory. When diffuse functions are added to the sulfur basis set, they have little effect on the geometry optimization but significantly improve the calculated VDE and ADE, which is important for the anionic reduced sites. When multiple polarization functions are added to the sulfur basis set, they lead to a slightly better description of the geometry by giving more angular flexibility but underestimate ADE and VDE, most likely due to overestimating the stabilizing energy of the oxidized sites. Overall, the B3LYP calculations with the more flexible full-core basis sets give a reasonable description both of the geometry and of the ADE and VDE. Thus, improving the basis sets seems to be an efficient and convenient way to obtain reliable reduction potentials of the high-spin iron-sulfur redox sites.

  13. Engineering Silicone Rubbers for In vitro Studies: Creating AAA Models and ILT Analogues with Physiological Properties

    PubMed Central

    Corbett, T.J.; Doyle, B.J.; Callanan, A.; Walsh, M.T.; McGloughlin, T.M

    2010-01-01

    Background In vitro studies of abdominal aortic aneurysm (AAA) have been widely reported. Frequently mock artery models with intraluminal thrombus (ILT) analogues are used to mimic the AAA in vivo. While the models used may be physiological, their properties are frequently either not reported or investigated. Method of Approach This study is concerned with the testing and characterisation of previously used vessel analogue materials and the development of new materials for the manufacture of AAA models. These materials were used in conjunction with a previously validated injection moulding technique to manufacture AAA models of ideal geometry. To determine the model properties (stiffness (?) and compliance) the diameter change of each AAA model was investigated under incrementally increasing internal pressures and compared to published in vivo studies to determine if the models behaved physiologically. A FEA study was implemented to determine if the pressure diameter change behaviour of the models could be predicted numerically. ILT analogues were also manufactured and characterised. Ideal models were manufactured with ILT analogue internal to the aneurysm region and the effect of the ILT analogue on the model compliance and stiffness was investigated. Results The wall materials had similar properties to aortic tissue at physiological pressures (Einit 2.22MPa and 1.57MPa (aortic tissue: 1.8MPa)). ILT analogues had similar Youngs modulus to the medial layer of ILT (0.24 and 0.33MPa (ILT: 0.28MPa)). All models had aneurysm sac compliance in the physiological range (2.62 8.0110-4/mmHg (AAA in vivo: 1.8 9.410-4/mmHg)). The necks of our AAA models had similar stiffness to healthy aortas (20.44 29.83 (healthy aortas in vivo: 17.55.5)). Good agreement was seen between the diameter changes due to pressurisation in the experimental and FEA wall models with a maximum error of 7.3% at 120mmHg. It was also determined that the inclusion of ILT analogue in the sac of our models could have an effect on the compliance of the model neck. Conclusions Ideal AAA models with physiological properties were manufactured. The behaviour of these models due to pressurisation was predicted using FEA, validating this technique for the future design of realistic, physiological AAA models. Addition of ILT analogues in the aneurysm sac was shown to affect neck behaviour. This could have implications for endovascular AAA repair due to the importance of the neck for stent-graft fixation. PMID:20524746

  14. The interaction of new piroxicam analogues with lipid bilayers--a calorimetric and fluorescence spectroscopic study.

    PubMed

    Maniewska, Jadwiga; Szcz??niak-Si?ga, Berenika; Po?a, Andrzej; Sroda-Pomianek, Kamila; Malinka, Wies?aw; Michalak, Krystyna

    2014-01-01

    The purpose of the present paper was to assess the ability of new piroxicam analogues to interact with the lipid bilayers. The results of calorimetric and fluorescence spectroscopic experiments of two new synthesized analogues of piroxicam, named PR17 and PR18 on the phase behavior of phospholipid bilayers and fluorescence quenching of fluorescent probes (Laurdan and Prodan), which molecular location within membranes is known with certainty, are shown in present work. The presented results revealed that, depending on the details of chemical structure, the studied compounds penetrated the lipid bilayers. PMID:25856831

  15. A natural analogue for high-level waste in tuff: Chemical analysis and modeling of the Valles site

    SciTech Connect

    Stockman, H.W.; Krumhansl, J.L.; Ho, C.K.; Kovach, L.; McConnell, V.S.

    1995-03-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a high-level waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock Tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, x-ray diffraction, and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 40}Ar isotopic composition. Overall, the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 m of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  16. Human insulin analogues modified at the B26 site reveal a hormone conformation that is undetected in the receptor complex

    SciTech Connect

    Žáková, Lenka; Kletvíková, Emília; Lepšík, Martin; Collinsová, Michaela; Watson, Christopher J.; Turkenburg, Johan P.; Jiráček, Jiří; Brzozowski, Andrzej M.

    2014-10-01

    [AsnB26]- and [GlyB26]-insulin mutants attain a B26-turn like fold without assistance of chemical modifications. Their structures match the insulin receptor interface and expand the spectrum of insulin conformations. The structural characterization of the insulin–insulin receptor (IR) interaction still lacks the conformation of the crucial B21–B30 insulin region, which must be different from that in its storage forms to ensure effective receptor binding. Here, it is shown that insulin analogues modified by natural amino acids at the TyrB26 site can represent an active form of this hormone. In particular, [AsnB26]-insulin and [GlyB26]-insulin attain a B26-turn-like conformation that differs from that in all known structures of the native hormone. It also matches the receptor interface, avoiding substantial steric clashes. This indicates that insulin may attain a B26-turn-like conformation upon IR binding. Moreover, there is an unexpected, but significant, binding specificity of the AsnB26 mutant for predominantly the metabolic B isoform of the receptor. As it is correlated with the B26 bend of the B-chain of the hormone, the structures of AsnB26 analogues may provide the first structural insight into the structural origins of differential insulin signalling through insulin receptor A and B isoforms.

  17. Chalcone based azacarboline analogues as novel antitubulin agents: design, synthesis, biological evaluation and molecular modelling studies.

    PubMed

    Sharma, Sahil; Kaur, Charanjit; Budhiraja, Abhishek; Nepali, Kunal; Gupta, Manish K; Saxena, A K; Bedi, P M S

    2014-10-01

    The present study involves the design of a series of 3-aryl-9-acetyl-pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The results indicated that 2a, 3a, 5a and 6a possessed significant cytotoxic potential with an IC50 value ranging from 1.13 to 5.76?M. Structure activity relationship revealed that the nature of both Ring A and Ring B influences the activity. Substitution of methoxy groups on the phenyl ring (Ring A) and unsubstituted phenyl ring (Ring B) were found to be the preferred structural features. The most potent compound 2a was further tested for tubulin inhibition. Compound 2a was found to significantly inhibit the tubulin polymerization (IC50 value - 2.41?M against THP-1). Compound 2a also caused disruption of microtubule assembly as evidenced by Immunoflourescence technique. The significant cytotoxicity and tubulin inhibition by 2a was rationalized by molecular modelling studies. The most potent structure was docked at colchicine binding site (PDB ID-1SA0) and was found to be stabilized in the cavity via various hydrophobic and hydrogen bonding interactions. PMID:25128667

  18. Attributions about Perpetrators and Victims of Interpersonal Abuse: Results from an Analogue Study

    ERIC Educational Resources Information Center

    Langhinrichsen-Rohling, Jennifer; Shlien-Dellinger, Rania K.; Huss, Matthew T.; Kramer, Vertrie L.

    2004-01-01

    This analogue study (written vignettes and videotapes) examines the influence of victim-perpetrator relationship (spouse or acquaintance), sex of perceiver, and type of abuse (psychological vs. physical) on attributions about victims and perpetrators of domestic abuse. College student participants (73 men, 108 women) were randomly assigned to

  19. A photoactive isoprenoid diphosphate analogue containing a stable phosphonate linkage: synthesis and biochemical studies with prenyltransferases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A number of biochemical processes rely on isoprenoids, including the post-translational modification of signaling proteins and the biosynthesis of a wide array of compounds. Photoactivatable analogues have been developed to study isoprenoid utilizing enzymes such as the isoprenoid synthases and pren...

  20. A Comprehensive Imaging and Raman Spectroscopy Study of ALH84001 and a Terrestrial Analogue from Svalbard

    NASA Astrophysics Data System (ADS)

    Steele, A.; Fries, M.; Amundsen, H. E. F.; Mysen, B.; Fogel, M.; Schweizer, M.; Boctor, N. Z.

    2006-03-01

    We have undertaken a comprehensive Raman microprobe study of a depth profile of ALH84001 and a terrestrial analogue. We find that ALH84001 globules contain hematite as well as magnetite. Macromolecular carbon is always associated with magnetite both in the carbonates and in the bulk matrix.

  1. Characterization of U-series disequilibria at the Pena Blanca natural analogue site, Chihuahua, Mexico

    SciTech Connect

    Wong, V.; Goodell, P.C.; Anthony, E.Y.

    1999-07-01

    The purpose of this study was to evaluate radionuclide migration from a uranium-mineralized breccia pipe. The site provides an excellent opportunity to evaluate radionuclide mobility in a geochemical environment similar to that around the proposed high-level waste repository at Yucca Mountain, Nevada. Samples represent fracture-infillings from both within and outside the breccia pipe. Mineral assemblages within the fractures include (1) pure kaolinite, (2) a mixture of iron-oxyhydroxides (goethite and hematite) with associated alunite and jarosite, which the authors refer to as the Fe-mineral assemblage, and (3) carbonates. Uranophane, weeksite, soddyite, and boltwoodite are associated with samples from within the breccia zone. The authors obtain radionuclide activities from gamma-ray rather than alpha spectroscopy, and the methodology for these measurements is presented in detail. Plots of {sup 230}Th/{sup 238}U vs. {sup 226}Ra/{sup 230}Th show three distinct mobility trends. (1) The majority of the Fe-mineral samples from within the breccia pipe yield values between 1.0 and 1.1 for both ratios, (2) Fe-mineral samples from outside the ore zone and a kaolinite from within the ore zone have {sup 230}Th/{sup 238}U of 0.58 to 0.83 and {sup 226}Ra/{sup 230}Th of 1.09 to 1.42, and (3) some Fe-mineral samples from within the breccia pipe have values of 1.2 and 0.9 respectively. These data, combined with those from other studies at Pena Blanca suggest that U and Ra are sometimes mobile in the near-surface environment and that multiple episodes of enrichment and leaching are required to explain the trends.

  2. XAFS And Molecular Dynamics Study of Natural Minerals, Analogues of Ceramics for Nuclear Waste Storage

    SciTech Connect

    Harfouche, M.; Farges, F.; Crocombette, J.P.; Flank, A.M.; /SLAC, SSRL

    2006-10-27

    Natural actinides (U and Th) are harmful for the crystalline structure of natural minerals, due to their irradiation. Natural minerals can then become amorphous to x-ray diffraction ('metamict') after being irradiated throughout a long period of time (10{sup 8} years). Then, they are used as natural analogues of ceramics for nuclear waste storage. XAFS studies were performed in zircon, monazite and titanite to understand the effect of radiation damage on the local structure around Th, U, Zr and P and compared to available molecular dynamics (MD) simulations. In zircon, a local expansion around actinides (when substituting for Zr) is found. The radial expansion is a function of the metamictisation degree: up to {approx}4 {angstrom} in crystalline zircon and larger in the metamict counterparts. Ab-initio calculations (FEFF7) were performed around Zr ({approx}23000 sites) and around U (1000 to 3000 sites) in various crystalline and alpha-decay damaged zircon MD simulations. The calculated averaged EXAFS spectra confirms this expansion, which validates the use of the potentials used in the simulations as well as the alpha decay damage model considered in these MD simulations. Tetravalent actinides were found to be 8-coordinated in the undamaged structure, whereas their coordination drops to 7 in the damaged structures. In contrast to zircon, no local expansion around actinides in monazite was detected, despite some polymerization around P is measured (related to radiation damage). Finally, in some phases (such as titanite), actinides are found as oxyde-type clusters (ThO{sub 2}, UO{sub 2}). Consequently, actinides do not 'systematically' substitute for major actions in these structure, in contrast to the common belief in mineralogy.

  3. Des analogues naturels de sites de stockage de dchets nuclaires vieux de 2 milliards d'annes : les racteurs de fission nuclaire naturels du Gabon (Afrique)

    NASA Astrophysics Data System (ADS)

    Gauthier-Lafaye, Franois

    2002-10-01

    Two billion years ago, the increase of oxygen in atmosphere and the high 235U/ 238U uranium ratio (>3%) made possible the occurrence of natural nuclear reactors on Earth. These reactors are considered to be a good natural analogue for nuclear waste disposal. Their preservation during such a long period of time is mainly due to the geological stability of the site, the occurrence of clays surrounding the reactors and acting as an impermeable shield, and the occurrence of organic matter that maintained the environment in reducing conditions, favourable for the stability of uraninite. Hydrogeochemical studies and modelling have shown the complexity of the geochemical system at Oklo and Bangomb (Gabon) and the lack of precise data about uranium and fission products retention and migration mechanisms in geological environments. To cite this article: F. Gauthier-Lafaye, C. R. Physique 3 (2002) 839-849.

  4. Import of amber and ochre suppressor tRNAs into mammalian cells: A general approach to site-specific insertion of amino acid analogues into proteins

    PubMed Central

    Khrer, Caroline; Xie, Liang; Kellerer, Susanne; Varshney, Umesh; RajBhandary, Uttam L.

    2001-01-01

    A general approach to site-specific insertion of amino acid analogues into proteins in vivo would be the import into cells of a suppressor tRNA aminoacylated with the analogue of choice. The analogue would be inserted at any site in the protein specified by a stop codon in the mRNA. The only requirement is that the suppressor tRNA must not be a substrate for any of the cellular aminoacyltRNA synthetases. Here, we describe conditions for the import of amber and ochre suppressor tRNAs derived from Escherichia coli initiator tRNA into mammalian COS1 cells, and we present evidence for their activity in the specific suppression of amber (UAG) and ochre (UAA) codons, respectively. We show that an aminoacylated amber suppressor tRNA (supF) derived from the E. coli tyrosine tRNA can be imported into COS1 cells and acts as a suppressor of amber codons, whereas the same suppressor tRNA imported without prior aminoacylation does not, suggesting that the supF tRNA is not a substrate for any mammalian aminoacyltRNA synthetase. These results open the possibility of using the supF tRNA aminoacylated with an amino acid analogue as a general approach for the site-specific insertion of amino acid analogues into proteins in mammalian cells. We discuss the possibility further of importing a mixture of amber and ochre suppressor tRNAs for the insertion of two different amino acid analogues into a protein and the potential use of suppressor tRNA import for treatment of some of the human genetic diseases caused by nonsense mutations. PMID:11717406

  5. Perspective of Using the Results of Monitoring and Modeling of the Chernobyl Nuclear Power Plant's Cooling Pond as Analogue for the US DOE Contaminated Sites

    NASA Astrophysics Data System (ADS)

    Faybishenko, B.; Voitsekhovich, O. V.; Bugay, D.; Skalskjj, A.; Shestopalov, V. M.; Zheleznyak, M.; Kashparov, V. A.; Antropov, A. S.; Kireev, S. I.; Bondarkov, M. D.; Ivanov, Y.; Oskolkov, B.; Marra, J.; Jannik, T.; Farfan, E.; Monken-Fernandes, H.; Hinton, T.; Smith, J.; Onishi, Y.; Konoplev, A.

    2010-12-01

    Although there are many contaminated sites that may be suitable candidates for providing analogue information for the development and testing of environmental modeling and risk assessment approaches, of particular scientific and practical interests is the feasibility study of planned decommissioning and remediation of the highly contaminated Chernobyl Cooling Pond (CP), located within the Chernobyl Exclusion Zone (ChEZ). The presence of the CP has caused an artificially high groundwater table within the ChEZ. After the planned cessation of water pumping from the Pripyat River to the CP, substantial areas of sediments, containing 137Cs, 90Sr, and hot particles with U, Pu, and Am. will be exposed to the atmosphere, and the groundwater level is expected to decline by as much as 7 m. The areal extent of the exposed zone, the dissolution rate, mobility and bioavailability of radionuclides will vary over time, depending on the dynamics of seepage losses from the pond and climatic conditions. The objective of the presentation is to discuss hydrological and geochemical processes, a conceptual model, and the results and perspectives of numerical modeling of coupled surface water-groundwater flow and transport, including the parameter estimation and uncertainty evaluation for various decommissioning and remediation options of the CP. In particular, the results of 1D, 2D, and 3D simulations of radionuclide transport in surface water and groundwater will be discussed, along with the evaluation of Kd parameters from the results of field monitoring and modeling of seasonal variations of 137Cs concentrations in pond water and sediments. It will be shown that the results of field monitoring and modeling of the Chernobyl CP can be used as analogue for several US DOE sites to improve scientific and practical understanding of subsurface hydrological and geochemical processes, as well as to obtain a better understanding of processes affecting natural attenuation of radionuclides in soils and groundwater.

  6. A Spectral, Chemical and Mineralogical Study of Mars Analogue Rocks

    NASA Technical Reports Server (NTRS)

    Bishop, J. L.; Pieters, C. M.; Dyar, M. D.; Hamilton, V. E.; Harloff, J.

    2002-01-01

    The macroscopic and microscopic properties of basaltic and andesitic rocks are under study for integration of diverse spectroscopic approaches to evaluate the composition and texture of Mars materials using both in situ and remote sensing techniques. Additional information is contained in the original extended abstract.

  7. Characterization of electronic structure and physicochemical properties of antiparasitic nifurtimox analogues: A theoretical study

    NASA Astrophysics Data System (ADS)

    Soriano-Correa, Catalina; Raya, A.; Esquivel, Rodolfo O.

    American trypanosomiasis, also known as Chagas' disease, is caused by Trypanosoma cruzi (T. cruzi). It is well known that trypanosomes, and particularly T. cruzi, are highly sensitive towards oxidative stress, i.e., to compounds than are able to produce free radicals. Generally, nifurtimox (NFX) and benznidazol are most effective in the acute phase of the disease; therefore, nitroheterocycles constitute good models to design other nitrocompounds with specific biological characteristics. Thus, we have performed an ab initio study at the Hartree-Fock and Density Functional Theory levels of theory of several NFX analogues recently synthesized, to characterize them by obtaining their electronic, structural, and physicochemical properties, which might be linked to the observed antichagasic activity. The antitrypanosomal activity scale previously reported for the NFX analogues studied in this work is in good agreement with our theoretical results, from which we can conclude that the activity seems to be related to the reactivity along with the acidity observed for the most active molecules.

  8. Planetary habitability: lessons learned from terrestrial analogues

    NASA Astrophysics Data System (ADS)

    Preston, Louisa J.; Dartnell, Lewis R.

    2014-01-01

    Terrestrial analogue studies underpin almost all planetary missions and their use is essential in the exploration of our Solar system and in assessing the habitability of other worlds. Their value relies on the similarity of the analogue to its target, either in terms of their mineralogical or geochemical context, or current physical or chemical environmental conditions. Such analogue sites offer critical ground-truthing for astrobiological studies on the habitability of different environmental parameter sets, the biological mechanisms for survival in extreme environments and the preservation potential and detectability of biosignatures. The 33 analogue sites discussed in this review have been selected on the basis of their congruence to particular extraterrestrial locations. Terrestrial field sites that have been used most often in the literature, as well as some lesser known ones which require greater study, are incorporated to inform on the astrobiological potential of Venus, Mars, Europa, Enceladus and Titan. For example, the possibility of an aerial habitable zone on Venus has been hypothesized based on studies of life at high-altitudes in the terrestrial atmosphere. We also demonstrate why many different terrestrial analogue sites are required to satisfactorily assess the habitability of the changing environmental conditions throughout Martian history, and recommend particular sites for different epochs or potential niches. Finally, habitable zones within the aqueous environments of the icy moons of Europa and Enceladus and potentially in the hydrocarbon lakes of Titan are discussed and suitable analogue sites proposed. It is clear from this review that a number of terrestrial analogue sites can be applied to multiple planetary bodies, thereby increasing their value for astrobiological exploration. For each analogue site considered here, we summarize the pertinent physiochemical environmental features they offer and critically assess the fidelity with which they emulate their intended target locale. We also outline key issues associated with the existing documentation of analogue research and the constraints this has on the efficiency of discoveries in this field. This review thus highlights the need for a global open access database for planetary analogues.

  9. QM/MM study of dehydro and dihydro β-ionone retinal analogues in squid and bovine rhodopsins: implications for vision in salamander rhodopsin.

    PubMed

    Sekharan, Sivakumar; Altun, Ahmet; Morokuma, Keiji

    2010-11-17

    Visual pigment rhodopsin provides a decisive crossing point for interaction between organisms and environment. Naturally occurring visual pigments contain only PSB11 and 3,4-dehydro-PSB11 as chromophores. Therefore, the ability of visual opsin to discriminate between the retinal geometries is investigated by means of QM/MM incorporation of PSB11, 6-s-cis and 6-s-trans forms of 3,4-dehydro-PSB11, and 3,4-dehydro-5,6-dihydro-PSB11 and 5,6-dihydro-PSB11 analogues into squid and bovine rhodopsin environments. The analogue-protein interaction reveals the binding site of squid rhodopsin to be malleable and ductile, while that of bovine rhodopsin is rigid and stiff. On the basis of these studies, a tentative model of the salamander rhodopsin binding site is also proposed. PMID:20964383

  10. Structure-activity relationship studies on cholecystokinin: Analogues with partial agonist activity

    SciTech Connect

    Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. )

    1988-02-01

    In the present study, hepta- and octapeptide analogues of the C-terminal part of cholecystokinin, modified on the C-terminal phenylalanine residue, were synthesized. CCK analogues were prepared in which the peptide bond between aspartic acid and phenylalanine had or had not been modified and were lacking the C-terminal primary amide function. These CCK derivatives were able to cause full stimulation of amylase release from rat pancreatic acini but without a decrease in amylase release at supramaximal concentrations. There was a close relationship between the abilities of these derivatives to stimulate amylase release and their abilities to inhibit binding of {sup 125}I-BH-CCK-9 to CCK receptors on rat and guinea pig pancreatic acini. These CCK analogues were also able to recognize the guinea pig brain CCK receptors, some of them being particularly potent. The findings indicate that the aromatic ring of phenylalanine is important for the binding to brain and pancreatic CCK receptors, whereas the C-terminal primary amide function is not essential for the binding to pancreatic CCK receptors but is crucial for biological activity of rat pancreatic acini.

  11. Comparison of shallow aquifer and soil gas monitoring approaches for detecting CO2 leakage at a natural analogue site in France

    NASA Astrophysics Data System (ADS)

    Widory, D.; Gal, F.; Proust, E.; Mayer, B.

    2011-12-01

    Natural analogue sites where geologic CO2 is leaking to the surface provide excellent opportunities to test approaches suitable for monitoring for potential CO2 leakage at carbon capture and storage sites. We tested isotope monitoring approaches for CO2 detection in shallow aquifers and the overlying soil zone at a CO2 analogue site near Sainte-Marguerite in the Massif Central (France). The Sainte-Marguerite area is located in the southern part of the Limagne graben (French Massif Central). The basement, composed of highly fractured granite, outcrops toward the west of the study area, notably around the Saladis spring. An intercalated arkosic permeable interval between fractured granite and Oligocene marls and limestones acts as a stratiform drain for fluid migration while the overlying thick Oligocene interval is impermeable and acts as a seal. The Allier river bed is located near the contact between the basement and the sedimentary rocks. Deep CO2-ladden fluids migrate through the arkose interval toward the Sainte-Marguerite area and sustain a number of local springs. The Sainte-Marguerite area is known for the travertine deposits associated with the CO2-rich natural springs. We collected water samples and effervescent gases at the springs as well as soil gases for chemical and isotopic analyses. The analytical parameters included major anions and cations, δ13C & δ18O of CO2, δD & δ18O of H2O and δ13C of dissolved inorganic carbon (DIC). Preliminary results revealed that δ13C values of CO2 in most groundwater and soil samples were similar. Oxygen isotope measurements revealed equilibrium between CO2 and H2O-oxygen in most samples, but except for a limited number of samples, δ18O values of water did not deviate significantly from the local meteoric water line. Our preliminary results suggest that both the groundwater and the soil sampling approaches should be capable of detecting leakage of CO2 provided that the leaking gas has a distinct isotopic composition. The thresholds of leakage detection are currently determined in laboratory column experiments, where CO2 of known isotopic composition is bubbled through a water-saturated sand at different rates and continuously measured for its δ13C and δ18O isotope composition using laser spectroscopy. The potential for isotope exchange between oxygen from water and oxygen from bubbling CO2 is also evaluated.

  12. Novobiocin Analogues That Inhibit the MAPK Pathway.

    PubMed

    Hall, Jessica A; Seedarala, Sahithi; Zhao, Huiping; Garg, Gaurav; Ghosh, Suman; Blagg, Brian S J

    2016-02-11

    Heat shock protein 90 (Hsp90) inhibition by modulation of its N- or C-terminal binding site has become an attractive strategy for the development of anticancer chemotherapeutics. The first Hsp90 C-terminus inhibitor, novobiocin, manifested a relatively high IC50 value of ?700 ?M. Therefore, investigation of the novobiocin scaffold has led to analogues with improved antiproliferative activity (nanomolar concentrations) against several cancer cell lines. During these studies, novobiocin analogues that do not inhibit Hsp90 were identified; however, these analogues demonstrated potent antiproliferative activity. Compound 2, a novobiocin analogue, was identified as a MAPK pathway signaling disruptor that lacked Hsp90 inhibitory activity. In addition, structural modifications of compound 2 were identified that segregated Hsp90 inhibition from MAPK signaling disruption. These studies indicate that compound 2 represents a novel scaffold for disruption of MAPK pathway signaling and may serve as a useful structure for the generation of new anticancer agents. PMID:26745854

  13. Interactions of taurine and structurally related analogues with the GABAergic system and taurine binding sites of rabbit brain

    PubMed Central

    Frosini, Maria; Sesti, Casilde; Dragoni, Stefania; Valoti, Massimo; Palmi, Mitri; Dixon, Henry B F; Machetti, Fabrizio; Sgaragli, Giampietro

    2003-01-01

    The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [3H]muscimol. Saturation experiments of the binding of [3H]GABA to GABAB receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [3H]taurine in a saturable manner (Kd=249.0±6.3 nM and Bmax=3.4±1.0 pmol mg−1 prot). Among the 19 structural analogues of taurine, 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (TAG), 2-aminoethylarsonic (AEA), 2-hydroxyethanesulfonic (ISE) and (±)cis-2-aminocyclohexane sulfonic acids (CAHS) displaced [3H]taurine binding (Ki=0.13, 0.13, 13.5 and 4.0 μM, respectively). These analogues did not interact with GABAA and GABAB receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 3-Aminopropanesulfonic acid (OMO), β-alanine, pyridine-3-sulfonic acid, N,N,N-trimethyltaurine (TMT), 2-(guanidino)ethanesulfonic acid (GES), ethanolamine-O-sulphate, N,N-dimethyltaurine (DMT), taurine and (±)piperidine-3-sulfonic acid (PSA) inhibited [3H]muscimol binding to GABAA receptors with different affinities (Ki=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 μM, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [3H]GABA to GABAB receptors with Ki's in the μM range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC50=3.72 μM) and PSA GABA transaminase activity (IC50=103.0 μM). In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents. PMID:12684273

  14. Use of a 'caged' analogue to study the traffic of choline within acetylcholinesterase by kinetic crystallography.

    PubMed

    Colletier, Jacques-Philippe; Royant, Antoine; Specht, Alexandre; Sanson, Benot; Nachon, Florian; Masson, Patrick; Zaccai, Giuseppe; Sussman, Joel L; Goeldner, Maurice; Silman, Israel; Bourgeois, Dominique; Weik, Martin

    2007-11-01

    Acetylcholinesterase plays a crucial role in nerve-impulse transmission at cholinergic synapses. The apparent paradox that it displays high turnover despite its active site being buried raises cogent questions as to how the traffic of substrates and products to and from the active site can occur so rapidly in such circumstances. Here, a kinetic crystallography strategy aimed at structurally addressing the issue of product traffic in acetylcholinesterase is presented, in which UV-laser-induced cleavage of a photolabile precursor of the enzymatic product analogue arsenocholine, 'caged' arsenocholine, is performed in a temperature-controlled X-ray crystallography regime. The 'caged' arsenocholine was shown to bind at both the active and peripheral sites of acetylcholinesterase. UV irradiation of a complex with acetylcholinesterase during a brief temperature excursion from 100 K to room temperature is most likely to have resulted in a decrease in occupancy by the caged compound. Microspectrophotometric experiments showed that the caged compound had indeed been photocleaved. It is proposed that a fraction of the arsenocholine molecules released within the crystal had been expelled from both the active and the peripheral sites. Partial q-weighted difference refinement revealed a relative movement of the two domains in acetylcholinesterase after photolysis and the room-temperature excursion, resulting in an increase in the active-site gorge volume of 30% and 35% in monomers A and B of the asymmetric unit, respectively. Moreover, an alternative route to the active-site gorge of the enzyme appeared to open. This structural characterization of acetylcholinesterase 'at work' is consistent with the idea that choline exits from the enzyme after catalysis either via the gorge or via an alternative 'backdoor' trajectory. PMID:18007027

  15. Synthesis of diosgenin analogues as potential anti-inflammatory agents.

    PubMed

    Singh, Monika; Hamid, A A; Maurya, Anil K; Prakash, Om; Khan, Feroz; Kumar, Anant; Aiyelaagbe, O O; Negi, Arvind S; Bawankule, Dnyaneshwar U

    2014-09-01

    We herein report the synthesis of diosgenin analogues from commercially available diosgenin as the starting material. The structures of newly synthesised compounds were confirmed by (1)H NMR, (13)C NMR and mass spectrometry. All analogues were evaluated for in-vitro anti-inflammatory profile against LPS-induced inflammation in primary peritoneal macrophages isolated from mice by quantification of pro-inflammatory (TNF-?, IL-6 and IL-1?) cytokines in cell culture supernatant using the ELISA technique followed by in-vitro cytotoxicity study. Among the synthesised analogues, analogue 15 [(E) 26-(3',4',5'-trimethoxybenzylidene)-furost-5en-3?-acetate)] showed significant anti-inflammatory activity by inhibiting LPS-induced pro-inflammatory cytokines in a dose-dependent manner without any cytotoxicity. Efficacy and safety of analogue 15 were further validated in an in-vivo system using LPS-induced sepsis model and acute oral toxicity in mice. Oral administration of analogue 15 inhibited the pro-inflammatory cytokines in serum, attenuated the liver and lung injury and reduced the mortality rate in sepsis mice. Acute oral toxicity study showed that analogue 15 is non-toxic at higher dose in BALB/c mice. Molecular docking study revealed the strong binding affinity of diosgenin analogues to the active site of the pro-inflammatory proteins. These findings suggested that analogue 15 may be a useful therapeutic candidate for the treatment of inflammatory diseases. PMID:24816230

  16. Laboratory studies of Mercury analogue materials: optical spectroscopy and space weathering simulation experiments

    NASA Astrophysics Data System (ADS)

    Moroz, Lyuba; Helbert, Jorn; Maturilli, Alessandro; Sasaki, Sho; Bischoff, Addi

    MERTIS (Mercury Thermal Infrared Imaging Spectrometer) is a part of ESA's BepiColombo mission payload and will map Mercury's surface from 7 to 14 µm with high spatial resolution. To support MERTIS and for cross-calibration with other instruments onboard BepiColombo (SYMBIO-SYS) and MESSENGER (MASCS) spacecraft, we compiled a list of Mercury analogue materials (Helbert et al., 2007, Adv. Space. Res. 40, p. 272-279). The list currently includes plagioclase and potassium feldspars, low Ca and high Ca pyroxenes, forsterite, elemental sulfur and an Apollo 16 lunar highland soil. For the spectral studies we prepared size fractions of ¡25, 25-63, 63-125, and 125-250 µm (except for the lunar soil). The samples were characterized in terms of chemical composition, mineralogy, and grain size distribution. Here we report the results of spectral reflectance measurements of these analogues from 0.5 to 18 µm. We compare the TIR reflectance spectra of the samples to their emissivity spectra from Berlin Emissivity Database (Maturilli et al., 2008, Planet. Space. Sci. 56, p. 420-425) to evaluate deviations from Kirchhoff's law for biconical reflectance. In addition, we report on a space weathering simulation experiment on plagioclase, and discuss future laboratory studies needed to support space missions to Mercury.

  17. Isolation of nucleotide binding site-leucine rich repeat and kinase resistance gene analogues from sugarcane (Saccharum spp.)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Resistance gene analogues (RGAs) offer great potential to breeding for disease resistance through marker assisted selection, either as closely linked markers or through candidate gene approaches. Many R-gene sequences contain kinase domains and indeed kinase genes have been reported as being proxim...

  18. Synthesis and polymerase-mediated bypass studies of the N2-deoxyguanosine DNA damage caused by a lucidin analogue.

    PubMed

    Ghodke, Pratibha P; Harikrishna, S; Pradeepkumar, P I

    2015-02-20

    Lucidin is a genotoxic and mutagenic hydroxyanthraquinone metabolite, which originates from the roots of Rubia tinctorum L. (madder root). It reacts with exocyclic amino groups of DNA nucleobases and forms adducts/lesions leading to carcinogenesis. To study the effect of lucidin-induced DNA damage, herein, we report the first synthesis of a structural analogue of lucidin [N(2)-methyl-(1,3-dimethoxyanthraquinone)-deoxyguanosine, LdG] embedded DNAs utilizing phosphoramidite strategy. LdG modification in a DNA duplex imparts destabilization (?Tm ?5 C/modification), which is attributed to the unfavorable contribution from the enthalpy. Primer extension studies using the Klenow fragment (exo(-)) of Escherichia coli DNA polymerase I demonstrate that bypass of LdG modification is error prone as well as slow compared to that across the unmodified sites. Molecular dynamics simulations of the binary complex of Bacillus fragment polymerase (homologue of the Klenow fragment) and LdG-DNA duplex elucidate the structural fluctuations imparted by the LdG lesion, as well as the molecular mechanism of bypass at the lesion site. Overall, the results presented here show that the lucidin adduct destabilizes DNA structure and reduces fidelity and processivity of DNA synthesis. PMID:25574682

  19. Study by electronic circular dichroism spectroscopy of the interaction between aminooxy analogues of biogenic polyamines and selected oligonucleotides

    NASA Astrophysics Data System (ADS)

    Ruiz-Chica, A. J.; Medina, M. A.; Snchez-Jimnez, F.; Ramrez, F. J.

    2005-06-01

    The interaction between a series of aminooxy analogues of the biogenic polyamines spermine and spermidine and selected 15-mer oligodeoxyribonucleotides with alternating purine-pyrimidine base sequences, adenine-thymine (AT) and guanine-cytosine (GC), has been studied using electronic circular dichroism (CD) spectroscopy. These analogues resulted from the substitution of the two terminal aminomethylene groups of the polyamines, -CH 2NH 2+, by an aminooxy one, -ONH 2. Since spermidine has no centre of symmetry, it gives rise to two different isosteric molecules, which have been named AOEPUT and APAPA. On the contrary, spermine gives rise to a single aminooxy analogue, named as AOSPM. As the p Ka of an aminooxy group (about 5) is not high enough to be protonated at a neutral pH, these analogues have a positive charge less than the corresponding polyamine under physiological settings, which makes them suitable models to investigate the roles of the charge and the structure in the polyamine-DNA interaction. At low pH values, both the biogenic polyamine and their aminooxy analogues have a similar positive charge. The CD spectra of solutions containing different concentrations of the three aminooxy analogues and a 15-mer oligonucleotide, containing either the GC or the AT sequence, at a fixed concentration 60 ?M in phosphate, were recorded. Solutions at pH values 7.5 and 5.0 were studied in order to investigate the role of the molecular charge. The spectra demonstrated that the interaction of these oligonucleotides with the aminooxy analogues had a significant sequence-selectivity. Spectra of the oligonucleotides in the presence of AOSMP showed two isodicroic points, thus indicating the presence of different oligonucleotide conformations in solution. The CD spectra of AOEPUT and APAPA supported the non-equivalent role that the outer ammonium groups of spermidine, N1 and N8 positions, could have in the interaction of this biogenic polyamine with DNA.

  20. Biological synthesis of a protein analogue of acetylcholinesterase: Monoclonal anti-idiotype antibody analogue of the esteratic site. Annual report, 15 May 1983-14 May 1984

    SciTech Connect

    August, J.T.

    1984-07-10

    The goal of this research during the first year of the contract was to develop a method for the purification of human erythrocyte acetylcholinesterase and to initiate the preparation and analysis of monoclonal antibodies. This was accomplished by the preparation of red blood cell membrane ghosts, enzyme solubilization with a non-ionic detergent, and enzyme purification by monoclonal antibody affinity chromatography. Sixty ml of packed red blood cells yielded a final fraction of 750 micrograms. approximately 20,000-fold purified. The purified fraction contained a single protein of about 75,000 daltons that was labeled with 3H-diisopropylfluorophosphate and gave a single peak during high-performance liquid chromatography on a TSK-SW3000 silica-enzyme for the preparation of monoclonal antibodies. anti-cholinesterase, anti-active site, and anti-idiotype monoclonal antibodies have been developed.

  1. VNIR spectroscopy of the Atacama salars: An analogue study for Mars evaporate deposits

    NASA Astrophysics Data System (ADS)

    Flahaut, J.; Martinot, M.; Potts, N. J.; Davies, G. R.

    2015-10-01

    A high priority for determining the past habitability of Mars includes identification and characterization of hydrated minerals within ancient Martian aqueous environments. Sulfates, found in a variety of hydrous environments on Earth, can aide our understanding of past Martian environments if their context can be constrained. In the present study, we combine both spaceborne (Landsat, Hyperion) and field (ASDinc FieldSpec) VNIR observations to study the mineralogy of various sulfate-rich salt flats (salars) in the Atacama desert region of Chile as an analogue for Nartian evaporites. There is good agreement between remote sensing and field observations on the major classes of minerals present in the salars and their spatial distribution, that are easily identified from VNIR spectroscopic data.

  2. Curcumin in cancer management: recent results of analogue design and clinical studies and desirable future research.

    PubMed

    Steward, William P; Gescher, Andreas J

    2008-09-01

    The ability of the curry constituent curcumin to delay the onset of cancer has been the topic of extensive research for many years. Abundant literature is devoted to mechanisms by which curcumin may mediate this activity. These insights have prompted investigations in which curcumin as lead molecule serves as a scaffold for synthetic chemical attempts to optimize pharmacological potency. Among the published analogues with notable efficacy are dimethylcurcumin, 1,5-bis(3-pyridyl)-1,4-pentadien-3-one and 3,5-bis-(2-fluorobenzylidene)-piperidinium-4-one acetate. Results of a small number of clinical pilot studies conducted with curcumin at doses of up to 12 g suggest tentatively that it is safe in humans. Prevention of adenoma recurrence constitutes a clinical paradigm worthy of further investigation for curcumin. Future clinical study should include measurement of mechanism-based pharmacodynamic parameters. PMID:18186103

  3. A study of tumour growth based on stoichiometric principles: a continuous model and its discrete analogue

    PubMed Central

    Saleem, M.; Agrawal, Tanuja; Anees, Afzal

    2014-01-01

    In this paper, we consider a continuous mathematically tractable model and its discrete analogue for the tumour growth. The model formulation is based on stoichiometric principles considering tumour-immune cell interactions in potassium (K +)-limited environment. Our both continuous and discrete models illustrate cancer immunoediting as a dynamic process having all three phases namely elimination, equilibrium and escape. The stoichiometric principles introduced into the model allow us to study its dynamics with the variation in the total potassium in the surrounding of the tumour region. It is found that an increase in the total potassium may help the patient fight the disease for a longer period of time. This result seems to be in line with the protective role of the potassium against the risk of pancreatic cancer as has been reported by Bravi et al. [Dietary intake of selected micronutrients and risk of pancreatic cancer: An Italian case-control study, Ann. Oncol. 22 (2011), pp. 202206]. PMID:24963981

  4. Social Studies. [SITE 2002 Section].

    ERIC Educational Resources Information Center

    2002

    This document contains the following papers on social studies from the SITE (Society for Information Technology & Teacher Education) 2002 conference: (1) "Technology Portfolios in Pre-Service Social Studies Teacher Education" (Marsha Alibrandi); (2) "North Carolina's Sixth Graders Go to Russia: A Global Education/Curriculum Integration Project

  5. Towards peakless, reproducible and long-acting insulins. An assessment of the basal analogues based on isoglycaemic clamp studies.

    PubMed

    Heise, T; Pieber, T R

    2007-09-01

    While the advantages of the two basal insulin analogues, glargine and detemir, over neutral protamine Hagedorn are well established, the relative merit of the two compared with each other has been a matter of some controversy. The two analogues are popularly perceived to differ from each other in their pharmacodynamic (PD) profiles, in particular with regard to 'flatness' and duration of action. The aim of this review, therefore, is to give a complete overview on the available PD data of both analogues as derived with the glucose clamp technique. In order to improve parity across studies, a common definition for duration of action (time from injection to plasma glucose >8.3 mmol/l) was applied and study data were recalculated when necessary. Despite differences in methodological details, the results of most clamp studies were very consistent. Glargine and detemir both typically show a gentle rise and fall in glucose-lowering action over time. Duration of action with both analogues is dose dependent, but in the clinically relevant range of 0.35-0.8 U/kg it is close to 24 h in people with type 1 diabetes and in excess of this in people with type 2 diabetes. While both analogues seem to be very similar with regard to the mean shape of their PD profile and duration of action, detemir shows less within-subject variability in its metabolic effect. These findings in experimental glucose clamp studies are consistent with observations in clinical trials and support routine once daily use with either analogue, in particular in people with type 2 diabetes. PMID:17645556

  6. Simulation of traumatic brain injury symptoms on the Personality Assessment Inventory: an analogue study.

    PubMed

    Keiski, Michelle A; Shore, Douglas L; Hamilton, Joanna M; Malec, James F

    2015-04-01

    The purpose of this study was to characterize the operating characteristics of the Personality Assessment Inventory (PAI) validity scales in distinguishing simulators feigning symptoms of traumatic brain injury (TBI) while completing the PAI (n = 84) from a clinical sample of patients with TBI who achieved adequate scores on performance validity tests (n = 112). The simulators were divided into two groups: (a) Specific Simulators feigning cognitive and somatic symptoms only or (b) Global Simulators feigning cognitive, somatic, and psychiatric symptoms. The PAI overreporting scales were indeed sensitive to the simulation of TBI symptoms in this analogue design. However, these scales were less sensitive to the feigning of somatic and cognitive TBI symptoms than the feigning of a broad range of cognitive, somatic, and emotional symptoms often associated with TBI. The relationships of TBI simulation to consistency and underreporting scales are also explored. PMID:24965838

  7. New Insights into Nisin's Antibacterial Mechanism Revealed by Binding Studies with Synthetic Lipid II Analogues.

    PubMed

    't Hart, Peter; Oppedijk, Sabine F; Breukink, Eefjan; Martin, Nathaniel I

    2016-01-12

    Nisin is the preeminent lantibiotic, and to date its antibacterial mechanism has been investigated using a variety of techniques. While nisin's lipid II-mediated mode of action is well-established, a detailed analysis of the thermodynamic parameters governing this interaction has not been previously reported. We here describe an approach employing isothermal titration calorimetry to directly measure the affinity of nisin for lipid II and a number of synthetic lipid II precursors and analogues. Our measurements confirm the pyrophosphate unit of lipid II as the primary site of nisin binding and also indicate that the complete MurNAc moiety is required for a high-affinity interaction. Additionally, we find that while the pentapeptide unit of the lipid II molecule is not required for strong binding by nisin, it does play an important role in stabilizing the subsequently formed nisin-lipid II pore complex, albeit at an entropic cost. The anchoring of lipid II in a membrane environment was also found to play a significant role in enhancing nisin binding and is required in order to achieve a high-affinity interaction. PMID:26653142

  8. Mauna Kea, Hawaii as an Analogue Site for Future Planetary Resource Exploration: Results from the 2010 ILSO-ISRU Field-Testing Campaign

    NASA Technical Reports Server (NTRS)

    ten Kate, I. L.; Armstrong, R.; Bernhardt, B.; Blummers, M.; Boucher, D.; Caillibot, E.; Captain, J.; Deleuterio, G.; Farmer, J. D.; Glavin, D. P.; Hamilton, J. C.; Klingelhoefer, G.; Morris, R. V.; Nunez, J. I.; Quinn, J. W.; Sanders, G. B.; Sellar, R. G.; Sigurdson, L.; Taylor, R.; Zacny, K.

    2010-01-01

    Within the framework of the International Lunar Surface Operation - In-Situ Resource Utilization Analogue Test held on January 27 - February 11, 2010 on the Mauna Kea volcano in Hawaii, a number of scientific instrument teams collaborated to characterize the field site and test instrument capabilities outside laboratory environments. In this paper, we provide a geological setting for this new field-test site, a description of the instruments that were tested during the 2010 ILSO-ISRU field campaign, and a short discussion for each instrument about the validity and use of the results obtained during the test. These results will form a catalogue that may serve as reference for future test campaigns. In this paper we provide a description and regional geological setting for a new field analogue test site for lunar resource exploration, and discuss results obtained from the 2010 ILSO-ISRU field campaign as a reference for future field-testing at this site. The following instruments were tested: a multispectral microscopic imager, MMI, a Mossbauer spectrometer, an evolved gas analyzer, VAPoR, and an oxygen and volatile extractor called RESOLVE. Preliminary results show that the sediments change from dry, organic-poor, poorly-sorted volcaniclastic sand on the surface, containing basalt, iron oxides and clays, to more water- and organic-rich, fine grained, well-sorted volcaniclastic sand, primarily consisting of iron oxides and depleted of basalt and clays. Furthermore, drilling experiments showed a very close correlation between drilling on the Moon and drilling at the test site. The ILSO-ISRU test site was an ideal location for testing strategies for in situ resource exploration at the lunar or martian surface.

  9. Selection of Actinide Chemical Analogues for WIPP Tests: Potential Nonradioactive Sorbing and Nonsorbing Tracers for Study of Ion Transport in the Environment

    SciTech Connect

    Dale Spall; Robert Villarreal

    1998-08-01

    Chemical characteristics of the actinides (Th, U, Np, Pu, Am) have been studied relative to nonradioactive chemical elements that have similar characteristics in an attempt to identify a group of actinide chemical analogues that are nonradioactive. In general, the chemistries of the actinides, especially U, Np, Pu, and Am, are very complex and attempts to identify a single chemical analogue for each oxidation state were not successful. However, the rationale for selecting a group of chemical analogues that would mimic the actinides as a group is provided. The categorization of possible chemical analogues (tracers) with similar chemical properties was based on the following criteria. Categorization was studied according.

  10. Deception island, Antarctica: a terrestrial analogue for the study and understanding of the martian permafrost and subsurface glaciers

    NASA Astrophysics Data System (ADS)

    Hernandez de Pablo, M. A.; Ramos, M.; Vieira, G.; Gilichinsky, D.; Gmez, F.; Molina, A.; Segovia, R.

    2009-04-01

    The existence of permafrost on Mars was widely studied since Viking era and its presence is fundamental in the understanding of the water-cycle, the geological history of Mars, and the evolution of the martian hydrosphere. Viking, MOC, THEMIS, HRSC and HiRISE images allowed increase our knowledge about the role of ice on the martian landscapes. Polygonal terrains, glacial-like features, "basketball terrain" or pingos are some of the landforms that reveal the existence of frozen ice near the surface and in the ground forming the martian permafrost on present, recent or ancient times. The field observations and analyses done by Phoenix mission seem to confirm the existence of the martian permafrost hypothesized by the analyses of the images acquired by the previous missions to Mars. Moreover, the recent interpretations of the (RADAR) sensor on board of MRO mission also revealed that the surface of Mars seems to cover an important volume of ice forming glaciers covered by different materials. Here we propose the study of the glaciers and permafrost of Deception Island (Antarctica) such as a terrestrial analogue of the glaciers and permafrost of Mars. This active volcanic island is an exceptional site to study the permafrost since the climatic conditions maintain the surface covered by the ice and snow during the main part of the year. This characteristic allows the existence of an important permafrost layer also during the summer, and permanent glaciers in the higher part of the island. In addition, Deception Island is an active volcano. Some of the glaciers are covered by the ash and tephra what made difficult to distinguish between the covered glacier and the permafrost. The eruptive volcanic materials could have similar characteristics than some martian regolith by lithology, granulometry and texture. In this way, the study of the permafrost and glaciers in Deception Island could help to understand the martian permafrost and glaciers at present. On the other hand, the objectives of our Antarcti research program in this island include some activities focused on drill shallow and depth (about 25 m) boreholes to extract ice-rich permafrost cores that will be analyzed to study the habitability on the permafrost. Results of these analyses could also used in astrobiological studies of the martian permafrost. In this work we show the most important characteristics of glaciers and permafrost in Deception Island, and some possible analogues from Mars.

  11. Synthesis, biological activity, and conformational study of N-methylated allatostatin analogues inhibiting juvenile hormone biosynthesis.

    PubMed

    Xie, Yong; Zhang, Li; Zhang, Chuanliang; Wu, Xiaoqing; Deng, Xile; Yang, Xinling; Tobe, Stephen S

    2015-03-25

    An allatostatin (AST) neuropeptide mimic (H17) is a potential insect growth regulator, which inhibits the production of juvenile hormone (JH) by the corpora allata. To determine the effect of conformation of novel AST analogues and their ability to inhibit JH biosynthesis, eight insect AST analogues were synthesized using H17 as the lead compound by N-methylation scanning, which is a common strategy for improving the biological properties of peptides. A bioassay using JH production by corpora allata of the cockroach Diploptera punctata indicated that single N-methylation mimics (analogues 1-4) showed more activity than double N-methylation mimics (analogues 5-8). Especially, analogues 1 and 4 showed roughly equivalent activity to that of H17, with IC50 values of 5.17 10(-8) and 6.44 10(-8) M, respectively. Molecular modeling based on nuclear magnetic resonance data showed that the conformation of analogues 1 and 4 seems to be flexible, whereas analogues 2 and 3 showed a type IV ?-turn. This flexible linear conformation was hypothesized to be a new important and indispensable structural element beneficial to the activity of AST mimics. PMID:25751662

  12. Mars Analog Site Study (MASS)

    NASA Technical Reports Server (NTRS)

    Greeley, R.; Kuzmin, R.; Costard, F.; Anderson, F. S.; Geringer, M. A.; Landheim, R.; Wenrich, M. L.

    1993-01-01

    Many proposed missions to Mars involve landing vehicles, including the Mars 94/96 (Russia), Mars Environmental Survey (MESUR, US), and the Marsnet (ESA) missions. Most landers involve in situ measurements of rock and soil compositions, study of local geology by imaging, and establishment of seismic and meteorological networks. The selection of landing sites on Mars is a complex process that must meet engineering constraints and scientific objectives, using available and anticipated data. The goal of the MASS project is to conduct an 'end-to-end' test of the site selection process using Earth analogs.

  13. Study of a CCP RF Dusty Plasma for the Production of Titan's Aerosols Analogues

    SciTech Connect

    Alcouffe, G.; Cernogora, G.; Ouni, F.; Correia, J. J.; Cavarroc, M.; Boufendi, L.; Szopa, C.

    2008-09-07

    The CCP-RF discharge PAMPRE experiment produces analogues of Titan's aerosols. Here are presented the plasma characteristics as a function of gas mixtures and dust formation. Electronic density, optical emission spectroscopy, and self-bias voltage measurements are presented.

  14. Structure-activity studies on the anti-proliferation activity of ajoene analogues in WHCO1 oesophageal cancer cells.

    PubMed

    Kaschula, Catherine H; Hunter, Roger; Stellenboom, Nashia; Caira, Mino R; Winks, Susan; Ogunleye, Thozama; Richards, Philip; Cotton, Jonathan; Zilbeyaz, Kani; Wang, Yabing; Siyo, Vuyolwethu; Ngarande, Ellen; Parker, M Iqbal

    2012-04-01

    The organosulfur compound ajoene derived from the rearrangement of allicin found in crushed garlic can inhibit the proliferation of tumour cells by inducing G(2)/M cell cycle arrest and apoptosis. We report on the application of a concise four-step synthesis (Hunter etal., 2008 [1]) that allows access to ajoene analogues with the end allyl groups substituted. A library of twelve such derivatives tested for their anti-proliferation activity against WHCO1 oesophageal cancer cells has identified a derivative containing p-methoxybenzyl (PMB)-substituted end groups that is twelve times more active than Z-ajoene, with an IC(50) of 2.1?M (Kaschula etal., 2011 [2]). Structure-activity studies involving modification of the sulfoxide and vinyl disulfide groups of this lead have revealed that the disulfide is the ajoene pharmacophore responsible for inhibiting WHCO1 cell growth, inducing G(2)/M cell cycle arrest and apoptosis by caspase-3 activation, and that the vinyl group serves to enhance the anti-proliferation activity a further eightfold. Reaction of the lead with cysteine in refluxing THF as a model reaction for ajoene's mechanism of action based on a thiol/disulfide exchange reveals that the allylic sulfur of the vinyl disulfide is the site of thiol attack in the exchange. PMID:22381354

  15. Measuring Fast-Temporal Sediment Fluxes with an Analogue Acoustic Sensor: A Wind Tunnel Study

    PubMed Central

    Poortinga, Ate; van Minnen, Jan; Keijsers, Joep; Riksen, Michel; Goossens, Dirk; Seeger, Manuel

    2013-01-01

    In aeolian research, field measurements are important for studying complex wind-driven processes for land management evaluation and model validation. Consequently, there have been many devices developed, tested, and applied to investigate a range of aeolian-based phenomena. However, determining the most effective application and data analysis techniques is widely debated in the literature. Here we investigate the effectiveness of two different sediment traps (the BEST trap and the MWAC catcher) in measuring vertical sediment flux. The study was performed in a wind tunnel with sediment fluxes characterized using saltiphones. Contrary to most studies, we used the analogue output of five saltiphones mounted on top of each other to determine the total kinetic energy, which was then used to calculate aeolian sediment budgets. Absolute sediment losses during the experiments were determined using a balance located beneath the test tray. Test runs were conducted with different sand sizes and at different wind speeds. The efficiency of the two traps did not vary with the wind speed or sediment size but was affected by both the experimental setup (position of the lowest trap above the surface and number of traps in the saltation layer) and the technique used to calculate the sediment flux. Despite this, good agreement was found between sediment losses calculated from the saltiphone and those measured using the balance. The results of this study provide a framework for measuring sediment fluxes at small time resolution (seconds to milliseconds) in the field. PMID:24058512

  16. Deposition of latex colloids at rough mineral surfaces: an analogue study using nanopatterned surfaces.

    PubMed

    Krishna Darbha, Gopala; Fischer, Cornelius; Michler, Alex; Luetzenkirchen, Johannes; Schfer, Thorsten; Heberling, Frank; Schild, Dieter

    2012-04-24

    Deposition of latex colloids on a structured silicon surface was investigated. The surface with well-defined roughness and topography pattern served as an analogue for rough mineral surfaces with half-pores in the submicrometer size. The silicon topography consists of a regular pit pattern (pit diameter = 400 nm, pit spacing = 400 nm, pit depth = 100 nm). Effects of hydrodynamics and colloidal interactions in transport and deposition dynamics of a colloidal suspension were investigated in a parallel plate flow chamber. The experiments were conducted at pH ? 5.5 under both favorable and unfavorable adsorption conditions using carboxylate functionalized colloids to study the impact of surface topography on particle retention. Vertical scanning interferometry (VSI) was applied for both surface topography characterization and the quantification of colloidal retention over large fields of view. The influence of particle diameter variation (d = 0.3-2 ?m) on retention of monodisperse as well as polydisperse suspensions was studied as a function of flow velocity. Despite electrostatically unfavorable conditions, at all flow velocities, an increased retention of colloids was observed at the rough surface compared to a smooth surface without surface pattern. The impact of surface roughness on retention was found to be more significant for smaller colloids (d = 0.3, 0.43 vs. 1, 2 ?m). From smooth to rough surfaces, the deposition rate of 0.3 and 0.43 ?m colloids increased by a factor of ?2.7 compared to a factor of 1.2 or 1.8 for 1 and 2 ?m colloids, respectively. For a substrate herein, with constant surface topography, the ratio between substrate roughness and radius of colloid, Rq/rc, determined the deposition efficiency. As Rq/rc increased, particle-substrate overall DLVO interaction energy decreased. Larger colloids (1 and 2 ?m) beyond a critical velocity (7 10(-5) and 3 10(-6) m/s) (when drag force exceeds adhesion force) tend to detach from the surface irrespective of the impact of roughness. For polydisperse solutions, an increase in the polydispersity and flow velocity resulted in a reduction of colloid deposition efficiency due to the resulting enhanced double-layer repulsion. Quantification of surface topography variations of two endmembers of natural grain surfaces showed that half-pore depths and roughness of sedimentary quartz grains are mainly in the micrometer range. Grains with diagenetically formed quartz overgrowths, however, show surface roughness mainly in the submicrometer range. Thus, surface topography features applied in the here presented analogue study and resulting variation in particle retention can serve as quantitative analogue for particle reactions in diagenetically altered quartz sands and sandstones. The reported impact of particle polydispersity can have an important application for quantitative prediction of retention of varying types of minerals, such as different clay minerals in the environment under prevailing unfavorable conditions. PMID:22448713

  17. Valuing states from multiple measures on the same visual analogue sale: a feasibility study.

    PubMed

    Rowen, Donna; Brazier, John; Tsuchiya, Aki; Alava, Mnica Hernndez

    2012-06-01

    Previous methods of empirical mapping involve using regressions on patient or general population self-reported data from datasets involving two or more measures. This approach relies on overlap in the descriptive systems of the measures and assumes it is appropriate to use different measures on the same population, which may not always be the case. This paper presents a feasibility study for a new approach to mapping between preference-based measures (PBM) using general population visual analogue scale (VAS) values as a common yardstick. We use data from a valuation study of 502 members of the UK general population, where, using ranking and VAS tasks, interviewees simultaneously valued health states defined by three of six PBM: EQ-5D (generic), SF-6D (generic), HUI2 (generic for children and adults), AQL-5D (asthma specific), OPUS (social care specific) and ICECAP (capabilities). Regression techniques are used to estimate the relationship between these VAS values and the original value set (i.e. 'tariff'). These results are subsequently used to estimate the relationship between all six PBM to enable 'value-based mapping' between measures. This new method of mapping potentially has a useful role in evidence synthesis and cross programme comparisons in studies using different measures. PMID:21626608

  18. Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists.

    PubMed

    Banerjee, Ashutosh; Schepmann, Dirk; Köhler, Jens; Würthwein, Ernst-Ulrich; Wünsch, Bernhard

    2010-11-15

    A series of chiral non-racemic dexoxadrol analogues with various substituents in position 4 of the piperidine ring was synthesized and pharmacologically evaluated. Only the enantiomers having (S)-configuration at the 2-position of the piperidine ring and 4-position of the dioxolane ring were considered. Key steps in the synthesis were an imino-Diels-Alder reaction of enantiomerically pure imine (S)-13, which had been obtained from d-mannitol, with Danishefsky's Diene 14 and the replacement of the p-methoxybenzyl protective group with a Cbz-group. It was shown that (S,S)-configuration of the ring junction (position 2 of the piperidine ring and position 4 of the dioxolane ring) and axial orientation of the C-4-substituent ((4S)-configuration) are crucial for high NMDA receptor affinity. 2-(2,2-Diphenyl-1,3-dioxolan-4-yl)piperidines with a hydroxy moiety ((S,S,S)-5, K(i)=28nM), a fluorine atom ((S,S,S)-6, WMS-2539, K(i)=7nM) and two fluorine atoms ((S,S)-7, K(i)=48nM) in position 4 represent the most potent NMDA antagonists with high selectivity against σ(1) and σ(2) receptors and the polyamine binding site of the NMDA receptor. The NMDA receptor affinities of the new ligands were correlated with their electrostatic potentials, calculated gas phase proton affinities (negative enthalpies of deprotonation) and dipole moments. According to these calculations decreasing proton affinity and increasing dipole moment are correlated with decreasing NMDA receptor affinity. PMID:20965735

  19. Indenes and tetralenes analogues attenuates lipopolysaccharide-induced inflammation: An in-vitro and in-vivo study.

    PubMed

    Mohanty, Shilpa; Gautam, Yashveer; Maurya, Anil Kumar; Negi, Arvind S; Prakash, Om; Khan, Feroz; Bawankule, Dnyaneshwar Umrao

    2016-02-01

    In an effort to evaluate novel pharmacological activity of 1-chloro-2-formyl indene and tetralene analogues possessing potential antitubercular and antistaphylococcal agents, we explored its anti-inflammatory potential against lipopolysaccharide(LPS)-induced inflammation using in-vitro and in-vivo bioassay. Synthesized analogues significantly inhibited the production and expression of pro-inflammatory cytokines against LPS-induced inflammation in macrophages isolated from mice. Among all the analogues, TAF-5 (1-Chloro-2-formyl-1-tetralene) exhibited most potent anti-inflammatory activity without any cytotoxic effect. We have further evaluated the therapeutic efficacy and safety of TAF-5 in in-vivo system using LPS-induced sepsis, a systemic inflammation model and acute oral toxicity respectively in mice. Oral administration of TAF-5 inhibited the pro-inflammatory cytokines in serum, attenuated the organs injuries and improved host survival in dose dependent manner. Acute oral toxicity study showed TAF-5 is non-toxic at higher dose in mice. These results suggest the suitability of indene and tetralene analogues as new chemical entities for further investigation towards the management of inflammation related diseases. PMID:26731479

  20. Phenylpropanoid Glycoside Analogues: Enzymatic Synthesis, Antioxidant Activity and Theoretical Study of Their Free Radical Scavenger Mechanism

    PubMed Central

    Lpez-Mungua, Agustn; Hernndez-Romero, Yanet; Pedraza-Chaverri, Jos; Miranda-Molina, Alfonso; Regla, Ignacio; Martnez, Ana; Castillo, Edmundo

    2011-01-01

    Phenylpropanoid glycosides (PPGs) are natural compounds present in several medicinal plants that have high antioxidant power and diverse biological activities. Because of their low content in plants (less than 5% w/w), several chemical synthetic routes to produce PPGs have been developed, but their synthesis is a time consuming process and the achieved yields are often low. In this study, an alternative and efficient two-step biosynthetic route to obtain natural PPG analogues is reported for the first time. Two galactosides were initially synthesized from vanillyl alcohol and homovanillyl alcohol by a transgalactosylation reaction catalyzed by Kluyveromyces lactis ?-galactosidase in saturated lactose solutions with a 30%35% yield. To synthesize PPGs, the galactoconjugates were esterified with saturated and unsaturated hydroxycinnamic acid derivatives using Candida antarctica Lipase B (CaL-B) as a biocatalyst with 40%60% yields. The scavenging ability of the phenolic raw materials, intermediates and PPGs was evaluated by the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) method. It was found that the biosynthesized PPGs had higher scavenging abilities when compared to ascorbic acid, the reference compound, while their antioxidant activities were found similar to that of natural PPGs. Moreover, density functional theory (DFT) calculations were used to determine that the PPGs antioxidant mechanism proceeds through a sequential proton loss single electron transfer (SPLET). The enzymatic process reported in this study is an efficient and versatile route to obtain PPGs from different phenylpropanoid acids, sugars and phenolic alcohols. PMID:21674039

  1. New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C[superscript 8] Substitution in Structural Analogues of S-Adenosylmethionine

    SciTech Connect

    McCloskey, Diane E.; Bale, Shridhar; Secrist, III, John A.; Tiwari, Anita; Moss, III, Thomas H.; Valiyaveettil, Jacob; Brooks, Wesley H.; Guida, Wayne C.; Pegg, Anthony E.; Ealick, Steven E.

    2009-04-02

    S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C{sup 8}-substituted adenine analogues bound in the active site.

  2. The crystal structure of an isopenicillin N synthase complex with an ethereal substrate analogue reveals water in the oxygen binding site.

    PubMed

    Clifton, Ian J; Ge, Wei; Adlington, Robert M; Baldwin, Jack E; Rutledge, Peter J

    2013-08-19

    Isopenicillin N synthase (IPNS) is a non-heme iron oxidase central to the biosynthesis of ?-lactam antibiotics. IPNS converts the tripeptide ?-(L-?-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue ?-(L-?-aminoadipoyl)-L-cysteinyl-O-methyl-D-threonine (ACmT) is not turned over by IPNS. Epimeric ?-(L-?-aminoadipoyl)-L-cysteinyl-O-methyl-D-allo-threonine (ACmaT) is converted to a bioactive penam product. ACmT and ACmaT differ from each other only in the stereochemistry at the ?-carbon atom of their third residue. These substrates both contain a methyl ether in place of the isopropyl group of ACV. We report an X-ray crystal structure for the anaerobic IPNS:Fe(II):ACmT complex. This structure reveals an additional water molecule bound to the active site metal, held by hydrogen-bonding to the ether oxygen atom of the substrate analogue. PMID:23860486

  3. Matrix Metalloproteinase 2 (MMP2) Inhibition: DFT and QM/MM Studies of the Deprotonation Initialized Ring Opening Reaction of Sulfoxide Analogue of SB-3CT

    PubMed Central

    Tao, Peng; Fisher, Jed F.; Shi, Qicun; Mobashery, Shahriar; Schlegel, H. Bernhard

    2010-01-01

    (4-Phenoxyphenylsulfonyl)methylthiirane (SB-3CT) is the selective inhibitor of matrix metalloproteinase 2 (MMP2). The inhibition mechanism of MMP2 by SB-3CT involves CH deprotonation with concomitant opening of the three-membered heterocycle. In this study, the energetics of the deprotonation-induced ring opening of (4-phenoxyphenylsulfinyl)methylthiirane, the sulfoxide analogue of SB-3CT, are examined computationally using DFT and QM/MM calculations. A model system, 2-(methylsulfinylmethyl)thiirane, is used to study the stereoelectronic and conformational effects of reaction barriers in methanol. For the model system in methanol solution (using polarizable continuum model), the reaction barriers range from 17 to 23 kcal/mol with significant stereoelectronic effects. However, the lowest barriers of the (R, R) and (S, R) diastereomers are similar. Two diastereomers of the sulfoxide analogue of SB-3CT are studied in the active site of MMP2 by QM/MM methods with an accurate partial charge fitting procedure. The ring opening reactions of these two diastereomers have similar reaction energetics. Both are exothermic from the reactant to the ring opening product (thiolate). The protonation of the thiolate by a water molecule is endothermic in both cases. However, the deprotonation / ring opening barriers in the MMP2 active site using QM/MM methods for the (R, R) and (S, R) inhibitions are quite different (23.3 and 28.5 kcal/mol, respectively). The TSs identified in QM/MM calculations were confirmed by vibrational frequency analysis and reaction path following. The (R, R) diastereomer has hydrogen bond between the sulfoxide oxygen and the backbone NH of Leu191, while the (S, R) has hydrogen bond between the sulfoxide oxygen and a water molecule. The dissimilar strengths of these hydrogen bonds as well as minor differences in the TS structures contribute to the difference between the barriers. Compared to SB-3CT, both diastereomers of the sulfoxide analogue have higher reaction barriers, and have less exothermic reaction energies. This agrees well with the experiments that SB-3CT is a more effective inhibitor of MMP2 than its sulfoxide analogue. PMID:20039633

  4. Synthesis and StructureActivity Relationship Study of 5a-Carbasugar Analogues of SL0101

    PubMed Central

    2014-01-01

    The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The l-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay. PMID:25589938

  5. Experimental and Theoretical Studies of the Structures and Interactions of Vancomycin Antibiotics with Cell Wall Analogues

    SciTech Connect

    Yang, Zhibo; Vorpagel, Erich R.; Laskin, Julia

    2008-10-01

    Surface-induced dissociation (SID) of the singly protonated complex of vancomycin antibiotic with cell wall peptide analogue (Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala) was studied using a 6 T Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (FT-ICR MS) specially configured for SID experiments. The binding energy between the vancomycin and the peptide was obtained from the RRKM modeling of the time- and energy resolved fragmentation efficiency curves (TFECs) of the precursor ion and its fragments. Electronic structure calculations of the geometries, proton affinities and binding energies were performed for several model systems including vancomycin (V), vancomycin aglycon (VA), Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala, and non-covalent complexes of VA with N-acetyl-D-Ala-D-Ala and Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala at the B3LYP/6-31G(d) level of theory. Comparison between the experimental and computational results suggests that the most probable structure of the complex observed in our experiments corresponds to the neutral peptide bound to the vancomycin protonated at the secondary amino group of the N-methyl-leucine residue. The experimental binding energy of 30.9 ± 1.8 kcal/mol is in good agreement with the binding energy of 29.3 ± 2.5 kcal/mol calculated for the model system representing the preferred structure of the complex.

  6. In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt(1)-DALDA Analogues.

    PubMed

    Ballet, Steven; Betti, Cecilia; Novoa, Alexandre; Tmbly, Csaba; Nielsen, Carsten Uhd; Helms, Hans Christian; Lesniak, Anna; Kleczkowska, Patrycja; Chung, Nga N; Lipkowski, Andrzej W; Brodin, Birger; Tourw, Dirk; Schiller, Peter W

    2014-04-10

    In this study the ? opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH2) and Dmt(1)-DALDA (Dmt-d-Arg-Phe-Lys-NH2, Dmt = 2',6'-dimethyltyrosine) were glycosylated at the N- or C-terminus. Subsequently, the modified peptides were subjected to in vitro and in vivo evaluation. In contrast to the N-terminally modified peptide (3), all peptide analogues derivatized at the C-terminus (4-7) proved to possess high affinity and agonist potency at both MOR and DOR (? opioid receptor). Results of the Caco-2 monolayer permeation, as well as in vitro blood-brain barrier model experiments, showed that, in the case of compound 4, the glycosylation only slightly diminished the lumen-to-blood and blood-to-lumen transport. Altogether, these experiments were indicative of transcellular transport but not active transport. In vivo assays demonstrated that the peptides were capable of (i) crossing the blood-brain barrier (BBB) and (ii) activating both the spinal ascending as well as the descending opioid pathways, as determined by the tail-flick and hot-plate assays, respectively. In contrast to the highly selective MOR agonist Dmt(1)-DALDA 1, compounds 4-7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects. PMID:24839540

  7. Circulatory effects of prostaglandin endoperoxide analogues studied in the dog during left ventricular bypass.

    PubMed Central

    Alter, I; Kot, P A; Ramwell, P W; Rose, J C; Shnider, M R

    1977-01-01

    1. Intravenous administration of both the 9alpha,11alpha-(epoxymethano) and 11alpha,9alpha-(epoxymethano) analogues of prostaglandin H2 (0.25 microgram/kg) produced a prominent rise in pulmonary arterial pressure and a moderate increase in systemic arterial pressure. 2. Direct administration of the endoperoxide analogues (1.25 microgram/kg) into the bypass reservoir produced a greater rise in systemic arterial pressure and less prominent rise in pulmonary arterial pressure. 3. An intravenous dose of prostaglandin F2alpha that was 20 times larger was needed to produce a comparable rise in pulmonary arterial pressure. 4. The pulmonary and systemic pressor responses produced by the endoperoxide analogues were due to a direct increase in the vascular resistance. PMID:588804

  8. Fluorinated pseudopeptide analogues of the neuropeptide 26RFa: synthesis, biological, and structural studies.

    PubMed

    Pierry, Camille; Couve-Bonnaire, Samuel; Guilhaudis, Laure; Neveu, Cindy; Marotte, Amlie; Lefranc, Benjamin; Cahard, Dominique; Sgalas-Milazzo, Isabelle; Leprince, Jrme; Pannecoucke, Xavier

    2013-09-01

    A series of four fluorinated dipeptide analogues each containing a fluoro-olefin moiety as peptide bond surrogate has been designed and synthesized. These motifs have been successfully introduced into the bioactive C-terminal heptapeptide of the neuropeptide 26RFa by conventional SPPS. We then evaluated the ability of the generated pseudopeptides to increase [Ca?](i) in GPR103-transfected cells. For these fluorinated analogues, greater stability in human serum was observed. Their conformations were also investigated, leading to the valuable identification of differences depending on the position of the fluoro-olefin moiety in the sequence. PMID:23940098

  9. Insulin lispro (Humalog), the first marketed insulin analogue: indications, contraindications and need for further study.

    PubMed Central

    Puttagunta, A L; Toth, E L

    1998-01-01

    OBJECTIVE: To review the available literature on the new insulin analogue insulin lispro and provide information on its efficacy, indications for use and contraindications. DATA SOURCES: MEDLINE searches were made for articles published from 1966 to 1996 using the indexing term "lispro", "Humalog" and "insulin analogs". STUDY SELECTION: About 30 studies and review articles were selected based on their relevance to the stated objective. These were critically appraised for the purpose of writing the review article so that it would be relevant to general practitioners, internists and nurse educators. DATA SYNTHESIS: The therapeutic challenge when treating diabetic patients is to bring the blood glucose level into as normal a range as possible, with minimal hypoglycemia and hyperinsulinemia. Insulin lispro has a much faster, higher and shorter-lasting peak serum insulin level than regular human insulin, thus mimicking physiologic secretion of insulin more closely. As a result, there is improvement in postprandial blood glucose levels and decreased episodes of hypoglycemia, with no change in the hemoglobin A1c (HgbA1c) level. The ability to inject insulin lispro immediately before the meal allows greater flexibility of lifestyle. Compared with regular insulin, insulin lispro is associated with a lower risk of hypoglycemia with exercise several hours after a meal. It is therefore most useful for the motivated, compliant diabetic patient who would like to achieve a better hypoglycemia-HgbA1c ratio as well as for patients desiring further flexibility with premeal insulin injections. Use of insulin lispro has been shown to improve HgbA1c levels in patients using insulin pumps. It is well tolerated, and therapy is often continued after studies are completed. Further study is needed to establish optimal basal regimens. PMID:9627564

  10. Analysis of a pentacoordinate iron dicarbonyl as synthetic analogue of the Hmd or mono-iron hydrogenase active site.

    PubMed

    Liu, Tianbiao; Li, Bin; Popescu, Codrina V; Bilko, Andrey; Prez, Lisa M; Hall, Michael B; Darensbourg, Marcetta Y

    2010-03-01

    Pentacoordinate iron dicarbonyls, (NS)Fe(CO)(2)P (NS=2-amidothiophenylate, P=PCy(3) (4), PPh(3), (5), and P(OEt)(3) (6)) were prepared as potential biomimetics of the active site of the mono-iron hydrogenase, [Fe]-H(2)ase. Full characterization including X-ray diffraction, density functional theory (DFT) computations, and Mssbauer studies for complexes 5 and 6 find that, despite similar infrared v(CO) pattern and absorption frequencies as the active site of the [Fe]-H(2)ase, the geometrical distortions towards trigonal bipyramidal, the negative isomer shift parameters, and the differences in CO-uptake reactivity are due to the "non-innocence" of the NS ligand. Ligand-based protonation with a strong acid, HBF(4).Et(2)O, interrupted the extensive pi-delocalization over Fe and NS ligand of complex 4 and switched on CO uptake (1 bar) to form a CO adduct, mer-[(H-NS)Fe(CO)(3)(PCy(3))](+) or 4(CO)-H(+). The extrinsic CO is reversibly removed on deprotonation with Et(3)N to regenerate complex 4. In a (13)CO atmosphere, concomitant CO uptake by 4-H(+) and exchange with intrinsic CO groups provide a facile route to (13)C-labeled 4(CO)-H(+) and, upon deprotonation, (13)C-labeled complex 4. DFT calculations show substantial Fe character in the LUMO of 4-H(+) typical of the d(6) Fe(II) in a regular square-pyramidal geometry. Thus, the Lewis acidity of 4-H(+) makes it amenable for CO binding, whereas the dianionic NS ligand renders the iron center of 4 insufficiently electrophilic and largely of Fe(I) character. PMID:20119989

  11. Interaction of tachykinins with their receptors studied with cyclic analogues of substance P and neurokinin B

    SciTech Connect

    Ploux, O.; Lavielle, S.; Chassaing, G.; Julien, S.; Marquet, A.; D'Orleans-Juste, P.; Dion, S.; Regoli, D.; Beaujouan, J.C.; Bergstroem, L.

    1987-11-01

    The activities of two groups of cyclic agonists of substance P (SP) have been studied. The disulfide bridge constraints have been designed on the basis of conformational studies on SP and physalaemin indicating an ..cap alpha..-helical structure for the core of these two tachykinins (group I) and a folding of the C-terminal carboxamide towards the side chains of the glutamines 5 and 6 (group II). Only peptides simulating the ..cap alpha..-helix present substantial potencies. (Cys/sup 3,6/)SP is as active as SP in inhibiting /sup 125/I-labeled Bolton and Hunter SP-specific binding on rat brain synaptosomes and on dog carotid bioassay, two assays specific for the neurokinin 1 receptor. Moreover, (Cys/sup 3,6/)SP is a potent as neurokinin B in inhibiting /sup 125/I-labeled Bolton and Hunter eledoisin-specific binding on rat cortical synaptosomes as well as in stimulating rat portal vein, two tests specific for the neurokinin 3 receptor. Interestingly, in contrast to neurokinin B, (Cys/sup 3,6/)SP is a weak agonist of the neurokinin 2 receptor subtype, as evidenced by its binding potency in inhibiting /sup 3/H-labeled neurokinin A-specific binding on rat duodenum and in inducing the contractions of the rabbit pulmonary artery, a neurokinin 2-type bioassay. To increase the specificity of the cyclic analogue (Cys/sup 3,6/)SP positions 8 and 9 were modified. Collectively, these results suggest that the neurokinin 1 and neurokinin 3 tachykinin receptors may recognize a similar three-dimensional structure of the core of the tachykinins. Different orientations of the common C-terminal tripeptide may be related to the selectivity for the different receptor subtypes.

  12. Site locality identification study: Hanford Site. Volume II. Data cataloging

    SciTech Connect

    Not Available

    1980-07-01

    Data compilation and cataloging for the candidate site locality identification study were conducted in order to provide a retrievable data cataloging system for the present siting study and future site evaluation and licensng processes. This task occurred concurrently with and also independently of other tasks of the candidate site locality identification study. Work in this task provided the data utilized primarily in the development and application of screening and ranking processes to identify candidate site localities on the Hanford Site. The overall approach included two steps: (1) data acquisition and screening; and (2) data compilation and cataloging. Data acquisition and screening formed the basis for preliminary review of data sources with respect to their probable utilization in the candidate site locality identification study and review with respect to the level of completeness and detail of the data. The important working assumption was that the data to be used in the study be based on existing and available published and unpublished literature. The data compilation and cataloging provided the basic product of the Task; a retrievable data cataloging system in the form of an annotated reference list and key word index and an index of compiled data. The annotated reference list and key word index are cross referenced and can be used to trace and retrieve the data sources utilized in the candidate site locality identification study.

  13. Revisiting sesquiterpene biosynthetic pathways leading to santalene and its analogues: a comprehensive mechanistic study.

    PubMed

    Jindal, Garima; Sunoj, Raghavan B

    2012-10-21

    Santalene and bergamotene are the major olefinic sesquiterpenes responsible for the fragrance of sandalwood oil. Herein we report the details of density functional theory investigations on the biosynthetic pathway of this important class of terpenes. The mechanistic study has been found to be effective toward gaining significant new insight into different possibilities for the formation of the key intermediates involved in santalene and bergamotene biosynthesis. The stereoelectronic features of the transition states and intermediates for (i) ring closure of the initial bisabolyl cation, and (ii) skeletal rearrangements in the ensuing bicyclic carbocationic intermediates leading to (-)-epi-?-santalene, (-)-?-santalene, (-)-?-santalene, (+)-epi-?-santalene, exo-?-bergamotene, endo-?-bergamotene, exo-?-bergamotene, and endo-?-bergamotene are presented. Interesting structural features pertaining to certain new carbocationic intermediates (such as b) resulting from the ring closure of bisabolyl cation are discussed. Extensive conformational sampling of all key intermediates along the biosynthetic pathway offered new insight into the role of the isoprenyl side chain conformation in the formation of santalene and its analogues. Although the major bicyclic products in Santalum album appear to arise from the right or left handed helical form of farnesyl pyrophosphate (FPP), different alternatives for their formation are found to be energetically feasible. The interconversion of the exo and endo isomers of bisabolyl cation and a likely epimerization, both with interesting mechanistic implications, are presented. The exo to endo conversion is identified to be energetically more favorable than another pathway emanating from the left handed helical FPP. The role of pyrophosphate (OPP(-)) in the penultimate deprotonation step leading to olefinic sesquiterpenes is also examined. PMID:22951817

  14. Novel Penicillin Analogues as Potential Antimicrobial Agents; Design, Synthesis and Docking Studies

    PubMed Central

    Ashraf, Zaman; Bais, Abdul; Manir, Md. Maniruzzaman; Niazi, Umar

    2015-01-01

    A number of penicillin derivatives (4a-h) were synthesized by the condensation of 6-amino penicillinic acid (6-APA) with non-steroidal anti-inflammatory drugs as antimicrobial agents. In silico docking study of these analogues was performed against Penicillin Binding Protein (PDBID 1CEF) using AutoDock Tools 1.5.6 in order to investigate the antimicrobial data on structural basis. Penicillin binding proteins function as either transpeptidases or carboxypeptidases and in few cases demonstrate transglycosylase activity in bacteria. The excellent antibacterial potential was depicted by compounds 4c and 4e against Escherichia coli, Staphylococcus epidermidus and Staphylococcus aureus compared to the standard amoxicillin. The most potent penicillin derivative 4e exhibited same activity as standard amoxicillin against S. aureus. In the enzyme inhibitory assay the compound 4e inhibited E. coli MurC with an IC50 value of 12.5 μM. The docking scores of these compounds 4c and 4e also verified their greater antibacterial potential. The results verified the importance of side chain functionalities along with the presence of central penam nucleus. The binding affinities calculated from docking results expressed in the form of binding energies ranges from -7.8 to -9.2kcal/mol. The carboxylic group of penam nucleus in all these compounds is responsible for strong binding with receptor protein with the bond length ranges from 3.4 to 4.4 Ǻ. The results of present work ratify that derivatives 4c and 4e may serve as a structural template for the design and development of potent antimicrobial agents. PMID:26267242

  15. A numerical and analogue study of dike ascent in asymmetric continental rift zones

    NASA Astrophysics Data System (ADS)

    Schierjott, Jana; Maccaferri, Francesco; Keir, Derek; Kemna, Andreas; Rivalta, Eleonora

    2015-04-01

    In continental rift zones, tectonic extension is responsible for the creation of deep topographic depressions bordered by large border faults. Volcanism may be distributed within, at the border and outside of the depressions, and the mechanisms controlling this distribution are debated. Recently, Maccaferri et al. (2014) proposed that the reorientation of the principal stresses linked to crustal thinning and overall crustal mass redistribution in rift zones modifies the expected trajectory of ascending magma pockets and plays a fundamental role in the distribution of volcanism at the surface. However, the model does not explain why volcanism is asymmetric in most continental rift zones. The goal of this study is to investigate the relation between the characteristic distribution of volcanism at the surface, the distribution and geometry of magma storage at depth, and the observed geometric asymmetry of the grabens at most rift zones. By using a boundary element model for dike propagation and analogue laboratory experiments we evaluate the ascent path of magmatic dikes in asymmetric continental rifts. We find that introducing asymmetry of various degrees into the models has a huge impact on the modeled location of the surface volcanic activity. In particular, varying model parameters such as the half-graben width and depth and the degree of asymmetry leads to numerous different scenarios, including one-sided volcanic activity when the degree of asymmetry is very high and the half-graben is not too deep. For wider or deeper half-grabens and moderate asymmetry a larger proportion of the magma tends to become arrested as horizontal intrusions at depth.

  16. Structure of Bacillus subtilis γ-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue

    SciTech Connect

    Ida, Tomoyo; Suzuki, Hideyuki; Fukuyama, Keiichi; Hiratake, Jun; Wada, Kei

    2014-02-01

    The binding modes of acivicin, a classical and an electrophilic active-site-directed glutamate analogue, to bacterial γ-glutamyltranspeptidases were found to be diverse. γ-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8 Å resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp{sup 2} hybridization to Thr403 O{sup γ}, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs.

  17. A CoMSIA study on the adenosine kinase inhibition of pyrrolo[2,3-d]pyrimidine nucleoside analogues.

    PubMed

    Caballero, Julio; Fernndez, Michael; Gonzlez-Nilo, Fernando D

    2008-05-01

    The structural requirements of pyrrolo[2,3-d]pyrimidine nucleoside (PPN) analogues as adenosine kinase (AK) inhibitors were in silico studied by using CoMSIA method. All models were trained with 32 compounds, after which they were evaluated for predictive ability with additional 5 compounds. Quantitative information on structure-activity trends is provided for further rational development and direction of selective synthesis. The best CoMSIA model included hydrophobic, H-bond donor and H-bond acceptor fields and had a good predictive quality according to internal validation criteria. In addition, this model predicted adequately the compounds contained in the test set. The analysis of the model gives a comprehensive qualitative and quantitative description of the molecular features at C4 and C5 positions of the pyrrolo[2,3-d]pyrimidine scaffold and C5-position of the beta-d-ribofuranose of PPN analogues, relevant for a high AK inhibitory activity. PMID:18359230

  18. Using stressful films to analyze risk factors for PTSD in analogue experimental studies--which film works best?

    PubMed

    Weidmann, Anke; Conradi, Ania; Groger, Kathrin; Fehm, Lydia; Fydrich, Thomas

    2009-10-01

    To understand mental disorders, analogue paradigms provide an indispensable contribution. In posttraumatic stress disorder (PTSD), the stressful film paradigm is a frequently used analogue approach: Films depicting traumatic events are shown to non-clinical participants in order to elicit stress responses analogue to responses to traumatic events in real life. Previous studies used a large variety of films, which is problematic with regard to the comparability of results. The main goal of this study was to identify a film clip that (a) consistently provokes stress reactions and (b) provokes reactions that are as similar as possible to traumatic stress. We randomly exposed 105 male and female participants to one of four stressful films, differing, e.g., in content and origin. Intrusive memories of the film, reported immediately after the film and during a diary phase of three days, as well as distress, heart rate, and several mood states were measured. A film clip depicting rape elicited the most consistent reactions that were characterized by a higher heart rate, more distress and more intrusive memories, compared to the other three clips. Intrusive memories across all films were especially related to an increase in heart rate and disgust in response to the film. PMID:19347765

  19. Combinatorial libraries: a tool to design antimicrobial and antifungal peptide analogues having lytic specificities for structure-activity relationship studies.

    PubMed

    Blondelle, S E; Lohner, K

    2000-01-01

    In the race for supremacy, microbes are sprinting ahead. This warning by the World Health Organization clearly demonstrates that the spread of antibiotic-resistant bacteria leads to a global health problem and that antibiotics never seen before by bacteria are urgently needed. Antimicrobial peptides represent such a source for novel antibiotics due to their rapid lytic activity (within minutes) through disruption of cell membranes. However, due to the similarities between bacterial, fungal, and mammalian plasma cell membranes, a large number of antimicrobial peptides have low lytic specificities and exhibit a broad activity spectrum and/or significant toxic effect toward mammalian cells. Mutation strategies have allowed the development of analogues of existing antimicrobial peptides having greater lytic specificities, although such methods are lengthy and would be more efficient if the molecular mechanisms of action of antimicrobial peptides were clearly elucidated. Synthetic combinatorial library approaches have brought a new dimension to the design of novel biologically active compounds. Thus, a set of peptide analogues were generated based on the screening of a library built around an existing lytic peptide, and on a deconvolution strategy directed toward activity specificity. These peptide analogues also served as model systems to further study the effect of biomembrane mimetic systems on the peptides structural behavior relevant to their biological activities. PMID:10931443

  20. Theoretical study on the influence of different para-substituents on 13C NMR of the single carbonyl curcumin analogues

    NASA Astrophysics Data System (ADS)

    Jia, Fei-yun; Ran, Ming; Zhang, Bo

    2015-12-01

    The structure of eight kinds of different para-substituents curcumin analogues has been optimized at the level of B3LYP/6-31G( d, p), under which the stability has been verified by means of vibration analysis. Moreover, NMR spectra of curcumin analogues compounds have been studied at the level of B3LYP/6-311G( d, p) by GIAO method. The results show that the structure of eight compounds, a larger conjugated system, has good planarity. The effect of ortho-substituents on bond lengths and bond angles is greater than para and meta. Different substituents and different positions of substituents all have different influence on NMR of the single carbonyl curcumin analogues. In general, after the hydrogen atom on the benzene ring is substituted by other groups, the δ value of α-C changes significantly, the δ value of ortho-carbon atom may also have great change, but the δ value change of meta-carbon atoms is not too obvious. The effect of substituent electronegativity on α-C atoms presents obvious regularity, while the influence of conjugate effect on carbon atoms of benzene ring is more complex. Finally, the bigger substituted alkyl is, the more the δ value of α-C increases.

  1. Structure-function relationship studies of PTH(1-11) analogues containing D-amino acids.

    PubMed

    Caporale, Andrea; Biondi, Barbara; Schievano, Elisabetta; Wittelsberger, Angela; Mammi, Stefano; Peggion, Evaristo

    2009-06-01

    Parathyroid hormone (PTH) is an 84-amino acid peptide hormone. Produced in the parathyroid glands, it acts primarily on bone and kidney to maintain extracellular calcium levels within normal limits. It has been shown that the 1-34 amino acid fragment of PTH is sufficient to bind and activate the PTH type-I receptor. Recent investigations focusing on the interaction of N-terminal fragments of PTH with PTH type-I receptor showed that certain modifications can increase signalling potency in peptides as short as 11 amino acids. To understand the role of the side chains of all the amino acid residues in PTH(1-11), we synthesized all-D PTH, three retro-inverso analogues of the most active modified PTH(1-11), H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH(2), and we substituted every L-AA of the latter with the corresponding D-AA, obtaining a library of PTH(1-11) analogues that were tested as agonists. The library was synthesized by SPPS, employing the Fmoc protocol. The biological tests showed that the activity of the D-Har11 analogue is of the same order of magnitude of that of the most active modified PTH(1-11). This behaviour is paralleled by an increase of the helical content on going from the D-Val(2) to the D-Har(11) analogue. This is in agreement with previous work where a correlation between activity and helical content has been demonstrated. The importance of a positively charged group in the C-terminal position is shown to be independent of the configuration of the C(alpha)-carbon. PMID:19303868

  2. Anomeric selectivity and influenza A virus inhibition study on methoxylated analogues of Pentagalloylglucose.

    PubMed

    Qurat-ul-ain, Shaikh; Wang, Wei; Yang, Meiting; Du, Na; Wan, Shengbiao; Zhang, Lijuan; Jiang, Tao

    2015-01-30

    Anomeric selectivity in galloylation of D-glucose and D-mannose with carboxylic acid was explored under steglich conditions. Base catalyst 4-dimethylaminopyridine favored the formation of alpha-anomers, while adding an acid and carbodiimide favored the formation of beta-anomers. Steric hindrance between α,β-unsaturated acid and C-2 OH stereochemistry (adjacent carbon to anomeric) influenced anomeric selectivity for both D-glucose and D-mannose. The influenza A virus inhibition activities of the synthesized compounds were evaluated in Madin-Darby canine kidney cell line using the cytopathic effect inhibition assay. All the synthetic methoxylated analogues showed more considerable activity against influenza A virus than their corresponding acids, which indicated the sugar core as key functionality for anti-viral activity. The activities of trimethoxy-cinnamic acid Pentagalloylglucose analogues, 3α, 3β, 4α, and 4β (IC50, 109.1 μM, 134.4 μM, 119.5 μM, 111.1 μM, respectively) were better than those of trimethoxy-benzoic acid Pentagalloylglucose analogues, 1-αβ and 2α, 2β (IC50, 209.8 μM, 132.9 μM, 161.2 μM, respectively), which suggested that the double bond in cinnamic acid Pentagalloylglucose analogues makes the major contribution for influenza A virus inhibitory activity. Notably, several anomeric mixtures showed better activities than pure alpha or beta anomer and were almost two times more effective than Ribavirin, a clinically used anti-viral drug. PMID:25498015

  3. Structure-activity relationship studies of flavonol analogues on pollen germination.

    PubMed

    Forbes, Alaina M; Meier, G Patrick; Haendiges, Stacey; Taylor, Loverine P

    2014-03-12

    Flavonoids are polyphenolic compounds required in the fertilization process in many, if not all, plants. However, the exact biological mechanism(s) and the interacting proteins are unknown. To determine the characteristics important in activating or inhibiting the pollination sequence, a structure-activity relationship analysis of natural and synthetic flavonols was conducted. Flavonol analogues were synthesized through a modified "one-pot" procedure that utilized a Baker-Venkataraman type rearrangement and a Suzuki-Miyaura cross-coupling of a halo-flavonol with an organotrifluoroborate. Of the flavonols tested, kaempferol was the only compound to act as a full agonist. The other smaller, less sterically hindered flavonols (galangin, kaempferide, and 4'-methyl flavonol) acted as partial agonists. Larger more hydrophobic flavonol analogues (3'- and 4'-benzoyl, 3'- and 4'-phenyl, and 3'- and 4'-iodo flavonols) had minimal or no agonist activity. Competition assays between kaempferol and these minimally activating flavonols showed that these analogues inhibited the action of kaempferol in a manner consistent with noncompetitive antagonism. The results suggest that steric hindrance is the most important factor in determining a good agonist. Hydrogen bonding also had a positive effect as long as the substituent did not cause any steric hindrance. PMID:24524670

  4. Studies of Titan s aerosols analogues produced by radio frequency dischare

    NASA Astrophysics Data System (ADS)

    Szopa, C.; Cernogora, G.; Boufendi, L.; Correia, J. J.; Ausset, P.

    Titan s organic aerosols play a significant role in the physico-chemical mechanisms of the Titan s atmosphere and heat transfer on the Titan s surface. As a matter of fact, the increase of surface temperature due to the methane green house effect is reduced by the solar flux absorption due to the haze layers of Titan s atmosphere. The presented laboratory experiment is developed to produce analogues of Titan s aerosols. The photo chemistry of the N2-CH4 mixture representative of Titan s atmosphere is simulated by a low pressure Radio Frequency plasma discharge. In this plasma, solid particles are produced in the gas. They are maintained in levitation by electrostatic force and they grow in the gas, away from the reactor walls. This phenomena was first observed in Argon Silane RF plasmas used for micro-electronic component production. The aim of this paper is to present new results obtained in N2-CH4 RF plasma. In this plasma the gas mixture is injected continuously and pumped with a mechanical vacuum pump, in order to maintain the plasma in low pressure conditions. In the studied pressure range, the plasma is not in thermal equilibrium, i.e neutral gas remains at room temperature, when electrons have a mean energy of about 1eV. Solid particles produced into the plasma are ejected when their weight is too high to be balanced by electrostatic force. The collected particles are observed and analysed. We observe that their colour changes from clear brown to dark brown following the plasma conditions. In order to change the composition of solid particles, total pressure is adjusted from 0.2 mbar to 3 mbar, and the CH4 percentage up to 10%. Solid particles are also observed by Scanning Electron Microscopy (SEM). They present a regular spherical shape and a size dispersion with a mean diameter of 0.8 mm. Their composition is investigated by pyrolysis-Gas-Chromatography-Mass Spectrometry (pyr-GC-MS) and elementary analysis. In order to correlate the solid particles composition to the plasma properties, plasma is studied by UV visible Optical Emission Spectroscopy (OES). Presence of reactive radicals like CN is observed. Moreover, from OES it is possible to point out an evolution of the electron mean energy with total pressure. From these data, it is possible to have information on the Electron Energy Distribution Function (EEDF) which is important for the modelling of the physico-chemical mechanisms of the plasma, and to compare these mechanisms to that of Titan s atmosphere.

  5. TAME5OX, abiotic siderophore analogue to enterobactin involving 8-hydroxyquinoline subunits: Thermodynamic and photophysical studies

    NASA Astrophysics Data System (ADS)

    Akbar, Rifat; Baral, Minati; Kanungo, B. K.

    2015-05-01

    The synthesis, thermodynamic and photophysical properties of trivalent metal complexes of biomimetic nonadentate analogue, 5,5‧-(2-(((8-hydroxyquinolin-5-yl)methylamino)methyl)-2-methylpropane-1,3-diyl)bis(azanediyl)bis(methylene)diquinolin-8-ol (TAME5OX), have been described. Combination of absorption and emission spectrophotometry, potentiometry, electrospray mass spectrometry, IR, and theoretical investigation were used to fully characterize metal (Fe+3, Al+3 and Cr+3) chelates of TAME5OX. In solution, TAME5OX forms protonated complexes [M(H3L)]3+ below pH 3.4, which consecutively deprotonates through one to three-proton processes with rise of pH. The formation constants (Log β11n) of neutral complexes formed at or above physiological pH, have been determined to be 30.18, 23.27 and 22.02 with pM values of 31.16, 18.07 and 18.12 for Fe+3, Al+3 and Cr+3 ions, respectively, calculated at pH 7.4, indicating TAME5OX is a powerful among synthetic metal chelator. The results clearly demonstrate that the ligand in a tripodal orchestration firmly binds these ions over wide pH range and forms distorted octahedral complexes. The binding and the coordination event could be monitored from absorption and fluorescence spectroscopy. The high thermodynamic stability in water at physiological pH of ferric complex of TAME5OX indicates that these complexes are resistant to hydrolysis and therefore are well suited for the development of device for applications as probes. The ligand displays high sensitive fluorescence enhancement to Al3+ at pH 7.4, in water. Moreover, TAME5OX can distinguish Al3+ from Fe3+ and Cr3+ via two different sensing mechanisms: photoinduced electron transfer (PET) for Al3+ and internal charge transfer (ICT) for Fe3+ and Cr3+. Density functional theory was employed for optimization and evaluation of vibrational modes, NBO analysis, excitation and emission properties of the different species of metal complexes observed by solution studies.

  6. Synthetic routes to the Neuropeptide Y Y1 receptor antagonist 1229U91 and related analogues for SAR studies and cell-based imaging.

    PubMed

    Mountford, Simon J; Liu, Mengjie; Zhang, Lei; Groenen, Marleen; Herzog, Herbert; Holliday, Nicholas D; Thompson, Philip E

    2014-05-28

    The potent Y1 receptor antagonist, 1229U91 has an unusual cyclic dimer structure that makes syntheses of analogue series quite challenging. We have examined three new routes to the synthesis of such peptides that has given access to novel structural variants including heterodimeric compounds, ring size variants and labelled conjugates. These compounds, including a fluorescently labelled analogue VIII show potent antagonism that can be utilised in studying Y1 receptor pharmacology. PMID:24733083

  7. TREATABILITY STUDIES FOR WOOD PRESERVING SITES

    EPA Science Inventory

    The U.S. Environmental Protection Agency (EPA), National Risk Management Research Laboratory (NRMRL), Site Management Support Branch, conducted a comprehensive treatability project for wood preserving sites in 1995 and 1996. This is a compilation report on the treatability studi...

  8. Three-dimensional quantitative structure-activity relationship study on antioxidant capacity of curcumin analogues

    NASA Astrophysics Data System (ADS)

    Chen, Bohong; Zhu, Zhibo; Chen, Min; Dong, Wenqi; Li, Zhen

    2014-03-01

    A comparative molecular similarity indices analysis (CoMSIA) was performed on a set of 27 curcumin-like diarylpentanoid analogues with the radical scavenging activities. A significant cross-validated correlation coefficient Q2 (0.784), SEP (0.042) for CoMSIA were obtained, indicating the statistical significance of the correlation. Further we adopt a rational approach toward the selection of substituents at various positions in our scaffold,and finally find the favored and disfavoured regions for the enhanced antioxidative activity. The results have been used as a guide to design compounds that, potentially, have better activity against oxidative damage.

  9. The project De Caldas International Project: An example of a large-scale radwaste isolation natural analogue study

    SciTech Connect

    Shea, M.

    1995-09-01

    The proper isolation of radioactive waste is one of today`s most pressing environmental issues. Research is being carried out by many countries around the world in order to answer critical and perplexing questions regarding the safe disposal of radioactive waste. Natural analogue studies are an increasingly important facet of this international research effort. The Pocos de Caldas Project represents a major effort of the international technical and scientific community towards addressing one of modern civilization`s most critical environmental issues - radioactive waste isolation.

  10. 2,14-Dithiacalix[4]arene and its homooxa analogues: synthesis and dynamic NMR study of conformational behaviour.

    PubMed

    Hucko, Michal; Dvorkov, Hana; Eigner, Vclav; Lhotk, Pavel

    2015-04-25

    A simple and scalable synthesis of 2,14-dithiacalix[4]arene with alternating bridges (-CH2- and -S-) is reported. Proper selection of the bisphenol-based starting building blocks can provide not only the title compound (58%) but also yet unreported homooxa analogues possessing three different bridging units (-CH2-, -S- and -CH2-O-CH2-) in the molecule. These systems exhibit interesting conformational behaviour allowing for the study of flip-flop motion of the circular hydrogen bond arrays using dynamic NMR techniques. PMID:25807186

  11. Maltose neopentyl glycol-3 (MNG-3) analogues for membrane protein study.

    PubMed

    Cho, Kyung Ho; Husri, Mohd; Amin, Anowarul; Gotfryd, Kamil; Lee, Ho Jin; Go, Juyeon; Kim, Jin Woong; Loland, Claus J; Guan, Lan; Byrne, Bernadette; Chae, Pil Seok

    2015-05-01

    Detergents are typically used to both extract membrane proteins (MPs) from the lipid bilayers and maintain them in solution. However, MPs encapsulated in detergent micelles are often prone to denaturation and aggregation. Thus, the development of novel agents with enhanced stabilization characteristics is necessary to advance MP research. Maltose neopentyl glycol-3 (MNG-3) has contributed to >10 crystal structures including G-protein coupled receptors. Here, we prepared MNG-3 analogues and characterised their properties using selected MPs. Most MNGs were superior to a conventional detergent, n-dodecyl-?-D-maltopyranoside (DDM), in terms of membrane protein stabilization efficacy. Interestingly, optimal stabilization was achieved with different MNG-3 analogues depending on the target MP. The origin for such detergent specificity could be explained by a novel concept: compatibility between detergent hydrophobicity and MP tendency to denature and aggregate. This set of MNGs represents viable alternatives to currently available detergents for handling MPs, and can be also used as tools to estimate MP sensitivity to denaturation and aggregation. PMID:25813698

  12. Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone release.

    PubMed

    Small, C J; Morgan, D G; Meeran, K; Heath, M M; Gunn, I; Edwards, C M; Gardiner, J; Taylor, G M; Hurley, J D; Rossi, M; Goldstone, A P; O'Shea, D; Smith, D M; Ghatei, M A; Bloom, S R

    1997-10-14

    Hypothalamic neuropeptide Y (NPY) is thought to be important in the regulation of feeding and also in the release of Adrenocorticotrophic hormone (ACTH). Intracerebroventricular administration of NPY to male rats significantly increased plasma ACTH 10 min after injection and stimulated 2-h food intake. A series of analogues of NPY that have a greatly reduced affinity for the Y1 [human pancreatic polypeptide (human PP), NPY(3-36)], the Y2 ([Pro34]NPY, human PP), the Y3 (peptide YY), and the Y6 (human PP) receptor, all markedly stimulated ACTH release. Rat PP, which binds with high affinity to the Y4 receptor, was unable to stimulate ACTH release. A novel analogue fragment [Pro34]NPY(13-36) was synthesized as a ligand with low Y1 and Y2 receptor affinity. Interestingly, neither [Pro34]NPY(13-36) nor the selective Y5 receptor agonist [D-Trp32]NPY stimulated food intake, whereas both significantly increased plasma ACTH. Thus the hypothalamic NPY receptor mediating increases in plasma ACTH has a fragment activation profile unlike the Y1-Y4 or Y6 receptors and appears distinct from the NPY receptor controlling food intake. PMID:9326671

  13. Peptide analogue studies of the hypothalamic neuropeptide Y receptor mediating pituitary adrenocorticotrophic hormone?release

    PubMed Central

    Small, C. J.; Morgan, D. G. A.; Meeran, K.; Heath, M. M.; Gunn, I.; Edwards, C. M. B.; Gardiner, J.; Taylor, G. M.; Hurley, J. D.; Rossi, M.; Goldstone, A. P.; OShea, D.; Smith, D. M.; Ghatei, M. A.; Bloom, S. R.

    1997-01-01

    Hypothalamic neuropeptide Y (NPY) is thought to be important in the regulation of feeding and also in the release of Adrenocorticotrophic hormone (ACTH). Intracerebroventricular administration of NPY to male rats significantly increased plasma ACTH 10 min after injection and stimulated 2-h food intake. A series of analogues of NPY that have a greatly reduced affinity for the Y1 [human pancreatic polypeptide (human PP), NPY(336)], the Y2 ([Pro34]NPY, human PP), the Y3 (peptide YY), and the Y6 (human PP) receptor, all markedly stimulated ACTH release. Rat PP, which binds with high affinity to the Y4 receptor, was unable to stimulate ACTH release. A novel analogue fragment [Pro34]NPY(1336) was synthesized as a ligand with low Y1 and Y2 receptor affinity. Interestingly, neither [Pro34]NPY(1336) nor the selective Y5 receptor agonist [d-Trp32]NPY stimulated food intake, whereas both significantly increased plasma ACTH. Thus the hypothalamic NPY receptor mediating increases in plasma ACTH has a fragment activation profile unlike the Y1Y4 or Y6 receptors and appears distinct from the NPY receptor controlling food intake. PMID:9326671

  14. Developing Study Stations on Your School Site.

    ERIC Educational Resources Information Center

    Ohio State Dept. of Natural Resources, Columbus. Office of Information and Education.

    The school site is a convenient location for study stations since it is available for short periods of time and can be used consistently. Special preparations, such as transportation, required for off-site fieldtrips can be eliminated. In addition, on-site activities provide students with concrete experiences necessary to understand difficult

  15. Developing Study Stations on Your School Site.

    ERIC Educational Resources Information Center

    Ohio State Dept. of Natural Resources, Columbus. Office of Information and Education.

    The school site is a convenient location for study stations since it is available for short periods of time and can be used consistently. Special preparations, such as transportation, required for off-site fieldtrips can be eliminated. In addition, on-site activities provide students with concrete experiences necessary to understand difficult…

  16. Alternating-Site Mechanism of Kinesin-1 Characterized by Single-Molecule FRET Using Fluorescent ATP Analogues

    PubMed Central

    Verbrugge, Sander; Lechner, Bettina; Woehlke, Gnther; Peterman, Erwin J.G.

    2009-01-01

    Abstract Kinesin-1 motor proteins move along microtubules in repetitive steps of 8 nm at the expense of ATP. To determine nucleotide dwell times during these processive runs, we used a Frster resonance energy transfer method at the single-molecule level that detects nucleotide binding to kinesin motor heads. We show that the fluorescent ATP analog used produces processive motility with kinetic parameters altered <2.5-fold compared with normal ATP. Using our confocal fluorescence kinesin motility assay, we obtained fluorescence intensity time traces that we then analyzed using autocorrelation techniques, yielding a time resolution of ?1 ms for the intensity fluctuations due to fluorescent nucleotide binding and release. To compare these experimental autocorrelation curves with kinetic models, we used Monte-Carlo simulations. We find that the experimental data can only be described satisfactorily on the basis of models assuming an alternating-site mechanism, thus supporting the view that kinesin's two motor domains hydrolyze ATP and step in a sequential way. PMID:19580755

  17. Invariom based electron density studies on the C/Si analogues haloperidol/sila-haloperidol and venlafaxine/sila-venlafaxine.

    PubMed

    Luger, Peter; Dittrich, Birger; Tacke, Reinhold

    2015-09-14

    The subjects of this study are the structures and electron densities of the carbon/silicon analogues haloperidol/sila-haloperidol (1a/1b) and venlafaxine/sila-venlafaxine (2a/2b). The parent carbon compounds 1a (an antipsychotic agent) and 2a (an antidepressant) are both in clinical use. For haloperidol/sila-haloperidol, three published structures were studied in more detail: the structures of haloperidol hydrochloride (1aHCl), haloperidol hydropicrate (1aHPic) and sila-haloperidol hydrochloride (1bHCl). For venlafaxine/sila-venlafaxine, the published structures of venlafaxine (2a), venlafaxine hydrochloride (2aHCl; as orthorhombic (2aHCl-ortho) and monoclinic polymorph (2aHCl-mono)) and sila-venlafaxine hydrochloride (2bHCl) were investigated. Based on these structures, the molecular electron densities were reconstructed by using the invariom formalism. They were further analysed in terms of Bader's quantum theory of atoms in molecules, electrostatic potentials mapped onto electron density isosurfaces and Hirshfeld surfaces. These studies were performed with a special emphasis on the comparison of the corresponding carbon/silicon analogues. PMID:26222713

  18. Antimicrobial activities and action mechanism studies of transportan 10 and its analogues against multidrug-resistant bacteria.

    PubMed

    Xie, Junqiu; Gou, Yuanmei; Zhao, Qian; Li, Sisi; Zhang, Wei; Song, Jingjing; Mou, Lingyun; Li, Jingyi; Wang, Kairong; Zhang, Bangzhi; Yang, Wenle; Wang, Rui

    2015-07-01

    The increased emergence of multidrug-resistant bacteria is perceived as a critical public health threat, creating an urgent need for the development of novel classes of antimicrobials. Cell-penetrating peptides that share common features with antimicrobial peptides have been found to have antimicrobial activity and are currently being considered as potential alternatives to antibiotics. Transportan 10 is a chimeric cell-penetrating peptide that has been reported to transport biologically relevant cargoes into mammalian cells and cause damage to microbial membranes. In this study, we designed a series of TP10 analogues and studied their structure-activity relationships. We first evaluated the antimicrobial activities of these compounds against multidrug-resistant bacteria, which are responsible for most nosocomial infections. Our results showed that several of these compounds had potent antimicrobial and biofilm-inhibiting activities. We also measured the toxicity of these compounds, finding that Lys substitution could increase the antimicrobial activity but significantly enhanced the cytotoxicity. Pro introduction could reduce the cytotoxicity but disrupted the helical structure, resulting in a loss of activity. In the mechanistic studies, TP10 killed bacteria by membrane-active and DNA-binding activities. In conclusion, TP10 and its analogues could be developed into promising antibiotic candidates for the treatment of infections caused by multidrug-resistant bacteria. PMID:25891396

  19. Hemisynthesis, Antitumoral Effect, and Molecular Docking Studies of Ferutinin and Its Analogues.

    PubMed

    Safi, Rémi; Rodriguez, Fréderic; Hilal, Georges; Diab-Assaf, Mona; Diab, Youssef; El-Sabban, Marwan; Najjar, Fadia; Delfourne, Evelyne

    2016-03-01

    The natural product ferutinin was shown to act as an agonist to estrogen receptor ERα and agonist/antagonist to ERβ featuring a weak antiproliferative activity toward breast cancer cells. To enhance this activity, ferutinin analogues were synthesized by esterification of jaeschkenadiol with different acids. These compounds were assayed for their in vitro antiproliferative activity against estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cell lines. Among the compounds, 3c' exhibited a potent inhibitory selective activity against MCF-7 with IC50 value of 1 μm. Docking simulation of 3c' in the ligand binding domain of the ERs indicated a potential antagonism interaction with both ER subtypes. Functional assay showed that 3c' binds as an antagonist to ERα protein while ferutinin acts as an agonist. PMID:26432755

  20. Photophysical and nonlinear optical studies of tetraakynyl zincphthalocyanine and its "clicked" analogue

    NASA Astrophysics Data System (ADS)

    Bankole, Owolabi M.; Nyokong, Tebello

    2015-06-01

    We report here for the first time on the photophysical and nonlinear optical behavior of tetra-substituted alkynyl zinc phthalocyanine and its "clicked" analogue (4 and 5). The compounds exhibited high triplet quantum yields in dimethylsulphoxide (DMSO). Nonlinear optical (NLO) properties were also evaluated for the two compounds at 532 nm and 10 ns in DMSO. We observed two-photon absorption (2PA) and strong reverse saturable absorption (RSA) as the dominant mechanisms at nanosecond laser excitation. The presence of electron acceptor groups fused with triazole linkers in the peripheral positions of 4 provide excellent coexistent features, such as enhanced triplet quantum yields and lifetimes compared to 5. Large third-order susceptibility (2.09 × 10-11 and 3.53 × 10-9 esu) and hyperpolarizability (1.09 × 10-30 and 9.13 × 10-29 esu) were estimated for complexs 4 and 5, respectively.

  1. Thyroxine analogues. 23. Quantitative structure-activity correlation studies of in vivo and in vitro thyromimetic activities.

    PubMed

    Dietrich, S W; Bolger, M B; Kollman, P A; Jorgensen, E C

    1977-07-01

    Quantitative structure-activity correlation studies of thyroid hormone analogues have been utilized to examine (1) in vivo rat antigoiter activities; (2) in vitro binding affinities to intact rat hepatic nuclei, solubilized rat hepatic nuclear protein receptors, and the plasma protein thyroxine binding globulin; and (3) correlations between in vivo antigoiter activities and in vitro binding to nuclear receptors. These studies provide a more precise elucidation of the relative importance of the physiochemical factors which influence thyromimetic activities. In particular, they (1) provide the first systematic QSAR examination of drug-receptor interactions and of the dependence of in vivo activity on such interactions; (2) demonstrate the importance of the interactive effects of the 3' and 5' substituents and of the 4'-OH with each other as well as with nuclear receptors in influencing binding affinity; (3) support the hypothesis that binding to nuclear receptors is the first step in initiating the events which lead to subsequent hormonal expression; (4) show that the free energy of binding to nuclear receptors can be factored into the contributing physicochemical properties of the substituents; and (5) suggest factors that need to be considered in designing new analogues. PMID:195056

  2. Immunogenicity study of Globo H analogues with modification at the reducing or nonreducing end of the tumor antigen.

    PubMed

    Lee, Hsin-Yu; Chen, Chien-Yu; Tsai, Tsung-I; Li, Shiou-Ting; Lin, Kun-Hsien; Cheng, Yang-Yu; Ren, Chien-Tai; Cheng, Ting-Jen R; Wu, Chung-Yi; Wong, Chi-Huey

    2014-12-01

    Globo H-based therapeutic cancer vaccines have been tested in clinical trials for the treatment of late stage breast, ovarian, and prostate cancers. In this study, we explored Globo H analogue antigens with an attempt to enhance the antigenic properties in vaccine design. The Globo H analogues with modification at the reducing or nonreducing end were synthesized using chemoenzymatic methods, and these modified Globo H antigens were then conjugated with the carrier protein diphtheria toxoid cross-reactive material (CRM) 197 (DT), and combined with a glycolipid C34 as an adjuvant designed to induce a class switch to form the vaccine candidates. After Balb/c mice injection, the immune response was studied by a glycan array and the results showed that modification at the C-6 position of reducing end glucose of Globo H with the fluoro, azido, or phenyl group elicited IgG antibody response to specifically recognize Globo H (GH) and the GH-related epitopes, stage-specific embryonic antigen 3 (SSEA3) (also called Gb5) and stage-specific embryonic antigen 4 (SSEA4). However, only the modification of Globo H with the azido group at the C-6 position of the nonreducing end fucose could elicit a strong IgG immune response. Moreover, the antibodies induced by these vaccines were shown to recognize GH expressing tumor cells (MCF-7) and mediate the complement-dependent cell cytotoxicity against tumor cells. Our data suggest a new potential approach to cancer vaccine development. PMID:25371992

  3. An NHC-Stabilized Silicon Analogue of Acylium Ion: Synthesis, Structure, Reactivity, and Theoretical Studies.

    PubMed

    Ahmad, Syed Usman; Szilvsi, Tibor; Irran, Elisabeth; Inoue, Shigeyoshi

    2015-05-01

    The silicon analogues of an acylium ion, namely, sila-acylium ions 2a and 2b [RSi(O)(NHC)2]Cl stabilized by two N-heterocyclic carbenes (NHC = 1,3,4,5-tetramethylimidazol-2-ylidene), and having chloride as a countercation were successfully synthesized by the reduction of CO2 using the donor stabilized silyliumylidene cations 1a and 1b [RSi(NHC)2]Cl (1a, 2a; R = m-Ter = 2,6-Mes2C6H3, Mes = 2,4,6-Me3C6H2 and 1b, 2b; R = Tipp = 2,4,6-iPr3C6H2). Structurally, compound 2a features a four coordinate silicon center together with a double bond between silicon and oxygen atoms. The reaction of sila-acylium ions 2a and 2b with water afforded different products which depend on the bulkiness of aryl substituents. Although the exposure of 2a to H2O afforded a stable silicon analogue of carboxylate anion as a dimer form, [m-TerSi(O)O]2(2-)2[NHC-H](+) (3), the same reaction with the less bulkier triisopropylphenyl substituted sila-acylium ion 2b afforded cyclotetrasiloxanediol dianion [{TippSi(O)}4{(O)OH}2](2-)2[NHC-H](+) (4). Metric and DFT (Density Functional Theory) evidence support that 2a and 2b possess strong Si?O double bond character, while 3 and 4 contain more ionic terminal Si-O bonds. Mechanistic details of the formation of different (SiO)n (n = 2, 3, 4) core rings were explored using DFT to explain the experimentally characterized products and a proposed stable intermediate was identified with mass spectrometry. PMID:25871835

  4. Study of the conformational profile of the norbornane analogues of phenylalanine.

    PubMed

    Cordom, Arnau; Gomez-Catalan, Jesus; Jimenez, Ana I; Cativiela, Carlos; Perez, Juan J

    2002-06-01

    The conformational profile of the eight stereoisomeric 2-amino-3-phenylnorbornane-2-carboxylic acids (2-amino-3-phenylbicyclo[2.2.1]heptane-2-carboxylic acids) has been assessed by computational methods. These molecules constitute a series of four enantiomeric pairs that can be considered as rigid analogues of either L- or D-phenylalanine. The conformational space of their N-acetyl methylamide derivatives has been explored within the molecular mechanics framework, using the parm94 set of parameters of the AMBER force field. Local minimum energy conformations have been further investigated at the ab initio level by means of the Hartree-Fock and second order Moller-Plesset perturbation energy calculations using a 6-31G(d) basis set. The results of the present work suggest that the bulky norbornane structure induces two kinds of conformational constraints on the residues. On one hand, those of a steric nature directly imposed by the bicycle on the peptide backbone and, on the other hand, those that limit the orientations attainable by the phenyl ring which, in turn, reduces further the flexibility of the peptide backbone. A comparative analysis of the conformational profile of the phenylnorbornane amino acids with that of the norbornane amino acids devoid of the beta-phenyl substituent suggests that the norbornane system hampers the residue to adopt extended conformations in favour of C7-like structures. However, the bicycle itself does not impart a clear preference for any of the two possible C7 minima. It is the aromatic side chain, which is forced to adopt an almost eclipsed orientation, that breaks this symmetry introducing a marked preference for a single region of the (phi, psi) conformational space in each of the phenylalanine norbornane analogues investigated. PMID:12093002

  5. The Cheb Basin (Czech Republic) as a Potential Natural Analogue Site for Geological Carbon Storage - Past, Current and Planned Activities

    NASA Astrophysics Data System (ADS)

    Schuetze, C.; Dietrich, P.; Strauch, G.; Braeuer, K.; Schloemer, S.; Faber, E.; Kaempf, H.; Flechsig, C.

    2011-12-01

    General difficulties for evaluating methods for the detection and monitoring of CO2 spreading and degassing to the atmosphere induced by CO2 sequestration are the time scale of transport processes and the desired situation of a non-release of sequestered CO2 from the subsurface. The unique structures of the Cheb Basin (western Eger rift / Czech Republic) provide excellent opportunities for further direct investigations of transport processes along migration paths caused by cap rock failures and the development and validation of adequate monitoring tools. The Eger rift belongs to the European Cenozoic rift system and represents an approximately 50 km wide and 300 km long ENE-WSW striking continental rift that formed during the Upper Cretaceous-Tertiary transition. This rift zone is one of the most active seismic regions in Central Europe. This rift zone is one of the most active seismic regions in Central Europe. There are a lot of gas emanations (cold vents) with high CO2 contents (> 99 vol% CO2). The CO2-fluxes vary in a wide range between smaller than 1 up to 4000 L/h per vent. The degassing activity is assumed to be generally connected to the seismic activity, which has mainly a swarm-like character, and is originated in the upper mantle. Comprehensive studies of CO2-rich fluids have been started 20 years ago and have in particular included two extended chemical and isotope monitoring studies lasting for several years. These studies result in the identification of the fluid component sources. The CO2 stems from the lithospheric mantle - a deeper source area as in the case of CO2 sequestration. A distinct relationship was found between the steadily magmatic CO2-degassing and the recurrence of swarm earthquakes in the Novy Kostel focal zone close to the Cheb basin. Such areas with permanent CO2 fluxes from a well-known characterized deep source are especially suitable to study and test methods and method combinations for CO2 degassing monitoring. Several past and ongoing geophysical investigations concerning the geodynamical activity and the structural settings have been carried out to characterize the active fault systems. The lateral distribution of swarm seismicity is limited to a small number of focal zones, which have been periodically reactivated during the last years. The migration of fluids, uprising in permeable channels, is assumed to be the trigger of these earthquake swarms. Tectonic setting and sedimentary layers in the area have a great influence on the degassing situation of CO2 at the surface. Due to their permeability, faults act as preferential pathways for the upward migration and deep gases can escape to the atmosphere. Furthermore, regional patterns of diffuse CO2 emissions have been intensely studied to obtain insights into spatial and temporal variations of soil gas fluxes and concentrations.

  6. A perfusion study of the handling of urea and urea analogues by the gills of the dogfish shark (Squalus acanthias).

    PubMed

    Wood, Chris M; Liew, Hon Jung; De Boeck, Gudrun; Walsh, Patrick J

    2013-01-01

    The branchial mechanism of urea retention in elasmobranchs was investigated using an in vitro isolated-perfused head preparation, as well as in vivo samples, in the spiny dogfish shark. Both in vivo and in control saline perfusions containing 350mmolL(-1) urea, calculated intracellular urea concentrations in gill epithelial cells were close to extracellular concentrations. Urea efflux to the external water fell only non-significantly, and calculated gill intracellular urea concentration did not change when perfusate urea concentration was reduced from 350 to 175mmol?L(-1) with osmotic compensation by 175mmolL(-1) mannitol. However, when the urea analogues thiourea or acetamide were present in the perfusate at concentrations equimolar (175mmolL(-1)) to those of urea (175mmolL(-1)), urea efflux rates were increased 4-fold and 6.5-fold respectively, and calculated gill intracellular urea concentrations were depressed by about 55%. Analogue efflux rates were similar to urea efflux rates. Previous studies have argued that either the basolateral or apical membranes provided the limiting permeability barrier, and/or that a back-transporter on the basolateral membranes of gill cells is responsible for urea retention. The present results provide new evidence that the apical membrane is the limiting factor in maintaining gill urea impermeability, and raise the prospect that a urea back-transporter, which can be competitively inhibited by thiourea and acetamide, operates at the apical membrane. PMID:23638369

  7. Synthesis and renin inhibitory activity of angiotensinogen analogues having dehydrostatine, Leu psi [CH2S]Val, or Leu psi [CH2SO]Val at the P1-P1' cleavage site.

    PubMed

    Smith, C W; Saneii, H H; Sawyer, T K; Pals, D T; Scahill, T A; Kamdar, B V; Lawson, J A

    1988-07-01

    The synthesis and in vitro renin inhibitory potencies of angiotensinogen (ANG) analogues having amide (CONH) bond replacements at P1-P1', the Leu-Val cleavage site, corresponding to Leu psi[CH2SO]Val, and the trans olefinic analogue of statine (Sta), 4(S)-amino-6-methyl-2(E)-heptenoic acid (dehydrostatine, Dhs), are reported. These are compared to P1-P1' Leu psi[CH2NH]Val-, Sta-, or Phe-Phe-substituted analogues of the same template. The Dhs pseudodipeptide was found to be an adequate mimic of a trans CONH bond and gave a peptide, H-Pro-His-Pro-Phe-His-Dhs-Ile-His-D-Lys-OH, approximately equal in potency to a Phe-Phe-containing inhibitor, but 200-fold less potent than its Sta-substituted congener. That the enhanced potency of the Sta-containing peptide most likely depends on hydrogen bonding as well as tetrahedral geometry is indicated by the 50-100-fold lower potency of the tetrahedral Leu psi[CH2S]Val and Leu psi[CH2SO]Val analogues as compared to the Leu psi[CH2NH]Val-containing congener. PMID:3290486

  8. Development predictive QSAR models for artemisinin analogues by various feature selection methods: a comparative study.

    PubMed

    Abbasitabar, F; Zare-Shahabadi, V

    2012-01-01

    Quantitative structure-activity relationship (QSAR) models were derived for 179 analogues of artemisinin, a potent antimalarial agent. The activities of these compounds were investigated by means of multiple linear regression (MLR). To select relevant descriptors, several methods including stepwise selection, successive projection algorithm and an ant colony optimization algorithm (called memorized_ACS) were employed. A wide variety of molecular descriptors belonging to various structural properties were calculated for each molecule. Two matrixes (D1 and D2) of molecular properties were built. The D1 matrix included the calculated descriptors and the D2 matrix contained the first to third orders of the calculated descriptors and the logarithm of absolute values of the calculated descriptors. For both data matrixes, significant QSAR models were obtained by the memorized_ACS algorithm. The reactive and PEOE (partial equalization of orbital electronegativity) descriptors represented the highest impact on the antimalarial activity. The PEOE descriptors belong to partial charge descriptors and the reactive descriptor is an indicator of the presence of the reactive groups in the molecule. The best MLR model has a training error of 0.71 log RA units (r (2 )= 0.81) and a prediction error of 0.48 log RA units (r (2) = 0.88). PMID:22040327

  9. Talking about depression: An analogue study of physician gender and communication style on patient disclosures

    PubMed Central

    Roter, Debra L.; Erby, Lori H.; Adams, Ann; Buckingham, Christopher D; Vail, Laura; Realpe, Alba; Larson, Susan; Hall, Judith A.

    2014-01-01

    Objectives To disentangle the effects of physician gender and patient-centered communication style on patients oral engagement in depression care. Methods Physician gender, physician race and communication style (high patient-centered (HPC) and low patient-centered (LPC)) were manipulated and presented as videotaped actors within a computer simulated medical visit to assess effects on analogue patient (AP) verbal responsiveness and care ratings. 307 APs (56% female; 70% African American) were randomly assigned to conditions and instructed to verbally respond to depression-related questions and indicate willingness to continue care. Disclosures were coded using Roter Interaction Analysis System (RIAS). Results Both male and female APs talked more overall and conveyed more psychosocial and emotional talk to HPC gender discordant doctors (all p <.05). APs were more willing to continue treatment with gender-discordant HPC physicians (p<.05). No effects were evident in the LPC condition. Conclusions Findings highlight a role for physician gender when considering active patient engagement in patient-centered depression care. This pattern suggests that there may be largely under-appreciated and consequential effects associated with patient expectations in regard to physician gender that these differ by patient gender. Practice Implications High patient-centeredness increases active patient engagement in depression care especially in gender discordant dyads. PMID:24882087

  10. Studies on the mechanisms of the radiosensitizing and cytotoxic properties of RSU-1069 and its analogues

    SciTech Connect

    Walling, J.M.; Stratford, I.J.; Adams, G.E.; Silver, A.R.; Ahmed, I.; Jenkins, T.C.; Fielden, E.M.

    1986-07-01

    RSU 1069 is a substantially more efficient sensitizer than misonidazole when hypoxic Chinese hamster V79 cells are irradiated in vitro at room temperature; such that for 0.5 mmol dm-3 sensitizer an ER of 3.0 is obtained for RSU 1069 whereas an ER of only 1.6 is obtained for misonidazole. However, when irradiation is done at 4/sup 0/C, the radiosensitization caused by RSU 1069 is reduced to a level close to that obtained with misonidazole, the action remaining unaltered at the lower temperature. This temperature dependent component of sensitization for RSU 1069 suggests the involvement of a slow biochemical process that has an appreciable activation energy. The RSU 1069 analogue RB 7040 is a more efficient radiosensitizer than RSU 1069 particularly at lower concentrations. This compound has a pKa value of 8.45, in contrast to that of RSU 1069 which is 6.04. Weak bases with pKa values in excess of average intra-cellular pH can be taken up preferentially into cells from medium at pH 7.4. It is shown that RB 7040 has a 4 X higher intracellular concentration than RSU 1069 for a similar extracellular concentration. This will explain, at least in part, the greater sensitizing efficiency of this compound when compared to RSU 1069 in vitro.

  11. Chemical diffusivity of perovskite and post-perovskite from studies of fluoride analogues.

    NASA Astrophysics Data System (ADS)

    Dobson, D. P.; Lindsay-Scott, A.; Wood, I. G.; Bailey, E.; Brodholt, J. P.; Vocadlo, L.

    2014-12-01

    The physical properties of post-perovskite are thought to strongly influence the dynamics of the D'' region at the base of the Earth's mantle, however many of these properties are difficult to directly measure on MgSiO3 post-perovskite. Ab initio simulations (1) predicted that chemical diffusivity of Mg and Si in post-perovskite MgSiO3 is significantly anisotropic (with 8 orders of magnitude difference between the fast [001] and slow [010] directions) and with the fast direction some four orders of magnitude faster than diffusion in perovskite. While the simulations reproduced the available experiments on perovskite very well the surprising result for post-perovskite merits testing.Post-perovskite CaIrO3 does not show strong anisotropy in Ir-Pt interdiffusivity by either experiment or simulation (2) but the fluoride analogue systems are predicted by ab initio simulations to show very similar anisotropy to MgSiO3 and the difference between perovskite and post-perovskite are, likewise, similar to the silicate system. Here we present measured and simulated diffusivities for NaXF3 perovskite and post-perovskite (X = Zn, Mn, Co, Ni).References:1) Ammann, M.W., Brodholt, J.P., Wookey, J. and Dobson, D.P. First Principles Constraints on Diffusion in Lower Mantle Minerals and a Weak D'' Layer. Nature, 465, 462-465, 2010.2) McCormack, R. Ph.D thesis University College London, 2012.

  12. Cyclopenta[c]selenophene based cooligomers and their polymers: comparative study with thiophene analogues.

    PubMed

    Das, Soumyajit; Bedi, Anjan; Krishna, G Rama; Reddy, C Malla; Zade, Sanjio S

    2011-10-21

    Selenophene and thiophene capped cyclopenta[c]selenophenes were synthesized and characterized. Crystal structure determination of some representative compounds revealed that the substitution at 3,4-position in the form of cyclopentane ring of selenophene or thiophene does not make any significant twist in the trimer backbone, making the cooligomer nearly planar. All the cooligomers were electrochemically polymerized and compared with thiophene capped cyclopenta[c]thiophene polymer. DFT calculations predict that the cyclopentane substitution on the third repeating unit (and in general) of one dimensional polymer neither disturb the planarity nor causes any significant twist on the polymeric backbone unlike the 3,4-dialkyl substitution. The electrochemically prepared selenophene based polymers showed low band gap compared to that of thiophene analogues. Cyclopentane substitution on selenophene as well as thiophene makes the resulting polymer oxidatively more stable when compared to more familiar poly-ethylenedioxythiophene (PEDOT) or poly-ethylenedioxyselenophene (PEDOS) systems. Alternate polymers of cyclopenta[c]selenophenes (CPS)/cyclopenta[c]thiophene (CPT) and thiophene/selenophene possess the energy of HOMO and LUMO significantly lower than that of homopolymers of CPS and CPT, however, possess higher band gap than PCPS. PMID:21879128

  13. Aspartame and Its Analogues

    NASA Astrophysics Data System (ADS)

    Pavlova, L. A.; Komarova, T. V.; Davidovich, Yurii A.; Rogozhin, S. V.

    1981-04-01

    The results of studies on the biochemistry of the sweet taste are briefly reviewed. The methods of synthesis of "aspartame" — a sweet dipeptide — are considered, its structural analogues are described, and quantitative estimates are made of the degree of sweetness relative to sucrose. Attention is concentrated mainly on problems of the relation between the structure of the substance and its taste in the series of aspartyl derivatives. The bibliography includes 118 references.

  14. Synthesis of a tritium-labeled indolidan analogue and its use as a radioligand for phosphodiesterase-inhibitor cardiotonic binding sites

    SciTech Connect

    Robertson, D.W.; Krushinski, J.H.; Utterback, B.G.; Kauffman, R.F.

    1989-07-01

    We have radiolabeled a structural analogue of indolidan, a potent phosphodiesterase-inhibitor cardiotonic, to permit biochemical studies regarding the interaction of this class of drugs with their pharmacological receptor. (/sup 3/H)-LY186126 (1,3-dihydro-3,3-dimethyl-1-(/sup 3/H3)methyl-5-(1,4,5,6-tetrahydro-4-me thyl-6- oxo-3-pyridazinyl)-2H-indol-2-one; (/sup 3/H)-3) was selected as a synthetic target because of its potency as a cardiotonic and the ability to readily incorporate three tritia via the indolone N-CH3 substituent. Alkylation of a desmethyl precursor with tritium-labeled iodomethane resulted in (/sup 3/H)-3 with a radiochemical purity of 98% and a specific activity of 79.2 Ci/mmol. This radioligand binds with high affinity to myocardial membrane vesicles. The binding was saturable, and Kd and Bmax values of 4.1 nM and 383 fmol/mg protein were obtained. A series of indolidan congeners displaced (/sup 3/H)-3 bound to myocardial vesicles, and Ki values for inhibition of binding were highly correlated with canine inotropic ED50 values, suggesting the specific binding of (/sup 3/H)-3 to cardiac vesicles is pharmacologically relevant.

  15. Formation of DNA nanoparticles in the presence of novel polyamine analogues: a laser light scattering and atomic force microscopic study

    PubMed Central

    Vijayanathan, Veena; Thomas, Thresia; Antony, Thomas; Shirahata, Akira; Thomas, T. J.

    2004-01-01

    We synthesized a pentamine (3-3-3-3) and two hexamine (3-3-3-3-3 and 3-4-3-4-3) analogues of the natural polyamine, spermine (3-4-3) and studied their effectiveness in condensing pGL3 plasmid DNA, using light scattering and atomic force microscopic (AFM) techniques. The midpoint concentration of the polyamines on pGL3 condensation (EC50) was 11.3, 10.6, 1.5, 0.49 and 0.52 M, respectively, for 3-4-3, norspermine (3-3-3), 3-3-3-3, 3-3-3-3-3 and 3-4-3-4-3 in 10 mM Na cacodylate buffer. Dynamic laser light scattering study showed a decrease in hydrodynamic radii of plasmid DNA particles as the number of positive charges on the polyamines increased. AFM data showed the presence of toroids with outer diameter of 117191 nm for different polyamines, and a mean height of 2.61 0.77 nm. AFM results also revealed the presence of intermediate structures, including those showing circumferential winding of DNA to toroids. The dependence of the EC50 on Na+ concentration suggests different modes of binding of spermine and its higher valent analogues with DNA. Our results show a 20-fold increase in the efficacy of hexamines for DNA condensation compared to spermine, and provide new insights into the mechanism(s) of DNA nanoparticle formation. These studies might help to develop novel nonviral gene delivery vehicles. PMID:14704349

  16. Formation of DNA nanoparticles in the presence of novel polyamine analogues: a laser light scattering and atomic force microscopic study.

    PubMed

    Vijayanathan, Veena; Thomas, Thresia; Antony, Thomas; Shirahata, Akira; Thomas, T J

    2004-01-01

    We synthesized a pentamine (3-3-3-3) and two hexamine (3-3-3-3-3 and 3-4-3-4-3) analogues of the natural polyamine, spermine (3-4-3) and studied their effectiveness in condensing pGL3 plasmid DNA, using light scattering and atomic force microscopic (AFM) techniques. The midpoint concentration of the polyamines on pGL3 condensation (EC50) was 11.3, 10.6, 1.5, 0.49 and 0.52 micro M, respectively, for 3-4-3, norspermine (3-3-3), 3-3-3-3, 3-3-3-3-3 and 3-4-3-4-3 in 10 mM Na cacodylate buffer. Dynamic laser light scattering study showed a decrease in hydrodynamic radii of plasmid DNA particles as the number of positive charges on the polyamines increased. AFM data showed the presence of toroids with outer diameter of 117-191 nm for different polyamines, and a mean height of 2.61 +/- 0.77 nm. AFM results also revealed the presence of intermediate structures, including those showing circumferential winding of DNA to toroids. The dependence of the EC50 on Na+ concentration suggests different modes of binding of spermine and its higher valent analogues with DNA. Our results show a 20-fold increase in the efficacy of hexamines for DNA condensation compared to spermine, and provide new insights into the mechanism(s) of DNA nanoparticle formation. These studies might help to develop novel nonviral gene delivery vehicles. PMID:14704349

  17. Sphingolipid metabolism in cultured fibroblasts: microscopic and biochemical studies employing a fluorescent ceramide analogue.

    PubMed Central

    Lipsky, N G; Pagano, R E

    1983-01-01

    A fluorescent analogue of ceramide, N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)]-epsilon-aminocaproyl sphingosine (C6-NBD-ceramide), was used to investigate sphingolipid metabolism in Chinese hamster fibroblasts. C6-NBD-ceramide was incorporated into small unilamellar dioleoyl phosphatidylcholine vesicles and incubated with cells in monolayer culture at 2 degrees C, resulting in rapid and preferential transfer of the labeled ceramide from vesicles to cells. The cells were then washed and subsequently incubated at 37 degrees C for various intervals. The metabolism of C6-NBD-ceramide was monitored by lipid extraction and analysis, and the intracellular distribution of the labeled molecule was followed by fluorescence microscopy. Initially, fluorescence was detected almost exclusively in mitochondria, with over 90% of the extractable lipid fluorescence due to C6-NBD-ceramide. After 30 min at 37 degrees C, intense fluorescence appeared in the Golgi apparatus. This organelle was identified by colocalization of NBD fluorescence with a Golgi-apparatus-specific stain. At later times the plasma membrane became visibly labeled as well, at which point 90% of the cell-associated fluorescence was recovered as NBD-labeled sphingomyelin and NBD-labeled cerebroside. These metabolites were identified by enzymatic and biochemical analysis and by thin-layer chromatography of the fluorescent lipid extracts. The finding that C6-NBD-ceramide is used by these cells in standard pathways of sphingolipid biosynthesis suggests that this fluorescent precursor will be a valuable tool for correlating the metabolism of sphingolipids with their intracellular distribution and translocation. In addition, during its metabolism by Chinese hamster fibroblasts, this compound acts as a vital stain for the Golgi apparatus. Images PMID:6573674

  18. Kinetic and in silico studies of novel hydroxy-based thymol analogues as inhibitors of mushroom tyrosinase.

    PubMed

    Ashraf, Zaman; Rafiq, Muhammad; Seo, Sung-Yum; Kwon, Kang Sung; Babar, Mustafeez Mujtaba; Zaidi, Najam-us-Sahar Sadaf

    2015-06-15

    The present studies reports the synthesis of hydoxylated thymol analogues (4a-e) and (6a-c) as mushroom tyrosinase inhibitors. The title compounds were obtained in good yield and characterized by FTIR, (1)H NMR, (13)C NMR, Mass spectral data and X-ray crystallography in case of compound (6a). The inhibitory effects on mushroom tyrosinase and DPPH were evaluated and it was observed that 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl (2E)-3-(4-hydroxyphenyl)prop-2-enoate (6b) showed tyrosinase inhibitory activity (IC50 15.20 μM) comparable to kojic acid (IC50 16.69 μM) while 2-[5-methyl-2-(propan-2-yl)phenoxy]-2-oxoethyl 3,4-dihydroxybenzoate (4d) exhibited higher antioxidant potential (IC50 11.30 μM) than standard ascorbic acid (IC50 24.20 μM). The docking studies of synthesized thymol analogues was also performed against tyrosinase protein (PDBID 2ZMX) to compare the binding affinities with IC50 values. The predicted binding affinities are in good agreement with the IC50 values as compound (6b) showed highest binding affinity -7.1 kcal/mol. The kinetic mechanism analyzed by Lineweaver-Burk plots exhibited that compound (4d) and (6b) inhibit the enzyme by two different pathways displayed mixed-type inhibition. The inhibition constants Ki calculated from Dixon plots for compounds (4d) and (6b) are 34 μM and 25 μM respectively. It was also found from kinetic analysis that derivative (6b) formed reversible enzyme inhibitor complex. It is propose on the basis of our investigation that title compound (6b) may serve as lead structure for the design of more potent tyrosinase inhibitors. PMID:26025140

  19. QM/MM Studies of the Matrix Metalloproteinase 2 (MMP2) Inhibition Mechanism of (S)-SB-3CT and its Oxirane Analogue

    PubMed Central

    Zhou, Jia; Tao, Peng; Fisher, Jed F.; Shi, Qicun; Mobashery, Shahriar; Schlegel, H. Bernhard

    2010-01-01

    SB-3CT, (4-phenoxyphenylsulfonyl)methylthiirane, is a potent, mechanism-based inhibitor of the gelatinase sub-class of the matrix metalloproteinase (MMP) family of zinc proteases. The gelatinase MMPs are unusual in that there are several examples where both enantiomers of a racemic inhibitor have comparable inhibitory abilities. SB-3CT is one such example. Here, the inhibition mechanism of the MMP2 gelatinase by the (S)-SB-3CT enantiomer and its oxirane analogue is examined computationally, and compared to the mechanism of (R)-SB-3CT. Inhibition of MMP2 by (R)-SB-3CT was shown previously to involve enzyme-catalyzed CH deprotonation adjacent to the sulfone, with concomitant opening by ?-elimination of the sulfur of the three-membered thiirane ring. Similarly to the R enantiomer, (S)-SB-3CT was docked into the active site of MMP2, followed by molecular dynamics simulation to prepare the complex for combined quantum mechanics and molecular mechanics (QM/MM) calculations. QM/MM calculations with B3LYP/6-311+G(d,p) for the QM part (46 atoms) and the AMBER force field for the MM part were used to compare the reaction of (S)-SB-3CT and its oxirane analogue in the active site of MMP2 (9208 atoms). These calculations show that the barrier for the proton abstraction coupled ring opening reaction of (S)-SB-3CT in the MMP2 active site is 4.4 kcal/mol lower than its oxirane analogue, and the ring opening reaction energy of (S)-SB-3CT is only 1.6 kcal/mol less exothermic than its oxirane analogue. Calculations also show that the protonation of the ring-opened products by water is thermodynamically much more favorable for the alkoxide obtained from the oxirane, than for the thiolate obtained from the thiirane. In contrast to (R)-SB-3CT and the R-oxirane analogue, the double bonds of the ring-opened products of (S)-SB-3CT and its S-oxirane analogue have the cis-configuration. Vibrational frequency and intrinsic reaction path calculations on a reduced size QM/MM model (2747 atoms) provide additional insight into the mechanism. These calculations yield 5.9 and 6.7 for the deuterium kinetic isotope effect for CH bond cleavage in the transition state for the R and S enantiomers of SB-3CT, in good agreement with the experimental results. PMID:21076643

  20. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide

    PubMed Central

    Barnett, A H

    2012-01-01

    In people with type 2 diabetes mellitus (T2DM), the incretin effect is reduced, but the recent advent of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide (GLP)-1 agonists/analogues has enabled restoration of at least some of the function of the incretin system, with accompanying improvements in glycaemic control. Two GLP-1 receptor agonists/analogues are currently approved for the treatment of T2DM—exenatide (Byetta®, Eli Lilly & Co., Indianapolis, IN, US) and liraglutide (Victoza®, Novo Nordisk, Bagsvaerd, Denmark); a once-weekly formulation of exenatide (Bydureon®, Eli Lilly & Co.) has also been approved by the European Medicines Agency. The National Institute for Health and Clinical Excellence (NICE) has recently published guidance on the use of liraglutide in T2DM, based on evidence from the Liraglutide Effect and Action in Diabetes (LEAD) Phase III trial programme, which compared liraglutide with existing glucose-lowering therapies, such as exenatide and insulin glargine. The LEAD programme reported HbA1c reductions from 0.8 to 1.5% with liraglutide (1.2 and 1.8 mg), accompanied by low rates of hypoglycaemia and some weight loss; side effects were primarily gastrointestinal in nature (e.g. nausea and diarrhoea). Based on the findings of the LEAD studies and the NICE recommendation, liraglutide now represents an important therapy widely available in the UK for certain patient groups, including those with a body mass index (BMI) ≥35.0 kg/m2, and patients with a BMI <35 kg/m2 who are considered unsuitable for insulin and are failing to meet targets for glycaemic control with oral agents. NICE guidelines still suggest that most patients without considerable obesity (BMI <35 kg/m2) are probably best managed using insulin therapy. Evidence also suggests a future role for GLP-1 mimetics in combination with basal insulin. PMID:22051096

  1. Migrastatin analogues target fascin to block tumour metastasis

    SciTech Connect

    Chen, L.; Jakoncic, J.; Yang, S.; Zhang, J.; Huang, X.Y.

    2010-04-15

    Tumour metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumour metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and synthesized migrastatin analogues such as macroketone are potent inhibitors of metastatic tumour cell migration, invasion and metastasis. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins such as fascin can be explored as new molecular targets for cancer treatment, in a similar manner to the microtubule protein tubulin.

  2. Migrastatin Analogues Target Fascin to Block Tumor Metastasis

    PubMed Central

    Chen, Lin; Yang, Shengyu; Jakoncic, Jean; Zhang, J. Jillian; Huang, Xin-Yun

    2010-01-01

    Tumor metastasis is the primary cause of death of cancer patients. Development of new therapeutics preventing tumor metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces 1,2, and synthesized migrastatin analogues are potent inhibitors of metastatic tumor cell migration, invasion and tumor metastasis 3–6. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit its activity. X-ray crystal structural studies reveal that migrastatin analogues bind to one of the actin-binding sites on fascin. Our data demonstrate that actin cytoskeletal proteins, such as fascin, can be explored as new molecular targets for cancer treatment, similar to the microtubule protein tubulin. PMID:20393565

  3. Pre-clinical and Clinical Safety Studies of CMX-2043: a cytoprotective lipoic acid analogue for ischaemia-reperfusion injury.

    PubMed

    Kates, Steven A; Lader, Alan S; Casale, Ralph; Beeuwkes, Reinier

    2014-11-01

    CMX-2043 is an ?-lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemia-reperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4?g/mL (10?M). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial. PMID:24751172

  4. Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for IschaemiaReperfusion Injury

    PubMed Central

    Kates, Steven A; Lader, Alan S; Casale, Ralph; Beeuwkes, Reinier

    2014-01-01

    CMX-2043 is an ?-lipoic acid analogue targeted to reduction of cellular injury and organ damage due to ischaemiareperfusion injury (IRI). It has been shown to be effective in a rat model of cardiac IRI. The studies here reported evaluate its safety and pharmacokinetic profile in preparation for human clinical studies in procedures associated with IRI. Safety and tolerability were tested in standard pre-clinical in vitro and animal models and in a Phase 1 human clinical trial. CMX-2043 did not bind to a wide range of receptors and specific targets at approximately 4?g/mL (10?M). It was not mutagenic by Ames assay, did not produce chromosome aberrations in Chinese hamster ovary (CHO) cells, and was negative for clastogenic potential. Toxicological studies in rats including both single and 14-day repeat intravenous doses and in dogs (single intravenous dose) with a 2-week recovery period were conducted. The NOAEL in rats and dogs was 30 and >10mg/kg, respectively. No serious adverse events were reported in a placebo-controlled, sequential dose escalation Phase 1 clinical trial. The low toxicity in the pre-clinical studies and the absence of adverse events in the Phase 1 trial have supported investigation of CMX-2043 in a human efficacy trial. PMID:24751172

  5. Anesthesia and critical-care delivery in weightlessness: A challenge for research in parabolic flight analogue space surgery studies

    NASA Astrophysics Data System (ADS)

    Ball, Chad G.; Keaney, Marilyn A.; Chun, Rosaleen; Groleau, Michelle; Tyssen, Michelle; Keyte, Jennifer; Broderick, Timothy J.; Kirkpatrick, Andrew W.

    2010-03-01

    BackgroundMultiple nations are actively pursuing manned exploration of space beyond low-earth orbit. The responsibility to improve surgical care for spaceflight is substantial. Although the use of parabolic flight as a terrestrial analogue to study surgery in weightlessness (0 g) is well described, minimal data is available to guide the appropriate delivery of anesthesia. After studying anesthetized pigs in a 0 g parabolic flight environment, our group developed a comprehensive protocol describing prolonged anesthesia in a parabolic flight analogue space surgery study (PFASSS). Novel challenges included a physically remote vivarium, prolonged (>10 h) anesthetic requirements, and the provision of veterinary operating room/intensive care unit (ICU) equivalency on-board an aircraft with physical dimensions of <1.5 m 2 (Falcon 20). Identification of an effective anesthetic regime is particularly important because inhalant anesthesia cannot be used in-flight. MethodsAfter ethical approval, multiple ground laboratory sessions were conducted with combinations of anesthetic, pre-medication, and induction protocols on Yorkshire-cross specific pathogen-free (SPF) pigs. Several constant rate infusion (CRI) intravenous anesthetic combinations were tested. In each regimen, opioids were administered to ensure analgesia. Ventilation was supported mechanically with blended gradients of oxygen. The best performing terrestrial 1 g regime was flight tested in parabolic flight for its effectiveness in sustaining optimal and prolonged anesthesia, analgesia, and maintaining hemodynamic stability. Each flight day, a fully anesthetized, ventilated, and surgically instrumented pig was transported to the Flight Research Laboratory (FRL) in a temperature-controlled animal ambulance. A modular on-board surgical/ICU suite with appropriate anesthesia/ICU and surgical support capabilities was employed. ResultsThe mean duration of anesthesia (per flight day) was 10.28 h over four consecutive days. A barbiturate and ketamine-based CRI anesthetic regimen supplemented with narcotic analgesia by bolus administration offered the greatest prolonged hemodynamic stability through an IV route (within multiple transport vehicles and differing gravitational environments). Standardization and pre-packaging of anesthesia, emergency pharmaceuticals, and consumables were found to facilitate the interchange of the veterinary anesthesia team members between flights. This operational process was extremely challenging. ConclusionsWith careful organization of caregivers, equipment and protocols, providing anesthesia and life support in weightlessness is theoretically possible. Unfortunately, human resource costs are extensive and likely overwhelming. Comprehensive algorithms for extended spaceflight must recognize these costs prior to making assumptions or attempting to provide critical care in space.

  6. Kinetic studies of the predicted substrate-binding site of varicella-zoster virus thymidine kinase.

    PubMed

    Suzutani, T; Davies, L C; Honess, R W

    1993-06-01

    To investigate the mechanism of kinetic action and substrate recognition of varicella-zoster virus (VZV) thymidine kinase (TK), we designed and isolated a site-directed mutant VZV TK which has double amino acid substitutions, 136threonine to leucine and 137isoleucine to leucine (SDM TK). This mutant was designed to alter the substrate-binding site of the VZV TK to duplicate that of the herpes simplex virus type 2 enzyme. Kinetic studies of the activity of wild-type TK indicated that the binding order of ATP and thymidine is random and that wild-type VZV TK possessed high thymidylate kinase (TM-K) activity. The sensitivity of VZV TK to bisubstrate analogues, dinucleotides of adenosine and thymidine, showed that the optimum distance between the ATP- and substrate-binding sites is two phosphoryl groups greater than with the natural substrate for TK activity. SDM TK lost deoxycytidine kinase activity and had reduced TK and TM-K activities. Inhibition studies on both WT and SDM TK by 5-halogenovinyluridine analogues and their 5' monophosphate derivatives revealed that amino acids at positions 136 and 137 are involved in substrate binding, probably through a role in the formation of the binding pocket for bulky substrates. PMID:8389797

  7. Influence of the Charge State on the Structures and Interactions of Vancomycin Antibiotics with Cell-Wall Analogue Peptides: Experimental and Theoretical Studies

    SciTech Connect

    Yang, Zhibo; Vorpagel, Erich R.; Laskin, Julia

    2009-02-16

    In this study we examined the effect of the charge state on the energetics and dynamics of dissociation of the non-covalent complex between the vancomycin and the cell wall peptide analogue Nα,Nε-diacetyl-L-Lys-D-Ala-D-Ala (V-Ac2KDADA). The binding energies between the vancomycin and the peptide were obtained from the RRKM modeling of the time- and energy resolved surface-induced dissociation (SID) experiments. Our results demonstrate that the stability of the complex toward fragmentation increases in the order: [V+Ac2KDADA+H]+2 < [V+Ac2KDADA+H]+ < [V+Ac2KDADA-H]-. Dissociation of the singly protonated and singly deprotonated complex is characterized by very large entropy effects indicating substantial increase in the conformational flexibility of the resulting products. The experimental threshold energies of 1.75 eV and 1.34 eV obtained for the [V+Ac2KDADA-H]- and [V+Ac2KDADA+H]+ , respectively, are in excellent agreement with the results of density functional theory (DFT) calculations. The increased stability of the deprotonated complex observed experimentally is attributed to the presence of three charged sites in the deprotonated complex as compared to only one charged site in the singly protonated complex. The low binding energy of 0.93 eV obtained for the doubly protonated complex suggests that this ion is destabilized by Coulomb repulsion between the singly protonated vancomycin and the singly protonated peptide comprising the complex.

  8. Astrobiology through the ages of Mars: the study of terrestrial analogues to understand the habitability of Mars.

    PubMed

    Fairn, Alberto G; Davila, Alfonso F; Lim, Darlene; Bramall, Nathan; Bonaccorsi, Rosalba; Zavaleta, Jhony; Uceda, Esther R; Stoker, Carol; Wierzchos, Jacek; Dohm, James M; Amils, Ricardo; Andersen, Dale; McKay, Christopher P

    2010-10-01

    Mars has undergone three main climatic stages throughout its geological history, beginning with a water-rich epoch, followed by a cold and semi-arid era, and transitioning into present-day arid and very cold desert conditions. These global climatic eras also represent three different stages of planetary habitability: an early, potentially habitable stage when the basic requisites for life as we know it were present (liquid water and energy); an intermediate extreme stage, when liquid solutions became scarce or very challenging for life; and the most recent stage during which conditions on the surface have been largely uninhabitable, except perhaps in some isolated niches. Our understanding of the evolution of Mars is now sufficient to assign specific terrestrial environments to each of these periods. Through the study of Mars terrestrial analogues, we have assessed and constrained the habitability conditions for each of these stages, the geochemistry of the surface, and the likelihood for the preservation of organic and inorganic biosignatures. The study of these analog environments provides important information to better understand past and current mission results as well as to support the design and selection of instruments and the planning for future exploratory missions to Mars. PMID:21087162

  9. Synthesis, screening and quantitative structure-activity relationship (QSAR) studies of some glutamine analogues for possible anticancer activity.

    PubMed

    Srikanth, K; Kumar, Ch Anil; Ghosh, Balaram; Jha, Tarun

    2002-07-01

    We described the syntheses, biological activities and QSAR studies of 36 new 5-n-substituted-2-(substituted benzenesulphonyl) glutamines 6-41 with different substitutions. These compounds were designed as structural analogues of most reactive amino acid, 'glutamine' (GLN), especially in the tumor cells. They present the new basic lateral chains at R(5) position as well as different substitutions at 2', 3', 4', and 5' positions on the benzene ring. The synthesized compounds have been tested for antitumor activity against Ehrlich ascites carcinoma (EAC) in Swiss albino mice using percentage inhibition of tumor weight as inhibitory parameter. In order to elucidate the structural requirements for antitumor activity, quantitative structure-activity relationship (QSAR) studies have been performed using extra thermodynamic model of Hansch. QSAR equations showed that the electronic parameter (sigma) on the aromatic ring system, steric parameter (Es) and to some extent Sterimol length of the substituent (L) on the aliphatic side chain correlate significantly with the antitumor activity. Resonance factor occupies the major electronic contribution on the aromatic ring system to the activity. PMID:11983508

  10. Structure Activity Relationship and Mechanism of Action Studies of Manzamine Analogues for the Control of Neuroinflammation and Cerebral Infections

    PubMed Central

    Peng, Jiangnan; Kudrimoti, Sucheta; Prasanna, Sivaprakasam; Odde, Srinivas; Doerksen, Robert J.; Pennaka, Hari K; Choo, Yeun-Mun; Rao, Karumanchi V.; Tekwani, Babu L.; Madgula, Vamsi; Khan, Shabana I.; Wang, Bin; Mayer, Alejandro M. S.; Jacob, Melissa R.; Tu, Lan Chun; Gertsch, Jürg; Hamann, Mark T.

    2010-01-01

    Structure-activity relationship studies were carried out by chemical modification of manzamine A (1), 8-hydroxymanzamine A (2), manzamine F (14), and ircinol isolated from the sponge Acanthostrongylophora. The derived analogues were evaluated for antimalarial, antimicrobial, and antineuroinflammatory activities. Several modified products exhibited potent and improved in vitro antineuroinflammatory, antimicrobial, and antimalarial activity. 1 showed improved activity against malaria compared to chloroquine in both multi- and single-dose in vivo experiments. The significant antimalarial potential was revealed by a 100% cure rate of malaria in mice with one administration of 100 mg/kg of 1. The potent antineuroinflammatory activity of the manzamines will provide great benefit for the prevention and treatment of cerebral infections (e.g. Cryptococcus and Plasmodium). In addition, 1 was shown to permeate across the blood-brain barrier (BBB) in an in vitro model using a MDR-MDCK monolayer. Docking studies support that 2 binds to the ATP-noncompetitive pocket of glycogen synthesis kinase-3β (GSK-3β), which is a putative target of manzamines. Based on the results presented here it will be possible to initiate rational drug design efforts around this natural product scaffold for the treatment of several different diseases. PMID:20017491

  11. Upper Ottawa street landfill site health study.

    PubMed

    Hertzman, C; Hayes, M; Singer, J; Highland, J

    1987-11-01

    This report describes the design and conduct of two sequential historical prospective morbidity surveys of workers and residents from the Upper Ottawa Street Landfill Site in Hamilton, Ontario. The workers study was carried out first and was a hypothesis-generating study. Workers and controls were administered a health questionnaire, which was followed by an assessment of recall bias through medical chart abstraction. Multiple criteria were used to identify health problems associated with landfill site exposure. Those problems with highest credibility included clusters of respiratory, skin, narcotic, and mood disorders. These formed the hypothesis base in the subsequent health study of residents living adjacent to the landfill site. In that study, the association between mood, narcotic, skin, and respiratory conditions with landfill site exposure was confirmed using the following criteria: strength of association; consistency with the workers study; risk gradient by duration of residence and proximity to the landfill; absence of evidence that less healthy people moved to the area; specificity; and the absence of recall bias. The validity of these associations were reduced by three principal problems: the high refusal rate among the control population; socioeconomic status differences between the study groups; and the fact that the conditions found in excess were imprecisely defined and potentially interchangeable with other conditions. Offsetting these problems were the multiple criteria used to assess each hypothesis, which were applied according to present rules. Evidence is presented that supports the hypothesis that vapors, fumes, or particulate matter emanating from the landfill site, as well as direct skin exposure, may have lead to the health problems found in excess. Evidence is also presented supporting the hypothesis that perception of exposure and, therefore, of risk, may explain the results of the study. However, based on the analyses performed, it is the conclusion of the authors that the adverse effects seen were more likely the result of chemical exposure than of perception of risk. PMID:3691438

  12. Upper Ottawa street landfill site health study.

    PubMed Central

    Hertzman, C; Hayes, M; Singer, J; Highland, J

    1987-01-01

    This report describes the design and conduct of two sequential historical prospective morbidity surveys of workers and residents from the Upper Ottawa Street Landfill Site in Hamilton, Ontario. The workers study was carried out first and was a hypothesis-generating study. Workers and controls were administered a health questionnaire, which was followed by an assessment of recall bias through medical chart abstraction. Multiple criteria were used to identify health problems associated with landfill site exposure. Those problems with highest credibility included clusters of respiratory, skin, narcotic, and mood disorders. These formed the hypothesis base in the subsequent health study of residents living adjacent to the landfill site. In that study, the association between mood, narcotic, skin, and respiratory conditions with landfill site exposure was confirmed using the following criteria: strength of association; consistency with the workers study; risk gradient by duration of residence and proximity to the landfill; absence of evidence that less healthy people moved to the area; specificity; and the absence of recall bias. The validity of these associations were reduced by three principal problems: the high refusal rate among the control population; socioeconomic status differences between the study groups; and the fact that the conditions found in excess were imprecisely defined and potentially interchangeable with other conditions. Offsetting these problems were the multiple criteria used to assess each hypothesis, which were applied according to present rules. Evidence is presented that supports the hypothesis that vapors, fumes, or particulate matter emanating from the landfill site, as well as direct skin exposure, may have lead to the health problems found in excess. Evidence is also presented supporting the hypothesis that perception of exposure and, therefore, of risk, may explain the results of the study. However, based on the analyses performed, it is the conclusion of the authors that the adverse effects seen were more likely the result of chemical exposure than of perception of risk. PMID:3691438

  13. Simulations & Case Studies. [SITE 2002 Section].

    ERIC Educational Resources Information Center

    Seymour, Cathy R., Ed.

    This document contains the following papers on simulations and case studies from the SITE (Society for Information Technology & Teacher Education) 2002 conference: "3-D Virtual Classroom Technology" (Kimberly Arseneau Miller, Angela Glod); "Simulated Lesson Design Studios" (Willis Copeland); "Lights, Camera, Integration: Presentation Programs and

  14. A clinical phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly.

    PubMed

    Dawson, L K; Jodrell, D I; Bowman, A; Rye, R; Byrne, B; Bernareggi, A; Camboni, G; Smyth, J F

    2000-12-01

    The anthracenedione analogue, BBR 2778 is an active antitumour agent preclinically and has reduced potential for cardiotoxicity compared with other similar drugs in preclinical models. BBR 2778 was administered 3 weekly by a 1 h intravenous (i.v.) infusion to 24 patients and the dose escalated rapidly from 20 to 240 mg/m2. The dose-limiting toxicity (DLT) was neutropenia, common toxicity criteria (CTC) grade 4 in 3/5 patients at 240 mg/m2. Other toxicities > or = CTC grade 3 were: vomiting, lymphopenia, thrombocytopenia and lethargy. Blue discoloration of veins and urine was also noted. In 1 patient (120 mg/m2, four cycles) left ventricular ejection reaction (LVEF) fell (CTC grade 2) but with no clinical sequelae. BBR 2778 plasma pharmacokinetics were biphasic (mean t(1/2) at 180 mg/m2 = 14.1 h) and the urinary elimination of the unchanged drug was < 10%. In a patient with previously treated small cell lung carcinoma (SCLC), a 49% reduction in measurable disease was noted with resolution of pericardial and pleural effusions (120 mg/m2 x eight cycles). From the results of this phase I study a dose of 180 mg/m2 as a 1 h infusion every 3 weeks would be recommended for phase II trials. PMID:11094309

  15. Anion Recognition by Pyrylium Cations and Thio-, Seleno- and Telluro- Analogues: A Combined Theoretical and Cambridge Structural Database Study.

    PubMed

    Quionero, David

    2015-01-01

    Pyrylium salts are a very important class of organic molecules containing a trivalent oxygen atom in a six-membered aromatic ring. In this manuscript, we report a theoretical study of pyrylium salts and their thio-, seleno- and telluro- analogues by means of DFT calculations. For this purpose, unsubstituted 2,4,6-trimethyl and 2,4,6-triphenyl cations and anions with different morphologies were chosen (Cl-, NO3- and BF4-). The complexes were characterized by means of natural bond orbital and "atoms-in-molecules" theories, and the physical nature of the interactions has been analyzed by means of symmetry-adapted perturbation theory calculations. Our results indicate the presence of anion-? interactions and chalcogen bonds based on both ?- and ?-hole interactions and the existence of very favorable ?-complexes, especially for unsubstituted cations. The electrostatic component is dominant in the interactions, although the induction contributions are important, particularly for chloride complexes. The geometrical features of the complexes have been compared with experimental data retrieved from the Cambridge Structural Database. PMID:26114926

  16. Reducing unwanted trauma memories by imaginal exposure or autobiographical memory elaboration: An analogue study of memory processes

    PubMed Central

    Ehlers, Anke; Mauchnik, Jana; Handley, Rachel

    2012-01-01

    Unwanted memories of traumatic events are a core symptom of post-traumatic stress disorder. A range of interventions including imaginal exposure and elaboration of the trauma memory in its autobiographical context are effective in reducing such unwanted memories. This study explored whether priming for stimuli that occur in the context of trauma and evaluative conditioning may play a role in the therapeutic effects of these procedures. Healthy volunteers (N=122) watched analogue traumatic and neutral picture stories. They were then randomly allocated to 20min of either imaginal exposure, autobiographical memory elaboration, or a control condition designed to prevent further processing of the picture stories. A blurred picture identification task showed that neutral objects that preceded traumatic pictures in the stories were subsequently more readily identified than those that had preceded neutral stories, indicating enhanced priming. There was also an evaluative conditioning effect in that participants disliked neutral objects that had preceded traumatic pictures more. Autobiographical memory elaboration reduced the enhanced priming effect. Both interventions reduced the evaluative conditioning effect. Imaginal exposure and autobiographical memory elaboration both reduced the frequency of subsequent unwanted memories of the picture stories. PMID:21227404

  17. Women’s Preference of Therapist Based on Sex of Therapist and Presenting Problem: An Analogue Study

    PubMed Central

    Landes, Sara J.; Burton, Jessica R.; King, Kevin M.; Sullivan, Bryce F.

    2013-01-01

    An analogue study was conducted to examine differences in women’s preference for and anticipated comfort self-disclosing to hypothetical therapists of different sexes based on the type of hypothetical presenting problem. The impact of general level of self-disclosure was also examined. Participants included female college students (n=187). Anticipated comfort self-disclosing to male or female therapist was rated by subjects when presented with therapists of each sex with the same qualifications. Women preferred and reported higher levels of anticipated comfort self-disclosing to a female therapist. Type of hypothetical presenting problem and general level of self-disclosure also impacted anticipated comfort self-disclosing. There was an interaction between general level self-disclosure and the sex of therapist on anticipated comfort self-disclosing. General level of self-disclosure only impacted anticipated comfort self-disclosing when the therapist was male. This information is relevant for therapists or organizations that provide psycho-social services to women. Organizations may want to inquire about a client’s preferences about sex of therapist beforehand and, if possible, cater to the client’s preference. PMID:24578592

  18. Reducing unwanted trauma memories by imaginal exposure or autobiographical memory elaboration: an analogue study of memory processes.

    PubMed

    Ehlers, Anke; Mauchnik, Jana; Handley, Rachel

    2012-12-01

    Unwanted memories of traumatic events are a core symptom of post-traumatic stress disorder. A range of interventions including imaginal exposure and elaboration of the trauma memory in its autobiographical context are effective in reducing such unwanted memories. This study explored whether priming for stimuli that occur in the context of trauma and evaluative conditioning may play a role in the therapeutic effects of these procedures. Healthy volunteers (N = 122) watched analogue traumatic and neutral picture stories. They were then randomly allocated to 20 min of either imaginal exposure, autobiographical memory elaboration, or a control condition designed to prevent further processing of the picture stories. A blurred picture identification task showed that neutral objects that preceded traumatic pictures in the stories were subsequently more readily identified than those that had preceded neutral stories, indicating enhanced priming. There was also an evaluative conditioning effect in that participants disliked neutral objects that had preceded traumatic pictures more. Autobiographical memory elaboration reduced the enhanced priming effect. Both interventions reduced the evaluative conditioning effect. Imaginal exposure and autobiographical memory elaboration both reduced the frequency of subsequent unwanted memories of the picture stories. PMID:21227404

  19. Geothermal energy from the Pannonian Basins System: An outcrop analogue study of exploration target horizons in Hungary

    NASA Astrophysics Data System (ADS)

    Götz, Annette E.; Sass, Ingo; Török, Ákos

    2015-04-01

    The characterization of geothermal reservoirs of deep sedimentary basins is supported by outcrop analogue studies since reservoir characteristics are strongly related to the sedimentary facies and thus influence the basic direction of geothermal field development and applied technology (Sass & Götz, 2012). Petro- and thermophysical rock properties are key parameters in geothermal reservoir characterization and the data gained from outcrop samples serve to understand the reservoir system. New data from the Meso- and Cenozoic sedimentary rocks of Budapest include carbonates and siliciclastics of Triassic, Eocene, Oligocene and Miocene age, exposed on the western side of the river Danube in the Buda Hills (Götz et al., 2014). Field and laboratory analyses revealed distinct horizons of different geothermal potential and thus, enable to identify and interpret corresponding exploration target horizons in geothermal prone depths in the Budapest region as well as in the Hungarian sub-basins of the Pannonian Basins System (Zala and Danube basins, Great Plain) exhibiting geothermal anomalies. References Götz, A.E., Török, Á., Sass, I., 2014. Geothermal reservoir characteristics of Meso- and Cenozoic sedimentary rocks of Budapest (Hungary). German Journal of Geosciences, 165, 487-493. Sass, I., Götz, A.E., 2012. Geothermal reservoir characterization: a thermofacies concept. Terra Nova, 24, 142-147.

  20. Semisynthetic analogues of toxiferine I and their pharmacological properties at ?7 nAChRs, muscle-type nAChRs, and the allosteric binding site of muscarinic M2 receptors.

    PubMed

    Zlotos, Darius P; Trnkle, Christian; Holzgrabe, Ulrike; Gndisch, Daniela; Jensen, Anders A

    2014-09-26

    A new series of analogues of the calabash curare alkaloid toxiferine I was prepared and pharmacologically evaluated at ?7 and muscle-type nAChRs and the allosteric site of muscarinic M2 receptors. The new ligands differ from toxiferine I by the absence of one (2a-c) or two (3a-c) hydroxy groups, saturation of the exocyclic double bonds, and various N-substituents (methyl, allyl, 4-nitrobenzyl). At the muscle-type nAChRs, most ligands showed similar binding to the muscle relaxant alcuronium, indicating neuromuscular blocking activity, with the nonhydroxylated analogues 3b (Ki = 75 nM) and 3c (Ki = 82 nM) displaying the highest affinity. At ?7 nAChRs, all ligands showed a moderate to low antagonistic effect, suggesting that the alcoholic functions are not necessary for antagonistic action. Compound 3c exerted the highest preference for the muscle-type nAChRs (Ki = 82 nM) over ?7 (IC50 = 21 ?M). As for the allosteric site of M2 receptors, binding was found to be dependent on N-substitution rather than on the nature of the side chains. The most potent ligands were the N-allyl analogues 2b and 3b (EC0.5,diss = 12 and 36 nM) and the N-nitrobenzyl derivatives 2c and 3c (EC0.5,diss = 32 and 49 nM). The present findings should help delineate the structural requirements for activity at different types of AChRs and for the design of novel selective ligands. PMID:25192059

  1. Bioluminescence of beetle luciferases with 6'-amino-D-luciferin analogues reveals excited keto-oxyluciferin as the emitter and phenolate/luciferin binding site interactions modulate bioluminescence colors.

    PubMed

    Viviani, Vadim R; Neves, Deimison Rodrigues; Amaral, Danilo Trabuco; Prado, Rogilene A; Matsuhashi, Takuto; Hirano, Takashi

    2014-08-19

    Beetle luciferases produce different bioluminescence colors from green to red using the same d-luciferin substrate. Despite many studies of the mechanisms and structural determinants of bioluminescence colors with firefly luciferases, the identity of the emitters and the specific active site interactions responsible for bioluminescence color modulation remain elusive. To address these questions, we analyzed the bioluminescence spectra with 6'-amino-D-luciferin (aminoluciferin) and its 5,5-dimethyl analogue using a set of recombinant beetle luciferases that naturally elicit different colors and different pH sensitivities (pH-sensitive, Amydetes vivianii ?max=538 nm, Macrolampis sp2 ?max=564 nm; pH-insensitive, Phrixotrix hirtus ?max=623 nm, Phrixotrix vivianii ?max=546 nm, and Pyrearinus termitilluminans ?max=534 nm), a luciferase-like enzyme (Tenebrionidae, Zophobas morio ?max=613 nm), and mutants of C311 (S314). The green-yellow-emitting luciferases display red-shifted bioluminescence spectra with aminoluciferin in relation to those with D-luciferin, whereas the red-emitting luciferases displayed blue-shifted spectra. Bioluminescence spectra with 5,5-dimethylaminoluciferin, in which enolization is blocked, were almost identical to those of aminoluciferin. Fluorescence probing using 2-(4-toluidino)naphthalene-6-sulfonate and inference with aminoluciferin confirm that the luciferin binding site of the red-shifted luciferases is more polar than in the case of the green-yellow-emitting luciferases. Altogether, the results show that the keto form of excited oxyluciferin is the emitter in beetle bioluminescence and that bioluminescence colors are essentially modulated by interactions of the 6'-hydroxy group of oxyluciferin and basic moieties under the influence of the microenvironment polarity of the active site: a strong interaction between a base moiety and oxyluciferin phenol in a hydrophobic microenvironment promotes green-yellow emission, whereas a more polar environment weakens such interaction promoting red shifts. In pH-sensitive luciferases, a pH-mediated switch from a closed hydrophobic conformation to a more open polar conformation promotes the typical red shift. PMID:25025160

  2. Application of molecular docking and ONIOM methods for the description of interactions between anti-quorum sensing active (AHL) analogues and the Pseudomonas aeruginosa LasR binding site.

    PubMed

    Ahumedo, Maicol; Drosos, Juan Carlos; Vivas-Reyes, Ricardo

    2014-05-01

    Molecular docking methods were applied to simulate the coupling of a set of nineteen acyl homoserine lactone analogs into the binding site of the transcriptional receptor LasR. The best pose of each ligand was explored and a qualitative analysis of the possible interactions present in the complex was performed. From the results of the protein-ligand complex analysis, it was found that residues Tyr-64 and Tyr-47 are involved in important interactions, which mainly determine the antagonistic activity of the AHL analogues considered for this study. The effect of different substituents on the aromatic ring, the common structure to all ligands, was also evaluated focusing on how the interaction with the two previously mentioned tyrosine residues was affected. Electrostatic potential map calculations based on the electron density and the van der Waals radii were performed on all ligands to graphically aid in the explanation of the variation of charge density on their structures when the substituent on the aromatic ring is changed through the elements of the halogen group series. A quantitative approach was also considered and for that purpose the ONIOM method was performed to estimate the energy change in the different ligand-receptor complex regions. Those energy values were tested for their relationship with the corresponding IC50 in order to establish if there is any correlation between energy changes in the selected regions and the biological activity. The results obtained using the two approaches may contribute to the field of quorum sensing active molecules; the docking analysis revealed the role of some binding site residues involved in the formation of a halogen bridge with ligands. These interactions have been demonstrated to be responsible for the interruption of the signal propagation needed for the quorum sensing circuit. Using the other approach, the structure-activity relationship (SAR) analysis, it was possible to establish which structural characteristics and chemical requirements are necessary to classify a compound as a possible agonist or antagonist against the LasR binding site. PMID:24626770

  3. Novel renin inhibitors containing analogues of statine retro-inverted at the C-termini: specificity at the P2 histidine site.

    PubMed

    Rosenberg, S H; Plattner, J J; Woods, K W; Stein, H H; Marcotte, P A; Cohen, J; Perun, T J

    1987-07-01

    Substituted 1,3- and 1,4-diamines were prepared from epoxides derived from Boc-leucine or Boc-cyclohexylalanine. These diamines were incorporated into renin inhibitors (IC50 = 4-1500 nM) replacing the Leu-Val scissile bond in small peptide analogues of angiotensinogen. Replacement of the P2 histidine imidazole with other heterocycles maintained or enhanced binding while changing the overall basicity of the inhibitor. Finally, substitution of O-methyltyrosine for the P3 phenylalanine suppressed chymotrypsin cleavage of the P3-P2 bond. PMID:3298652

  4. Preparation, magnetic and EPR spectral studies of copper(II) complexes of an anticancer drug analogue

    NASA Astrophysics Data System (ADS)

    Manoj, E.; Kurup, M. R. Prathapachandra; Punnoose, Alex

    2009-04-01

    Ten new copper(II) complexes of five potential bisthiocarbohydrazone and biscarbohydrazone ligands were synthesized and physico-chemically characterized. The spectral and magnetic studies of compounds are consistent with the formation of asymmetric di-, tri- or tetranuclear copper(II) complexes of deprotonated forms of respective ligands. The variable temperature magnetic susceptibility measurements of all complexes show antiferromagnetic interactions between the Cu(II) centers, in agreement with very broad powder EPR spectra. However, frozen solution EPR spectral studies are found in contradiction with the solid-state magnetic studies and indicate that the complexes are not very stable in solutions; the possible fragmentations of complexes are found in agreement with MALDI MS results. The EPR spectral simulation of most of the compounds is in agreement with the presence of two uncoupled Cu(II) species in solution.

  5. Medical Diagnostic Consultation concerning Mental Retardation: An Analogue Study of School Psychologists' Attitudes

    ERIC Educational Resources Information Center

    Wodrich, David L.; Tarbox, Jennifer; Balles, John; Gorin, Joanna

    2010-01-01

    Recent research of relevance to school psychologists suggests that the cause, or etiology, of mental retardation can be established by medical diagnosticians in approximately one-half of cases. In the current study, 109 practicing school psychologists considered a hypothetical case of an elementary student with mental retardation and indicated

  6. Astrobiology in the Field: Studying Mars by Analogue Expeditions on Earth

    NASA Technical Reports Server (NTRS)

    Conrad, Pamela G.

    2011-01-01

    We will present a strategy for how one prepares to engage in fieldwork on another planets by practicing in analogous environments on the Earth, including at Mono Lake. As an example, we will address the problem of how to study the habitability of an environment when you have no idea what kind of life might be there to exploit it. This will all be related to the upcoming launch of the Mars Science Laboratory to Mars in late November this year.

  7. DNA interactions and cytotoxic studies of cis-platin analogues of substituted 2,2'-bipyridines

    NASA Astrophysics Data System (ADS)

    Patel, Mohan N.; Parmar, Pradhuman A.; Gandhi, Deepen S.; Patidar, Anshul P.

    2012-11-01

    Platinum(II) complexes [Pt(4?-fpbpy)Cl2] (1), [Pt(4?-mepbpy)Cl2] (2), [Pt(4?-mpbpy)Cl2] (3) and [Pt(4?-bopbpy)Cl2] (4) {where 4?-fpbpy = 4-(4?-fluorophenyl)-6-phenyl-2,2'-bipyridine, 4?-mepbpy = 4-(4?-methylphenyl)-6-phenyl-2,2'-bipyridine, 4?-mpbpy = 4-(4?-methoxyphenyl)-6-phenyl-2,2'-bipyridine, 4?-bopbpy = 4-(4?-benzyloxyphenyl)-6-phenyl-2,2'-bipyridine} have been synthesized and characterized. The binding strength and binding mode of the complexes with HS DNA (Herring Sperm) have been investigated by absorption titration and viscosity measurement studies. The results have been revealed that the complexes bind to DNA by covalent mode with intrinsic binding constant Kb ranging from 6.05 104 M-1 to 3.48 105 M-1. The unwinding angle of pUC19 DNA has been evaluated by gel electrophoresis assay. The brine shrimp bioassay has been performed to study the in vitro cytotoxic properties of the synthesized metal complexes.

  8. Stardust: Studies in microgravity of condensation and agglomeration of cosmic dust analogue

    NASA Astrophysics Data System (ADS)

    Ferguson, F.; Lilleleht, L. U.; Nuth, J.; Stephens, J. R.; Bussoletti, E.; Carotenuto, L.; Colangeli, L.; Dellaversana, P.; Mele, F.; Mennella, V.

    1992-07-01

    A short description of the program Stardust whose goal is to study the formation and properties of high temperature particles and gases, including silicate and carbonaceous materials, that are of interest in astrophysics and planetary science, is given. The international program was carried out in microgravity conditions in parabolic flight. A description of the laboratory equipment, conceived to perform experimental tests in reduced gravity conditions, and which is based on the gas evaporation technique, is given. The gas evaporation technique utilizes one or more heated crucible to vaporize solids materials (SiO, Mg) in a low pressure of inert or reactive gas inside of a vacuum bell jar. The vapor pressures of the materials are controlled by the temperature of the crucibles. The temperature and pressure of inert gas are also controlled. By varying the vapor pressure relative to the gas temperature and pressure, the conditions for substantial grain condensation can be controlled and grain formation measured using light scattering techniques. Thus the partial pressure for grain condensation, can be measured as a function of temperature. The gas evaporation technique has the advantage that complex chemical systems can be studied by using multiple crucibles each containing solid source material. Experimental results and future trends are addressed.

  9. Stardust: Studies in microgravity of condensation and agglomeration of cosmic dust analogue

    NASA Technical Reports Server (NTRS)

    Ferguson, F.; Lilleleht, L. U.; Nuth, J.; Stephens, J. R.; Bussoletti, E.; Carotenuto, L.; Colangeli, L.; Dellaversana, P.; Mele, F.; Mennella, V.

    1992-01-01

    A short description of the program Stardust whose goal is to study the formation and properties of high temperature particles and gases, including silicate and carbonaceous materials, that are of interest in astrophysics and planetary science, is given. The international program was carried out in microgravity conditions in parabolic flight. A description of the laboratory equipment, conceived to perform experimental tests in reduced gravity conditions, and which is based on the gas evaporation technique, is given. The gas evaporation technique utilizes one or more heated crucible to vaporize solids materials (SiO, Mg) in a low pressure of inert or reactive gas inside of a vacuum bell jar. The vapor pressures of the materials are controlled by the temperature of the crucibles. The temperature and pressure of inert gas are also controlled. By varying the vapor pressure relative to the gas temperature and pressure, the conditions for substantial grain condensation can be controlled and grain formation measured using light scattering techniques. Thus the partial pressure for grain condensation, can be measured as a function of temperature. The gas evaporation technique has the advantage that complex chemical systems can be studied by using multiple crucibles each containing solid source material. Experimental results and future trends are addressed.

  10. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Harry Cordatos

    2010-11-08

    Overview of an ongoing, 2 year research project partially funded by APRA-E to create a novel, synthetic analogue of carbonic anhydrase and incorporate it into a membrane for removal of CO2 from flue gas in coal power plants. Mechanism background, preliminary feasibility study results, molecular modeling of analogue-CO2 interaction, and program timeline are provided.

  11. Outcrop Analogue Studies in Geothermal Exploration - Characterization of fault zones in Triassic Muschelkalk limestones of the Upper Rhine Graben

    NASA Astrophysics Data System (ADS)

    Meier, S.; Bauer, J. F.; Philipp, S. L.

    2013-12-01

    The characterization of fault zones is of particular importance in geothermal reservoirs since there may be great effects on fluid flow. Fault zones generally consist of two major hydromechanical units: the fault core and the damage zone, surrounded by the host rock. To improve predictions of fracture system parameters for each unit and resulting estimations of reservoir permeabilities at depths we perform outcrop analogue studies. We analyze Middle Triassic Muschelkalk limestones that form one geothermal reservoir formation in the Upper Rhine Graben (southwest Germany) in quarries on its eastern graben shoulder. We measure the orientations and displacements of various fault zones and characterize the fracture systems within the fault zone units and in the host rock. Our studies show that damage zones are well developed even in smaller fault zones. Their fault cores, however, are narrow compared with that of fault zones with large displacements and comprise brecciated material, clay smear, host rock lenses or zones of mineralization. Based on the field data we use analytical models to estimate the permeabilities of the analyzed fracture systems. Results show increased fracture frequencies in the fault zone damage zones and larger fracture apertures parallel or subparallel to fault zone strike that lead to enhanced permeability compared with other orientations. Mineralized fractures accumulated in this direction in the 'Nussloch'-quarry indicate that these fractures were pathways for fault zone parallel fluid flow in the past. This shows that open fractures with orientations parallel to fault zones may be pathways for fault zone parallel fluid flow in geothermal reservoirs. By contrast, well-developed fault cores may be potential barriers for fluid flow in inactive fault zones. To build numerical models to analyze local stress fields and effects on fracture propagation for different fault zone types and geometries information on rock mechanical properties is necessary. Therefore we take representative rock samples in the quarries to determine uniaxial compressive and tensile strengths as well as Young's Moduli in the laboratory. Additionally we measure the rebound hardness distribution across fault zones with a 'Schmidt-Hammer' to analyze mechanical property variations. First results show that the rebound hardness increases with increasing distance from the fault core. The presented studies help to predict the permeability of fault-related geothermal reservoir rocks and minimize the exploration risk of geothermal projects. This project is part of the Research and Development Project AuGE (Outcrop Analogue Studies in Geothermal Exploration). Project partners are the companies Geothermal Engineering GmbH and GeoEnergy GmbH as well as the Universities of Heidelberg and Erlangen. The project is funded by the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) within the framework of the 5th Energy Research Program (FKZ 0325302).

  12. Analytic Study of Three-Dimensional Rupture Propagation in Strike-Slip Faulting with Analogue Models

    NASA Astrophysics Data System (ADS)

    Chan, Pei-Chen; Chu, Sheng-Shin; Lin, Ming-Lang

    2014-05-01

    Strike-slip faults are high angle (or nearly vertical) fractures where the blocks have moved along strike way (nearly horizontal). Overburden soil profiles across main faults of Strike-slip faults have revealed the palm and tulip structure characteristics. McCalpin (2005) has trace rupture propagation on overburden soil surface. In this study, we used different offset of slip sandbox model profiles to study the evolution of three-dimensional rupture propagation by strike -slip faulting. In strike-slip faults model, type of rupture propagation and width of shear zone (W) are primary affecting by depth of overburden layer (H), distances of fault slip (Sy). There are few research to trace of three-dimensional rupture behavior and propagation. Therefore, in this simplified sandbox model, investigate rupture propagation and shear zone with profiles across main faults when formation are affecting by depth of overburden layer and distances of fault slip. The investigators at the model included width of shear zone, length of rupture (L), angle of rupture (θ) and space of rupture. The surface results was follow the literature that the evolution sequence of failure envelope was R-faults, P-faults and Y-faults which are parallel to the basement fault. Comparison surface and profiles structure which were curved faces and cross each other to define 3-D rupture and width of shear zone. We found that an increase in fault slip could result in a greater width of shear zone, and proposed a W/H versus Sy/H relationship. Deformation of shear zone showed a similar trend as in the literature that the increase of fault slip resulted in the increase of W, however, the increasing trend became opposite after a peak (when Sy/H was 1) value of W was reached (small than 1.5). The results showed that the W width is limited at a constant value in 3-D models by strike-slip faulting. In conclusion, this study helps evaluate the extensions of the shear zone influenced regions for strike-slip faults.

  13. Acyclic purine nucleoside analogues: computational and NMR studies of conformational behaviour

    NASA Astrophysics Data System (ADS)

    Rai?, Silvana; Mintas, Mladen; Danilovski, Aleksandar; Vinkovi?, Mladen; Pongra?i?, Mario; Plavec, Janez; Viki?-Topic, Draen

    1997-06-01

    The conformational space of N-7- and N-9-(2-hydroxypropyl)-6-( N-pyrrolyl)purine as well as of N-7- and N-9-(2,3-dihydroxypropyl)-6-( N-pyrrolyl)purine has been studied by molecular mechanics (MMX force field) and semiempirical (PM3) calculations. Eight local minima were obtained for the N-7-(2-hydroxypropyl) regioisomer by the MMX force field and reoptimised by the PM3 method to locate the global minimum. The conformation of the N-7-(2,3-dihydroxypropyl) regioisomer is locked by intramolecular H-bonding and therefore more rigid. The results of theoretical calculations are in agreement with 1H and 13C NMR analysis of substituent chemical shifts, C?H and H?H coupling constants and connectivities in 2D homo- and heteronuclear correlation spectra.

  14. A phase I study of the vitamin D analogue EB 1089 in patients with advanced breast and colorectal cancer.

    PubMed Central

    Gulliford, T.; English, J.; Colston, K. W.; Menday, P.; Moller, S.; Coombes, R. C.

    1998-01-01

    Preclinical studies have shown that the vitamin D analogue EB 1089 has significantly less calcaemic activity than its parent compound 1,25-dihydroxyvitamin D (1,25(OH)2D3) and significant anti-tumour activity. This phase I trial was designed to evaluate the calcaemic effect of the drug in patients with advanced cancer. EB 1089 was given to 36 patients with advanced breast and colorectal cancer in doses of between 0.15 and 17.0 microg m(-2) day(-1). Serial serum and urine calcium, urine creatinine and serum parathyroid hormone (PTH) were monitored. Hypercalcaemia was seen in all patients receiving 17.0 microg m(-2) day(-1). Hypercalcaemia attributable to EB 1089 was reversible by discontinuing or reducing EB 1089 therapy. During the first 5 days of treatment, urine calcium (P = 0.0001) and serum-corrected calcium (P = 0.027) were related to EB 1089 dose, whereas serum parathyroid hormone (P = 0.0001) showed an inverse relationship. Twenty-one patients received compassionate treatment for between 10 and 234 days. No complete or partial responses were seen. Six patients on treatment for more than 90 days showed stabilization of disease. EB 1089 was well tolerated and adverse events considered to be caused by EB 1089 were limited to dose-dependent effects on calcium metabolism. The dose estimated to be tolerable for most patients from this study is around 7 microg m(-2) day(1). These data support previous work that has demonstrated EB 1089 to be significantly less calcaemic than 1,25-dihydroxyvitamin D3. PMID:9662243

  15. Dynamics and Conformational Studies of TOAC Spin Labeled Analogues of Ctx(Ile21)-Ha Peptide from Hypsiboas albopunctatus

    PubMed Central

    Vicente, Eduardo F.; Basso, Luis Guilherme M.; Cespedes, Graziely F.; Lorenzón, Esteban N.; Castro, Mariana S.; Mendes-Giannini, Maria José S.; Costa-Filho, Antonio José; Cilli, Eduardo M.

    2013-01-01

    Antimicrobial peptides (AMPs) isolated from several organisms have been receiving much attention due to some specific features that allow them to interact with, bind to, and disrupt cell membranes. The aim of this paper was to study the interactions between a membrane mimetic and the cationic AMP Ctx(Ile21)-Ha as well as analogues containing the paramagnetic amino acid 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid (TOAC) incorporated at residue positions n = 0, 2, and 13. Circular dichroism studies showed that the peptides, except for [TOAC13]Ctx(Ile21)-Ha, are unstructured in aqueous solution but acquire different amounts of α-helical secondary structure in the presence of trifluorethanol and lysophosphocholine micelles. Fluorescence experiments indicated that all peptides were able to interact with LPC micelles. In addition, Ctx(Ile21)-Ha and [TOAC13]Ctx(Ile21)-Ha peptides presented similar water accessibility for the Trp residue located near the N-terminal sequence. Electron spin resonance experiments showed two spectral components for [TOAC0]Ctx(Ile21)-Ha, which are most likely due to two membrane-bound peptide conformations. In contrast, TOAC2 and TOAC13 derivatives presented a single spectral component corresponding to a strong immobilization of the probe. Thus, our findings allowed the description of the peptide topology in the membrane mimetic, where the N-terminal region is in dynamic equilibrium between an ordered, membrane-bound conformation and a disordered, mobile conformation; position 2 is most likely situated in the lipid polar head group region, and residue 13 is fully inserted into the hydrophobic core of the membrane. PMID:23585852

  16. Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic and molecular study including 2 cases harboring ETV6-X fusion.

    PubMed

    Ito, Yohei; Ishibashi, Kenichiro; Masaki, Ayako; Fujii, Kana; Fujiyoshi, Yukio; Hattori, Hideo; Kawakita, Daisuke; Matsumoto, Manabu; Miyabe, Satoru; Shimozato, Kazuo; Nagao, Toshitaka; Inagaki, Hiroshi

    2015-05-01

    Mammary analogue secretory carcinoma (MASC) is a recently described low-grade carcinoma with morphologic and genetic similarity, including ETV6-NTRK3 fusion, to secretory carcinoma of the breast. ETV6 is frequently involved in other epithelial and nonepithelial tumors, and many fusion partners of ETV6 have been reported. In the present study, 14 Japanese MASC cases were clinicopathologically and molecularly analyzed. The median age of the patients was 39 years, and the male:female ratio was 6:8. All cases showed histopathologic findings compatible with those previously described for MASC and harbored an ETV6 split as visualized by fluorescence in situ hybridization. Two cases showed thick fibrous septa and invasive features including vascular or perineural tumor involvement, findings that are rare in MASC. In addition, in these 2 cases, non-NTRK3 genes appeared to fuse with ETV6 (ETV6-X fusion). NTRK1 and NTRK2, both members of the NTRK family, were not involved. Of the 14 MASC cases, the ETV6-NTRK3 fusion transcript was positive in 6 cases, and the relative expression level of the ETV6-NTRK3 fusion transcript was variable, ranging from 1 to 5.8. Results of the present study of MASC suggest that (1) ETV6 occasionally fuses with unknown non-NTRK3 genes, (2) ETV6-X cases might have an invasive histology, (3) for molecular diagnosis of MASC, fluorescence in situ hybridization to detect ETV6 splits is the method of choice, and (4) the expression level of the ETV6-NTRK3 fusion transcript is considerably variable. These findings provide a novel insight into the oncogenesis, histopathology, diagnosis, treatment, and prognosis of this newly recognized carcinoma. PMID:25651470

  17. Collaborative Student Laboratory Exercise Using FT-IR Spectroscopy for the Kinetics Study of a Biotin Analogue

    ERIC Educational Resources Information Center

    Leong, Jhaque; Ackroyd, Nathan C.; Ho, Karen

    2014-01-01

    The synthesis of N-methoxycarbonyl-2-imidazolidone, an analogue of biotin, was conducted by organic chemistry students and confirmed using FT-IR and H NMR. Spectroscopy students used FT-IR to measure the rate of hydrolysis of the product and determined the rate constant for the reaction using the integrated rate law. From the magnitude of the rate…

  18. Collaborative Student Laboratory Exercise Using FT-IR Spectroscopy for the Kinetics Study of a Biotin Analogue

    ERIC Educational Resources Information Center

    Leong, Jhaque; Ackroyd, Nathan C.; Ho, Karen

    2014-01-01

    The synthesis of N-methoxycarbonyl-2-imidazolidone, an analogue of biotin, was conducted by organic chemistry students and confirmed using FT-IR and H NMR. Spectroscopy students used FT-IR to measure the rate of hydrolysis of the product and determined the rate constant for the reaction using the integrated rate law. From the magnitude of the rate

  19. Potential desiccation cracks on Mars: A synthesis from modeling, analogue-field studies, and global observations

    NASA Astrophysics Data System (ADS)

    El-Maarry, M. R.; Watters, W.; McKeown, N. K.; Carter, J.; Noe Dobrea, E.; Bishop, J. L.; Pommerol, A.; Thomas, N.

    2014-10-01

    Potential desiccation polygons (PDPs) are polygonal surface patterns that are a common feature in Noachian-to-Hesperian-aged phyllosilicate- and chloride-bearing terrains and have been observed with size scales that range from cm-wide (by current rovers) to 10s of meters-wide. The global distribution of PDPs shows that they share certain traits in terms of morphology and geologic setting that can aid identification and distinction from fracturing patterns caused by other processes. They are mostly associated with sedimentary deposits that display spectral evidence for the presence of Fe/Mg smectites, Al-rich smectites or less commonly kaolinites, carbonates, and sulfates. In addition, PDPs may indicate paleolacustrine environments, which are of high interest for planetary exploration, and their presence implies that the fractured units are rich in smectite minerals that may have been deposited in a standing body of water. A collective synthesis with new data, particularly from the HiRISE camera suggests that desiccation cracks may be more common on the surface of Mars than previously thought. A review of terrestrial research on desiccation processes with emphasis on the theoretical background, field studies, and modeling constraints is presented here as well and shown to be consistent with and relevant to certain polygonal patterns on Mars.

  20. Interaction of chloroquine and its analogues with heme: An isothermal titration calorimetric study.

    PubMed

    Bachhawat, K; Thomas, C J; Surolia, N; Surolia, A

    2000-10-01

    Quinoline-containing drugs such as chloroquine and quinine have had a long and successful history in antimalarial chemotherapy. Identification of ferriprotoporphyrin IX ([Fe(III)PPIX], haematin) as the drug receptors for these antimalarials called for investigations of the binding affinity, mode of interaction, and the conditions affecting the interaction. The parameters obtained are significant in recent times with the emergence of chloroquine resistant strains of the malaria parasites. This has underlined the need to unravel the molecular mechanism of their action so as to meet the requirement of an alternative to the existing antimalarial drugs. The isothermal titration calorimetric studies on the interaction of chloroquine with haematin lead us to propose an altered mode of binding. The initial recognition is ionic in nature mediated by the propionyl group of haematin with the quaternary nitrogen on CQ. This ionic interaction induces a conformational change, such as to favour binding of subsequent CQ molecules. On the contrary, conditions emulating the cytosolic environment (pH 7.4 and 150 mM salt) reveal the hydrophobic force to be the sole contributor driving the interaction. Interaction of a carefully selected panel of quinoline antimalarial drugs with monomeric ferriprotoporphyrin IX has also been investigated at pH 5.6 mimicking the acidic environment prevalent in the food vacuoles of parasite, the center of drug activity, which are consistent with their antimalarial activity. PMID:11027592

  1. Molecular modeling studies, synthesis and biological evaluation of dabigatran analogues as thrombin inhibitors.

    PubMed

    Dong, Ming-Hui; Chen, Hai-Feng; Ren, Yu-Jie; Shao, Fang-Ming

    2016-01-15

    In this work, 48 thrombin inhibitors based on the structural scaffold of dabigatran were analyzed using a combination of molecular modeling techniques. We generated three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on three alignments for both comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) to highlight the structural requirements for thrombin protein inhibition. In addition to the 3D-QSAR study, Topomer CoMFA model also was established with a higher leave-one-out cross-validation q(2) and a non-cross-validation r(2), which suggest that the three models have good predictive ability. The results indicated that the steric, hydrophobic and electrostatic fields play key roles in QSAR model. Furthermore, we employed molecular docking and re-docking simulation explored the binding relationship of the ligand and the receptor protein in detail. Molecular docking simulations identified several key interactions that were also indicated through 3D-QSAR analysis. On the basis of the obtained results, two compounds were designed and predicted by three models, the biological evaluation in vitro (IC50) demonstrated that these molecular models were effective for the development of novel potent thrombin inhibitors. PMID:26690913

  2. Theoretical Studies on the Intermolecular Interactions of Potentially Primordial Base-Pair Analogues

    SciTech Connect

    Leszczynski, Jerzy; Sponer, Judit; Sponer, Jiri; Sumpter, Bobby G; Fuentes-Cabrera, Miguel A; Vazquez-Mayagoitia, Alvaro

    2010-01-01

    Recent experimental studies on the Watson Crick type base pairing of triazine and aminopyrimidine derivatives suggest that acid/base properties of the constituent bases might be related to the duplex stabilities measured in solution. Herein we use high-level quantum chemical calculations and molecular dynamics simulations to evaluate the base pairing and stacking interactions of seven selected base pairs, which are common in that they are stabilized by two NH O hydrogen bonds separated by one NH N hydrogen bond. We show that neither the base pairing nor the base stacking interaction energies correlate with the reported pKa data of the bases and the melting points of the duplexes. This suggests that the experimentally observed correlation between the melting point data of the duplexes and the pKa values of the constituent bases is not rooted in the intrinsic base pairing and stacking properties. The physical chemistry origin of the observed experimental correlation thus remains unexplained and requires further investigations. In addition, since our calculations are carried out with extrapolation to the complete basis set of atomic orbitals and with inclusion of higher electron correlation effects, they provide reference data for stacking and base pairing energies of non-natural bases.

  3. Study on the phase I metabolism of novel synthetic cannabinoids, APICA and its fluorinated analogue.

    PubMed

    Sobolevsky, Tim; Prasolov, Ilya; Rodchenkov, Grigory

    2015-02-01

    The data are reported for an in vitro metabolism study of two novel synthetic cannabinoids, N-(1-adamantyl)-1-pentyl-1H-indole-3-carboxamide (APICA) and its fluorinated analog N-(1-adamantyl)-1-(5-fluoropentyl)-1H-indole-3-carboxamide (5F-APICA, STS-135), which are active ingredients of smoking mixtures sold in Russia since 2012. The cannabinoids were isolated from herbal mixtures using preparative liquid chromatography and then incubated with human liver microsomes (HLMs). The formed metabolites were characterized by liquid chromatography - triple quadrupole mass spectrometry and high-resolution mass spectrometry with electrospray ionization in positive ion mode. It was found that HLMs produce mono-, di-, and trihydroxylated metabolites, as well as N-desalkyl metabolites, which can be further hydroxylated; the amide bond resisted the metabolic cleavage. For 5F-APICA, a series of oxidative defluorination products formed as well. For in vivo confirmation of the formed in vitro metabolites, spot urine samples from drug users were analyzed with the created method. It was shown that for the detection of APICA abuse, the preferred metabolites are the di- and tri-hydroxylated species, while in case of 5F-APICA, a monohydroxy metabolite is a better target. The N-despentyl (desfluoropentyl) hydroxyadamantyl metabolite also provides good retrospectivity to confirm the administration of any of these cannabinoids. PMID:25428705

  4. TEM study of an analogue of the Earth's inner core ?-Fe

    NASA Astrophysics Data System (ADS)

    Poirier, J. P.; Langenhorst, F.

    2002-02-01

    Metallurgists know that a hexagonal close-packed phase (?-martensite) is formed by straining at low temperature or pressurization of nickel-chromium stainless steels. In many respects, the ?-martensite is similar to the hexagonal phase of iron thought to constitute the Earth's inner core (?-Fe), but, contrary to ?-Fe, it is metastable at atmospheric pressure. Observation of dislocations in ?-martensite in transmission electron microscopy (TEM) may thus provide information on the deformation mechanisms of the inner core alloy. Samples of 18 Cr-8 Ni austenitic stainless steel have been pressurized at 13 GPa and 800 C, in a multi-anvil press and 30 GPa and RT, in a diamond-anvil cell. Subsequent TEM study shows that thin lamellae of ?-phase form on {1 1 1} planes of the fcc austenite. They were accompanied by crystals of bcc ?'-martensite. In one case, a few dislocations were observed in a glide band of the ?-phase, compatible with second order pyramidal slip {1 1 2 2}<1 1 2 3> . The observations suggest that ?-martensite, hence presumably ?-Fe, deforms by slip on the basal plane and second order pyramidal planes, as hexagonal cobalt.

  5. Natural glass analogues to alteration of nuclear waste glass: A review and recommendations for further study

    SciTech Connect

    McKenzie, W.F.

    1990-01-01

    The purpose of this report is to review previous work on the weathering of natural glasses; and to make recommendations for further work with respect to studying the alteration of natural glasses as it relates quantifying rates of dissolution. the first task was greatly simplified by the published papers of Jercinovic and Ewing (1987) and Byers, Jercinovic, and Ewing (1987). The second task is obviously the more difficult of the two and the author makes no claim of completeness in this regard. Glasses weather in the natural environment by reacting with aqueous solutions producing a rind of secondary solid phases. It had been proposed by some workers that the thickness of this rind is a function of the age of the glass and thus could be used to estimate glass dissolution rates. However, Jercinovic and Ewing (1987) point out that in general the rind thickness does not correlate with the age of the glass owing to the differences in time of contact with the solution compared to the actual age of the sample. It should be noted that the rate of glass dissolution is also a function of the composition of both the glass and the solution, and the temperature. Quantification of the effects of these parameters (as well as time of contact with the aqueous phase and flow rates) would thus permit a prediction of the consequences of glass-fluid interactions under varying environmental conditions. Defense high- level nuclear waste (DHLW), consisting primarily of liquid and sludge, will be encapsulated by and dispersed in a borosilicate glass before permanent storage in a HLW repository. This glass containing the DHLW serves to dilute the radionuclides and to retard their dispersion into the environment. 318 refs.

  6. Pico de Orizaba as an analogue to study planetary ecosynthesis on Mars

    NASA Astrophysics Data System (ADS)

    Navarro-González, R.

    2010-03-01

    Studies of Mars by spacecrafts, landers and rovers have indicated that it was once a wetter, more habitable world than the cold desert planet of today. If water was once stable as a liquid on the surface and flowed in such vast quantities, then the atmosphere must have been denser and the climate warmer in the past. The same processes that led to the origin of life on Earth may have occurred simultaneously on Mars, and living organisms may have colonized the planet. It is unclear how or when Mars lost its thicker atmosphere and as a result lost its habitable environment. The Viking landers of the mid-1970s carried experiments designed to detect the presence of extant life and showed the martian soil to be lifeless on the surface. Future space missions will continue to explore if there was or still is life on Mars, perhaps in the subsurface. However, if there is no life on Mars, there is an opportunity to explore the potential for survival and biological evolution for terrestrial life beyond their place of origin, and do planetary ecosynthesis on Mars, a process of making the planet habitable for terrestrial organisms. The evidence that Mars was once habitable is important for planetary ecosynthesis as it provides a proof in principle that Mars can support a habitable state on timescales that, while short over the age of the solar system, are long in human terms. Artificial greenhouse gases, such as perfluorocarbons, appear to be the best method for warming Mars and increase its atmospheric density so that liquid water becomes stable. The process of introducing terrestrial ecosystems to Mars can be compared with a descent down a high mountain. Each drop in elevation results in a warmer, wetter climate and more diverse biological community. This is shown in Pico de Orizaba which is located at 19.03°N, 97.27°W and rises 5,636 meters above sea level. It is the highest mountain in Mexico, the third highest in the tropics after Mount Kilimanjaro (5,892) in Tanzania and Pico Cristóbal Colón (5,700 m) in Columbia but with the highest tropical treeline in the world. Pico de Orizaba is a good analog on Earth of a warmer and wetter Mars with trees confined to tropical regions.

  7. A laboratory study of meteor smoke analogues: Composition, optical properties and growth kinetics

    NASA Astrophysics Data System (ADS)

    Saunders, Russell W.; Plane, John M. C.

    2006-12-01

    Meteoric smoke forms in the mesosphere from the recondensation of the metallic species and silica produced by meteoric ablation. A photochemical flow reactor was used to generate meteoric smoke mimics using appropriate photolytic precursors of Fe and Si atoms in an excess of oxidant. The following systems were studied: (i) Fe+O3/O2, (ii) Fe+O3/O2+H2O, (iii) Fe+Si/SiO+O3/O2 and (iv) Si/SiO+O3/O2. The resulting nano-particles were captured for imaging by transmission electron microscopy, combined with elemental analysis using X-ray (EDX) and electron energy loss (EELS) techniques. These systems generated particle compositions consistent with: (i) Fe2O3 (hematite), (ii) FeOOH (goethite), (iii) Fe2SiO4 (fayalite) and (iv) SiO2 (silica). Electron diffraction revealed that the Fe-containing particles were entirely amorphous, while the SiO2 particles displayed some degree of crystallinity. The Fe-containing particles formed fractal aggregates with chain-like morphologies, whereas the SiO2 particles were predominantly spherical and compact in appearance. The optical extinction spectra of the Fe-containing particles were measured from 300 nm<λ<650 nm. Excellent agreement was found with the extinction calculated from Mie theory using the refractive indices for the bulk compounds, and assuming that the fractal aggregates are composed of poly-disperse distributions of constituent particles with radii ranging from ˜5 to 100 nm. These sizes were confirmed from measurements of the particle size distributions and microscopic imaging. Finally, the particle growth kinetics of the Fe-containing systems exhibit unexpectedly rapid agglomerative coagulation. This was modelled by assuming an initial period of coalescent particle growth resulting from diffusional (Brownian) coagulation to form primary particles; further growth of these particles is then dominated by long-range magnetic dipole dipole interactions, leading to the fractal aggregates observed. The atmospheric implications of this work are then discussed.

  8. Comparative study of the effect of BPA and its selected analogues on hemoglobin oxidation, morphological alterations and hemolytic changes in human erythrocytes.

    PubMed

    Ma?czak, Aneta; Bukowska, Bo?ena; Micha?owicz, Jaromir

    2015-01-01

    Bisphenol A (BPA) has been shown to provoke many deleterious impacts on human health, and thus it is now successively substituted by BPA analogues, whose effects have been poorly investigated. Up to now, only one study has been realized to assess the effect of BPA on human erythrocytes, which showed its significant hemolytic and oxidative potential. Moreover, no study has been conducted to evaluate the effect of BPA analogues on red blood cells. The purpose of the present study was to compare the impact of BPA and its selected analogues such as bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF) on hemolytic and morphological changes and hemoglobin oxidation (methemoglobin formation) of human erythrocytes. The erythrocytes were incubated with different bisphenols concentrations ranging from 0.5 to 500?g/ml for 1, 4 and 24h. The compounds examined caused hemolysis in human erythrocytes with BPAF exhibiting the strongest effect. All bisphenols examined caused methemoglobin formation with BPA inducing the strongest oxidative potential. Flow cytometry analysis showed that all bisphenols (excluding BPS) induced significant changes in erythrocytes size. Changes in red blood cells shape were conducted using phase contrast microscopy. It was noticed that BPA and BPAF induced echinocytosis, BPF caused stomatocytosis, while BPS did not provoke significant changes in shape of red blood cells. Generally, the results showed that BPS, which is the main substituent of bisphenol A in polymers and thermal paper production, exhibited significantly lower disturbance of erythrocyte functions than BPA. PMID:26232583

  9. QSAR analyses of DDT analogues and their in silico validation using molecular docking study against voltage-gated sodium channel of Anopheles funestus.

    PubMed

    Saini, V; Kumar, A

    2014-01-01

    DDT has enjoyed the reputation of a successful pesticide in disease control programme and agricultural practices along with the serious opposition and ban later on due to its biomagnification and toxic action against non-target organisms. The present work was carried out to develop QSAR models for analysing DDT analogues for their pesticidal activity and in silico validation of these models. A 2D-QSAR model was generated using stepwise with multiple regression, and the model with a value of r(2) = 0.7324; q(2) = 0.6215; pred r(2) = 0.7038, containing five descriptors, was selected for further study. The 3D QSAR with CoMFA analysis showed that steric contribution of 21% and electrostatic contribution of about 79% were required for larvicidal activity of DDT analogues. A set of 3430 molecules was generated using the basic DDT skeleton as template, and these were evaluated for their mosquito larvicidal activity using the generated QSAR models and DDT as standard. Eleven molecules were selected for in silico validation of these models. For this, a docking study of the selected molecules against the homology-modelled voltage-gated sodium channel of Anopheles funestus was conducted. The study showed that the activities of these analogues as predicted by 2D-QSAR, 3D-QSAR with CoMFA and dock score were observed to be well correlated. PMID:25271473

  10. Structure-Activity Relationships (SAR) studies of benzoxazinones, their degradation products and analogues. phytotoxicity on standard target species (STS).

    PubMed

    Macías, Francisco A; Marín, David; Oliveros-Bastidas, Alberto; Castellano, Diego; Simonet, Ana M; Molinillo, José M G

    2005-02-01

    Benzoxazinones 2,4-dihydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (DIMBOA) and 2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one (DIBOA) have been considered key compounds for understanding allelopathic phenomena in Gramineae crop plants such as corn (Zea mays L.), wheat (Triticum aestivum L.), and rye (Secale cereale L.). The degradation processes in the environment observed for these compounds, in which soil microbes are directly involved, could affect potential allelopathic activity of these plants. We present in this work a complete structure-activity relationships study based on the phytotoxic effects observed for DIMBOA, DIBOA, and their main degradation products, in addition to several synthetic analogues of them. Their effects were evaluated on standard target species (STS), which include Triticum aestivum L. (wheat) and Allium cepa L. (onion) as monocots and Lepidium sativum L. (cress), Lactuca sativa L. (lettuce), and Lycopersicon esculentum Will. (tomato) as dicots. This permitted us to elucidate their ecological role and to propose new herbicide models based on their structures. The best phytotoxicity results were shown by the degradation chemical 2-aminophenoxazin-3-one (APO) and several 2-deoxy derivatives of natural benzoxazinones, including 4-acetoxy-(2H)-1,4-benzoxazin-3(4H)-one (ABOA), 4-hydroxy-(2H)-1,4-benzoxazin-3(4H)-one (D-DIBOA), and 4-hydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one (D-DIMBOA). They showed high inhibitory activity over almost all species growth. The fact that APO is a degradation product from DIBOA with high phytotoxicity and stability makes it possible to assign an important ecological role regarding plant defense mechanisms. 2-Deoxy derivatives of natural benzoxazinones display a wide range of activities that allow proposing them as new leads for natural herbicide models with a 1,4-benzoxazine skeleton. PMID:15686399

  11. First-principles study of energetic complexes (II): (5-cyanotetrazolato-N2) pentaammine cobalt (III) perchlorate (CP) and Ni, Fe and Zn analogues.

    PubMed

    Shang, Jing; Zhang, Jian-Guo; Zhang, Tong-Lai; Huang, Hui-Sheng; Zhang, Shao-Wen; Zhou, Zun-Ning

    2012-06-01

    First-principles methods using the TPSS density functional level of theory with the basis set 6-31G** were applied to study (5-cyanotetrazolato-N(2)) pentaammine cobalt (III) perchlorate (CP) and Ni, Fe and Zn analogues in the gas phase. The optimized lowest-energy geometry of CP was calculated from reported experimental structural data using the TPSS method. The calculated values are in good agreement with those measured by X-ray diffraction. Ni, Fe and Zn analogues were constructed and calculated on the same basis. NBO results showed that the metal-ligand interactions have covalent character. Donor-acceptor analyses predicted that the delocalization energy E(2) decreases from Co to Zn, so the covalent nature of the complexes increases in the order Co>Fe>Ni>Zn. In addition, HOMO-LUMO composition was investigated to determine the stability of the title compounds. PMID:22127608

  12. Legumes and meat analogues consumption are associated with hip fracture risk independently of meat intake among Caucasian men and women: the Adventist Health Study-2

    PubMed Central

    Lousuebsakul-Matthews, Vichuda; Thorpe, Donna L; Knutsen, Raymond; Beeson, W Larry; Fraser, Gary E; Knutsen, Synnove F

    2014-01-01

    Objective In contrast to non-vegetarians, vegetarians consume more legumes and meat analogues as sources of protein to substitute for meat intake. The present study aimed to assess the association between foods with high protein content (legumes, meat, meat analogues) by dietary pattern (vegetarians, non-vegetarians) and hip fracture incidence, adjusted for selected lifestyle factors. Design A prospective cohort of Adventist Health Study-2 (AHS-2) enrollees who completed a comprehensive lifestyle and dietary questionnaire between 2002 and 2007. Setting Every two years after enrolment, a short questionnaire on hospitalizations and selected disease outcomes including hip fractures was sent to these members. Subjects Respondents (n 33 208) to a baseline and a follow-up questionnaire. Results In a multivariable model, legumes intake of once daily or more reduced the risk of hip fracture by 64% (hazard ratio=036, 95% CI 021, 061) compared with those with legumes intake of less than once weekly. Similarly, meat intake of four or more times weekly was associated with a 40% reduced risk of hip fracture (hazard ratio=060, 95% CI 041, 087) compared with those whose meat intake was less than once weekly. Furthermore, consumption of meat analogues once daily or more was associated with a 49% reduced risk of hip fracture (hazard ratio=051, 95% CI 027, 098) compared with an intake of less than once weekly. Conclusions Hip fracture incidence was inversely associated with legumes intake and, to a lesser extent, meat intake, after accounting for other food groups and important covariates. Similarly, a high intake of meat analogues was associated with a significantly reduced risk of hip fracture. PMID:24103482

  13. The novel lipophilic camptothecin analogue gimatecan is very active in vitro in human neuroblastoma: a comparative study with SN38 and topotecan.

    PubMed

    Di Francesco, Angela Maria; Riccardi, Anna; Riccardi, Anna Shirley; Barone, Giuseppe; Rutella, Sergio; Meco, Daniela; Frapolli, Roberta; Zucchetti, Massimo; D'Incalci, Maurizio; Pisano, Claudio; Carminati, Paolo; Riccardi, Riccardo

    2005-10-15

    Neuroblastoma is one of the most common extracranial solid tumours in childhood with a poor prognosis in its advanced stage. Treatment failure is often associated to the occurrence of drug resistance. To date, treatment of paediatric neuroblastoma is still dismal, and therefore novel effective drugs are awaited. In recent years, an increasing interest has concentrated on camptothecin analogues. Topotecan and irinotecan, the only two clinically relevant camptothecin derivatives to date, have entered clinical trials in neuroblastoma but so far the results have been disappointing. Gimatecan (ST1481, LBQ707; 7-t-butoxyiminomethylcamptothecin), is a novel lipophilic camptothecin derivative that was selected from a series of lipophilic analogues rationally designed and synthesized in order to overcome some of the main drawbacks of conventional camptothecins, limiting their clinical efficacy. Gimatecan is endowed with potent antitumour activity, strong topoisomerase I inhibition, stable drug-target interactions and a better pharmacological profile. The present study deals with the comparative evaluation of cellular pharmacology features of gimatecan, topotecan and SN38 in neuroblastoma cell lines. We show that, despite the lowest intracellular accumulation, gimatecan was the most active among the camptothecin analogues studied. Our findings suggest that the high activity of gimatecan in neuroblastoma is related to the ability of this novel analogue to cause a very high number of DNA breaks as assessed by the Comet assay in both cellular or sub-cellular systems. We propose that DNA strand breaks efficiency as measured by the Comet assay might provide important information about the stability of the ternary complexes induced by camptothecin compounds. PMID:16139802

  14. Mapping the Catechol Binding Site in Dopamine D1 Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

    PubMed Central

    Bonner, Lisa A.; Laban, Uros; Chemel, Benjamin R.; Juncosa, Jose I.; Lill, Markus A.; Watts, Val J.; Nichols, David E.

    2012-01-01

    A novel class of isochroman dopamine analogues, 1, originally reported by Abbott Laboratories, had greater than 100-fold selectivity for D1-like vs. D2-like receptors. We synthesized a parallel series of chroman compounds, 2, and showed that repositioning the oxygen in the heterocyclic ring reduced potency and conferred D2-like receptor selectivity to these compounds. In silico modeling supported the hypothesis that the altered pharmacology for 2 was due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxyl of the catechol moiety. This interaction realigns the catechol hydroxyl groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D1-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds, 3. Our results suggest that when the potential for intramolecular hydrogen bonding is removed, D1-like receptor potency and selectivity is restored. PMID:21538900

  15. Studies on Labour Safety in Construction Sites.

    PubMed

    Kanchana, S; Sivaprakash, P; Joseph, Sebastian

    2015-01-01

    Construction industry has accomplished extensive growth worldwide particularly in past few decades. For a construction project to be successful, safety of the structures as well as that of the personnel is of utmost importance. The safety issues are to be considered right from the design stage till the completion and handing over of the structure. Construction industry employs skilled and unskilled labourers subject to construction site accidents and health risks. A proper coordination between contractors, clients, and workforce is needed for safe work conditions which are very much lacking in Indian construction companies. Though labour safety laws are available, the numerous accidents taking place at construction sites are continuing. Management commitment towards health and safety of the workers is also lagging. A detailed literature study was carried out to understand the causes of accidents, preventive measures, and development of safe work environment. This paper presents the results of a questionnaire survey, which was distributed among various categories of construction workers in Kerala region. The paper examines and discusses in detail the total working hours, work shifts, nativity of the workers, number of accidents, and type of injuries taking place in small and large construction sites. PMID:26839916

  16. Studies on Labour Safety in Construction Sites

    PubMed Central

    Kanchana, S.; Sivaprakash, P.; Joseph, Sebastian

    2015-01-01

    Construction industry has accomplished extensive growth worldwide particularly in past few decades. For a construction project to be successful, safety of the structures as well as that of the personnel is of utmost importance. The safety issues are to be considered right from the design stage till the completion and handing over of the structure. Construction industry employs skilled and unskilled labourers subject to construction site accidents and health risks. A proper coordination between contractors, clients, and workforce is needed for safe work conditions which are very much lacking in Indian construction companies. Though labour safety laws are available, the numerous accidents taking place at construction sites are continuing. Management commitment towards health and safety of the workers is also lagging. A detailed literature study was carried out to understand the causes of accidents, preventive measures, and development of safe work environment. This paper presents the results of a questionnaire survey, which was distributed among various categories of construction workers in Kerala region. The paper examines and discusses in detail the total working hours, work shifts, nativity of the workers, number of accidents, and type of injuries taking place in small and large construction sites. PMID:26839916

  17. Pena Blanca Natural Analogue Project: Summary of activities

    SciTech Connect

    Levy, S.; Goldstein, S.; Dobson, P.F.; Goodell, P.; Ku, T.-L.; Abdel-Fattah, A.; Saulnier, G.; Fayek, M.; de la Garza, R.

    2011-02-01

    The inactive Nopal I uranium mine in silicic tuff north of Chihuahua City, Chihuahua, Mexico, was studied as a natural analogue for an underground nuclear-waste repository in the unsaturated zone. Site stratigraphy was confirmed from new drill cores. Data from site studies include chemical and isotopic compositions of saturated- and unsaturated-zone waters. A partial geochronology of uranium enrichment and mineralization was established. Evidence pertinent to uranium-series transport in the soil zone and changing redox conditions was collected. The investigations contributed to preliminary, scoping-level performance assessment modeling.

  18. Pena blanca natural analogue project: summary of activities

    SciTech Connect

    Levy, Schon S; Goldstein, Steven J; Abdel - Fattah, Amr I

    2010-12-08

    The inactive Nopal I uranium mine in silicic tuff north of Chihuahua City, Chihuahua, Mexico, was studied as a natural analogue for an underground nuclear-waste repository in the unsaturated zone. Site stratigraphy was confirmed from new drill core. Datafrom site studies include chemical and isotopic compositions of saturated- and unsaturated-zone waters. A partial geochronology of uranium enrichment and mineralization was established. Evidence pertinent to uranium-series transport in the soil zone and changing redox conditions was collected. The investigations contributed to preliminary, scoping-level performance assessment modeling.

  19. Synthesis and biological properties of novel brefeldin A analogues.

    PubMed

    Seehafer, Kai; Rominger, Frank; Helmchen, Gnter; Langhans, Markus; Robinson, David G; zata, Ba?ak; Brgger, Britta; Strating, Jeroen R P M; van Kuppeveld, Frank J M; Klein, Christian D

    2013-07-25

    New brefeldin A (1) analogues were obtained by introducing a variety of substituents at C15. Most of the analogues exhibited significant biological activity. (15R)-Trifluoromethyl-nor-brefeldin A (3), (15R)-vinyl-nor-brefeldin A (5), their epimers 4 and 6 as well as (15S)-ethyl-nor-brefeldin A (2) were prepared from the key building blocks 12 or 24 by Julia-Kocienski olefination with tetrazolyl sulfones and subsequent macrolactonization. The vinyl derivative 5 allowed analogues to be synthesized by hydroboration and Suzuki-Miyaura coupling. The following biological properties were assessed: (a) inhibition of cell growth of human cancer cells (NCI), (b) induction of morphological changes of the Golgi apparatus of plant and mammalian cells, and (c) influence on the replication of the enterovirus CVB3. Furthermore, conformational aspects were studied by X-ray crystal structure analysis and molecular mechanics calculations, including docking of the analogues into the brefeldin A binding site of an Arf1/Sec7-complex. PMID:23805957

  20. A comparative study on the crystal structure of bicycle analogues to the natural phytotoxin helminthosporins

    NASA Astrophysics Data System (ADS)

    Barbosa, Luiz Cláudio de Almeida; Teixeira, Robson Ricardo; Nogueira, Leonardo Brandão; Maltha, Celia Regina Alvares; Doriguetto, Antônio Carlos; Martins, Felipe Terra

    2016-02-01

    Herein we described structural insights of a series of analogues to helminthosporin phytotoxins. The key reaction used to prepare the compounds corresponded to the [3 + 4] cycloaddition between the oxyallyl cation generated from 2,4-dibromopentan-3-one and different furans. Their structures were confirmed upon IR, NMR and X-ray diffraction analyses. While bicycles 7, 8 and 9 crystallize in the centrosymmetric monoclinic space group P21/c, compound 10 was solved in the noncentrosymmetric orthorhombic space group P212121. The solid materials obtained were shown to be racemic crystals (7, 8, 9) or racemic conglomerate (10). In all compounds, there is formation of a bicycle featured by fused tetrahydropyranone and 2,5-dihydrofuran rings. They adopt chair and envelope conformations, respectively. Crystal packing of all compounds is stabilized through C-H•••O contacts. Conformational aspects as well as similarities and differences among the crystal structures of the synthesized analogues are discussed.

  1. Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study.

    PubMed

    Prez, Sheila; Vale, Carmen; Alonso, Eva; Fuwa, Haruhiko; Sasaki, Makoto; Konno, Yu; Goto, Tomomi; Suga, Yuto; Vieytes, Mercedes R; Botana, Luis M

    2012-09-17

    The polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 ?g/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases. PMID:22894724

  2. Luminescence studies of perturbation of tryptophan residues of tubulin in the complexes of tubulin with colchicine and colchicine analogues.

    PubMed

    Sardar, Pinki Saha; Maity, Shyam Sundar; Das, Lalita; Ghosh, Sanjib

    2007-12-18

    Tubulin, a heterodimeric (alphabeta) protein, the main constituent of microtubules, binds efficiently with colchicine (consisting of a trimethoxybenzene ring, a seven-member ring and methoxy tropone moiety) and its analogues, viz., demecolcine and AC [2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone]. Tubulin contains eight tryptophan (Trp) residues at A21, A346, A388, A407, B21, B103, B346, and B407 in the two subunits. The role of these eight Trp residues in this interaction and also their perturbation due to binding have been explored via time-resolved fluorescence at room temperature and low-temperature (77 K) phosphorescence in a suitable cryosolvent. Both the time-resolved fluorescence data and 77 K phosphorescence spectra indicate that the emitting residues move toward a more hydrophobic and less polar environment after complex formation. The environment of emitting Trps in the complex also becomes slightly more heterogeneous. Our analysis using the experimental results, the calculation of the accessible surface area (ASA) of all the Trps in the wild type and tubulin-colchicine complex [Ravelli, R. B. G., et al. (2004) Nature 428, 198-202], the distance of the Trp residues from the different moieties of the colchicine molecule, the knowledge of the nature of the immediate residues (<5 A) present near each Trp residue, and the calculation of the intramolecular Trp-Trp energy transfer efficiencies indicate that Trp A346, Trp A407, Trp B21, and Trp B407 are the major contributors to the emission in the free protein, while Trp B21 and Trp B103 are mainly responsible for the emission of the complexes. A comparative account of the photophysical aspects of the drug molecules bound to protein in aqueous buffer and in buffer containing 40% ethylene glycol has been presented. The quantum yield and average lifetime of fluorescence in tubulin and its complexes with colchicine are used to predict the possible donors and the energy transfer (ET) efficiency in the ET process from Trps to colchicine in the complex. This study is a unique attempt to identify the Trp residues contributing to the emission in the free protein and in a complex of a multi-Trp protein with a drug molecule without performing the mutation of the protein. PMID:18041823

  3. A solid-state hybrid density functional theory study of Prussian blue analogues and related chlorides at pressure

    NASA Astrophysics Data System (ADS)

    Middlemiss, Derek S.; Lawton, Lorreta M.; Wilson, Chick C.

    2008-08-01

    The variations with pressure in the structural, electronic and magnetic properties of a series of Prussian blue analogues (PBAs) KIMII[CrIII(CN)6] (M = VII, MnII and NiII) and associated isomorphous chlorides KIMIICrIIICl6 are investigated within a series of solid-state hybrid density functional calculations. The sensitivity of the computed properties to the choice of Hamiltonian is tested by application of functionals containing 35%, 65% and 100% admixtures of Fock exchange. Magnetic coupling constants (J) are obtained at a range of cell volumes (V), with fits of the Bloch relationship (J \\propto V^{-\\varepsilon } , ɛ typically 3-4) yielding exponents ɛ in the ranges 5.16-6.34, 8.48-12.07 and 4.00-4.51 for the antiferromagnetic (AF) VIICrIII-, ferrimagnetic (FI) MnIICrIII- and ferromagnetic (FO) NiIICrIII PBAs, respectively; and 3.33-4.99, 1.86-3.09 and 1.65-3.28 for the AF VIICrIII-, FO MnIICrIII- and FO NiIICrIII chlorides, respectively. The MnIICrIII PBA range encloses the high values ɛ~9-10 obtained in a recent joint experimental and theoretical study, and it is suggested that this strong magnetostructural effect arises due to the presence of competing AF and FO interactions in this material. Estimates of the spin ordering temperatures derived from the combination of the 35%-functional couplings with a mean field approach are in good agreement with experiment in the VIICrIII and NiIICrIII PBAs, but are too low in the MnIICrIII system. The variations with pressure in the structural parameters, charges and spin moments are also detailed, the PBA and chloride energy-volume data yielding bulk moduli in the ranges 39-53 and 36-50 GPa, respectively. Finally, the energies governing CN- ligand isomerization are estimated and successfully interpreted in terms of a simple crystal field stabilization model.

  4. Assessment of CO2 discharge in a spring using time-variant stable carbon isotope data as a natural analogue study of CO2 leakage

    NASA Astrophysics Data System (ADS)

    Yu, Soonyoung; Chae, Gitak; Jo, Minki; Kim, Jeong-Chan; Yun, Seong-Taek

    2015-04-01

    CO2-rich springs have been studied as a natural analogue of CO2 leakage through shallow subsurface environment, as they provide information on the behaviors of CO2 during the leakage from geologic CO2 storage sites. For this study, we monitored the ?13C values as well as temperature, pH, EC, DO, and alkalinity for a CO2-rich spring for 48 hours. The water samples (N=47) were collected every hour in stopper bottles without headspace to avoid the interaction with air and the CO2 degassing. The ?13C values of total dissolved inorganic carbon (TDIC) in the water samples were analyzed using a cavity ring-down spectroscopy (CRDS) system (Picarro). The values of ?13CTDIC, temperature, pH, EC, DO, and alkalinity were in the range of -9.43 ~ -8.91 o 12.3 ~ 13.2oC, 4.86 ~ 5.02, 186 ~ 189 ?S/cm, 1.8 ~ 3.4 mg/L, and 0.74 ~ 0.95 meq/L, respectively. The concentrations of TDIC calculated using pH and alkalinity values were between 22.5 and 34.8 mmol/L. The ?13CTDIC data imply that dissolved carbon in the spring was derived from a deep-seated source (i.e., magmatic) that was slightly intermixed with soil CO2. Careful examination of the time-series variation of measured parameters shows the following characteristics: 1) the ?13CTDIC values are negatively correlated with pH (r = -0.59) and positively correlated with TDIC (r = 0.58), and 2) delay times of the change of pH and alkalinity following the change of ?13CTDIC values are 0 and -3 hours, respectively; the pH change occurs simultaneously with the change of ?13CTDIC, while the alkalinity change happens before 3 hours. Our results indicate that the studied CO2-rich spring is influenced by the intermittent supply of deep-seated CO2. [Acknowledgment] This work was financially supported by the fundamental research project of KIGAM and partially by the "Geo-Advanced Innovative Action (GAIA) Project (2014000530003)" from Korea Ministry of Environment (MOE).

  5. Pepstatin analogues as novel renin inhibitors.

    PubMed

    Gugan, R; Diaz, J; Cazaubon, C; Beaumont, M; Carlet, C; Clment, J; Demarne, H; Mellet, M; Richaud, J P; Segondy, D

    1986-07-01

    Pepstatin analogues corresponding to the general formula A-X-Y-Sta-Ala-Sta-R were synthesized in solution phase. Various changes in the nature of the A, X, and Y groups were made to improve the inhibitory potency against human plasma renin activity. The results were interpreted by use of the active-site model based on the sequence of human angiotensinogen. The tert-butyloxycarbonyl group and the isovaleryl group were found to be the most effective acyl groups (A). The analogues having a Phe residue in place of Val1 (X) and His or amino acid with an aliphatic side chain such as norleucine or norvaline in the Y position showed the highest inhibition of human plasma renin activity with IC50 values of about 10(-8)M. Esterification or amidification of the carboxyl group of the C-terminal statine did not change the inhibitory potency. The selectivity for rat, dog, pig, and monkey plasma renin of the most interesting compounds was studied. PMID:3543358

  6. Base oxidation at 5' site of GG sequence in double-stranded DNA induced by UVA in the presence of xanthone analogues: relationship between the DNA-damaging abilities of photosensitizers and their HOMO energies.

    PubMed

    Hirakawa, Kazutaka; Yoshida, Mami; Oikawa, Shinji; Kawanishi, Shosuke

    2003-04-01

    UVA contributes to skin cancer by solar UV light. Photosensitizers are believed to play an important role in UVA carcinogenesis. We investigated the mechanism of DNA damage induced by photoexcited xanthone (XAN) analogues (XAN, thioxanthone [TXAN] and acridone [ACR]), exogenous photosensitizers, and the relationship between the DNA-damaging abilities and their highest occupied molecular orbital (HOMO) energies. DNA damage by these photosensitizers was examined using 32P-labeled DNA fragments obtained from the p53 tumor suppressor gene. Photoexcited XAN caused DNA cleavage specifically at 5'-G of the GG sequence in the double-stranded DNA only when the DNA fragments were treated with piperidine, suggesting that DNA cleavage is due to base modification with little or no strand breakage. With denatured single-stranded DNA, the extent of XAN-sensitized photodamage was decreased. An oxidative product of G, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo), was formed by photoexcited XAN, and the 8-oxo-dGuo formation was decreased in single-stranded DNA. TXAN and ACR induced DNA photodamage as did XAN, although the order of DNA-damaging ability was XAN > TXAN > ACR. These findings suggest that photoexcited XAN analogues induce nucleobase oxidation at 5'-G of GG sequence in double-stranded DNA through electron transfer. The HOMO energies of these photosensitizers, estimated from ab initio molecular orbital (MO) calculation, decreased in the following order: XAN > TXAN > ACR. Extents of DNA damage increased exponentially with the HOMO energies of XAN analogues. This study suggests that DNA-damaging abilities of photosensitizers can be estimated from their HOMO energies. PMID:12733645

  7. Density Functional Theory Calculations of Redox Properties of Iron–Sulphur Protein Analogues

    SciTech Connect

    Niu, Shuqiang; Ichiye, Toshiko

    2011-06-08

    A central issue in understanding redox properties of iron–sulphur (Fe–S) proteins is determining the factors that tune the reduction potentials of the Fe–S clusters. Studies of redox site analogues play an important role, particularly because individual factors can be examined independently of the environment by combining calculations and experiments of carefully designed ligands for the analogues. For iron–sulphur analogues, our study has shown that broken-symmetry density functional theory gives good energetics when the geometry is optimised using B3LYP with a double-ζ basis set with polarisation functions, and the energies of these geometries are calculated using B3LYP with additional diffuse functions added to the sulphurs. A comparison of our calculated energies for redox site analogues in the gas phase against electron detachment energies measured by a combination of electrospray ionisation and photoelectron spectroscopy (EI–PES) by Wang and co-workers has been essential because the comparison is for exactly the same molecule with no approximation for the environment. Overall, the correlation of our B3LYP/ 6-31(++)SG**//B3LYP/6-31G** detachment energies with EI–PES experiments is excellent for a wide variety of analogues. Moreover, our calculations at this level have provided insight into a wide variety of properties of iron–sulphur proteins.

  8. Plant Volatile Analogues Strengthen Attractiveness to Insect

    PubMed Central

    Sun, Yufeng; Yu, Hao; Zhou, Jing-Jiang; Pickett, John A.; Wu, Kongming

    2014-01-01

    Green leaf bug Apolygus lucorum (Meyer-Dr) is one of the major pests in agriculture. Management of A. lucorum was largely achieved by using pesticides. However, the increasing population of A. lucorum since growing Bt cotton widely and the increased awareness of ecoenvironment and agricultural product safety makes their population-control very challenging. Therefore this study was conducted to explore a novel ecological approach, synthetic plant volatile analogues, to manage the pest. Here, plant volatile analogues were first designed and synthesized by combining the bioactive components of ?-ionone and benzaldehyde. The stabilities of ?-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than ?-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than ?-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

  9. Bradykinin and its gly sup 6 analogue are substrates of cyclophilin: A fluorine-19 magnetization transfer study

    SciTech Connect

    London, R.E.; Davis, D.G. ); Vavrek, R.J.; Stewart, J.M. ); Handschumacher, R.E. )

    1990-11-01

    Fluorine-19 magnetization transfer experiments have been used to determine the rates of cis/trans isomerization about the X-Pro{sup 7} peptide bond in (p-fluoro-Phe{sup 8})bradykinin and its Gly{sup 6} analogue. The measurements were carried out both prior to and after the addition of cyclophilin, which has recently been shown to have peptidyl-proline cis/trans isomerase activity and is the apparent target enzyme of the immunosuppressive agent cyclosporin A. Magnetization transfer measurements over the temperature range 40-75 {degree}C in the absence of enzyme give activation energies of 22.8 and 23.0 kcal/mol for (p-fluoro-Phe{sup 8})bradykinin and its Gly{sup 6} analogue, respectively. The values for the uncatalyzed cis {r arrow} trans rate constant, k{sub c}, are determined by extrapolation to be 4.8 {times} 10{sup {minus}2} and 2.1 {times} 10{sup {minus}2} s{sup {minus}1} for the two peptides at 25 {degree}C. The enzyme-catalyzed enhancement of the cis/trans interconversion rate was proportional to added cyclophilin concentration and was strongly sequence specific, with bradykinin a much better substrate than (Gly{sup 6})bradykinin. At a peptide concentration of 2.2 mM, the catalytic activity expressed as k{sub c} per micromolar cyclophilin was determined to be 1.2 s{sup {minus}1}/{mu}M for (p-fluoro-Phe{sup 8})bradykinin and 0.13 s{sup {minus}1}/{mu}M for the Gly{sup 6}analogue. The increased cis {r arrow} trans interconversion rates were strongly inhibited by cyclosporin A and the 6-(methylalanine) derivative, which bind to cyclophilin, but not by the 1-(tetrahydrofurfuryl) derivative of cyclosporin that binds weakly.

  10. Anti-tumour and pharmacokinetics study of 2-Formyl-8-hydroxy-quinolinium chloride as Galipea longiflora alkaloid analogue.

    PubMed

    Lam, Kim-Hung; Lee, Kenneth Ka-Ho; Gambari, Roberto; Kok, Stanton Hon-Lung; Kok, Tsz-Wai; Chan, Albert Sun-Chi; Bian, Zhao-Xiang; Wong, Wai-Yeung; Wong, Raymond Siu-Ming; Lau, Fung-Yi; Tong, See-Wai; Chan, Kit-Wah; Cheng, Chor-Hing; Chui, Chung-Hin; Tang, Johnny Cheuk-On

    2014-05-15

    The quinolinium chloride salt of 8-hydroxyqinolinecarbaldehyde (2-Formyl-8-hydroxy-quinolinium chloride) was prepared as Galipea longiflora alkaloid analogue and its anticancer activity was evaluated both in vitro and in vivo. This chloride salt was found to show certain degree of selectivity between hepatoma cells and normal hepatocytes in vitro. Athymic nude mice Hep3B xenograft model further demonstrated that this 2-Formyl-8-hydroxy-quinolinium chloride could execute strong anti-tumour activity with the identification of extensive necrotic feature from the tumour xenograft and limited adverse toxicological effect. PMID:24680618

  11. A New View on Interstellar Dust - High Fidelity Studies of Interstellar Dust Analogue Tracks in Stardust Flight Spare Aerogel

    NASA Technical Reports Server (NTRS)

    Zolensky, Michael E.; Postberg F.; Allen, C.; Bajt, S.; Bechtel, H. A.; Borg, J.; Brenker, F.; Bridges, J.; Brownlee, D. E.; Bugiel, S.; Burchell, M.; Burghammer, M.; Butterworth, A. L.; Cloetens, P.; Davis, A. M.; Floss, C.; Flynn, G. J.; Frank, D.; Gainsforth, Z.

    2011-01-01

    In 2000 and 2002 the Stardust Mission exposed aerogel collector panels for a total of about 200 days to the stream of interstellar grains sweeping through the solar system. The material was brought back to Earth in 2006. The goal of this work is the laboratory calibration of the collection process by shooting high speed [5 - 30km/s] interstellar dust (ISD) analogues onto Stardust aerogel flight spares. This enables an investigation into both the morphology of impact tracks as well as any structural and chemical modification of projectile and collector material. First results indicate a different ISD flux than previously assumed for the Stardust collection period.

  12. Ab initio calculations as a quantitative tool in the inelastic neutron scattering study of a single-molecule magnet analogue.

    PubMed

    Vonci, Michele; Giansiracusa, Marcus J; Gable, Robert W; Van den Heuvel, Willem; Latham, Kay; Moubaraki, Boujemaa; Murray, Keith S; Yu, Dehong; Mole, Richard A; Soncini, Alessandro; Boskovic, Colette

    2016-01-26

    Ab initio calculations carried out on the Tb analogue of the single-molecule magnet family Na9[Ln(W5O18)2] (Ln = Nd, Gd, Ho and Er) have allowed interpretation of the inelastic neutron scattering spectra. The combined experimental and theoretical approach sheds new light on the sensitivity of the electronic structure of the Tb(iii) ground and excited states to small structural distortions from axial symmetry, thus revealing the subtle relationship between molecular geometry and magnetic properties of the two isostructural species that comprise the sample. PMID:26690503

  13. Mineralogical, chemical, organic and microbial properties of subsurface soil cores from Mars Desert Research Station (Utah, USA): Phyllosilicate and sulfate analogues to Mars mission landing sites

    NASA Astrophysics Data System (ADS)

    Stoker, Carol R.; Clarke, Jonathan; Direito, Susana O. L.; Blake, David; Martin, Kevin R.; Zavaleta, Jhony; Foing, Bernard

    2011-07-01

    We collected and analysed soil cores from four geologic units surrounding Mars Desert Research Station (MDRS) Utah, USA, including Mancos Shale, Dakota Sandstone, Morrison formation (Brushy Basin member) and Summerville formation. The area is an important geochemical and morphological analogue to terrains on Mars. Soils were analysed for mineralogy by a Terra X-ray diffractometer (XRD), a field version of the CheMin instrument on the Mars Science Laboratory (MSL) mission (2012 landing). Soluble ion chemistry, total organic content and identity and distribution of microbial populations were also determined. The Terra data reveal that Mancos and Morrison soils are rich in phyllosilicates similar to those observed on Mars from orbital measurements (montmorillonite, nontronite and illite). Evaporite minerals observed include gypsum, thenardite, polyhalite and calcite. Soil chemical analysis shows sulfate the dominant anion in all soils and SO4>>CO3, as on Mars. The cation pattern Na>Ca>Mg is seen in all soils except for the Summerville where Ca>Na. In all soils, SO4 correlates with Na, suggesting sodium sulfates are the dominant phase. Oxidizable organics are low in all soils and range from a high of 0.7% in the Mancos samples to undetectable at a detection limit of 0.1% in the Morrison soils. Minerals rich in chromium and vanadium were identified in Morrison soils that result from diagenetic replacement of organic compounds. Depositional environment, geologic history and mineralogy all affect the ability to preserve and detect organic compounds. Subsurface biosphere populations were revealed to contain organisms from all three domains (Archaea, Bacteria and Eukarya) with cell density between 3.0106 and 1.8107 cells ml-1 at the deepest depth. These measurements are analogous to data that could be obtained on future robotic or human Mars missions and results are relevant to the MSL mission that will investigate phyllosilicates on Mars.

  14. Skrydstrup waste disposal site - a case study

    SciTech Connect

    Refsgaard, A.; Nilsson, B.; Flyvbjerg, J.

    1996-12-31

    The Skrydstrup waste disposal site and the unconfined aquifer downstream placed in the Southern Part of the peninsula Jutland, Denmark, is one of the most intensively investigated locations in Denmark. Deposits consist of a mixture of municipal waste, construction materials and chemical waste from a nearby refrigerator factory i.e. chlorinated hydrocarbon solvents and organic phosphorus components mostly stored in barrels. In 1986 it was discovered that a large part of the aquifer was polluted with both 1,1,1-trichloroethane, tri-chloroethylene and other chlorinated aliphatics and a pump-and-treat system has been in operation since 1999 in order to remediate the pollution and prevent further spreading. However, in 1991 detailed studies of the Geological and hydrogeological conditions as well as the contamination showed that the pollution had spread as far as two kilometers downstream the waste dump and approached the final recipient - a small stream. A three-dimensional Groundwater and solute transport model was constructed on the basis of the new investigations and the conclusions based on the model simulations were that (1) the remediation will have no significant effect on the future spreading of the pollution plume and will certainly not prevent the plume from leaching into the recipient located about two kilometers downstream the waste disposal site; (2) even with 3.5 times larger capacity of the water treatment plant i.e. a total abstraction of about 110 m{sup 3}/hour and a more optimal location of the remediation wells it is not possible to recover more than 50% of the present contamination in the aquifer; (3) the amount of contamination leaching to the stream within the next 10 years is almost independent of the remediation scheme adopted; and (4) more than 95% of the contaminated water will discharge to the stream within a distance of one and a half kilometer of the stream.

  15. Theoretical Study of Pd11 Si6 Nanosheet Compounds Including Seven-Coordinated Si Species and Its Ge Analogues.

    PubMed

    Chen, Yue; Sunada, Yusuke; Nagashima, Hideo; Sakaki, Shigeyoshi

    2016-01-01

    Nanosheet compounds Pd11 (SiiPr)2 (SiiPr2 )4 (CNtBu)10 (1) and Pd11 (SiiPr)2 (SiiPr2 )4 (CNMes)10 (2), containing two Pd7 (SiiPr)(SiiPr2 )2 (CNR)4 plates (R=tBu or Mes) connected with three common Pd atoms, were investigated with DFT method. All Pd atoms are somewhat positively charged and the electron density is accumulated between the Pd and Si atoms, indicating that a charge transfer (CT) occurs from the Pd to the Si atoms of the SiMe2 and SiMe groups. Negative regions of the Laplacian of the electron density were found between the Pd and Si atoms. A model of a seven-coordinated Si species, that is, Pd5 (Pd-SiMe), is predicted to be a stable pentagonal bipyramidal molecule. Five Pd atoms in the equatorial plane form bonding overlaps with two 3p orbitals of the Si atom. This is a new type of hypervalency. The Ge analogues have geometry and an electronic structure similar to those of the Si compounds. But their formation energies are smaller than those of the Si analogues. The use of the element Si is crucial to synthesize these nanoplate compounds. PMID:26663355

  16. 15N{31P} REDOR NMR Studies of the Binding of Phosphonate Reaction Intermediate Analogues to Saccharomyces cerevisiae Lumazine Synthase

    PubMed Central

    Yu, Tsyr-Yan; O'Connor, Robert D.; Sivertsen, Astrid C.; Chiauzzi, Colby; Poliks, Barbara; Fischer, Markus; Bacher, Adelbert; Haase, Ilka; Cushman, Mark; Schaefer, Jacob

    2009-01-01

    Lumazine synthase catalyzes the reaction of 5-amino-6-D-ribitylamino-2,4(1H,3H)-pyrimidinedione (1) with (S)-3,4-dihydroxybutanone 4-phosphate (2) to afford 6,7-dimethyl-8-D-ribityllumazine (3), the immediate biosynthetic precursor of riboflavin. The overall reaction implies a series of intermediates that are incompletely understood. The 15N{31P} REDOR NMR spectra of three metabolically stable phosphonate reaction intermediate analogues complexed to Saccharomyces cerevisiae lumazine synthase have been obtained at 7 and 12 T. Distances from the phosphorus atoms of the ligands to the side chain nitrogens of Lys92, His97, Arg136, and His148 have been determined. These distances were used in combination with the X-ray crystal coordinates of one of the intermediate analogues complexed with the enzyme in a series of distance-restrained molecular dynamics simulations. The resulting models indicate mobility of the Lys92 side chain, which could facilitate the exchange of inorganic phosphate eliminated from the substrate in one reaction, with the organic phosphate-containing substrate necessary for the next reaction. PMID:19117095

  17. Nitrenium ions and trivalent boron ligands as analogues of N-heterocyclic carbenes in olefin metathesis: a computational study.

    PubMed

    Pazio, A; Wo?niak, K; Grela, K; Trzaskowski, B

    2015-12-14

    We used the density functional theory to evaluate the suitability of nitrenium ions and trivalent boron ligands as analogues of N-heterocyclic carbenes in ruthenium-based metathesis catalysts. We demonstrate that these analogues induce only minor structural changes in Hoveyda-Grubbs-like precatalysts, but have major impact on precatalyst initiation. Nitrenium ion-modified precatalysts are characterized by a weak Ru-N bond resulting in a relatively strong Ru-O bond and large free energy barriers for initiation, making them good candidates for efficient latent Ru-based catalysts. On the other hand the trivalent boron ligand, bearing a formal -1 charge, binds strongly to the ruthenium ion, weakening the Ru-O bond and facilitating its dissociation, to promote fast reaction initiation. We show that the calculated bond dissociation energy of the Ru-C/N/B bond may serve as an accurate indicator of the Ru-O bond strength and the rate of metathesis initiation. PMID:26525899

  18. Effects of CO2-rich fluids on a redbed reservoir: outcrop analogue study from the Buntsandstein (Germany)

    NASA Astrophysics Data System (ADS)

    Kasch, N.; Kley, J.; Koester, J.; van Geldern, R.; Wehrer, M.; Wendler, J.

    2010-12-01

    Carbon capture and storage (CCS) in saline aquifers will induce fluid-rock interactions, with effects on the mineralogy and physical properties of the reservoir. These effects are difficult to study in real reservoirs. Outcrop analogues provide access to relatively large rock volumes, but it may be difficult to prove that CO2 was involved in the mineral reactions observed. We present circumstantial evidence for the presence of CO2-rich fluids during the alteration of Triassic Buntsandstein redbeds from Germany. Fluid-rock interaction there is evidenced by localized bleaching of the red sandstones in fringes of a few mm to a few cm width along joints and fine cracks. The fringes can be traced along individual joints for a few dm to m. 3D geometric analysis on a cm scale shows that the bleached cracks form a complex interconnected network. On the outcrop scale, bleaching is essentially restricted to one north-trending joint set which is parallel to Miocene basalt dikes in the area. In underground salt mines, the dikes have caused bleaching of potassium salt minerals along their contacts. In the same mines CO2 is found trapped within rock salt along north-trending fractures, sometimes causing violent gas eruptions during mining operations. Together, these observations suggest that bleaching along north-trending joints in the Buntsandstein is causally related to the migration of CO2-rich fluids associated with the basalt volcanism. Today, CO2 ascends in CO2-enriched waters. We analyzed 12 samples of such waters. Their ?18O values correspond to meteoric waters. The ?13C (DIC) values of four water samples show signatures typical of volcanogenic CO2. Five samples contain mixed signals of volcanogenic and carbonatic CO2 or biogenic CO2 from soil. Volcanogenic and carbonatic CO2 are restricted to waters interpreted to rise along NW-SE striking basement faults. The switch of preferential fluid channeling from N-trending fractures in Tertiary time to NW-trending fractures today is compatible with a coeval rotation of the largest horizontal stress from N to NW, corroborating the control of fluid pathways by the contemporary stress field. Geochemical analyses of the bleached fringes show that bleaching causes a decrease in Fe and Mn due to hematite dissolution. Using cathodoluminescence microscopy and -spectroscopy combined with electron microprobe analysis and stable carbon isotopes, we detected two major fluid-mineral interactions probably involving CO2: (1) precipitation of zoned, joint-filling calcites and pore-filling calcite cements, the latter replacing an earlier dolomite, and (2) alkali feldspar alteration. We interpret Fe-rich calcite crystal cores to reflect incorporation of iron released by coeval bleaching during the dolomite-calcite transformation. This recrystallisation was associated with a volume increase, possibly suggesting some degree of sealing and enhanced retention of CO2. On the other hand, feldspar alteration has a destructing effect on the feldspar grains, implying that bleaching creates pore space.

  19. Molecular Docking Evaluation of Imidazole Analogues as Potent Candida albicans 14?-Demethylase Inhibitors.

    PubMed

    Rani, Nidhi; Kumar, Praveen; Singh, Randhir; Sharma, Ajay

    2015-01-01

    Candida albicans is one of the most important causes of life-threating fungal infections. Lanosterol 14?-demethylase (Cytochrome P450DM) is the target enzyme of azole antifungal agents. The study involved selection and modeling of the target enzyme followed by refinement of the model using molecular dynamic simulation. The modeled structure of enzyme was validated using Ramachandran plot and Sequence determination technique. A series of chlorosubstituted imidazole analogues were evaluated for Cytochrome P450 inhibitory activity using molecular docking studies. The imidazole analogues were prepared using Chem sketch and molecular docking was performed using Molergo Virtual Docker program. The docking study indicated that all the imidazole analogues (AN1-AN45) and standard drugs i.e., Ketoconazole, Clotrimazole and Miconazole have interaction with protein residue of 14?-demethylase, Heme cofactor and the water molecules present in the active site. PMID:26081558

  20. Aqueous extracts of a Mars analogue regolith that mimics the Phoenix landing site do not inhibit spore germination or growth of model spacecraft contaminants Bacillus subtilis 168 and Bacillus pumilus SAFR-032

    NASA Astrophysics Data System (ADS)

    Nicholson, Wayne L.; McCoy, Lashelle E.; Kerney, Krystal R.; Ming, Douglas W.; Golden, D. C.; Schuerger, Andrew C.

    2012-08-01

    Because Mars is a primary target for life detection and habitability assessment missions, its exploration is also by necessity a Planetary Protection issue. The recent finding of significant levels of perchlorate (ClO4-) in regolith sampled from the Phoenix landing site raises the question of its potential biotoxicity to putative indigenous martian life, microbial forward contaminants from Earth, or future human visitors. To address this issue, an analogue regolith was constructed based on regolith chemistry data from the Phoenix landing site. A Mars Aqueous Regolith Extract (MARE) was prepared from the Phoenix analogue regolith and analyzed by ion chromatography. The MARE contained (mg/L) the cations Na+ (1411 ± 181), Mg2+ (1051 ± 160), Ca2+ (832 ± 125), and K+ (261 ± 29), and the anions SO42-(5911±993), ClO4-(5316±1767), Cl(171±25) and F- (2.0 ± 0.4). Nitrogen-containing species NO3-(773±113) and NO2-(6.9±2.3) were also present as a result of regolith preparation procedures, but their relevance to Mars is at present unknown. The MARE was tested for potential toxic effects on two model spacecraft contaminants, the spore-forming bacteria Bacillus subtilis strain 168 and Bacillus pumilus strain SAFR-032. In B. subtilis, spore germination and initial vegetative growth (up to ˜5 h) was not inhibited in a rich complex medium prepared with the MARE, but growth after 5 h was significantly suppressed in medium prepared using the MARE. Both B. subtilis and B. pumilus exhibited significantly higher rates of spore germination and growth in the MARE vs. DW with no additions (likely due to endogenous spore nutrients), but germination and growth was further stimulated by addition of glucose and a combination of buffered inorganic salts (K2HPO4, KH2PO4, (NH4)2SO4, and MgSO4). The data indicate that the aqueous environment in the regolith from the Phoenix landing site containing high levels of perchlorate does not pose a significant barrier to growth of putative forward contaminants such as B. subtilis and B. pumilus under Earth laboratory conditions.

  1. Pro Free Will Priming Enhances "Risk-Taking" Behavior in the Iowa Gambling Task, but Not in the Balloon Analogue Risk Task: Two Independent Priming Studies.

    PubMed

    Schrag, Yann; Tremea, Alessandro; Lagger, Cyril; Ohana, Noé; Mohr, Christine

    2016-01-01

    Studies indicated that people behave less responsibly after exposure to information containing deterministic statements as compared to free will statements or neutral statements. Thus, deterministic primes should lead to enhanced risk-taking behavior. We tested this prediction in two studies with healthy participants. In experiment 1, we tested 144 students (24 men) in the laboratory using the Iowa Gambling Task. In experiment 2, we tested 274 participants (104 men) online using the Balloon Analogue Risk Task. In the Iowa Gambling Task, the free will priming condition resulted in more risky decisions than both the deterministic and neutral priming conditions. We observed no priming effects on risk-taking behavior in the Balloon Analogue Risk Task. To explain these unpredicted findings, we consider the somatic marker hypothesis, a gain frequency approach as well as attention to gains and / or inattention to losses. In addition, we highlight the necessity to consider both pro free will and deterministic priming conditions in future studies. Importantly, our and previous results indicate that the effects of pro free will and deterministic priming do not oppose each other on a frequently assumed continuum. PMID:27018854

  2. A Biocatalytic Cascade for Versatile One-Pot Modification of mRNA Starting from Methionine Analogues.

    PubMed

    Muttach, Fabian; Rentmeister, Andrea

    2016-01-01

    Methyltransferases have proven useful to install functional groups site-specifically in different classes of biomolecules when analogues of their cosubstrate S-adenosyl-l-methionine (AdoMet) are available. Methyltransferases have been used to address different classes of RNA molecules selectively and site-specifically, which is indispensable for biophysical and mechanistic studies as well as labeling in the complex cellular environment. However, the AdoMet analogues are not cell-permeable, thus preventing implementation of this strategy in cells. We present a two-step enzymatic cascade for site-specific mRNA modification starting from stable methionine analogues. Our approach combines the enzymatic synthesis of AdoMet with modification of the 5' cap by a specific RNA methyltransferase in one pot. We demonstrate that a substrate panel including alkene, alkyne, and azido functionalities can be used and further derivatized in different types of click reactions. PMID:26694947

  3. Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model.

    PubMed

    O'Leary, J J; Shapiro, R L; Ren, C J; Chuang, N; Cohen, H W; Potmesil, M

    1999-01-01

    Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We have investigated the antiangiogenic properties of three camptothecin analogues, 9-amino-20(S)-camptothecin, topotecan, and camptosar (CPT-11), currently under investigation in clinical settings. Angiogenesis was induced by basic fibroblast growth factor in the cornea of inbred Swiss-Webster mice, with the aim of exploring the suppression of neovascularization by the analogues injected into the mice daily over a period of 6 days. The dose range chosen is known to inhibit, in the mouse model, the growth of various human tumor xenografts or murine tumors. The statistical analysis evaluated the association between the area of neoangiogenesis and the dose of the drugs tested and correlated the effects with observed drug toxicity. It was established that, as the drug doses increased, the area of neovascularization decreased, appearing to approximate a negative exponential curve. 9-Amino-20(S)-camptothecin at 6.89 and 8.26 micromol/kg (2.5 and 3.0 mg/kg) and topotecan at 8.31 micromol/kg (3.5 mg/kg), both drugs being delivered over a 6-day period, had statistically significant reduction (47.2-72.5%) of neoangiogenesis and acceptable toxicity. At higher doses of the two analogues, toxic body-weight losses and deaths were observed. CPT-11 showed statistically significant reduction of neoangiogenesis at a dose of 359 micromol/kg (210 mg/kg) delivered over a 6-day course. Unlike camptothecin analogues, the nontoxic dose of vincristine did not induce a statistically significant inhibition of angiogenesis, and there was no dose-dependent escalation of antiangiogenic effects. The results indicate that camptothecins are most likely cytotoxic against two tumor compartments: in addition to tumor cells of epithelial origin, the drugs act against endothelial cells and prevent the growth of the tumor microvessels. We have hypothesized that treatment failure in some patients is due to incomplete or inadequate inhibition of the microvessel growth by camptothecins. Presumably, an intensive inhibition of the remaining tumor microvasculature in such patients could be achieved by combining a camptothecin with another antiangiogenic anticancer agent or with a highly selective angiogenic inhibitor exerting minimal dose-limiting toxicity. Such treatment by a camptothecin plus a less toxic inhibitor of angiogenesis can improve antitumor efficacy. To validate this concept, preclinical studies followed by clinical trials are planned. PMID:9918217

  4. Policy issues in space analogues

    NASA Astrophysics Data System (ADS)

    Auger, Robin N.; Facktor, Debra D.

    Space mission planning is increasingly focusing on destinations beyond Earth orbit. Advancements in technology will inevitably be required to enable long-duration human spaceflight missions, and breakthroughs in the policy arena will also be needed to achieve success in such missions. By exploring how policy issues have been addressed in analogous extreme environments, policymakers can develop a framework for addressing these issues as they apply to long-term human spaceflight. Policy issues that need to be addressed include: crew selection, training, organization, and activities, medical testing, illness, injury, and death; communication; legal accountability and liability; mission safety and risk management; and environmental contamination. This paper outlines the approach of a study underway by The George Washington University and ANSER to examine how these policy issues have been addressed in several analogues and how the experiences of these analogues can help formulate policies for long-duration human spaceflight missions. Analogues being studied include Antarctic bases, submarine voyages, undersea stations, Biosphere 2, and the U.S. Skylab and Russian Mir space stations.

  5. Site locality identification study: Hanford Site. Volume I. Methodology, guidelines, and screening

    SciTech Connect

    Not Available

    1980-07-01

    Presented in this report are the results of the site locality identification study for the Hanford Site using a screening process. To enable evaluation of the entire Hanford Site, the screening process was applied to a somewhat larger area; i.e., the Pasco Basin. The study consisted of a series of screening steps that progressively focused on smaller areas which are within the Hanford Site and which had a higher potential for containing suitable repository sites for nuclear waste than the areas not included for further study. Five site localities, designated H-1, H-2, H-3, H-4, H-5 (Figure A), varying in size from approximately 10 to 50 square miles, were identified on the Hanford Site. It is anticipated that each site locality may contain one or more candidate sites suitable for a nuclear waste repository. The site locality identification study began with definition of objectives and the development of guidelines for screening. Three objectives were defined: (1) maximize public health and safety; (2) minimize adverse environmental and socioeconomic impacts; and (3) minimize system costs. The screening guidelines have numerical values that provided the basis for the successive reduction of the area under study and to focus on smaller areas that had a higher likelihood of containing suitable sites.

  6. Structure of Bacillus subtilis ?-glutamyltranspeptidase in complex with acivicin: diversity of the binding mode of a classical and electrophilic active-site-directed glutamate analogue.

    PubMed

    Ida, Tomoyo; Suzuki, Hideyuki; Fukuyama, Keiichi; Hiratake, Jun; Wada, Kei

    2014-02-01

    ?-Glutamyltranspeptidase (GGT) is an enzyme that plays a central role in glutathione metabolism, and acivicin is a classical inhibitor of GGT. Here, the structure of acivicin bound to Bacillus subtilis GGT determined by X-ray crystallography to 1.8? resolution is presented, in which it binds to the active site in a similar manner to that in Helicobacter pylori GGT, but in a different binding mode to that in Escherichia coli GGT. In B. subtilis GGT, acivicin is bound covalently through its C3 atom with sp2 hybridization to Thr403?O?, the catalytic nucleophile of the enzyme. The results show that acivicin-binding sites are common, but the binding manners and orientations of its five-membered dihydroisoxazole ring are diverse in the binding pockets of GGTs. PMID:24531494

  7. Prediction of high- and low-affinity quinol-analogue-binding sites in the aa3 and bo3 terminal oxidases from Bacillus subtilis and Escherichia coli1.

    PubMed

    Bossis, Fabrizio; De Grassi, Anna; Palese, Luigi Leonardo; Pierri, Ciro Leonardo

    2014-07-15

    Haem-copper oxidases are the terminal enzymes in both prokaryotic and eukaryotic respiratory chains. They catalyse the reduction of dioxygen to water and convert redox energy into a transmembrane electrochemical proton gradient during their catalytic activity. Haem-copper oxidases show substantial structure similarity, but spectroscopic and biochemical analyses indicate that these enzymes contain diverse prosthetic groups and use different substrates (i.e. cytochrome c or quinol). Owing to difficulties in membrane protein crystallization, there are no definitive structural data about the quinol oxidase physiological substrate-binding site(s). In the present paper, we propose an atomic structure model for the menaquinol:O2 oxidoreductase of Bacillus subtilis (QOx.aa3). Furthermore, a multistep computational approach is used to predict residues involved in the menaquinol/menaquinone binding within B. subtilis QOx.aa3 as well as those involved in quinol/quinone binding within Escherichia coli QOx.bo3. Two specific sequence motifs, R70GGXDX4RXQX3PX3FX[D/N/E/Q]X2HYNE97 and G159GSPX2GWX2Y169 (B. subtilis numbering), were highlighted within QOx from Bacillales. Specific residues within the first and the second sequence motif participate in the high- and low-affinity substrate-binding sites respectively. Using comparative analysis, two analogous motifs, R71GFXDX4RXQX8[Y/F]XPPHHYDQ101 and G163EFX3GWX2Y173 (E. coli numbering) were proposed to be involved in Enterobacteriales/Rhodobacterales/Rhodospirillales QOx high- and low-affinity quinol-derivative-binding sites. Results and models are discussed in the context of the literature. PMID:24779955

  8. Synthesis, antitumor activity and molecular docking study of some novel 3-benzyl-4(3H)quinazolinone analogues.

    PubMed

    Al-Suwaidan, Ibrahim A; Abdel-Aziz, Alaa A-M; Shawer, Taghreed Z; Ayyad, Rezk R; Alanazi, Amer M; El-Morsy, Ahmad M; Mohamed, Menshawy A; Abdel-Aziz, Naglaa I; El-Sayed, Magda A-A; El-Azab, Adel S

    2016-02-01

    A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI50 (10.47, 7.24 and 14.12?M. respectively), and are nearly 1.5-3.0-fold more potent compared with the positive control 5-FU with mean GI50, 22.60?M. On the other hand, compounds 6 and 10 yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9 showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032. PMID:25815668

  9. Desferrithiocin Analogue Uranium Decorporation Agents

    PubMed Central

    Bergeron, Raymond J.; Wiegand, Jan; Singh, Shailendra

    2010-01-01

    Purpose Previous systematic structure-activity studies of the desferrithiocin (DFT) platform have allowed the design and synthesis of analogues and derivatives of DFT that retain the exceptional iron-clearing activity of the parent, while eliminating its adverse effects. We hypothesized that a similar approach could be adopted to identify DFT-related analogues that could effectively decorporate uranium. Materials and Methods The decorporation properties of nine DFT-related analogues were determined in a bile duct-cannulated rat model. Diethylenetriaminepentaacetic acid (DTPA) served as a positive control. Selected ligands also underwent multiple and delayed dosing regimens. Uranium excretion in urine and bile or stool was determined by inductively coupled plasma mass spectroscopy (ICP-MS); tissue levels of uranium were also assessed. Results The two best clinical candidates are (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-4'-(HO)-DADFT-PE (9)], with a 57% reduction in kidney uranium levels on oral (p.o.) administration and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid [(S)-3'-(HO)-DADFT-PE (10)], with a 62% renal reduction on p.o. administration. The majority of the metal excretion promoted by these analogues is in the bile, thus further reducing kidney actinide exposure. Conclusions While 9 administered p.o. or subcutaneously (s.c.) immediately post-metal is an effective decorporation agent, withholding the dose (s.c.) until 4 h reduced the activity of the compound. Conversion of 9 to its isopropyl ester may circumvent this issue. PMID:19399680

  10. School Counseling Site Supervisor Training: An Exploratory Study

    ERIC Educational Resources Information Center

    DeKruyf, Lorraine; Pehrsson, Dale-Elizabeth

    2011-01-01

    This study explored the supervision training needs of site supervisors of master's program school counseling interns via the construct of self-efficacy. Using the Site Supervisor Self-Efficacy Survey developed for this study, the authors surveyed school counseling site supervisors in the states of Oregon and Washington (N = 147) regarding their

  11. Resolution and Determination of the Absolute Configuration of a Twisted Bis-Lactam Analogue of Tröger's Base: A Comparative Spectroscopic and Computational Study.

    PubMed

    Rúnarsson, Ögmundur Vidar; Benkhäuser, Christian; Christensen, Niels Johan; Ruiz, Josep Artacho; Ascic, Erhad; Harmata, Michael; Snieckus, Victor; Rissanen, Kari; Fristrup, Peter; Lützen, Arne; Wärnmark, Kenneth

    2015-08-21

    The first reported twisted bis-lactam, a racemic Tröger's base (TB) analogue (2), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (-)-2 was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G(d,p) level of theory. The absolute configuration of (+)-2 was also determined to (R,R)-2 by anomalous X-ray diffraction (AXRD) in a chiral space group P212121 using Cu-irradiation resulting in a very low Flack parameter of -0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Tröger's base (TB) analogue (2), we may rank the reliability of the individual methods for AC determination as AXRD ≫ VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(R,R)-2 and (-)-(S,S)-2. PMID:26244379

  12. Synthesis of three novel fluorine-18 labeled analogues of L-deprenyl for positron emission tomography (PET) studies of monoamine oxidase B (MAO-B).

    PubMed

    Nag, Sangram; Lehmann, Lutz; Heinrich, Tobias; Thiele, Andrea; Kettschau, Georg; Nakao, Ryuji; Gulyás, Balázs; Halldin, Christer

    2011-10-27

    The aim in this project was to synthesize and to study fluorine-18 labeled analogues of l-deprenyl which bind selectively to the enzyme monoamine oxidase B (MAO-B). Three fluorinated l-deprenyl analogues have been generated in multistep organic syntheses. The most promising fluorine-18 compound N-[(2S)-1-[(18)F]fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (4c) was synthesized by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography on human brain tissue sections demonstrated specific binding for compound 4c to brain regions known to have a high content of MAO-B. In addition, the corresponding nonradioactive fluorine-19 compound (13) inhibited recombinant human MAO-B with an IC(50) of 170.5 ± 29 nM but did not inhibit recombinant human MAO-A (IC(50) > 2000 nM), demonstrating its specificity. Biodistribution of 4c in mice showed high initial brain uptake leveling at 5.2 ± 0.04%ID/g after 2 min post injection. In conclusion, compound 4c is a specific inhibitor of MAO-B with high initial brain uptake in mice and is, therefore, a candidate for further investigation in PET. PMID:21923198

  13. Differential interaction of 1alpha,25-dihydroxyvitamin D3 analogues and their 20-epi homologues with the vitamin D receptor.

    PubMed

    Liu, Y Y; Collins, E D; Norman, A W; Peleg, S

    1997-02-01

    An important focus of structure-function studies of synthetic ligands for the vitamin D receptor (VDR) concerns the chiral center at carbon 20 of the steroid side chain; 20-epi analogues are 100-10, 000 times more potent transcriptionally than the natural hormone 1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3). We have compared the binding properties of three pairs of analogues either with a natural (N) or 20-epi (E) orientation. In intact cells, 45-60% of VDR.N-analogue complexes, but only 5-20% of VDR.E-analogue complexes, dissociated over a 3-h interval. The two groups of ligands induced distinct changes in VDR conformation as revealed by protease clipping assays. Mapping of ligand-VDR binding activity by deletions indicated that amino acids 420-427 were important for high affinity of VDR.N-analogue complexes, but not for VDR.E-analogue complexes. Site-directed mutagenesis revealed that residues 421 and 422 were essential for 1alpha,25-(OH)2D3-induced conformational changes, high affinity of 1alpha,25-(OH)2D3 for VDR, and transcriptional activity, but not for binding of its 20-epi analogue. In contrast, deletion of residues 396-427 abolished binding of 1alpha,25-(OH)2D3, but binding of its 20-epi analogue was still detectable. The results suggest that the ligand-binding domain of VDR has multiple and different contact sites for the two families of side chain-modified ligands, resulting in VDR.ligand complexes with different half-lives and transcriptional activities. PMID:9013574

  14. Pharmacological characterisation of strychnine and brucine analogues at glycine and alpha7 nicotinic acetylcholine receptors.

    PubMed

    Jensen, Anders A; Gharagozloo, Parviz; Birdsall, Nigel J M; Zlotos, Darius P

    2006-06-01

    Strychnine and brucine from the plant Strychnos nux vomica have been shown to have interesting pharmacological effects on several neurotransmitter receptors, including some members of the superfamily of ligand-gated ion channels. In this study, we have characterised the pharmacological properties of tertiary and quaternary analogues as well as bisquaternary dimers of strychnine and brucine at human alpha1 and alpha1beta glycine receptors and at a chimera consisting of the amino-terminal domain of the alpha7 nicotinic receptor (containing the orthosteric ligand binding site) and the ion channel domain of the 5-HT3A serotonin receptor. Although the majority of the analogues displayed significantly increased Ki values at the glycine receptors compared to strychnine and brucine, a few retained the high antagonist potencies of the parent compounds. However, mirroring the pharmacological profiles of strychnine and brucine, none of the analogues displayed significant selectivity between the alpha1 and alpha1beta subtypes. The structure-activity relationships for the compounds at the alpha7/5-HT3 chimera were significantly different from those at the glycine receptors. Most strikingly, quaternization of strychnine and brucine with substituents possessing different steric and electronic properties completely eliminated the activity at the glycine receptors, whereas binding affinity to the alpha7/5-HT3 chimera was retained for the majority of the quaternary analogues. This study provides an insight into the structure-activity relationships for strychnine and brucine analogues at these ligand-gated ion channels. PMID:16687139

  15. Synthesis and evaluation of bioorthogonal pantetheine analogues for in vivo protein modification.

    PubMed

    Meier, Jordan L; Mercer, Andrew C; Rivera, Heriberto; Burkart, Michael D

    2006-09-20

    In vivo carrier protein tagging has recently become an attractive target for the site-specific modification of fusion systems and new approaches to natural product proteomics. A detailed study of pantetheine analogues was performed in order to identify suitable partners for covalent protein labeling inside living cells. A rapid synthesis of pantothenamide analogues was developed and used to produce a panel which was evaluated for in vitro and in vivo protein labeling. Kinetic comparisons allowed the construction of a structure-activity relationship to pinpoint the linker, dye, and bioorthogonal reporter of choice for carrier protein labeling. Finally bioorthogonal pantetheine analogues were shown to target carrier proteins with high specificity in vivo and undergo chemoselective ligation to reporters in crude cell lysate. The methods demonstrated here allow carrier proteins to be visualized and isolated for the first time without the need for antibody techniques and set the stage for the future use of carrier protein fusions in chemical biology. PMID:16967968

  16. Electronic structure and vibrational spectra of cis-diammine(orotato)platinum(II), a potential cisplatin analogue: DFT and experimental study

    NASA Astrophysics Data System (ADS)

    Wysoki?ski, Rafa?; Hernik, Katarzyna; Szostak, Roman; Michalska, Danuta

    2007-03-01

    Orotic acid (vitamin B 13) is a key intermediate in biosynthesis of the pyrimidine nucleotides in living organisms, moreover, it may serve as the biological carrier for some metal ions. cis-Diammine(orotato)platinum(II), cis-[Pt(C 5H 2N 2O 4)(NH 3) 2] can be considered as a new potential cisplatin analogue. The FT-Raman and FT-IR spectra of the title complex are reported, for the first time. The molecular structure, vibrational frequencies, and the theoretical infrared and Raman intensities have been calculated by the density functional mPW1PW91 method. The detailed vibrational assignment has been made on the basis of the calculated potential energy distribution. The theoretically predicted IR and Raman spectra show very good agreement with experiment. Natural bond orbital (NBO) analyses were performed for cisplatin, carboplatin and the title complex. The results provided new data on the nature of platinum-ligand bonding in these compounds. Strong intramolecular hydrogen bond between the orotate ligand and the coordinated ammonia group stabilizes the structure of the platinum(II) complex. Thus, it is suggested that the orotate ligand in the title complex is more inert to the substitution reactions than the chloride ligands in cisplatin.

  17. Mitocans as anti-cancer agents targeting mitochondria: lessons from studies with vitamin E analogues, inhibitors of complex II.

    PubMed

    Neuzil, Jiri; Dyason, Jeffrey C; Freeman, Ruth; Dong, Lan-Feng; Prochazka, Lubomir; Wang, Xiu-Fang; Scheffler, Immo; Ralph, Stephen J

    2007-02-01

    Recently mitochondria in cancer cells have emerged as the Achilles heel for tumour destruction. Anti-cancer agents specifically targeting cancer cell mitochondria are referred to as 'mitocans'. These compounds act by destabilising these organelles, unleashing their apoptogenic potential, resulting in the efficient death of malignant cells and suppression of tumour growth. Importantly, at least some mitocans are selective for cancer cells, and these are represented by the group of redox-silent vitamin E analogues, epitomised by alpha-tocopheryl succinate (alpha-TOS). This compound has proven itself in pre-clinical models to be an efficient anti-cancer agent, targeting complex II of the respiratory chain to displace ubiquinone binding. We propose that disrupting the electron flow of mitochondrial complex II results in generation of superoxide, triggering mitochondrial destabilisation and initiation of apoptotic pathways. Moreover, alpha-TOS is selective for cancer cells with their reduced anti-oxidant defenses and lower esterase activity than the normal (non-malignant) counterparts. In this mini-review we discuss the emerging significance of mitocans, as exemplified by alpha-TOS. PMID:17294131

  18. Structural perturbation of a dipalmitoylphosphatidylcholine (DPPC) bilayer by warfarin and its bolaamphiphilic analogue: A molecular dynamics study.

    PubMed

    Ayee, Manuela Aseye Ayele; Roth, Charles William; Akpa, Belinda Sena

    2016-04-15

    Compounds with nominally similar biological activity may exhibit differential toxicity due to differences in their interactions with cell membranes. Many pharmaceutical compounds are amphiphilic and can be taken up by phospholipid bilayers, interacting strongly with the lipid-aqueous interface whether or not subsequent permeation through the bilayer is possible. Bolaamphiphilic compounds, which possess two hydrophilic ends and a hydrophobic linker, can likewise undergo spontaneous uptake by bilayers. While membrane-spanning bolaamphiphiles can stabilize membranes, small molecules with this characteristic have the potential to create membrane defects via disruption of bilayer structure and dynamics. When compared to the amphiphilic therapeutic anticoagulant, warfarin, the bolaamphiphilic analogue, brodifacoum, exhibits heightened toxicity that goes beyond superior inhibition of the pharmacological target enzyme. We explore, herein, the consequences of anticoagulant accumulation in a dipalmitoylphosphatidylcholine (DPPC) bilayer. Coarse-grained molecular dynamics simulations reveal that permeation of phospholipid bilayers by brodifacoum causes a disruption of membrane barrier function that is driven by the bolaamphiphilic nature and size of this molecule. We find that brodifacoum partitioning into bilayers causes membrane thinning and permeabilization and promotes lipid flip-flop - phenomena that are suspected to play a role in triggering cell death. These phenomena are either absent or less pronounced in the case of the less toxic, amphiphilic compound, warfarin. PMID:26852346

  19. The Valles natural analogue project

    SciTech Connect

    Stockman, H.; Krumhansl, J.; Ho, C.; McConnell, V.

    1994-12-01

    The contact between an obsidian flow and a steep-walled tuff canyon was examined as an analogue for a highlevel waste repository. The analogue site is located in the Valles Caldera in New Mexico, where a massive obsidian flow filled a paleocanyon in the Battleship Rock tuff. The obsidian flow provided a heat source, analogous to waste panels or an igneous intrusion in a repository, and caused evaporation and migration of water. The tuff and obsidian samples were analyzed for major and trace elements and mineralogy by INAA, XRF, X-ray diffraction; and scanning electron microscopy and electron microprobe. Samples were also analyzed for D/H and {sup 39}Ar/{sup 4O} isotopic composition. Overall,the effects of the heating event seem to have been slight and limited to the tuff nearest the contact. There is some evidence of devitrification and migration of volatiles in the tuff within 10 meters of the contact, but variations in major and trace element chemistry are small and difficult to distinguish from the natural (pre-heating) variability of the rocks.

  20. One-site versus two-site phacotrabeculectomy: a prospective randomized study

    PubMed Central

    Moschos, Marilita M; Chatziralli, Irini P; Tsatsos, Michael

    2015-01-01

    Purpose The purpose of this study is to compare the efficacy and safety of one-site and two-site combined phacotrabeculectomy with foldable posterior chamber intraocular lens implantation. Methods Thirty-four patients (41 eyes) with glaucoma and cataract were randomly assigned to undergo either a one-site (22 eyes) or a two-site (19 eyes) combined procedure. One-site approach consisted of a standard superior phacotrabeculectomy with a limbus-based conjunctival flap, while two-site approach consisted of a clear cornea phacoemulsification and a separate superior trabeculectomy with a limbus-based conjunctival flap. Results Mean follow-up period was 54 months (standard deviation [SD] 2.3). Mean preoperative intraocular pressure (IOP) in the one-site group was 21.3 mmHg (SD 2.8) and in the two-site group was 21.8 mmHg (SD 3.0) (P>0.1). Mean postoperative IOP significantly decreased in both groups compared to the preoperative level and was 15.6 mmHg (SD 3.5) in the one-site group and 14.9 mmHg (SD 2.7) in the two-site group. Three months later, the difference between the two groups was not statistically significant (P=0.058). The one-site group required significantly more medications than the two-site group (P=0.03). Best-corrected visual acuity (BCVA) improved similarly in both groups, but there was less postoperative (induced) astigmatism in the two-site group in a marginal statistical level (P=0.058). Intra- and postoperative complications were comparable in the two groups. Conclusion Both techniques yielded similar results concerning final BCVA and IOP reduction. However, the two-site group had less induced astigmatism and a better postoperative IOP control with less required postoperative antiglaucoma medications compared to the one-site group. PMID:26347460

  1. Potent in vivo inhibitors of rat renin: analogues of human and rat angiotensinogen sequences containing different classes of pseudodipeptides at the scissile site.

    PubMed

    Sueiras-Diaz, J; Jones, D M; Szelke, M; Leckie, B J; Beattie, S R; Beattie, C; Morton, J J

    1997-10-01

    Using solid-phase methodology we have synthesised peptides based on the 8-14 or 6-14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P1-P1' cleavage site: Leu-psi[CH2NH]Leu; Leu-psi[CH(OH)CH2]Val; Leu-psi[CH(OH)CH2]Leu and Leu-psi[CH(NH2)CH2]Val. In vitro, peptide Piv-His-Pro-Phe-His-Leu-psi[CH(OH)CH2]Leu-Tyr-Tyr-Ser-NH2(XXI) is the most potent inhibitor of rat plasma renin reported having an IC50 of 0.21 nM; it is a much weaker inhibitor of human renin (IC50 45 nM). Peptide Boc-His-Pro-Phe-His-Leu-psi[CH(OH)CH2] Leu-Val-Ile-His-NH2 (XX) was a highly effective inhibitor of rat renin in vivo. When infused (1 mg/kg/h) into two-kidney, one-clip chronic renal hypertensive rats, it lowered blood pressure and suppressed both plasma renin and angiotensin II. When given as a bolus (1 mg/kg) there was a divergence between the rapid rebound of renin levels and blood pressure, which remained suppressed. These results indicate that potent in vivo inhibitors of rat renin could be useful not only in examining the role of circulating renin but also in elucidating the equally important involvement of extracirculatory renin pools. PMID:9352462

  2. Does Balloon Kyphoplasty Deliver More Cement Safely into Osteoporotic Vertebrae with Compression Fractures Compared with Vertebroplasty? A Study in Vertebral Analogues

    PubMed Central

    Abduljabbar, Fahad H.; Al-jurayyan, Abdulaziz; Alqahtani, Saad; Sardar, Zeeshan M.; Saluja, Rajeet Singh; Ouellet, Jean; Weber, Michael; Steffen, Thomas; Beckman, Lorne; Jarzem, Peter

    2015-01-01

    Study Design?A biomechanical and radiographic study using vertebral analogues. Objectives?Kyphoplasty and vertebroplasty are widely used techniques to alleviate pain in fractures secondary to osteoporosis. However, cement leakage toward vital structures like the spinal cord can be a major source of morbidity and even mortality. We define safe cement injection as the volume of the cement injected into a vertebra before the cement leakage occurs. Our objective is to compare the amount of cement that can be safely injected into an osteoporotic vertebra with simulated compression fracture using either vertebroplasty or balloon kyphoplasty techniques. Methods?Forty artificial vertebral analogues made of polyurethane with osteoporotic cancellous matrix representing the L3 vertebrae were used for this study and were divided into four groups of 10 vertebrae each. The four groups tested were: low-viscosity cement injected using vertebroplasty, high-viscosity cement injected using vertebroplasty, low-viscosity cement injected using balloon kyphoplasty, and high-viscosity cement injected using balloon kyphoplasty. The procedures were performed under fluoroscopic guidance. The injection was stopped when the cement started protruding from the created vascular channel in the osteoporotic vertebral fracture model. The main outcome measured was the volume of the cement injected safely into a vertebra before leakage through the posterior vascular channel. Results?The highest volume of the cement injected was in the vertebroplasty group using high-viscosity cement, which was almost twice the injected volume in the other three groups. One-way analysis of variance comparing the four groups showed a statistically significant difference (p?

  3. An analogue study of the influence of solidification on the advance and surface thermal signature of lava flows

    NASA Astrophysics Data System (ADS)

    Garel, F.; Kaminski, E.; Tait, S.; Limare, A.

    2014-06-01

    The prediction of lava flow advance and velocity is crucial during an effusive volcanic crisis. The effusion rate is a key control of lava dynamics, and proxies have been developed to estimate it in near real-time. The thermal proxy in predominant use links the satellite-measured thermal radiated power to the effusion rate. It lacks however a robust physical basis to allow time-dependent modeling. We investigate here through analogue experiments the coupling between the spreading of a solidifying flow and its surface thermal signal. We extract a first order behavior from experimental results obtained using polyethylene glycol (PEG) wax, that solidifies abruptly during cooling. We find that the flow advance is discontinuous, with relatively low supply rates yielding long stagnation phases and compound flows. Flows with higher supply rates are less sensitive to solidification and display a spreading behavior closer to that of purely viscous currents. The total power radiated from the upper surface also grows by stages, but the signal radiated by the hottest and liquid part of the flow reaches a quasi-steady state after some time. This plateau value scales around half of the theoretical prediction of a model developed previously for the spreading and cooling of isoviscous gravity currents. The corrected scaling yields satisfying estimates of the effusion rate from the total radiated power measured on a range of basaltic lava flows. We conclude that a gross estimate of the supply rate of solidifying flows can be retrieved from thermal remote-sensing, but the predictions of lava advance as a function of effusion rate appears a more difficult task due to chaotic emplacement of solidifying flows.

  4. Multidisciplinary study on Wyoming test sites

    NASA Technical Reports Server (NTRS)

    Houston, R. S. (Principal Investigator); Marrs, R. W.; Borgman, L. E.

    1975-01-01

    The author has identified the following significant results. Ten EREP data passes over the Wyoming test site provided excellent S190A and S190B coverage and some useful S192 imagery. These data were employed in an evaluation of the EREP imaging sensors in several earth resources applications. Boysen Reservoir and Hyattsville were test areas for band to band comparison of the S190 and S192 sensors and for evaluation of the image data for geologic mapping. Contrast measurements were made from the S192 image data for typical sequence of sedimentary rocks. Histograms compiled from these measurements show that near infrared S192 bands provide the greatest amount of contrast between geologic units. Comparison was also made between LANDSAT imagery and S190B and aerial photography for regional land use mapping. The S190B photography was found far superior to the color composite LANDSAT imagery and was almost as effective as the 1:120,000 scale aerial photography. A map of linear elements prepared from LANDSAT and EREP imagery of the southwestern Bighorn Mountains provided an important aid in defining the relationship between fracture and ground water movement through the Madison aquifer.

  5. Arginine-, D-arginine-vasopressin, and their inverso analogues in micellar and liposomic models of cell membrane: CD, NMR, and molecular dynamics studies.

    PubMed

    Lubecka, Emilia A; Sikorska, Emilia; Sobolewski, Dariusz; Prahl, Adam; Slaninová, Jiřina; Ciarkowski, Jerzy

    2015-12-01

    We describe the synthesis, pharmacological properties, and structures of antidiuretic agonists, arginine vasopressin (AVP) and [D-Arg(8)]-vasopressin (DAVP), and their inverso analogues. The structures of the peptides are studied based on micellar and liposomic models of cell membranes using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy and molecular dynamics simulations. NMR data have shown that AVP and DAVP tend to adopt typical of vasopressin-like peptides β-turns: in the 2-5 and 3-6 fragments. The inverso-analogues also adopt β-turns in the 3-6 fragments. For this reason, their inactivity seems to be due to the difference in side chains orientations of Tyr(2), Phe(3), and Arg(8), important for interactions with the receptors. Again, the potent antidiuretic activity of DAVP can be explained by CD data suggesting differences in mutual arrangement of the aromatic side chains of Tyr(2) and Phe(3) in this peptide in liposomes rather than of native AVP. In the presence of liposomes, the smallest conformational changes of the peptides are noticed with DPPC and the largest with DPPG liposomes. This suggests that electrostatic interactions are crucial for the peptide-membrane interactions. We obtained similar, probably active, conformations of the antidiuretic agonists in the mixed DPC/SDS micelles (5:1) and in the mixed DPPC/DPPG (7:3) liposomes. Thus it can be speculated that the anionic-zwitterionic liposomes as well as the anionic-zwitterionic micelles, mimicking the eukaryotic cell membrane environment, partially restrict conformational freedom of the peptides and probably induce conformations resembling those of biologically relevant ones. PMID:26290060

  6. An exploratory study on the peroxyl-radical-scavenging activity of 2,6-dimethyl-5-hepten-2-ol and its heterocyclic analogues

    NASA Astrophysics Data System (ADS)

    Stobiecka, Agnieszka; Sikora, Magdalena; Bonikowski, Radosław; Kula, Józef

    2016-03-01

    The structural properties and radical scavenging activity of 2,6-dimethyl-5-hepten-2-ol (1) and its new heterocyclic analogues, i.e. 2-methyl-4-(5-methylfuran-2-yl)-butan-2-ol (2) and 2-methyl-4-(5-methylthiophen-2-yl)-butan-2-ol (3) and have been studied by using the experimental and theoretical methods for the first time. Activity of title compounds against the peroxyl radical was determined by using standard fluorimetric test, i.e. the Oxygen Radical Absorbance Capacity assay (ORACFL). Furthermore, the electron-donating ability of odorants has been evaluated by using colorimetric ABTS assay. According to the experimental results obtained from the ORACFL test 2,6-dimethyl-5-hepten-2-ol was characterized by the highest activity in comparison with the novel counterparts. Nevertheless, all investigated compounds exhibited pronounced anti-peroxyl radical activity comparable to that exerted by the one of the most prominent antioxidant among the monoterpene alcohols, i.e. by linalool. On the other hand, the title compounds exerted relatively low capacity to quench the radical cation of ABTS. Theoretical calculations based on the Density Functional Theory (DFT) method with the hybrid functional B3LYP were carried out in order to investigate selected structural and electronic properties including the geometrical parameters as well as the energy of frontier molecular orbitals of parent molecules and the resulting radicals. Furthermore, the possible mechanism of peroxyl-radical-scavenging has been determined by using the thermodynamic descriptors such as the bond dissociation enthalpies (BDEs) and ionization potentials (IPs). These theoretical data pointed out the relevance of HAT mechanism in the peroxyl-radical-scavenging exhibited by 2,6-dimethyl-5-hepten-2-ol and its new heterocyclic analogues in polar and non-polar medium.

  7. Site study plan for cultural resources, Deaf Smith County site, Texas: Environmental Field Program: Preliminary draft

    SciTech Connect

    Not Available

    1987-06-01

    The Cultural Resources Site Study Plan describes a field program to identify and evaluate the archaeological, historical, and Native American Indian resources of the site on local and regional perspectives; monitor and manage discovered cultural resources; and establish a worker education program. The archaeological field program consists of three pedestrian surveys: Survey 1 includes two EDBH seismic survey lines and the area within the exploratory shaft facility (ESF); Survey 2 includes the remainder of the site plus a 1/4 to 3/4-mi border area; and Survey 3 includes an assortment of offsite areas. The historical studies will identify and evaluate known and discovered historical sites and structures and the Native American Indian will identify and evaluate cultural and religious concerns expressed by Indian tribal groups. Prehistoric and historic sites will be evaluated to determine if they meet eligibility criteria for listing on the National Register of Historic Places. This site study plan describes the need for each study; its design and design rationale; analysis, management, and use of data; schedule of field activities; organization of field personnel and sample management; and quality assurance requirements. The cultural resource studies will provide data for satisfying the Programmatic Agreement, engineering design needs, and SRP requirements for permits and approvals, and for minimizing effects to any cultural properties discovered during site characterization. 75 refs., 10 figs., 2 tabs.

  8. Site study plan for Transportation, Deaf Smith County Site, Texas: Preliminary draft

    SciTech Connect

    Not Available

    1987-06-01

    This site study plan describes transportation field studies to be conducted during the characterization of the Deaf Smith County, Texas, site for the US Department of Energy's Salt Repository Project. The studies are needed to identify and assess potential project impacts to transportation infrastructure and systems in the project vicinity and along potential transportation routes to the site across the State of Texas. The studies are also needed to locate and design project transportation facilities, and to evaluate and design impact mitigation. After identifying the transportation information requirements needed to comply with Federal, State, and local regulations and repository program requirements, the site study plan describes the study design and rationale, the field data collection procedures and equipment, the data analysis methods and application of results, the data management strategy, the schedule of field activities, the management of the study, and the study's quality assurance program. The field data collection activities are organized into programs for the characterization of site vicinity rail corridors and highway corridors, characterization of alternative statewide transportation routes, monitoring of site characterization effects on transportation, characterization of aircraft overflight patterns and hazardous material transportation patterns, and assessment of emergency response preparedness along alternative statewide transportation routes. 34 refs., 10 figs., 2 tabs.

  9. Synthesis of chacotriose analogues.

    PubMed

    Lequart, Vincent; Goethals, Gérard; Usubillaga, Alfredo; Villa, Pierre; Cecchelli, Roméo; Martin, Patrick

    2004-06-01

    We report here the synthesis of three chacotriose analogues, namely beta-L-fucopyranosyl-(1-->2)-[beta-L-fucopyranosyl-(1-->4)]-D-glucopyranose, beta-L-fucopyranosyl-(1-->2)-[beta-L-fucopyranosyl-(1-->4)]-d-galactopyranose, and alpha-L-rhamnopyranosyl-(1-->2)-[alpha-L-rhamnopyranosyl-(1-->4)]-alpha-D-galactopyranose. PMID:15178395

  10. Germananes: Germanium Graphane Analogues

    NASA Astrophysics Data System (ADS)

    Goldberger, Joshua

    2014-03-01

    Graphene's success has shown that it is not only possible to create stable, single-atom thick sheets from a crystalline solid, but that these materials have fundamentally different properties than the parent material. Our interest focuses on the synthesis and properties of Group IV graphane analogues. We have synthesized for the first time, mm-scale crystals of a hydrogen-terminated germanium multilayered graphane analogue (germanane, GeH) from the topochemical deintercalation of CaGe2. This layered van der Waals solid is analogous to multilayered graphane. The surface layer of GeH only slowly oxidizes in air over the span of five months, while the underlying layers are resilient to oxidation. We demonstrate that it is possible to covalently terminate the external surface with organic substituents to tune the electronic structure, and enhance the stability. These materials represent a new class of covalently terminated graphane analogues having great potential for a wide range of optoelectronic and sensing applications, especially since theory predicts a direct band gap of 1.53 eV and an electron mobility of 18,000 cm2/Vs which is five times higher than that of bulk Ge.

  11. Quantum analogue computing.

    PubMed

    Kendon, Vivien M; Nemoto, Kae; Munro, William J

    2010-08-13

    We briefly review what a quantum computer is, what it promises to do for us and why it is so hard to build one. Among the first applications anticipated to bear fruit is the quantum simulation of quantum systems. While most quantum computation is an extension of classical digital computation, quantum simulation differs fundamentally in how the data are encoded in the quantum computer. To perform a quantum simulation, the Hilbert space of the system to be simulated is mapped directly onto the Hilbert space of the (logical) qubits in the quantum computer. This type of direct correspondence is how data are encoded in a classical analogue computer. There is no binary encoding, and increasing precision becomes exponentially costly: an extra bit of precision doubles the size of the computer. This has important consequences for both the precision and error-correction requirements of quantum simulation, and significant open questions remain about its practicality. It also means that the quantum version of analogue computers, continuous-variable quantum computers, becomes an equally efficient architecture for quantum simulation. Lessons from past use of classical analogue computers can help us to build better quantum simulators in future. PMID:20603371

  12. Mitochondrial DNA D-loop AG/TC transition mutation in cortical neurons of mice after long-term exposure to nucleoside analogues.

    PubMed

    Zhang, Yulin; Wang, Bishi; Liang, Qi; Qiao, Luxin; Xu, Bin; Zhang, Hongwei; Yang, Sufang; Chen, Jun; Guo, Hongliang; Wu, Jian; Chen, Dexi

    2015-10-01

    With the wide application of combined antiretroviral therapy, the prognosis of human immunodeficiency virus (HIV)-1 infected patient has been significantly improved. However, long-term administration of antiretroviral drugs can result in various drug-associated toxicities. Among them, nucleoside analogues were confirmed to inhibit DNA polymerase gamma, resulting in mitochondrial toxicity. Our previous study indicated that long-term exposure of mice to nucleoside analogue could induce mitochondria DNA (mtDNA) loss in cortical neurons. Herein, we further identify mitochondrial toxicity of four nucleoside analogues (zidovudine (AZT), stavudine (D4T), lamivudine (3TC), and didanosine (DDI)) by cloning and sequencing mtDNA D-loop region in mice neurons captured with laser capture microdissection. The results showed that mutation of neuronal mtDNA D-loop sequences increased in mice treated with each of the four nucleoside analogues for 4 months and D4T and DDI induced more severe D-loop lesion than the other two nucleoside analogues. The major type of D-loop point mutations induced by four nucleoside analogues was transition, in particular of "A→G" and "T→C" transition, but the point transition sites were variable. Our findings suggest that long-term exposure to nucleoside analogue can result in mtDNA D-loop region lesion in mouse cortical neurons. PMID:26015313

  13. Hanford tank initiative test facility site selection study

    SciTech Connect

    Staehr, T.W.

    1997-04-03

    The Hanford Tanks Initiative (HTI) project is developing equipment for the removal of hard heel waste from the Hanford Site underground single-shell waste storage tanks. The HTI equipment will initially be installed in the 241-C-106 tank where its operation will be demonstrated. This study evaluates existing Hanford Site facilities and other sites for functional testing of the HTI equipment before it is installed into the 241-C-106 tank.

  14. The Need for Analogue Missions in Scientific Human and Robotic Planetary Exploration

    NASA Technical Reports Server (NTRS)

    Snook, K. J.; Mendell, W. W.

    2004-01-01

    With the increasing challenges of planetary missions, and especially with the prospect of human exploration of the moon and Mars, the need for earth-based mission simulations has never been greater. The current focus on science as a major driver for planetary exploration introduces new constraints in mission design, planning, operations, and technology development. Analogue missions can be designed to address critical new integration issues arising from the new science-driven exploration paradigm. This next step builds on existing field studies and technology development at analogue sites, providing engineering, programmatic, and scientific lessons-learned in relatively low-cost and low-risk environments. One of the most important outstanding questions in planetary exploration is how to optimize the human and robotic interaction to achieve maximum science return with minimum cost and risk. To answer this question, researchers are faced with the task of defining scientific return and devising ways of measuring the benefit of scientific planetary exploration to humanity. Earth-based and spacebased analogue missions are uniquely suited to answer this question. Moreover, they represent the only means for integrating science operations, mission operations, crew training, technology development, psychology and human factors, and all other mission elements prior to final mission design and launch. Eventually, success in future planetary exploration will depend on our ability to prepare adequately for missions, requiring improved quality and quantity of analogue activities. This effort demands more than simply developing new technologies needed for future missions and increasing our scientific understanding of our destinations. It requires a systematic approach to the identification and evaluation of the categories of analogue activities. This paper presents one possible approach to the classification and design of analogue missions based on their degree of fidelity in ten key areas. Various case studies are discussed to illustrate the approach.

  15. The importance of geotechnical studies for siting an ELT

    NASA Astrophysics Data System (ADS)

    Pescador, German R.

    2004-07-01

    Site selection is, no doubt, one of the most important preliminary studies in any telescope project since the image quality of the telescope will be limited by the site quality. Traditionally, geotechnical studies have had relatively little importance, normally being carried out once the site was already selected. However, with the increase of the telescopes size and mechancial requirements, the geotechnical studies have become increasingly important. Soil characteristics can make a big difference to the cost of an ELT. A thorough geological and geotechnical investigation of the possible site for the erection of an ELT should be carried from the beginning of the site selection process. It is very important to know the geology of the subsoil to determine the geomechanical properties of the materials, to determine the most suitable layers for anchoring the foundations, and to be able to estimate construction costs.

  16. Study of structure and orientation of mesentericin Y105, a bacteriocin from Gram-positive Leuconostoc mesenteroides, and its Trp-substituted analogues in phospholipid environments.

    PubMed

    Castano, Sabine; Desbat, Bernard; Delfour, Antoine; Dumas, Jean Marie; da Silva, Alexandra; Dufourcq, Jean

    2005-02-01

    Mesentericin Y105 (Mes-Y105) is a bacteriocin secreted by Leuconostoc mesenteroides which is particularly active on Listeria. It is constituted by 37 residues and reticulated by one disulfide bridge. It has two W residues, W18 and W37, which can be studied by fluorescence. Two single substituted W/F analogues were synthesized (Mes-Y105/W18 and Mes-Y105/W37) to differentiate the local environment around each W and to study their changes in the presence of lipid vesicles. Fluorescence experiments show that, for the pure Trp-analogues, W18 and W37 are fully exposed to solvent whatever pH and buffer conditions. In the presence of lipid vesicles, both became buried. Lipid affinities were estimated: they are weak for zwitterionic phospholipids but an order of magnitude higher for negatively charged phosphatidylserine (PS) and phosphatidylglycerol (PG) lipids. On negatively charged PG lipids, Mes-Y105 and Mes-Y105/W37 display comparable lipid affinities. A decrease in lipid affinity is observed for Mes-Y105/W18 compared to Mes-Y105, which means that W37 would seem to be required for increased lipid selectivity. In the lipid-bound state W18 is strongly dehydrated, probably embedded into the acyl chains, while W37 stands more at the interface. Mes-Y105 was also studied by polarization modulation infrared reflection absorption spectroscopy (PMIRRAS), alone and in various phospholipid environments, to obtain structural information and to assess lipid perturbations. At nanomolar concentrations close to those required for anti-Listeria activity, Mes-Y105 forms films at the air/water interface and inserts into negatively charged lipid monolayers. In situ infrared data show that Mes-Y105 binding only affects the polar head group vibrations while the lipid order of the acyl chains remains unaffected. The PMIRRAS show that Mes-Y105 folds into an N-terminal antiparallel beta-sheet followed by an alpha-helix, both structures being tilted (40 degrees) compared to the normal at the interface, which is in agreement with the thickness estimated by Brewster angle microscopy (BAM). All these data support the proposal of a new model for Mes-Y105 at the membrane interface. PMID:15670734

  17. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents.

    PubMed

    Shrestha, Sanjib K; Fosso, Marina Y; Green, Keith D; Garneau-Tsodikova, Sylvie

    2015-08-01

    In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6?-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID:26033722

  18. Site Study Plan for Acoustics, Deaf Smith County Site, Texas: Environmental Field Program: Preliminary draft

    SciTech Connect

    Not Available

    1987-06-01

    The Acoustics site study plan describes a field program which characterizes existing sound levels, determines the area's sound propagation characteristics, and monitors the project-related sound emissions. The plan describes for each study: the need for the study, study design, data management and use, schedule, and quality assurance requirements. These studies will provide data needed to satisfy requirements contained in, or derived from, the Salt Repository Requirements Document. 37 refs., 9 figs., 3 tabs.

  19. Natural analogue synthesis report, TDR-NBS-GS-000027 rev00 icn02

    SciTech Connect

    Simmons, A.; Nieder-Westermann, G.; Stuckless, J.; Dobson, P.; Unger, A.J.A.; Kwicklis, E.; Lichtner, P.; Carey, B.; Wolde, G.; Murrel,M.; Kneafsey, T.J.; Meijer, A.; Faybishenko, B.

    2002-04-01

    The purpose of this report is to present analogue studies and literature reviews designed to provide qualitative and quantitative information to test and provide added confidence in process models abstracted for performance assessment (PA) and model predictions pertinent to PA. This report provides updates to studies presented in the Yucca Mountain Site Description (CRWMS M&O 2000 [151945], Section 13) and new examples gleaned from the literature, along with results of quantitative studies conducted specifically for the Yucca Mountain Site Characterization Project (YMP). The intent of the natural analogue studies was to collect corroborative evidence from analogues to demonstrate additional understanding of processes expected to occur during postclosure at a potential Yucca Mountain repository. The report focuses on key processes by providing observations and analyses of natural and anthropogenic (human-induced) systems to improve understanding and confidence in the operation of these processes under conditions similar to those that could occur in a nuclear waste repository. The process models include those that represent both engineered and natural barrier processes. A second purpose of this report is to document the various applications of natural analogues to geologic repository programs, focusing primarily on the way analogues have been used by the YMP. This report is limited to providing support for PA in a confirmatory manner and to providing corroborative inputs for process modeling activities. Section 1.7 discusses additional limitations of this report. Key topics for this report are analogues to emplacement drift degradation, waste form degradation, waste package degradation, degradation of other materials proposed for the engineered barrier, seepage into drifts, radionuclide flow and transport in the unsaturated zone (UZ), analogues to coupled thermal-hydrologic-mechanical-chemical processes, saturated zone (SZ) transport, impact of radionuclide release on the biosphere, and potentially disruptive events. Results of these studies will be used to corroborate estimates of the magnitude and limitation of operative processes in order to build realism into conceptual and numerical process models used as a foundation for PA in the representative case of postclosure safety.

  20. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues

    PubMed Central

    Wolin, Edward M; Jarzab, Barbara; Eriksson, Barbro; Walter, Thomas; Toumpanakis, Christos; Morse, Michael A; Tomassetti, Paola; Weber, Matthias M; Fogelman, David R; Ramage, John; Poon, Donald; Gadbaw, Brian; Li, Jiang; Pasieka, Janice L; Mahamat, Abakar; Swahn, Fredrik; Newell-Price, John; Mansoor, Wasat; berg, Kjell

    2015-01-01

    In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.271.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.894.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 not reached) with pasireotide versus 6.8 months (5.6 not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.200.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR. PMID:26366058

  1. Site study plan for routine laboratory rock mechanics, Deaf Smith County Site, Texas: Revision 1

    SciTech Connect

    Not Available

    1987-12-01

    This Site Study Plan for Routine Laboratory Rock Mechanics describes routine laboratory testing to be conducted on rock samples collected as part of the characterization of the Deaf Smith County site, Texas. This study plan describes the early laboratory testing. Additional testing may be required and the type and scope of testing will be dependent upon the results of the early testing. This study provides for measurements of index, hydrological, mechanical, and chemical properties with tests which are standardized and used widely in geotechnical investigations. Another Site Study Plan for Nonroutine Laboratory Rock Mechanics describes laboratory testing of samples from the site to determine mechanical, thermomechanical, and thermal properties by less widely used methods, many of which have been developed specifically for characterization of the site. Data from laboratory tests will be used for characterization of rock strata, design of shafts and underground facilities, and modeling of repository behavior in support of resolution of both preclosure and postclosure issues. A tentative testing schedule and milestone log are given. A quality assurance program will be utilized to assure that activities affecting quality are performed correctly and that appropriate documentation is maintained. 18 refs., 8 figs., 3 tabs.

  2. Site study plan for borehole search and characterization, Deaf Smith County Site, Texas: Revision 1

    SciTech Connect

    Not Available

    1987-12-22

    This site study plan describes the Borehole Search and Characterization field activities to be conducted during the early stages of Site Characterization at the Deaf Smith County site, Texas. The field program has been designed to provide data useful in addressing information/data needs resulting from Federal/State/Local regulatory requirements and repository program requirements. Air and ground surveys, an extensive literature search, and landowner interviews will be conducted to locate wells within and adjacent to the proposed nuclear waste repository site in Deaf Smith County. Initially, the study will center around the planned Exploratory Shaft Facilities location and will expand outward from that location. Findings from this study may lead to preparation of a new site study plan to search suspected borehole locations, and excavate or reenter known boreholes for additional characterization or remedial action. The Salt Repository Project (SRP) Networks specify the schedule under which the program will operate. The Technical Field Services Contractor (TFSC) is responsible for conducting the field program. Data will be handled and reported in accordance with established SRP procedures. A quality assurance program will be utilized to assure that activities affecting quality are performed correctly and that appropriate documentation is maintained. 13 refs., 6 figs., 3 tabs.

  3. High Plains Regional Ground-water Study web site

    USGS Publications Warehouse

    Qi, Sharon L.

    2000-01-01

    Now available on the Internet is a web site for the U.S. Geological Survey's (USGS) National Water-Quality Assessment (NAWQA) Program- High Plains Regional Ground-Water Study. The purpose of the web site is to provide public access to a wide variety of information on the USGS investigation of the ground-water resources within the High Plains aquifer system. Typical pages on the web site include the following: descriptions of the High Plains NAWQA, the National NAWQA Program, the study-area setting, current and past activities, significant findings, chemical and ancillary data (which can be downloaded), listing and access to publications, links to other sites about the High Plains area, and links to other web sites studying High Plains ground-water resources. The High Plains aquifer is a regional aquifer system that underlies 174,000 square miles in parts of eight States (Colorado, Kansas, Nebraska, New Mexico, Oklahoma, South Dakota, Texas, and Wyoming). Because the study area is so large, the Internet is an ideal way to provide project data and information on a near real-time basis. The web site will be a collection of living documents where project data and information are updated as it becomes available throughout the life of the project. If you have an interest in the High Plains area, you can check this site periodically to learn how the High Plains NAWQA activities are progressing over time and access new data and publications as they become available.

  4. Complexes of an anionic gallium(I) N-heterocyclic carbene analogue with group 14 element(II) fragments: synthetic, structural and theoretical studies.

    PubMed

    Green, Shaun P; Jones, Cameron; Lippert, Kai-Alexander; Mills, David P; Stasch, Andreas

    2006-09-01

    The reactions of the anionic gallium(I) N-heterocyclic carbene (NHC) analogue, [K(tmeda)][:Ga{[N(Ar)C(H)]2}], Ar = C6H3Pri2-2,6, with the heavier group 14 alkene analogues, R2E=ER2, E = Ge or Sn, R = -CH(SiMe3)2, have been carried out. In 2:1 stoichiometries, these lead to the ionic [K(tmeda)][R2EGa{[N(Ar)C(H)]2}] complexes which exhibit long E-Ga bonds. The nature of these bonds has been probed by DFT calculations, and the complexes have been compared to neutral NHC adducts of group 14 dialkyls. The 4:1 reaction of [K(tmeda)][:Ga{[N(Ar)C(H)]2}] with R2Sn=SnR2 leads to the digallyl stannate complex, [K(tmeda)][RSn[Ga{[N(Ar)C(H)]2}]2], presumably via elimination of KR. In contrast, the reaction of the gallium heterocycle with PbR2 affords the digallane4, [Ga{[N(Ar)C(H)]2}]2, via an oxidative coupling reaction. For sake of comparison, the reactions of [K(tmeda)][:Ga{[N(Ar)C(H)]2}] with Ar'2E=EAr'2, E = Ge, Sn or Pb, Ar' = C6H2Pri3-2,4,6, were carried out and led to either no reaction (E = Ge), the formation of [K(tmeda)][Ar'2SnGa{[N(Ar)C(H)]2}] (E = Sn), or the gallium(III) heterocycle, [Ar'Ga{[N(Ar)C(H)]2}] (E = Pb). Salt elimination reactions between [K(tmeda)][:Ga{[N(Ar)C(H)]2}] and the guanidinato group 14 complexes [(Giso)ECl], E = Ge or Sn, Giso = [Pri2NC{N(Ar)}2]-, gave the neutral [(Giso)EGa{[N(Ar)C(H)]2}] complexes. All complexes have been characterized by NMR spectroscopy and X-ray crystallographic studies. PMID:16933925

  5. Site Study Plan for salt, Deaf Smith County site, Texas: Environmental Field Program: Preliminary draft

    SciTech Connect

    Not Available

    1987-06-01

    The Salt Site Study Plan (SSP) describes a program for characterizing the existing salt environment in the site vicinity. A step-by-step approach is described which proceeds from published data and planned theoretical studies, to planned laboratory studies, and finally to planned field studies, to provide the necessary data to meet program requirements contained in the Salt Repository Project - Requirements Document (SRP-RD). The plan also draws on the results of other SSP's for certain data; for example, soil salinity data are to be provided under the Soils SSP. The salt studies consist of evaluation of control and mitigation measures, salt monitoring studies, emission factors development, air models development and validation, and risk assessment. For each study, its design and design rationale; analysis, management, and use of data; schedule of activities; organization of personnel and sample management; and quality assurance requirements are described. 90 refs., 9 figs., 7 tabs.

  6. Bioremediation demonstration on Kwajalein Island: Site characterization and on-site biotreatability studies

    SciTech Connect

    Siegrist, R.L.; Korte, N.E.; Pickering, D.A. ); Phelps, T.J. )

    1991-09-01

    An environmental study was conducted during February 1991 on Kwajalein Island, a US Army Kwajalein Atoll (USAKA) Base in the Republic of the Marshall Islands (RMI). This study was undertaken for the US Department of Energy (DOE) Hazardous Waste Remedial Actions Program (HAZWRAP) acting in behalf of USAKA. The purpose of the study was to determine if selected locations for new construction on Kwajalein Island were contaminated by petroleum hydrocarbons as suspected and, if so, whether bioremediation appeared to be a feasible technology for environmental restoration. Two different sites were evaluated: (1) the site planned freshwater production facility and (2) a site adjacent to an aboveground diesel fuel storage tank. Within the proposed construction zone for the freshwater production facility (a.k.a desalination plant), total petroleum hydrocarbons (TPH) where either absent or at low levels. Characterization data for another potential construction site adjacent to an aboveground diesel fuel storage tank southeast of the old diesel power plant revealed high concentrations of diesel fuel in the soil and groundwater beneath the site. Results of this investigation indicate that there are petroleum-contaminated soils on Kwajalein Island and bioremediation appears to be a viable environmental restoration technique. Further experimentation and field demonstration are required to determine the design and operating conditions that provide for optimum biodegradation and restoration of the petroleum-contaminated soils. 17 refs., 7 figs., 26 figs.

  7. Site Study Plan for laboratory soil mechanics, Deaf Smith County site, Texas: Revision 1

    SciTech Connect

    Not Available

    1987-12-01

    This Site Study Plan for laboratory soil mechanics describes the laboratory testing to be conducted on soil samples collected as part of the characterization of the Deaf Smith County site, Texas. This study provides for measurements of index, mechanical, thermal, hydrologic, chemical, and mineral properties of soils from boring throughout the site. Samples will be taken from Playa Borings/Trenching, Transportation/Utilities Foundation Borings, Repository Surface Facilities Design Foundation Borings, and Exploratory Shaft Facilities Design Foundation Borings. Data from the laboratory tests will be used for soil strata characterization, design of foundations for surface structures, design of transportation facilities and utility structures, design of impoundments, design of shaft lining, design of the shaft freeze wall, shaft permitting, performance assessment calculations, and other program requirements. A tentative testing schedule and milestone log are given. A quality assurance program will be utilized to assure that activities affecting quality are performed correctly and that appropriate documentation is maintained. 18 refs., 6 figs., 3 tabs.

  8. Normal and abnormal heme biosynthesis. Part 7. Synthesis and metabolism of coproporphyrinogen-III analogues with acetate or butyrate side chains on rings C and D. Development of a modified model for the active site of coproporphyrinogen oxidase.

    PubMed

    Lash, Timothy D; Lamm, Teresa R; Schaber, J Andy; Chung, Wen-hsiang; Johnson, Eric K; Jones, Marjorie A

    2011-02-15

    Analogues of coproporphyrinogen-III have been prepared with acetate or butyrate groups attached to the C and D pyrrolic subunits. The corresponding porphyrin methyl esters were synthesized by first generating a,c-biladienes by reacting a dipyrrylmethane with pyrrole aldehydes in the presence of HBr. Cyclization with copper(II) chloride in DMF, followed by demetalation with 15% H(2)SO(4)-TFA and reesterification, gave the required porphyrins in excellent yields. Hydrolysis with 25% hydrochloric acid and reduction with sodium-amalgam gave novel diacetate and dibutyrate porphyrinogens 9. Diacetate 9a was incubated with chicken red cell hemolysates (CRH), but gave complex results due to the combined action of two of the enzymes present in these preparations. Separation of uroporphyrinogen decarboxylase (URO-D) from coproporphyrinogen oxidase (CPO) allowed the effects of both enzymes on the diacetate substrate to be assessed. Porphyrinogen 9a proved to be a relatively poor substrate for CPO compared to the natural substrate coproporphyrinogen-III, and only the A ring propionate moiety was processed to a significant extent. Similar results were obtained for incubations of 9a with purified human recombinant CPO. Diacetate 9a was also a substrate for URO-D and a porphyrinogen monoacetate was the major product in this case; however, some conversion of a second acetate unit was also evident. The dibutyrate porphyrinogen 9b was only recognized by the enzyme CPO, but proved to be a modest substrate for incubations with CRH. However, 9b was an excellent substrate for purified human recombinant CPO. The major product for these incubations was a monovinylporphyrinogen, but some divinyl product was also generated in incubations using purified recombinant human CPO. The incubation products were converted into the corresponding porphyrin methyl esters, and these were characterized by proton NMR spectroscopy and mass spectrometry. The results extend our understanding of substrate recognition and catalysis for this intriguing enzyme and have allowed us to extend the active site model for CPO. In addition, the competitive action of both URO-D and CPO on the same diacetate porphyrinogen substrate provides additional perspectives on the potential existence of abnormal pathways for heme biosynthesis. PMID:21277781

  9. Improvement in chronic pelvic pain after gonadotropin releasing hormone analogue (GnRH-a) administration in premenopausal women suffering from adenomyosis or endometriosis: a retrospective study.

    PubMed

    Morelli, Michele; Rocca, Morena Luigia; Venturella, Roberta; Mocciaro, Rita; Zullo, Fulvio

    2013-04-01

    The aim of this study was to evaluate the improvement in catamenial chronic pelvic pain (CPP) after Gonadotropin Releasing Hormone analogue (GnRH-a) administration in women affected by adenomyosis or endometriosis. We retrospectively analysed clinical data of 63 premenopausal women with clinical suspect of adenomyosis (15 women, Group A) or endometriosis (48 women, Group B), which received GnRH-a in order to reduce CPP intensity during the time on surgery waiting list. Main outcome measures were variation of CPP intensity, numbers of days requiring analgesics and lost work productivity before and three months after GnRH-a administration. Compared to baseline, a significant decrease in CPP intensity (p < 0.05) was observed in both groups, even if this reduction was significantly higher in Group A than in Group B (p < 0.001). In both groups, moreover, a significant reduction in number of days requiring analgesics (p < 0.05) and lost work productivity (p < 0.05) was detected. In conclusion, GnRH-a administration in women with clinical suspect of adenomyosis induces a greater reduction in CPP when compared to women with endometriosis, thus representing a potential ex adiuvantibus criteria, helping TV-US in the clinical diagnosis of adenomyosis. PMID:23323768

  10. Comparative study of bisphenol A and its analogue bisphenol S on human hepatic cells: a focus on their potential involvement in nonalcoholic fatty liver disease.

    PubMed

    Peyre, Ludovic; Rouimi, Patrick; de Sousa, Georges; Hlis-Toussaint, Ccile; Carr, Benjamin; Barcellini, Sylvie; Chagnon, Marie-Christine; Rahmani, Roger

    2014-08-01

    For several decades, people have been in contact with bisphenol A (BPA) primarily through their diet. Nowadays it is gradually replaced by an analogue, bisphenol S (BPS). In this study, we compared the effects of these two bisphenols in parallel with the positive control diethylstilbestrol (DES) on different hepatocyte cell lines. Using a cellular impedance system we have shown that BPS is less cytotoxic than BPA in acute and chronic conditions. We have also demonstrated that, contrary to BPA, BPS is not able to induce an increase in intracellular lipid and does not activate the PXR receptor which is known to be involved in part, in this process. In parallel, it failed to modulate the expression of CYP3A4 and CYP2B6, the drug transporter ABCB1 and other lipid metabolism genes (FASN, PLIN). However, it appears to have a weak effect on GSTA4 protein expression and on the Erk1/2 pathway. In conclusion, in contrast to BPA, BPS does not appear to induce the metabolic syndrome that may lead to non-alcoholic fatty liver disease (NAFLD), in vitro. Although we have to pay special attention to BPS, its use could be less dangerous concerning this toxicological endpoint for human health. PMID:24793377

  11. Late Pleniglacial vegetation in eastern-central Europe: are there modern analogues in Siberia?

    NASA Astrophysics Data System (ADS)

    Magyari, Enik? Katalin; Kune, Petr; Jakab, Gusztv; Smegi, Pl; Pelnkov, Barbora; Schbitz, Frank; Braun, Mihly; Chytr, Milan

    2014-07-01

    To characterize Late Pleniglacial (LPG: 26.5-15 ka cal BP) and particularly Last Glacial Maximum (LGM: 21 2 ka cal BP) vegetation and climate, fossil pollen assemblages are often compared with modern pollen assemblages. Given the non-analogue climate of the LPG, a key question is how glacial pollen assemblages and thereby vegetation compare with modern vegetation. In this paper we present three LPG pollen records from the Carpathian Basin and the adjoining Carpathian Mountains to address this question and provide a concise compositional characterization of the LPG vegetation. Fossil pollen assemblages were compared with surface pollen spectra from the Altai-Sayan Mountains in southern Siberia. This area shows many similarities with the LPG vegetation of eastern-central Europe, and has long been considered as its best modern analogue. Ordination and analogue matching were used to characterize vegetation composition and find the best analogues. Our results show that few LPG pollen assemblages have statistically significant analogues in southern Siberia. When analogue pairings occur they suggest the predominance of wet and mesic grasslands and dry steppe in the studied region. Wooded vegetation types (continental and suboceanic hemiboreal forest, continental taiga) appear as significant analogues only in a few cases during the LGM and more frequently after 16 ka cal BP. These results suggest that the LPG landscape of the Carpathian Basin was dominated by dry steppe that occurred outside the river floodplains, while wet and mesic grasslands occurred in the floodplains and on other sites influenced by ground water. Woody vegetation mainly occurred in river valleys, on wet north-facing hillsides, and scattered trees were likely also present on the loess plateaus. The dominant woody species were Larix, Pinus sylvestris, Pinus mugo, Pinus cembra, Picea abies, Betula pendula/pubescens, Betula nana, Juniperus, Hippopha rhamnoides, Populus, Salix and Alnus. The pollen records suggest uninterrupted presence of mesophilous temperate trees (Quercus, Ulmus, Corylus, Fagus and Fraxinus excelsior) in the Eastern Carpathian Mountains throughout the LPG. We demonstrate that the LPG vegetation in this area was characterized by increasing grass cover and high frequency of wildfires. We conclude that pollen spectra over represent trees in the forest-steppe landscape of the LPG, furthermore pollen-based quantitative climate reconstructions for the LPG are challenging in this area due to the scarcity of modern analogues.

  12. Feasibility study for the United Heckathorn Superfund Site, Richmond, California

    SciTech Connect

    Lincoff, A.H.; Costan, G.P.; Montgomery, M.S.; White, P.J.

    1994-07-01

    The United Heckathom Superfund Site in Richmond, California, was used to formulate pesticides from approximately 1947 to 1966. Soils at the site and sediments in the harbor were contaminated with various chlorinated pesticides, primarily DDT, as a result of these activities. The US Environmental Protection Agency listed the site on the Superfund National Priorities List in 1990. This document is part of the Remedial Investigation and Feasibility Study phase of the Superfund response, which will provide the basis for selection of a final remedy that will protect human health and the environment and achieve compliance with federal and state envirorunental laws.

  13. Second Information Technology in Education Study: SITES 2006 Technical Report

    ERIC Educational Resources Information Center

    Carstens, Ralph, Ed.; Pelgrum, Willem J., Ed.

    2009-01-01

    The International Association for the Evaluation of Educational Achievement (IEA) has been conducting comparative studies for 50 years. SITES 2006 is the fifth wave of surveys related to information and communication technology (ICT), a wave that IEA started with its Computers in Education Study (two studies with data collection in 1989 and 1992),

  14. Site study plan for ecology, Deaf Smith County Site, Texas: Environmental Field Program: Preliminary Draft

    SciTech Connect

    Not Available

    1987-06-01

    The Ecology Site Study Plan describes a field program consisting of studies which include surveys for endangered, threatened, and candidate species; vegetation characterization, including mapping and cover typing, plant succession, wetlands description, and preexisting stresses; and wildlife community characterization, including availability and quality of habitats and descriptions of mammal, bird, reptile, amphibian, and invertebrate populations. The plan for each study describes the need for the study, study design, data management and use, schedule and personnel requirements, and quality assurance. These studies will provide data needed to satisfy requirements contained in, or derived from, the Salt Repository Project Requirements Document (SRP-RD). 83 refs., 3 tabs.

  15. TWRS privatization phase I site development engineering study

    SciTech Connect

    Shord, A.L.

    1996-09-30

    The DOE-RL is pursuing a new business strategy of hiring private contractors for treatment of Hanford Site tank wastes. This strategy is called `privatization` and includes design, permitting, construction, operation and deactivation of facilities for tank waste treatment. The TWRS Privatization Infrastructure Project consists of several sub-projects which will provide key services needed to support the privatization mission. One sub-project is to develop the selected site for the privatization facilities. This study addresses the pertinent issues related to the development of the site and specific parcels to be assigned to each of two private contractors. It also summarizes other studies that address provisions for utilities and other site services.

  16. Synthesis, antimycobacterial evaluation and pharmacophore modeling of analogues of the natural product formononetin.

    PubMed

    Mutai, Peggoty; Pavadai, Elumalai; Wiid, Ian; Ngwane, Andile; Baker, Bienyameen; Chibale, Kelly

    2015-06-15

    The synthesis and antimycobacterial activity of formononetin analogues is hereby reported. Formononetin and its analogue 11E showed 88% and 95% growth inhibition, respectively, against the H37Rv strain of Mycobacterium tuberculosis. Pharmacophore modeling studies indicated that the presence of a hydroxyl group in formononetin and its analogues, is crucial for maintaining activity. PMID:25977095

  17. Site-specific magnetization reversal studies of magnetite

    SciTech Connect

    Cady, A.; Haskel, D.; Lang, J. C.; Islam, Z.; Srajer, G.; Ankudinov, A.; Subias, G.; Garcia, J.

    2006-04-01

    The mechanism of magnetization reversal in magnetite (Fe{sub 3}O{sub 4}) single crystals was studied using site-specific magnetic sensitive diffraction anomalous near-edge structure. By exploiting the angular dependence of the cross section, we are able to show that the mechanism of reversal involves a mixture of coherent rotation and domain formation. The results reveal additional details to that provided by XMCD measurements, which average over nonequivalent sites.

  18. EPR study of thermally treated Archean microbial mats analogues and comparison with Archean cherts: towards a possible marker of oxygenic photosynthesis?

    NASA Astrophysics Data System (ADS)

    Bourbin, M.; Derenne, S.; Westall, F.; Gourier, D.; Gautret, P.; Rouzaud, J.-N.; Robert, F.

    2012-04-01

    The datation of photosynthesis apparition remains an open question nowadays: did oxygenic photosynthesis appear just before the Great Oxidation Event (GOE) of the atmosphere, 2.3 to 2.4 Gyr ago, or does it originate much earlier? It is therefore of uttermost interest to find markers of oxygenic photosynthesis, applicable to samples of archean age. In order to handle this problem, Microcoleus Chtonoplastes cyanobacteria and Chloroflexus-like non-oxygenic photosynthetic bacteria, were studied using Electron Paramagnetic Resonance (EPR) spectroscopy, a high sensitivity technique for the study of organic radicals in mature geological samples (coals, cherts, meteorites...). M. chtonoplastes and Chloroflexus-like bacteria were sampled in mats from the hypersaline lake "La Salada de Chiprana" (Spain), an analogue to an Archean environment, and were submitted to accelerated ageing through cumulative thermal treatments. For thermal treatment temperatures higher than 620° C, a drastic increase in the EPR linewidth of the oxygenic photosynthetic bacteria (M. chtonoplastes) occurred, as compared with the anoxygenic photosynthetic one (Chloroflexus-like). The EPR study of a thermally treated mixture of the two bacteria evidences that this linewidth increase is driven by catalytic reaction at high temperatures on an element selectively fixed by M. chtonoplastes. Based on comparative EDS analyses, Mg is a potential candidate for this catalytic activity but its precise role and the nature of the reaction are still to be determined. The EPR study of organic radicals in chert rocks of ages ranging from 0.42 to 3.5 Gyr, from various localities and that underwent various metamorphisms, revealed a dispersion of the signal width for the most mature samples. This comparative approach between modern bacterial samples and Precambrian cherts leads to propose the EPR linewidth of mature organic matter in cherts as a potential marker of oxygenic photosynthesis. If confirmed, this marker would support the hypothesis of oxygenic photosynthesis apparition at least 3.5 Gyr ago, long before the GOE.

  19. Site Study Plan for Aesthetics, Deaf Smith County Site, Texas: Environmental Field Program: Preliminary draft

    SciTech Connect

    Not Available

    1987-06-01

    The Aesthetic Site Study Plan describes a field program consisting of identification of the visually affected area; determination of scenic quality, visual sensitivity, and visual management classes of the site and vicinity; and analysis of the level of visual contrast that would be created by the project. Field ratings of scenic quality, visual sensitivity, and visual contrast will be supplemented by a public perception survey designed to incorporate the views of the public. This plan describes the need for the study, the study design, data management and use, schedule for proposed activities, and quality assurance program. This study will provide data needed to satisfy requirements contained in, or derived from, SRPO Requirement Document (SRP-RD). 35 refs., 6 figs., 2 tabs.

  20. A single-center, randomized, open-label, dose-escalation study to evaluate the pharmacokinetics of tacrine analogue octahydrogenacridine succinate tablets in healthy Chinese subjects.

    PubMed

    Zhao, Xia; Liang, Yan; Xu, Junyu; Zhang, Dongmei; Wang, Depu; Gu, Jingkai; Cui, Yimin

    2012-01-01

    The objectives of the present study were to investigate the pharmacokinetics (PK) of tacrine analogue octahydrogenacridine (OHA) succinate tablets in healthy Chinese subjects. A single-center, randomized, open-label, dose-escalation study was conducted in 42 healthy Chinese subjects. Part I of the study (n=30, 16 male and 14 female) evaluated the PK profiles of OHA in healthy Chinese subjects (aged 18-45 years) after single and multiple doses of 2?mg, 4?mg and 8?mg. Part II (n=10) assessed food effect on PK characteristics of OHA. The 10 participants of 4?mg dose group in part I were given another single dose of 4?mg OHA under fed condition. Part III (n=12, 7 male and 5 female) investigate PK behavior of OHA in elderly (aged 65-75 years) Chinese healthy subjects. In Part I, following a single- and multiple-dose, octahydrogenacridine succinate was rapidly absorbed with a median t(max) of 0.67 to 1.00?h, and was eliminated with a mean t1/2 of 2.27 to 2.98?h in all dose groups and did not appear to be dose dependent. In Part II, there were no significant differences in Cmax, AUC0-tn or tmax between 4?mg single dose fasting group and fed group (p=0.257, 0.153, 0.098, respectively). In Part III, both in single-dose and multiple-dose treatment, the main PK parameters of OHA in the elderly healthy Chinese subjects showed no statistical difference with those of non-elderly group. All these results indicated that OHA might be a promising drug under development for Alzheimer's disease (AD) therapy. PMID:22975501

  1. Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors.

    PubMed

    Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal

    2016-04-01

    Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 2-phenylpyrimidine series as PDE4B selective inhibitors. A five point pharmacophore model was developed using 87 molecules having pIC50 ranging from 8.52 to 5.07. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)=0.918), cross validation coefficient (Q(2)=0.852), and F value (175) at 4 component PLS factor. The external validation indicated that our QSAR model possessed high predictive power (R(2)=0.70). The generated model was further validated by enrichment studies using the decoy test. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviation. A 10ns molecular dynamics simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Further, similar orientation was observed between the superposition of the conformations of 85 after MD simulation and best XP-docking pose; MD simulation and 3D-QSAR pose; best XP-docking and 3D-QSAR poses. Outcomes of the present study provide insight in designing novel molecules with better PDE4B selective inhibitory activity. PMID:26804643

  2. Human Factor Studies on a Mars Analogue During Crew 100b International Lunar Exploration Working Group EuroMoonMars Crew: Proposed New Approaches for Future Human Space and Interplanetary Missions

    PubMed Central

    Rai, Balwant; Kaur, Jasdeep

    2012-01-01

    Knowing the risks, costs, and complexities associated with human missions to Mars, analogue research can be a great (low-risk) tool for exploring the challenges associated with the preparation for living, operating, and undertaking research in interplanetary missions. Short-duration analogue studies, such as those being accomplished at the Mars Desert Research Station (MDRS), offer the chance to study mission operations and human factors in a simulated environment, and therefore contribute to exploration of the Moon and Mars in planned future missions. This article is based upon previously published articles, abstracts, and presentations by a series of independent authors, human factor studies performed on mars analogue station by Crew 100B. The MDRS Crew 100B performed studies over 15 days providing a unique insight into human factor issues in simulated short-duration Mars mission. In this study, 15 human factors were evaluated and analyzed by subjective and objective means, and from the summary of results it was concluded that optimum health of an individual and the crew as a whole is a necessity in order to encourage and maintain high performance and the satisfaction of project goals. PMID:23181225

  3. Human Factor Studies on a Mars Analogue During Crew 100b International Lunar Exploration Working Group EuroMoonMars Crew: Proposed New Approaches for Future Human Space and Interplanetary Missions.

    PubMed

    Rai, Balwant; Kaur, Jasdeep

    2012-11-01

    Knowing the risks, costs, and complexities associated with human missions to Mars, analogue research can be a great (low-risk) tool for exploring the challenges associated with the preparation for living, operating, and undertaking research in interplanetary missions. Short-duration analogue studies, such as those being accomplished at the Mars Desert Research Station (MDRS), offer the chance to study mission operations and human factors in a simulated environment, and therefore contribute to exploration of the Moon and Mars in planned future missions. This article is based upon previously published articles, abstracts, and presentations by a series of independent authors, human factor studies performed on mars analogue station by Crew 100B. The MDRS Crew 100B performed studies over 15 days providing a unique insight into human factor issues in simulated short-duration Mars mission. In this study, 15 human factors were evaluated and analyzed by subjective and objective means, and from the summary of results it was concluded that optimum health of an individual and the crew as a whole is a necessity in order to encourage and maintain high performance and the satisfaction of project goals. PMID:23181225

  4. Mars sample return: Site selection and sample acquisition study

    NASA Astrophysics Data System (ADS)

    Nickle, N.

    1980-11-01

    Various vehicle and mission options were investigated for the continued exploration of Mars; the cost of a minimum sample return mission was estimated; options and concepts were synthesized into program possibilities; and recommendations for the next Mars mission were made to the Planetary Program office. Specific sites and all relevant spacecraft and ground-based data were studied in order to determine: (1) the adequacy of presently available data for identifying landing sites for a sample return mission that would assure the acquisition of material from the most important geologic provinces of Mars; (2) the degree of surface mobility required to assure sample acquisition for these sites; (3) techniques to be used in the selection and drilling of rock a samples; and (4) the degree of mobility required at the two Viking sites to acquire these samples.

  5. Reactions of trimethylphosphine analogues of auranofin with bovine serum albumin

    SciTech Connect

    Isab, A.A.; Shaw, C.F. III; Hoeschele, J.D.; Locke, J.

    1988-10-05

    The reactions of bovine serum albumin (BSA) with (trimethylphosphine)(2,3,4,6-tetra-O-acetyl-1-thio-..beta..-D-glucopyranosato-S)gold(I), Me/sub 3/PAuSAtg, and its chloro analogue, Me/sub 3/PAuCl, were studied to develop insights into the role of the phosphine ligand in the serum chemistry of the related antiarthritic drug auranofin (triethylphosphine)(2,3,4,6-tetra-O-acetyl-1-thio-..beta..-D-glucopyranosato-S)gold(I). /sup 31/P NMR spectroscopy, protein modification, and gel-exclusion chromatography methods were employed. Comparison of the reactions of the methyl derivatives to the previously reported reactions of auranofin and Et/sub 3/PAuCl with BSA demonstrated that similar chemical species are formed but revealed three major differences. Despite these differences, the results for the methyl analogues provide important confirmation for previously developed chemical models of auranofin reactions in serum. Me/sub 3/PO was not observed in reaction mixtures lacking tetraacetylthioglucose (AtgSH); this result affirms the role of AtgSH, displaced by the reaction of Me/sub 3/PAuSAtg at Cys-34, in the generation of the phosphine oxide (an important metabolite in vivo). The weak binding sites on albumin react with Me/sub 3/PAuCl, but not Me/sub 3/PAuSAtg, demonstrating the importance of the strength and reactivity of the anionic ligand-gold bond on the reactions of auranofin analogues. The gold binding capacity of albumin is enhanced after Me/sub 3/PO is formed, consistent with reductive cleavage of albumin disulfide bonds by trimethylphosphine. 24 references, 2 figures, 3 tables.

  6. Design, Synthesis, and SAR Studies of 4-Substituted Methoxylbenzoyl-aryl-thiazoles Analogues as Potent and Orally Bioavailable Anticancer Agents

    PubMed Central

    Lu, Yan; Li, Chien-Ming; Wang, Zhao; Chen, Jianjun; Mohler, Michael L.; Li, Wei; Dalton, James T.; Miller, Duane D.

    2016-01-01

    In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-arylthiazole (SMART) template, we explored chemodiverse B rings and B to C ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-aminothiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between A and B rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45ac (PAT) vs 1 (SMART)). PMID:21557538

  7. MODE OF ACTION OF ACETYLXYLAN ESTERASE FROM STREPTOMYCES LIVIDANS: A STUDY WITH DEOXY AND DEOXY-FLUORO ANALOGUES OF ACETYLATED METHYL BETA-D-XYLOPYRANOSIDE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The action of Streptomyces lividans acetylxylan esterase on methyl 2,4-di-O-acetyl- and 3,4-di-O-acetyl beta-D-xylopyranoside was compared with its action on the 2- and 3-deoxy and 2- and 3-deoxy-fluoro-analogues of the two diacetates in order to elucidate the role of the free hydroxyl group in the ...

  8. Overview of Ground-Water Recharge Study Sites

    USGS Publications Warehouse

    Constantz, Jim; Adams, Kelsey S.; Stonestrom, David A.

    2007-01-01

    Multiyear studies were done to examine meteorologic and hydrogeologic controls on ephemeral streamflow and focused ground-water recharge at eight sites across the arid and semiarid southwestern United States. Campaigns of intensive data collection were conducted in the Great Basin, Mojave Desert, Sonoran Desert, Rio Grande Rift, and Colorado Plateau physiographic areas. During the study period (1997 to 2002), the southwestern region went from wetter than normal conditions associated with a strong El Ni?o climatic pattern (1997?1998) to drier than normal conditions associated with a La Ni?a climatic pattern marked by unprecedented warmth in the western tropical Pacific and Indian Oceans (1998?2002). The strong El Ni?o conditions roughly doubled precipitation at the Great Basin, Mojave Desert, and Colorado Plateau study sites. Precipitation at all sites trended generally lower, producing moderate- to severe-drought conditions by the end of the study. Streamflow in regional rivers indicated diminishing ground-water recharge conditions, with annual-flow volumes declining to 10?46 percent of their respective long-term averages by 2002. Local streamflows showed higher variability, reflecting smaller scales of integration (in time and space) of the study-site watersheds. By the end of the study, extended periods (9?15 months) of zero or negligible flow were observed at half the sites. Summer monsoonal rains generated the majority of streamflow and associated recharge in the Sonoran Desert sites and the more southerly Rio Grande Rift site, whereas winter storms and spring snowmelt dominated the northern and westernmost sites. Proximity to moisture sources (primarily the Pacific Ocean and Gulf of California) and meteorologic fluctuations, in concert with orography, largely control the generation of focused ground-water recharge from ephemeral streamflow, although other factors (geology, soil, and vegetation) also are important. Watershed area correlated weakly with focused infiltration volumes, the latter providing an upper bound on associated ground-water recharge. Estimates of annual focused infiltration for the research sites ranged from about 105 to 107 cubic meters from contributing areas that ranged from 26 to 2,260 square kilometers.

  9. Pilot studies on scale-up biocatalysis of 7-?-xylosyl-10-deacetyltaxol and its analogues by an engineered yeast.

    PubMed

    Liu, Wan-Cang; Zhu, Ping

    2015-06-01

    Paclitaxel content in yew tree is extremely low, causing a worldwide shortage of this important anticancer drug. Yew tree can also produce abundant 7-?-xylosyl-10-deacetyltaxol that can be bio-converted into 10-deacetyltaxol for semi-synthesis of paclitaxel. However, the bio-conversion by the screened natural microorganisms was inefficient. We have constructed the recombinant yeast with a glycoside hydrolase gene from Lentinula edodes and explored the bioconversion. Based on previously established reaction conditions, the bioconversion of 7-?-xylosyl-10-deacetyltaxol or its extract was further optimized and scaled up with the engineered yeast harvested from 200-L scale high-cell-density fermentation. The optimization included the freeze-dried cell amount, dimethyl sulfoxide concentration, addition of 0.5% antifoam supplement, and substrate concentration. A 93-95% bioconversion and 83% bioconversion of 10 and 15 g/L 7-?-xylosyltaxanes in 10 L reaction volume were achieved, respectively. The yield of 10-deacetyltaxol reached 10.58 g/L in 1 L volume with 15 g/L 7-?-xylosyl-10-deacetyltaxol. The conversion efficiencies were not only much higher than those of other reports and our previous work, but also realized in 10 L reaction volume. A pilot-scale product purification was also established. Our study bridges the gap between the basic research and commercial utilization of 7-?-xylosyl-10-deacetyltaxol for the industrial production of semi-synthetic paclitaxel. PMID:25860125

  10. X-ray powder diffractometry and liquid chromatography studies of sibutramine and its analogues content in herbal dietary supplements.

    PubMed

    Stypu?kowska, K; B?a?ewicz, A; Maurin, J; Sarna, K; Fija?ek, Z

    2011-12-15

    The contemporary societies of the developed countries are prone to use traditional far-east medicines as remedies for all diseases. Some of them, such as obesity, might be classified as civilization diseases. Combating the problem, people try not only several miraculous diets but also herbal infusions (teas) and variety of "herbal" preparations. All these believing that such treatment is healthy and harmless as far as it is "natural". Leaving out of the way the question if herbal medicines can be taken safely without doctors' control the query arises if the common preparations are strictly natural and herbal. Here we report examples of quality studies of such medicines using both X-ray powder diffraction (XRPD) and liquid chromatography (LC) with various types of detection: ultraviolet (UV), coulometric electrode array (CEAD) and time-of-flight mass spectrometry (TOF-MS). Especially the XRPD assisted with an optical microscopy seems to be useful as a fast screening method of general sample composition of such preparations. First of all it can discriminate between capsules containing pure herbal materials and those with some chemical. PMID:21899974

  11. A Combined Gas-Phase Photoelectron Spectroscopic and Theoretical Study of Zeise's Anion and Its Bromine and Iodine Analogues

    SciTech Connect

    Hou, Gaolei; Wen, Hui; Lopata, Kenneth A.; Zheng, Weijun; Kowalski, Karol; Govind, Niranjan; Wang, Xue B.; Xantheas, Sotiris S.

    2012-06-25

    We report the first photoelectron spectroscopic study of Zeises anion, [PtCl3(C2H4)], and its Br- and I- analogs in the gas phase. Well-resolved and rich spectral features are obtained for each species, yielding detailed electronic structure information, which is assigned with the aid of highlevel electronic structure calculations at the Coupled Cluster (CC) level of theory. The electron binding energies of [PtX3(C2H4)] are found to decrease with the size of halogen (4.57, 4.51, and 4.18 eV for X = Cl, Br, and I, respectively). The calculations indicate a synergistic ?2 interaction [with interaction strengths of 1.54 (Cl), 1.37 (Br) and 1.10 eV (I)] between the perpendicular C2H4 fragment and the nearly horizontal planar PtX3- anions, resulting in activating the ethylene molecule. The detailed insights of the chemical bonding and underlying electronic structure can be used to benchmark interactions between olefins and transition metal complexes, which are crucial to a wide range of catalytic processes.

  12. A review of the archaeological analogue approaches to predict the long-term corrosion behaviour of carbon steel overpack and reinforced concrete structures in the French disposal systems

    NASA Astrophysics Data System (ADS)

    Neff, Delphine; Saheb, Mandana; Monnier, Judith; Perrin, Stphane; Descostes, Michael; L'Hostis, Valrie; Crusset, Didier; Millard, Alain; Dillmann, Philippe

    2010-07-01

    This paper gives a review of several years of research on archaeological analogues in order to predict the long term behaviour of the steel canisters or the reinforced concrete structures involved in disposal or interim storage of nuclear wastes in France. This article aims at showing the specific methodology, the complementariness with different other approaches and the complete integration of the research on analogues in the frame of research programs on long term prediction. Archaeological sites on which field measurement can be performed were referenced and described. A significant number of artefacts collected from these sites was selected for study. Detailed chemical and microstructural characterisation of the artefacts were undertaken by a combination of microbeam analytical techniques (?Raman, ?XRD, ?Raman spectroscopy,). Hypotheses on the corrosion mechanisms were then tested using specific isotopic markers during re-corroding experiments on analogues. Specific parameters were measured, allowing crucial steps in modelling long-term corrosion of steel.

  13. Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents.

    PubMed

    Palkar, Mahesh B; Singhai, Anuj S; Ronad, Pradeepkumar M; Vishwanathswamy, A H M; Boreddy, Thippeswamy S; Veerapur, Veeresh P; Shaikh, Mahamadhanif S; Rane, Rajesh A; Karpoormath, Rajshekhar

    2014-05-15

    A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1,3,4-oxadiazol-2(3H)-thione (4a-k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)-thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a-k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4thh, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand-protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC50 values. PMID:24751552

  14. Study on the Antifibrotic Effects of Recombinant Shark Hepatical Stimulator Analogue (r-sHSA) in Vitro and in Vivo

    PubMed Central

    Wang, Ying; Zhang, Xiaoyuan; Yang, Yang; Yang, Xiaohong; Ye, Boping

    2015-01-01

    Hepatic fibrosis is an effusive wound healing process, characterized by an excessive deposition of extracellular matrix (ECM), as the consequence of chronic liver injury of any etiology. Current therapeutic repertoire for hepatic fibrosis is limited to withdrawal of the noxious agent, which is not always feasible. Hence, in this article, the antifibrotic effects and possible mechanisms of r-sHSA, a recombinant protein with hepatoprotection potential, were investigated. Using NIH/3T3 (mouse embro-fibroblast cell line), skin fibroblasts (human skin fibroblasts, SFBs) and HSC-T6 (rat hepatic stellate cell line), the in vitro effect of r-sHSA was evaluated by measuring the expression levels of alpha-1 Type I collagen (Col1A1) and α-smooth muscle actin (α-SMA). It turned out those fibrosis indicators were typically inhibited by r-sHSA, suggesting its capacity in HSCs inactivation. The antifibrotic activity of r-sHSA was further investigated in vivo on CCl4-induced hepatic fibrosis, in view of significant improvement of the biochemical and histological indicators. More specifically, CCl4-intoxication induced a significant increase in serological biomarkers, e.g., transaminase (AST, ALT), and alkaline phosphatase (ALP), as well as disturbed hepatic antioxidative status; most of the parameters were spontaneously ameliorated to a large extent by withdrawal of CCl4, although the fibrotic lesion was observed histologically. In contrast, r-sHSA treatment markedly eliminated fibrous deposits and restored architecture of the liver in a dose dependent manner, concomitantly with the phenomena of inflammation relief and HSCs deactivation. To sum up, these findings suggest a therapeutic potential for r-sHSA in hepatic fibrosis, though further studies are required. PMID:26295240

  15. Internal rotation around single bonds and conformational preferences in heterocyclic analogues of benzyl methyl sulphoxide studied with NMR techniques

    NASA Astrophysics Data System (ADS)

    Folli, Ugo; Iarossi, Dario; Mucci, Adele; Taddei, Ferdinando

    1995-05-01

    The conformational equilibrium related to the internal rotation processes occurring in sulphoxides of the type ArCH 2SOCH 3 (where Ar=2-thienyl, 2-furyl, 2-pyridinyl and (3-methyl)2-pyridinyl rings) were studied with 1H and 13C NMR spectroscopy. Proton chemical shifts and long-range coupling constants nJ(H,H) were obtained from the iterative analysis of the multiplets and were employed, together with 13C chemical shifts, long-range nJ(C,H) and relaxation parameters (NOE and non-selective T1 values) to obtain stereochemical relationships between the protons present in these molecules. Conformational predictions at a qualitative level were also derived from total molecular energies calculated with the semi-empirical AM1/MNDO method as a function of internal coordinates. The different approaches converged to indicate that the heterocyclic rings adopt an average orientation similar to the perpendicular orientation of the phenyl ring in benzyl methyl sulphoxide and, as regards rotation around the CH 2?S bond, the prevalent conformer shows that the methyl group is symmetrically oriented with respect to the methylenic protons. The barriers for internal rotation are rather low and the equilibrium between conformers is dependent on the medium properties. Attempts to obtain conformational results were performed for the molecule of omeprazole, an antiulcer drug which contains the ArCH 2SO?R moiety (Ar and R are substituted 2-pyridinyl and 2-benzimidazolyl groups, respectively). With respect to the other compounds examined, the orientation of the Ar ring does not significantly differ and the benzimidazole ring seems to prefer an orientation stereochemically equivalent to that of the methyl group.

  16. Study on the Antifibrotic Effects of Recombinant Shark Hepatical Stimulator Analogue (r-sHSA) in Vitro and in Vivo.

    PubMed

    Wang, Ying; Zhang, Xiaoyuan; Yang, Yang; Yang, Xiaohong; Ye, Boping

    2015-08-01

    Hepatic fibrosis is an effusive wound healing process, characterized by an excessive deposition of extracellular matrix (ECM), as the consequence of chronic liver injury of any etiology. Current therapeutic repertoire for hepatic fibrosis is limited to withdrawal of the noxious agent, which is not always feasible. Hence, in this article, the antifibrotic effects and possible mechanisms of r-sHSA, a recombinant protein with hepatoprotection potential, were investigated. Using NIH/3T3 (mouse embro-fibroblast cell line), skin fibroblasts (human skin fibroblasts, SFBs) and HSC-T6 (rat hepatic stellate cell line), the in vitro effect of r-sHSA was evaluated by measuring the expression levels of alpha-1 Type I collagen (Col1A1) and ?-smooth muscle actin (?-SMA). It turned out those fibrosis indicators were typically inhibited by r-sHSA, suggesting its capacity in HSCs inactivation. The antifibrotic activity of r-sHSA was further investigated in vivo on CCl4-induced hepatic fibrosis, in view of significant improvement of the biochemical and histological indicators. More specifically, CCl4-intoxication induced a significant increase in serological biomarkers, e.g., transaminase (AST, ALT), and alkaline phosphatase (ALP), as well as disturbed hepatic antioxidative status; most of the parameters were spontaneously ameliorated to a large extent by withdrawal of CCl4, although the fibrotic lesion was observed histologically. In contrast, r-sHSA treatment markedly eliminated fibrous deposits and restored architecture of the liver in a dose dependent manner, concomitantly with the phenomena of inflammation relief and HSCs deactivation. To sum up, these findings suggest a therapeutic potential for r-sHSA in hepatic fibrosis, though further studies are required. PMID:26295240

  17. Study of Functional and Allosteric Sites in Protein Superfamilies

    PubMed Central

    Suplatov, D.; vedas, V.

    2015-01-01

    The interaction of proteins (enzymes) with a variety of low-molecular-weight compounds, as well as protein-protein interactions, is the most important factor in the regulation of their functional properties. To date, research effort has routinely focused on studying ligand binding to the functional sites of proteins (active sites of enzymes), whereas the molecular mechanisms of allosteric regulation, as well as binding to other pockets and cavities in protein structures, remained poorly understood. Recent studies have shown that allostery may be an intrinsic property of virtually all proteins. Novel approaches are needed to systematically analyze the architecture and role of various binding sites and establish the relationship between structure, function, and regulation. Computational biology, bioinformatics, and molecular modeling can be used to search for new regulatory centers, characterize their structural peculiarities, as well as compare different pockets in homologous proteins, study the molecular mechanisms of allostery, and understand the communication between topologically independent binding sites in protein structures. The establishment of an evolutionary relationship between different binding centers within protein superfamilies and the discovery of new functional and allosteric (regulatory) sites using computational approaches can improve our understanding of the structure-function relationship in proteins and provide new opportunities for drug design and enzyme engineering. PMID:26798490

  18. Structure-function studies on positions 17, 18, and 21 replacement analogues of glucagon: the importance of charged residues and salt bridges in glucagon biological activity.

    PubMed

    Sturm, N S; Lin, Y; Burley, S K; Krstenansky, J L; Ahn, J M; Azizeh, B Y; Trivedi, D; Hruby, V J

    1998-07-16

    We have designed and synthesized eight compounds 2-9 which incorporate various amino acid residues in positions 17, 18, and 21 of the glucagon molecule: 2, [Lys17]glucagon amide; 3, [Lys18]glucagon amide; 4, [Nle17,Lys18,Glu21]glucagon amide; 5, [Orn17,18, Glu21]glucagon amide; 6, [d-Arg17]glucagon; 7, [d-Arg18]glucagon; 8, [d-Phe17]glucagon; and 9, [d-Phe18]glucagon. Compared to glucagon (IC50 = 1.5 nM), analogues 2-9 were found to have binding affinity IC50 values (in nM) of 0.7, 4.1, 1.0, 2.0, 5.0, 25.0, 43.0, and 32.0, respectively. When these compounds were tested for their ability to stimulate adenylate cyclase (AC) activity, they were found to be full or partial agonists having maximum stimulation values of 100, 100, 100, 100, 87, 78, 94, and 100%, respectively. On the basis of the X-ray crystal structure of [Lys17,18,Glu21]glucagon amide reported here, the ability to form a salt bridge between Lys18 and Glu21 is probably key to their increased binding and second messenger activities. Among the eight analogues synthesized here, only analogue 4 preserves the ability to form a salt bridge between Lys18 and Glu21. However, since these modifications are minor they do not seem to change the amphiphilic character of the C-terminus, allowing these analogues to reach 78-100% stimulation in the adenylate cyclase assay. Biological data from analogues 6-9 supports the idea that position 18 of glucagon may influence binding only, while position 17 may influence both receptor recognition and transduction. PMID:9667960

  19. Targeted Melanoma Imaging and Therapy with Radiolabeled Alpha-Melanocyte Stimulating Hormone Peptide Analogues

    PubMed Central

    Quinn, Thomas; Zhang, Xiuli; Miao, Yubin

    2010-01-01

    Radiolabeled alpha-melanocyte stimulating hormone (?-MSH) analogues have been used to define the expression, affinity and function of the melanocortin-1 receptor (MC1-R). The MC1-R is one of a family of five G-protein linker receptors, which is primarily involved in regulation of skin pigmentation. Over-expression of the MC1-R on melanoma tumor cells has made it an attractive target for the development of ?-MSH peptide based imaging and therapeutic agents. Initially, the native ?-MSH peptide was radiolabeled directly, but it suffered from low specific activity and poor stability. The addition of non-natural amino acids yielded ?-MSH analogues with greater MC-1R affinity and stability. Furthermore, peptide cyclization via disulfide and lactam bond formation as well as site-specific metal coordination resulted in additional gains in receptor affinity and peptide stability in vitro and in vivo. Radiochemical stability of the ?-MSH analogues was improved through the conjugation of metal chelators to the peptides N-terminus or lysine residues for radionuclide coordination. In vitro cell binding studies demonstrated that the radiolabeled ?-MSH analogues had low to subnanomolar affinities for the MC1-R. Biodistribution and imaging studies in the B16 mouse melanoma modeled showed rapid tumor uptake of the radiolabeled peptides, with the cyclic peptides demonstrating prolonged tumor retention. Cyclic ?-MSH analogues labeled with beta and alpha emitting radionuclides demonstrated melanoma therapeutic efficacy in the B16 melanoma mouse model. Strong pre-clinical imaging and therapy data highlight the clinical potential use of radiolabeled ?-MSH peptides for melanoma imaging and treatment of disseminated disease. PMID:20467398

  20. Pesticides in roof runoff: study of a rural site and a suburban site.

    PubMed

    Vialle, C; Sablayrolles, C; Silvestre, J; Monier, L; Jacob, S; Huau, M-C; Montrejaud-Vignoles, M

    2013-05-15

    The quality of stored roof runoff in terms of pesticide pollution was assessed over a one-year period. Two tanks, located at a rural and suburban site, respectively, were sampled monthly. The two studied collection surface were respectively a tile slope roof and a bituminous flat roof. Four hundred and five compounds and metabolites were screened using liquid and gas chromatography coupled with various detection systems. Principal Component Analysis was applied to the data sets to elucidate patterns. At the rural site, two groups of compounds associated with two different types of agriculture, vineyard and crops, were distinguished. The most frequently detected compound was glyphosate (83%) which is the most commonly used herbicide in French vineyards. At the suburban site, quantified compounds were linked to agriculture rather than urban practices. In addition, all samples were contaminated with mecoprop which is a roof-protecting agent. Its presence was attributed to the nature of roofing material used for rainwater collection. For both sites, the highest number and concentrations of compounds and metabolites were recorded at the end of spring and through summer. These results are consistent with treatment periods and higher temperatures. PMID:23500648

  1. Polyamine analogues targeting epigenetic gene regulation

    PubMed Central

    Huang, Yi; Marton, Laurence J.; Woster, Patrick M.; Casero, Robert A.

    2013-01-01

    Over the past three decades the metabolism and functions of the polyamines have been actively pursued as targets for antineoplastic therapy. Interactions between cationic polyamines and negatively charged nucleic acids play a pivotal role in DNA stabilization and RNA processing that may affect gene expression, translation and protein activity. Our growing understanding of the unique roles that the polyamines play in chromatin regulation, and the discovery of novel proteins homologous with specific regulatory enzymes in polyamine metabolism, have led to our interest in exploring chromatin remodelling enzymes as potential therapeutic targets for specific polyamine analogues. One of our initial efforts focused on utilizing the strong affinity that the polyamines have for chromatin to create a backbone structure, which could be combined with active-site-directed inhibitor moieties of HDACs (histone deacetylases). Specific PAHAs (polyaminohydroxamic acids) and PABAs (polyaminobenzamides) polyamine analogues have demonstrated potent inhibition of the HDACs, re-expression of p21 and significant inhibition of tumour growth. A second means of targeting the chromatin-remodelling enzymes with polyamine analogues was facilitated by the recent identification of flavin-dependent LSD1 (lysine-specific demethylase 1). The existence of this enzyme demonstrated that histone lysine methylation is a dynamic process similar to other histone post-translational modifications. LSD1 specifically catalyses demethylation of mono- and di-methyl Lys4 of histone 3, key positive chromatin marks associated with transcriptional activation. Structural and catalytic similarities between LSD1 and polyamine oxidases facilitated the identification of biguanide, bisguanidine and oligoamine polyamine analogues that are potent inhibitors of LSD1. Cellular inhibition of LSD1 by these unique compounds led to the re-activation of multiple epigenetically silenced genes important in tumorigenesis. The use of these novel polyamine-based HDAC or LSD1 inhibitors represents a highly promising and novel approach to cancer prevention and therapy. PMID:20095972

  2. RPF151, a novel capsaicin-like analogue: in vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model.

    PubMed

    Ferreira, Adilson Kleber; Tavares, Maurcio Temotheo; Pasqualoto, Kerly Fernanda Mesquita; de Azevedo, Ricardo Alexandre; Teixeira, Sarah Fernandes; Ferreira-Junior, Wilson Alves; Bertin, Ariane Matiello; de-S-Junior, Paulo Luiz; Barbuto, Jos Alexandre Marzago; Figueiredo, Carlos Rogrio; Cury, Yara; Damio, Mariana Celestina Frojuello Costa Bernstorff; Parise-Filho, Roberto

    2015-09-01

    Capsaicin, the primary pungent component of the chili pepper, has antitumor activity. Herein, we describe the activity of RPF151, an alkyl sulfonamide analogue of capsaicin, against MDA-MB-231 breast cancer cells. RPF151 was synthetized, and molecular modeling was used to compare capsaicin and RPF151. Cytotoxicity of RPF151 on MDA-MB-231 was also evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyltetrazolium bromide (MTT) assay. Cell cycle analysis, by flow cytometry, and Western blot analysis of cycle-related proteins were used to evaluate the antiproliferative mechanisms. Apoptosis was evaluated by phosphatidyl-serine externalization, cleavage of Ac-YVAD-AMC, and Bcl-2 expression. The production of reactive oxygen species was evaluated by flow cytometry. RPF151 in vivo antitumor effects were investigated in murine MDA-MB-231 model. This study shows that RPF151 downregulated p21 and cyclins A, D1, and D3, leading to S-phase arrest and apoptosis. Although RPF151 has induced the activation of TRPV-1 and TRAIL-R1/DR4 and TRAIL-2/DR5 on the surface of MDA-MB-231 cells, its in vivo antitumor activity was TRPV-1-independent, thus suggesting that RPF151 should not have the same pungency-based limitation of capsaicin. In silico analysis corroborated the biological findings, showing that RPF151 has physicochemical improvements over capsaicin. Overall, the activity of RPF151 against MDA-MB-231 and its lower pungency suggest that it may have a relevant role in cancer therapy. PMID:25894379

  3. Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: in vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies.

    PubMed

    Tasdemir, Deniz; Kaiser, Marcel; Brun, Reto; Yardley, Vanessa; Schmidt, Thomas J; Tosun, Fatma; Redi, Peter

    2006-04-01

    Trypanosomiasis and leishmaniasis are important parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of flavonoid aglycones and glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for T. brucei rhodesiense was exerted by 7,8-dihydroxyflavone (50% inhibitory concentration [IC50], 68 ng/ml), followed by 3-hydroxyflavone, rhamnetin, and 7,8,3',4'-tetrahydroxyflavone (IC50s, 0.5 microg/ml) and catechol (IC50, 0.8 microg/ml). The activity against T. cruzi was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC50s less than 5.0 microg/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential. Fisetin, 3-hydroxyflavone, luteolin, and quercetin were the most potent, giving IC50s of 0.6, 0.7, 0.8, and 1.0 microg/ml, respectively. 7,8-Dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of 7,8-dihydroxyflavone and quercetin derivatives as potent and effective antiprotozoal agents. PMID:16569852

  4. Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue.

    PubMed

    Panten, U; Zielmann, S; Langer, J; Znkler, B J; Lenzen, S

    1984-04-01

    In mouse pancreatic islets the kinetics of insulin secretion and O2 uptake in response to the non-metabolizable leucine analogue (+/-)-BCH (2-endo- aminonorbornane -2-carboxylic acid) were compared. In addition, the fuel-mobilizing effect of (+/-)-BCH was studied with a mitochondrial fraction from islets. (1) Within 2 min 20 mM-(+/-)-BCH markedly enhanced insulin release or O2 consumption by islets respiring in the absence of exogenous fuels. During prolonged exposure to 20 mM-(+/-)-BCH secretion declined more rapidly than O2 uptake. (2) L-Glutamine (10 mM) prevented the decrease of both insulin release and O2 uptake of islets exposed to 20mM-(+/-)-BCH. During the second phase of insulin release in response to 20 mM-(+/-)-BCH + 10 mM-L-glutamine, kinetics of secretion and respiration correlated closely. (3) Initial peaks were consistently seen in the (+/-)-BCH-induced secretory profiles, but never in the respiratory profiles. (4) In contrast with L-glycerol 3-phosphate, L-malate or pyruvate, L-glutamine or L-glutamate maintained low rates of oxidative phosphorylation in B-cell mitochondria. The effects of L-glutamine or L-glutamate were potentiated severalfold by (+/-)-BCH. (5) The effects of other branched-chain amino acids on oxidative phosphorylation resembled their effects on insulin release, redox state of nicotinamide nucleotides and glutamate dehydrogenase activity. (6) The results support the view that (+/-)-BCH stimulates insulin secretion via a primary enhancement of hydrogen supply to the respiratory chain of B-cell mitochondria. PMID:6372787

  5. Chemical-mechanical coupling observed for depleted oil reservoirs subjected to long-term CO2-exposure - A case study of the Werkendam natural CO2 analogue field

    NASA Astrophysics Data System (ADS)

    Hangx, Suzanne; Bakker, Elisenda; Bertier, Pieter; Nover, Georg; Busch, Andreas

    2015-10-01

    Geological storage of CO2 is one of the most promising technologies to rapidly reduce anthropogenic emissions of carbon dioxide. In order to ensure storage integrity, it is important to understand the effect of long-term CO2/brine/rock interactions on the mechanical behaviour of a storage complex. As most of these reactions are too slow to reproduce on laboratory timescales, we studied a natural CO2 analogue reservoir (the Röt Fringe Sandstone, Werkendam field, the Netherlands; 125-135 Ma of CO2-exposure) and its unreacted counterpart. We focused on CO2-induced mineralogical and porosity-permeability changes, and their effect on mechanical behaviour of both intact rock and simulated fault gouge. Overall, CO2-exposure did not lead to drastic mineralogical changes. The CO2-exposed material shows a stronger dependence of permeability on porosity, which is attributed to differences in diagenesis (closed-system diagenesis and hydrocarbon emplacement) taking place before CO2 charging. The limited extent of reaction was in part the result of bitumen coatings protecting specific mineral phases from reaction. In local, mm-sized zones displaying significant anhydrite cement dissolution, enhanced porosity was observed. For most of the reservoir the long-term mechanical behaviour after CO2-exposure could be described by the behaviour of the unreacted sandstone, while these more 'porous' zones had a lower rock strength. In addition, CO2-exposure did not affect the fault friction behaviour, and slip is expected to result in stable sliding. Simple stress path calculations predict that reservoir failure due to depletion and injection is unlikely, even for the 'porous' zones, nor will fault reactivation occur for realistic injection scenarios.

  6. Adenosine analogues decrease myocardial. beta. -adrenergic receptor affinity for isoproterenol

    SciTech Connect

    Romano, F.D.; Fenton, R.A.; Dobson, J.G. Jr.

    1986-03-05

    Adenosine and its analogues have been shown to attenuate catecholamine-induced activation of adenylate cyclase in rat myocardial membranes via adenosine R/sub i/ (inhibitory) receptors. The effects of adenosine analogues on binding characteristics of ..beta..-adrenergic receptors (BAR) in rat heart ventricular membranes were examined in the present study. Neither phenylisopropyladenosine (PIA, 1..mu..M) nor 2-chloroadenosine (CADO, 10..mu..M) significantly influenced /sup 125/I-cyanopinodolol (ICYP) binding to membranes as assessed by BAR affinity (Kd, 20 pM) or concentration (B/sub max/, 35 fmol/mg protein). However, in isoproterenol (ISO)-ICYP competition experiments, PIA, an R/sub i/ agonist, significantly shifted the ISO competition curve to the right 3.6 fold. The IC/sub 50/s of control and PIA treated membranes were 5.04 x 10/sup -8/M, and 1.81 X 10/sup -7/M respectively. The slope of the control curve (-0.58) was also increased in the PIA treated membranes (-0.94). CADO, a less specific adenosine R/sub i/ receptor agonist, shifted the curve to the right only 2 fold and increased the slope from -0.5 to -0.75. 2',5'-dideoxyadenosine, an adenosine P-site agonist, had no significant effect on ISO binding. These data suggest that adenosine R/sub i/ agonists may attenuate catecholamine-induced activation of adenylate cyclase by decreasing the affinity of BAR for agonists.

  7. [The environment of tRNA 3'-terminus in 80S ribosome A and P sites].

    PubMed

    Bulygin, K N; Baouz-Drahy, S; Favre, A; Ven'iaminova, A G; Grafer, D M; Karpova, G G

    2008-01-01

    The environment of tRNA 3'-terminus in the 80S ribosomal A and P sites was studied with a tRNA(Asp) analogue that bears a 4-thiouridine residue (s4U) attached to the 3'-terminal adenosine. The tRNA(Asp) analogue was obtained by in vitro T7 transcription followed by crosslinking with [32P]ps4Up and removal of the 3'-terminal phosphate. It was shown that the presence of the additional nucleotide at the 3'-end does not to hinder the codon-dependent binding of the tRNA to the A and P sites of 80S ribosome. Mild UV-irradiation of the ribosomal complexes containing a short appropriately designed mRNA and the tRNA analogue resulted in crosslinking of the analogue exclusively to 28S rRNA. The crosslinking was completely dependent on the presence of s4U in the tRNA analogue. Using hydrolysis of the crosslinked 28S rRNA with RNase H in the presence of deoxyoligomers complementary to various rRNA sequences, we determined that the crosslinking occurred in fragment 4302-4540 of the 28S rRNA. This fragment is evolutionarily conservative and belongs to domain V that is involved in the formation of the peptidyl transferase site in prokaryotic ribosomes. The use of reverse transcription allowed the determination of the tRNA analogue crosslinking in the P site to nucleotides U4461 and U4502, and the analogue in the A site, to nucleotides U4469 and C4507. In addition, nucleotide C4462 was crosslinked to both P site and A site-bound tRNA analogue. An analysis of the results demonstrates that environments of the tRNA 3'-termini are closely similar in both prokaryotic and eukaryotic ribosomes. PMID:18365744

  8. Molecular dynamics study of the ribosomal A-site

    PubMed Central

    Romanowska, Julia; Setny, Piotr; Trylska, Joanna

    2009-01-01

    Many aminoglycosidic antibiotics target the A-site of 16S RNA in the small ribosomal subunit and affect the fidelity of protein translation in bacteria. Upon binding aminoglycosides displace two adenines (A1492 and A1493 for E. coli numbering) that are involved in tRNA anticodon loop recognition. The major difference in the aminoglycosidic binding site between the prokaryota and eukaryota is an adenine into guanine substitution in the position 1408. This mutation likely affects the dynamics of near A1492 and A1493 and hinders the binding of aminoglycosides to eukaryotic ribosomes. With multiple 20 ns long all-atom molecular dynamics simulations we study the flexibility of a 22-nucleotide RNA fragment which mimics the aminoglycosidic binding site. Simulations are carried out for both, native and A1408G mutated RNA, as well as for their complexes with aminoglycosidic representative – paromomycin. We observe intra- and extrahelical configurations of A1492 and A1493, which differ between the prokaryotic and the mutated structure. We obtained configurations of the A-site that were also observed in the NMR and crystal structures. Our studies show the differences in the internal mobility of the A-site, as well as in ion and water density distributions inside the binding cleft, between the prokaryotic and mutated RNA. We also compare the performance of two force field parameters for RNA – Amber and Charmm. PMID:18973356

  9. Energy conserving site design case study: Shenandoah, Georgia. Final report

    SciTech Connect

    Not Available

    1980-01-01

    The case study examines the means by which energy conservation can be achieved at an aggregate community level by using proper planning and analytical techniques for a new town, Shenandoah, Georgia, located twenty-five miles southwest of Atlanta's Hartsfield International Airport. A potentially implementable energy conservation community plan is achieved by a study team examining the land use options, siting characteristics of each building type, alternate infrastructure plans, possible decentralized energy options, and central utility schemes to determine how community energy conservation can be achieved by use of pre-construction planning. The concept for the development of mixed land uses as a passively sited, energy conserving community is based on a plan (Level 1 Plan) that uses the natural site characteristics, maximizes on passive energy siting requirement, and allows flexibility for the changing needs of the developers. The Level 2 Plan is identical with Level 1 plan plus a series of decentraized systems that have been added to the residential units: the single-family detached, the apartments, and the townhouses. Level 3 Plan is similar to the Level 1 Plan except that higher density dwellings have been moved to areas adjacent to central site. The total energy savings for each plan relative to the conventional plan are indicated. (MCW)

  10. Theoretical Study of 1,2-Hydride Shift Associated with the Isomerization of Glyceraldehyde to Dihydroxy Acetone by Lewis Acid Active Site Models

    SciTech Connect

    Assary, Rajeev S.; Curtiss, Larry A.

    2011-08-11

    The isomerization of glyceraldehyde to dihydroxy acetone catalyzed by the active site of Sn-beta zeolite is investigated using the B3LYP density functional and MP2 levels of theory. Structural studies were aimed to understanding the binding modes of glyceraldehyde with the active site, and the detailed free energy landscape was computed for the isomerization process. The rate-limiting step for the isomerization is the 1,2-hydride shift, which is enhanced by the active participation of the hydroxyl group in the hydrolyzed Sn-beta active site analogues to the one seen in the xylose isomerase. On the basis of the assessment of the activation barriers for isomerization by the Sn, Zr, Ti, and Si zeolite models, the activity of the catalysts are in the order of Sn > Zr > Ti > Si in aqueous dielectric media.

  11. Theoretical study of 1,2-hydride shift associated with the isomerization of glyceraldehyde to dihydroxy acetone by Lewis acid active site models.

    SciTech Connect

    Assary, R. S.; Curtiss, L. A.

    2011-08-01

    The isomerization of glyceraldehyde to dihydroxy acetone catalyzed by the active site of Sn-beta zeolite is investigated using the B3LYP density functional and MP2 levels of theory. Structural studies were aimed to understanding the binding modes of glyceraldehyde with the active site, and the detailed free energy landscape was computed for the isomerization process. The rate-limiting step for the isomerization is the 1,2-hydride shift, which is enhanced by the active participation of the hydroxyl group in the hydrolyzed Sn-beta active site analogues to the one seen in the xylose isomerase. On the basis of the assessment of the activation barriers for isomerization by the Sn, Zr, Ti, and Si zeolite models, the activity of the catalysts are in the order of Sn > Zr > Ti > Si in aqueous dielectric media.

  12. Analogue to digital transformation

    NASA Astrophysics Data System (ADS)

    1992-12-01

    ESDU 92044 examines the replacement of an analog controller element by an equivalent digital controller element while retaining for the new hybrid system performance characteristics that are acceptably similar to those of the original continuous system. The main features are described of a system containing both analog and digital elements within the same loop, and the analog-to-digital and digital-to-analog components that are then necessarily a part of the system. The frequency response characteristics of transformation are discussed, introducing the problem of aliasing whereby a digital output can be matched by continuous sine waves of different frequencies that are then indistinguishable to the digital sampler. The need to avoid aliasing is considered and the concept of a folding frequency introduced below which aliasing is impossible. Two transformation methods for designing digital filters equivalent to analog filters are discussed: the impulse invariance and bilinear transformations. They are compared by examining digital equivalents of such analogue filters as simple and compound first-order lag and lead filters, second-order lag filters and first-order notch filters. The methods are compared for two sampling rates using Bode plots illustrating the gain and phase variation with frequency. An example based on an electromechanical instrument servo illustrates the transformation of an analog lag-lead controller using the bilinear transformation.

  13. Site Study Plan for soils, Deaf Smith County site, Texas: Environmental Field Program: Preliminary draft

    SciTech Connect

    Not Available

    1987-06-01

    The Soils Site Study Plan describes a field program consisting of a soil characterization survey, impact monitoring of soils, predisturbance soil salinity survey, and a reclamation suitability study. This information will be used to plan for soil stripping, stockpiling, and replacement; reclamation of soils; determining predisturbance chemical and physical characteristics of the soils; including salinity levels; and monitoring for changes in chemical and physical characteristics of the soil. The SSP describes for each study the need for the study, the study design, data management and use, schedule of proposed activities, and the quality assurance program. These studies will provide data needed to satisfy requirements contained in, or derived from, the Salt Repository Project Requirements Document. 75 refs., 10 figs., 5 tabs.

  14. A CASE STUDY ILLUSTRATING THE IMPORTANCE OF ACCURATE SITE CHARACTERIZATION

    EPA Science Inventory

    Too frequently, researchers rely on incomplete site characterization data to determine the placement of the sampling wells. They forget that it is these sampling wells that will be used to evaluate the effectiveness of their research efforts. This case study illustrates the eff...

  15. Microbial studies of a selenium-contaminated mine site and potential for on-site remediation.

    PubMed

    Knotek-Smith, Heather M; Crawford, Don L; Mller, Gregory; Henson, Rachel A

    2006-11-01

    Surface water Selenium (Se) concentrations are above regulatory standards at several active and inactive phosphate mine sites in the US Western Phosphate Resource Area. The focus of the present study was to examine the impacts of the microbial communities on the oxidation state of Se in overburden waste from the Smoky Canyon phosphate mine in Idaho, USA. Microbial populations were found that reduce soluble selenate (SeO (4) (2-) ) to insoluble elemental Se. Microcosm experiments were conducted for molecular genetic analysis of this microbial community by rRNA gene profiling. An acetone pretreatment step was developed to remove interfering pre-petroleum hydrocarbons from the samples prior to extraction. PCR was used to amplify 16S and 18S rRNA genes present in the microbial community DNA. The amplified products were subjected to denaturing gradient gel electrophoresis (DGGE). Isolates and excised DGGE bands were amplified and sequenced for identification to determine the relative importance of culturable isolates to the total microbial population. Analysis of samples from different sites at the mine showed how Se contamination and previous remediation treatments changed the microbial populations across the site. Members of the family Enterobacteriaceae were dominant among the selenate reducing isolates from the site containing high Se levels. In particular, Serratia fonticola was isolated repeatedly from contaminated Smoky Canyon Mine site samples. Packed column studies were performed with seleniferous waste rock fractions from Smoky Canyon Mine. Column amendments consisted of combinations of iron, compost, and whey. Eh, pH, and extractable Se measurements were taken. Tests with infiltrated water showed columns containing an organic amendment combined with iron metal were the most resistant to Se leaching. Iron-based compounds from the corroding metal are thought to strongly bind the Se reduced by microbial activity, thereby stabilizing the Se in an insoluble form. We conclude that long-term stabilization of selenium at contaminated mine sites may require reductive microbial processes combined with abiotic immobilization by iron, either natural or engineered, to stabilize the Se and retard re-oxidation and release. Iron-selenide or iron-selenite compounds are more stable and resistant to leaching, especially when removed from active weathering. PMID:16804682

  16. Trustworthiness and Influence: A Reexamination in an Extended Counseling Analogue.

    ERIC Educational Resources Information Center

    Rothmeier, Rosemarie C.; Dixon, David N.

    1980-01-01

    The study demonstrated that: (1) interviewer trustworthiness can be manipulated in an analogue interview setting; and (2) interviewer trustworthiness is related to interpersonal influence in the interview setting. Findings follow a pattern of outcomes predicted by cognitive dissonance theory. (Author)

  17. Risk perception in context: the Savannah River Site Stakeholder Study.

    PubMed

    Williams, B L; Brown, S; Greenberg, M; Kahn, M A

    1999-12-01

    Environmental managers are increasingly charged with involving the public in the development and modification of policies regarding risks to human health and the environment. Involving the public in environmental decision making first requires a broad understanding of how and why the public perceives various risks. The Savannah River Stakeholder Study was conducted with the purpose of investigating individual, economic, and social characteristics of risk perceptions among those living near the Savannah River Nuclear Weapons Site. A number of factors were found to impact risk perceptions among those living near the site. One's estimated proximity to the site and relative river location surfaced as strong determinants of risk perceptions among SRS residents. Additionally, living in a quality neighborhood and demonstrating a willingness to accept health risks for economic gain strongly abated heightened risk perceptions. PMID:10765444

  18. Mars sample return: Site selection and sample acquisition study

    NASA Technical Reports Server (NTRS)

    Nickle, N. (Editor)

    1980-01-01

    Various vehicle and mission options were investigated for the continued exploration of Mars; the cost of a minimum sample return mission was estimated; options and concepts were synthesized into program possibilities; and recommendations for the next Mars mission were made to the Planetary Program office. Specific sites and all relevant spacecraft and ground-based data were studied in order to determine: (1) the adequacy of presently available data for identifying landing sities for a sample return mission that would assure the acquisition of material from the most important geologic provinces of Mars; (2) the degree of surface mobility required to assure sample acquisition for these sites; (3) techniques to be used in the selection and drilling of rock a samples; and (4) the degree of mobility required at the two Viking sites to acquire these samples.

  19. Wildlife studies on the Hanford site: 1994 Highlights report

    SciTech Connect

    Cadwell, L.L.

    1995-04-01

    The purposes of the project are to monitor and report trends in wildlife populations; conduct surveys to identify, record, and map populations of threatened, endangered, and sensitive plant and animal species; and cooperate with Washington State and federal and private agencies to help ensure the protection afforded by law to native species and their habitats. Census data and results of surveys and special study topics are shared freely among cooperating agencies. Special studies are also conducted as needed to provide additional information that may be required to assess, protect, or manage wildlife resources at Hanford. This report describes highlights of wildlife studies on the Site in 1994. Redd counts of fall chinook salmon in the Hanford Reach suggest that harvest restrictions directed at protecting Snake River salmon may have helped Columbia River stocks as well. The 1994 count (5619) was nearly double that of 1993 and about 63% of the 1989 high of approximately 9000. A habitat map showing major vegetation and land use cover types for the Hanford Site was completed in 1993. During 1994, stochastic simulation was used to estimate shrub characteristics (height, density, and canopy cover) across the previously mapped Hanford landscape. The information provided will be available for use in determining habitat quality for sensitive wildlife species. Mapping Site locations of plant species of concern continued during 1994. Additional sensitive plant species data from surveys conducted by TNC were archived. The 10 nesting pairs of ferruginous hawks that used the Hanford Site in 1993 represented approximately 25% of the Washington State population.

  20. Studies of Potential Mars Surveyor 1998 Landing Sites

    NASA Technical Reports Server (NTRS)

    Herkenhoff, K. E.

    1998-01-01

    The 1998 lander payload consists of a descent imager, the Mars Volatiles and Climate Surveyor (MVACS) instruments (lander stereo camera, arm-mounted close-up imager, meteorology package, thermal and evolved gas analyzer), and a LIDAR instrument. The mission focuses on assessment of near-surface water ice in the south polar region, and the volatile and climate history of Mars. In order to achieve these objectives, the landing site must allow access to polar layered deposits by the robotic arm, which may be able to dig as much as 0.5 m below the surface. Hence, the presence of recent aeolian debris at the landing site may adversely affect the ability of the MVACS instruments to gather the samples and acquire data needed to properly address the science objectives. The studies described here include mapping surface units in the landing region (73S - 77S, 140W - 230W) to infer the distribution of aeolian debris and to identify potential landing sites where mantling is minimal. Because the '98 lander will not be able to survive very low temperature conditions, this study also includes mapping of south polar seasonal frost retreat based on Viking Orbiter images. The results of this work, in conjunction with complementary studies by other investigators, will facilitate the selection of the Mars Surveyor 1998 landing site (and backup) by the summer of 1998.

  1. Syntheses of Cyclotriveratrylene Analogues and Their Long Elusive Triketone Congeners

    PubMed Central

    2015-01-01

    Although interest in cyclotriveratrylene and its analogues has been significant, limitations in the ability to adjust its structure fully have hampered studies into their complete range of properties. A unique strategy to synthesize a previously unobtainable cyclotriveratrylene analogue and a procedure which adjusts the inner methylene bridges of that material to a triketone is reported. A second triketone synthesis and computational studies indicate the parameters needed for success. PMID:24987807

  2. Western Maryland power plant siting study: air-quality assessment of three candidate sites. Final report

    SciTech Connect

    Weil, J.C.; Pierce, T.E.; Corio, L.A.

    1985-01-01

    This report presents the detailed analyses of air-quality impacts related to three candidate sites under consideration in the Western Maryland Power Plant Siting Study. Both EPA-approved and state-of-the-art dispersion models were used to evaluate ground-level concentrations against NAAQS and PSD Class II limits for both flat and elevated terrain areas. Candidate areas are described and stack and fugitive emissions and plant operating parameters are provided. Local meteorological data are used to predict ground-level concentrations for primary stack pollutants, fugitive dust, and fluoride levels. Visibility degradation and cooling-tower moisture effects are also evaluated. PSD Class II limits for SO/sub 2/ could be met at all candidate sites based on state-of-the-art modeling. EPA-approved models indicate that both Washington County options could realize greater potential emissions than the Frederick County option. No difference is anticipated in visible cooling-tower plume frequency, salt deposition, or enhanced icing.

  3. Influence of bulky 3,3'-diphenylalanine enantiomers replacing position 2 of AVP analogues on their conformations: NMR and molecular modeling studies.

    PubMed

    Sikorska, Emilia; Kwiatkowska, Anna; Sobolewski, Dariusz; Slusarz, Rafa?; Slusarz, Magdalena J

    2010-09-01

    In this paper we use NMR spectroscopy and molecular modeling to examine four vasopressin analogues substituted with bulky 3,3'-diphenylalanine (Dpa) enantiomers: [Mpa(1),Dpa(2),Val(4),D-Arg(8)]VP (I), [Mpa(1),D-Dpa(2),Val(4),D-Arg(8)]VP (II), [D-Dpa(2),D-Arg(8)]VP (III) and [Mpa(1),D-Dpa(2)]AVP (IV). All the peptides exhibit a strong and prolonged antidiuretic activity. Additionally, analogues II, III and IV display antiuterotonic activity and analogue II is also a weak V(1a) receptor blocker. The conformational analysis has shown that beta-turns at positions 2,3 and/or 3,4 are characteristic of OT antagonists. In turn, the beta-turn in the Cys(6)-Gly(9) fragment seems to be crucial for enhancement of the antidiuretic activity. The high accessibility of aromatic side chains at positions 2 and 3 plays a crucial role in antagonist-receptor binding. Moreover, orientation of the Phe(3) side chain is claimed to be important for V(1a) receptor affinity. PMID:20580135

  4. Does Nucleos(t)ide Analogues Treatment Affect Renal Function in Chronic Hepatitis B Patients Who Have Already Decreased eGFR? A Longitudinal Study

    PubMed Central

    Tsai, Ming-Chao; Chen, Chien-Hung; Tseng, Po-Lin; Hung, Chao-Hung; Chiu, King-Wah; Chang, Kuo-Chin; Yen, Yi-Hao; Lin, Ming-Tsung; Hu, Tsung-Hui

    2016-01-01

    This study aimed to assess the renal function in chronic hepatitis B (CHB) patients who received nucleos(t)ide analogues (NAs) therapy using estimated glomerular filtration rate (eGFR) titer. We performed a longitudinal observational study of 37 tenofovir-, 42 telbivudine-, and 62 entecavir-naïve CHB patients, who had impaired renal function (eGFR, 90–30 ml/min/1.73m2) without history of diabetes, hypertension, and chemotherapy. Calculation and evaluation of eGFR was performed with the Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Cockcroft-Gault formula at pretreatment, at baseline, and after the 1st and 2nd year of treatment. The eGFR was significantly increased in patients given telbivudine or entecavir (p = 0.003 and p = 0.012, respectively), but the eGFR was decreased in patients given tenofovir (p = 0.001) after 2 years of treatment. Of all patients, eGFR was stable one year prior to treatment. If we analyzed the renal function by change of chronic kidney disease (CKD) category with a change of 25% of eGFR, the proportion of uncertain drop (drop in CKD category with <25% decrease in eGFR) and certain drop (drop in CKD category with ≧25% decrease in eGFR) in tenofovir group was smaller (5.4%) than those of telbivudine (12.9%) or entecavir (6.5%). Furthermore, telbivudine had the lowest stable rate (76.2%), the highest certain rise rate (9.5%), and certain drop rate (7.1%) compared to the other groups (p = 0.049). In conclusion, in NAs-naïve CHB patients with impaired renal function, telbivudine and entecavir resulted in a significant increase in eGFR while tenofovir resulted in a significant decrease after a 2-year treatment. Interestingly, TDF had the lowest proportion of patients reclassified to certain and uncertain drop groups; in contrast, LdT had a higher proportion in both raise and drop groups. The outcomes of this renal effect remain to be determined. PMID:26964034

  5. Scale-integrated spectral characterisation of mineralogical analogues to Mars at Rio Tinto

    NASA Astrophysics Data System (ADS)

    Gleeson, Damhnait; Fernandez-Remolar, David; Martin, Patrick; Moissl, Richard; Ruiz, Vicente

    2013-04-01

    Iron-sulfur assemblages within the Rio Tinto basin of Huelva province in Spain show mineralogical similarities to sites on the surface of Mars as determined by orbital and lander datasets. Exploration of Mars surface environments is intermittent and resolution-limited, and additional layers of information available for terrestrial analogue sites may extend incomplete planetary datasets. Characterising mineralogy in satellite, field and laboratory reflectance spectra of Rio Tinto sites can determine how accurately Mars-relevant mineralogies are represented in orbital data. Comparisons with Mars datasets, such as OMEGA and CRISM, can provide insights into planetary surface conditions. Interaction between materials in field mixtures can lead to potential interferences between endmembers and/or offsets in spectral features, which can obscure or hinder the identification of certain minerals. Such interactions can be difficult to predict on the basis of library spectra collected using pure materials. Determination of which diagnostic spectral features can be identified in field mixtures is an advantage of collecting data in real world environments, and can be used to aid interpretation of planetary datasets. This study utilizes the dynamic sulfur and iron deposits of Rio Tinto as an analogue of Mars sites such as Meridiani Planum, using the many scales of observation available for the terrestrial sites as a means of extending our view of Mars surface conditions from the orbital view to which we are frequently limited.

  6. Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors

    PubMed Central

    2013-01-01

    Background Lipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on Toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was conducted to determine the maximum tolerated dose, the recommended phase II dose and biological response associated with OM-174 administered as intravenous infusion. Methods Patients received OM-174 twice weekly for a total of 5, 10 or 15 injections of either 600, 800 or 1000 ?g/m2. Blood samples for pharmacokinetic analysis and cytokine dosages were collected. NK cells activity and Toll-like receptors 4 polymorphism analysis were also performed. Results Seventeen patients were included. The highest dose administered was 1000 ?g/m2 repeated in 15 injections. The most common toxicities were a chills, fever, nausea/vomiting, diarrhea, fatigue and headache. No patient experienced haematological side effects. As no dose limiting toxicity was observed, despite a grade 3 respiratory complication, the maximal tolerated dose and recommended dose were not established. Three patients exhibited disease stabilization with a mean duration of 4 months. Pharmacokinetic profile of OM-174 was characterized by a low distribution volume and clearance. Analysis of TLR 4 polymorphysm showed that most (16/17) patients carried the wild type alleles. A progressive increase in NK cell number and activity was observed only in patients receiving 1000 ?g/m2 of OM-174. A peak of IL-8 and IL-10 concentrations were observed after each OM-174 injection. Peaks of TNF-alpha and IL-6 concentrations were detected after the first infusion and decreased progressively suggesting tolerance. Conclusion OM-174 therapy was well tolerated at biologically active concentrations. Whereas the recommended dose was not determined, further studies are planned in combination with chemotherapy as animal models suggest a strong synergistic antitumor effect. Trial registration NCT01800812 (ClinicalTrials.gov Identifier). PMID:23547558

  7. Monometallic osmium(II) complexes with bis(N-methylbenzimidazolyl)benzene or -pyridine: a comparison study with ruthenium(II) analogues.

    PubMed

    Shao, Jiang-Yang; Zhong, Yu-Wu

    2013-06-01

    Seven bis-tridentate osmium complexes with Mebib or Mebip (Mebib is the 2-deprotonated form of 1,3-bis(N-methylbenzimidazolyl)benzene and Mebip is bis(N-methylbenzimidazolyl)pyridine) have been prepared, and their electrochemical and spectroscopic properties are compared with ruthenium structural analogues. Among them, four complexes have the [Os(NCN)(NNN)]-type coordination, including [Os(Mebib)(Mebip)](PF6)2 (1(PF6)2), [Os(dpb)(Mebip)](PF6) (2(PF6), dpb is the 2-deprotonated form of 1,3-di(pyrid-2-yl)benzene), [Os(Mebib)(ttpy)](PF6) (3(PF6), ttpy = 4'-tolyl-2,2':6',2"-terpyridine), and [Os(dpb)(ttpy)](PF6) (4(PF6)). The other three complexes are [Os(Mebip)2](PF6)2 (5(PF6)2), [Os(Mebip)(tpy)](PF6)2 (6(PF6)2, tpy = 2,2':6',2"-terpyridine), and [Os(ttpy)2](PF6)2 (7(PF6)2) with the [Os(NNN)(NNN)]-type coordination. Single crystals of 2(PF6) and 6(PF6)2 have been obtained, and their structures are studied by X-ray crystallographic analysis. The Os(II/III) redox potentials of 1(PF6)2 to 7(PF6)2 progressively increase from +0.04, +0.23, +0.24, +0.36, +0.56, +0.79 to +0.94 V vs Ag/AgCl, which are 200-300 mV less positive relative to the Ru(II/III) potentials of their ruthenium counterparts. The highest occupied molecular orbital energy levels of 1(+)-7(2+) are calculated to vary in a descending order. The ruthenium and osmium complexes have singlet metal-to-ligand charge-transfer (MLCT) transitions of similar energies and band shapes, while the osmium complexes display additional (3)MLCT transitions in the lower-energy region. Complexes 6(PF6)2 and 7(PF6)2 emit weakly at 780 and 740 nm, respectively. Complex 1(PF6)2 was synthesized as the oxidized Os(III) salt because of the low Os(II/III) potential. The transformation of 1(2+) to 1(+) by chemical reduction or electrolysis led to the emergence of the (1)MLCT transitions in the visible region. PMID:23688019

  8. Behavior-based safety on construction sites: a case study.

    PubMed

    Choudhry, Rafiq M

    2014-09-01

    This work presents the results of a case study and describes an important area within the field of construction safety management, namely behavior-based safety (BBS). This paper adopts and develops a management approach for safety improvements in construction site environments. A rigorous behavioral safety system and its intervention program was implemented and deployed on target construction sites. After taking a few weeks of safety behavior measurements, the project management team implemented the designed intervention and measurements were taken. Goal-setting sessions were arranged on-site with workers' participation to set realistic and attainable targets of performance. Safety performance measurements continued and the levels of performance and the targets were presented on feedback charts. Supervisors were asked to give workers recognition and praise when they acted safely or improved critical behaviors. Observers were requested to have discussions with workers, visit the site, distribute training materials to workers, and provide feedback to crews and display charts. They were required to talk to operatives in the presence of line managers. It was necessary to develop awareness and understanding of what was being measured. In the process, operatives learned how to act safely when conducting site tasks using the designed checklists. Current weekly scores were discussed in the weekly safety meetings and other operational site meetings with emphasis on how to achieve set targets. The reliability of the safety performance measures taken by the company's observers was monitored. A clear increase in safety performance level was achieved across all categories: personal protective equipment; housekeeping; access to heights; plant and equipment, and scaffolding. The research reveals that scores of safety performance at one project improved from 86% (at the end of 3rd week) to 92.9% during the 9th week. The results of intervention demonstrated large decreases in unsafe behaviors and significant increases in safe behaviors. The results of this case study showed that an approach based on goal setting, feedback, and an effective measure of safety behavior if properly applied by committed management, can improve safety performance significantly in construction site environments. The results proved that the BBS management technique can be applied to any country's culture, showing that it would be a good approach for improving the safety of front-line workers and that it has industry wide application for ongoing construction projects. PMID:24686162

  9. Geophysical study of the Peinan Archaeological Site, Taiwan

    NASA Astrophysics Data System (ADS)

    Tong, Lun-Tao; Lee, Kun-Hsiu; Yeh, Chang-Keng; Hwang, Yan-Tsong; Chien, Jeng-Ming

    2013-02-01

    The Peinan archaeological site is the most intact Neolithic village with slate coffin burial complexes in Taiwan. However, the area that potentially contains significant ancient remains is covered by dense vegetation. No reliable data show the distribution of the ancient village, and no geophysical investigation has been performed at this site. To evaluate various geophysical methods under the geological setting and surface condition of the site, the physical properties of the remains were measured and four geophysical methods involving magnetic, electromagnetic (EM), electrical resistivity tomography (ERT), and ground-penetrating radar (GPR) were tested along three parallel profiles. The results imply that the EM and magnetic methods are much cost-effective and suitable for investigating the entire area. GPR and ERT methods can provide high resolution subsurface image, which are much suitable for subsequently detail investigation. The EM and magnetic surveys were thus conducted over the entire Peinan Cultural Park to understand the distribution of the ancient building remains at the Peinan site. The results of this study were verified by subsequent excavations, which indicate that the EM survey was successful in delineating the majority of the ancient village because the basements of building are highly resistive in comparison to the background sediment. The results of this investigation suggest that the ancient village was broadly distributed over the eastern part of the Peinan Culture Park and extended to the southeast.

  10. Nevada Test Site tortoise population monitoring study. Final report

    SciTech Connect

    Mueller, J.M.; Zander, K.K.

    1994-12-01

    A Tortoise Population Monitoring Study was initiated to determine and monitor the density of desert tortoises (Gopherus agassizii) on the Nevada Test Site. Quadrat sampling was conducted following methodology described in the Draft Desert Tortoise Recovery Plan (FWS, 1993). So few tortoises were found that densities could not be calculated. Based on estimates of capture probabilities and densities from other studies, it was determined that 1-km{sup 2} (0.4 mi{sup 2}) plots did not contain enough tortoises for estimating densities with the Recovery Plan methods. It was recommended that additional surveys on the Nevada Test Site using those methods not be conducted. Any future efforts to monitor desert tortoise densities should start by identifying other possible methods, determining their relative power to detect changes, and estimating their cost.

  11. Somatostatin Analogues for Receptor Targeted Photodynamic Therapy

    PubMed Central

    Ka?kov, Slvka; Hofland, Leo J.; De Bruijn, Henriette S.; Ye, Yunpeng; Achilefu, Samuel; van der Wansem, Katy; van der Ploeg-van den Heuvel, Angelique; van Koetsveld, Peter M.; Brugts, Michael P.; van der Lelij, Aart-Jan; Sterenborg, Henricus J. C. M.; ten Hagen, Timo L. M.; Robinson, Dominic J.; van Hagen, Martin P.

    2014-01-01

    Photodynamic therapy (PDT) is an established treatment modality, used mainly for anticancer therapy that relies on the interaction of photosensitizer, light and oxygen. For the treatment of pathologies in certain anatomical sites, improved targeting of the photosensitizer is necessary to prevent damage to healthy tissue. We report on a novel dual approach of targeted PDT (vascular and cellular targeting) utilizing the expression of neuropeptide somatostatin receptor (sst2) on tumor and neovascular-endothelial cells. We synthesized two conjugates containing the somatostatin analogue [Tyr3]-octreotate and Chlorin e6 (Ce6): Ce6-K3-[Tyr3]-octreotate (1) and Ce6-[Tyr3]-octreotate-K3-[Tyr3]-octreotate (2). Investigation of the uptake and photodynamic activity of conjugates in-vitro in human erythroleukemic K562 cells showed that conjugation of [Tyr3]-octreotate with Ce6 in conjugate 1 enhances uptake (by a factor 2) in cells over-expressing sst2 compared to wild-type cells. Co-treatment with excess free Octreotide abrogated the phototoxicity of conjugate 1 indicative of a specific sst2-mediated effect. In contrast conjugate 2 showed no receptor-mediated effect due to its high hydrophobicity. When compared with un-conjugated Ce6, the PDT activity of conjugate 1 was lower. However, it showed higher photostability which may compensate for its lower phototoxicity. Intra-vital fluorescence pharmacokinetic studies of conjugate 1 in rat skin-fold observation chambers transplanted with sst2+ AR42J acinar pancreas tumors showed significantly different uptake profiles compared to free Ce6. Co-treatment with free Octreotide significantly reduced conjugate uptake in tumor tissue (by a factor 4) as well as in the chamber neo-vasculature. These results show that conjugate 1 might have potential as an in-vivo sst2 targeting photosensitizer conjugate. PMID:25111655

  12. Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

    PubMed Central

    Shrestha, Sanjib K.; Fosso, Marina Y.; Green, Keith D.

    2015-01-01

    In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6″-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C12 and C14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C4, C6, and C8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC50s) for the most potent TOB analogues (C12 and C14) against A549 and Beas 2B cells were 4- to 64-fold and 32- to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C12 and C14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs. PMID:26033722

  13. Similarity in drugs: reflections on analogue design.

    PubMed

    Wermuth, Camille G

    2006-04-01

    A survey of novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition implies that the analogue of an existing drug molecule shares structural and pharmacological similarities with the original compound. Formally, this definition allows the establishment of three categories of drug analogues: analogues possessing chemical and pharmacological similarities (direct analogues); analogues possessing structural similarities only (structural analogues); and chemically different compounds displaying similar pharmacological properties (functional analogues). PMID:16580977

  14. Antimicrobial activity of resveratrol analogues.

    PubMed

    Chalal, Malik; Klinguer, Agns; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle

    2014-01-01

    Stilbenes, especially resveratrol and its derivatives, have become famous for their positive effects on a wide range of medical disorders, as indicated by a huge number of published studies. A less investigated area of research is their antimicrobial properties. A series of 13 trans-resveratrol analogues was synthesized via Wittig or Heck reactions, and their antimicrobial activity assessed on two different grapevine pathogens responsible for severe diseases in the vineyard. The entire series, together with resveratrol, was first evaluated on the zoospore mobility and sporulation level of Plasmopara viticola (the oomycete responsible for downy mildew). Stilbenes displayed a spectrum of activity ranging from low to high. Six of them, including the most active ones, were subsequently tested on the development of Botrytis cinerea (fungus responsible for grey mold). The results obtained allowed us to identify the most active stilbenes against both grapevine pathogens, to compare the antimicrobial activity of the evaluated series of stilbenes, and to discuss the relationship between their chemical structure (number and position of methoxy and hydroxy groups) and antimicrobial activity. PMID:24918540

  15. Site study plan for exploratory shaft monitoring wells, Deaf Smith County Site, Texas: Preliminary Draft

    SciTech Connect

    Not Available

    1988-01-01

    As part of site characterization studies, two exploratory shafts will be constructed at the Deaf Smith County site, Texas. Twelve wells at five locations have been proposed to monitor potential impacts of shaft construction on water-bearing zones in the Ogallala Formation and the Dockum Group. In addition, tests have been proposed to determine the hydraulic properties of the water-bearing zones for use in design and construction of the shafts. Samples of the Blackwater Draw Formation, Ogallala Formation, and Dockum Group will be obtained during construction of these wells. Visual indentification, laboratory testing, and in situ testing will yield data necessary for Exploratory Shaft Facility design and construction. This activity provides the earliest data on the Blackwater Drew Formation, Ogallala Formation, and Dockum Group near the exploratory shaft locations. Drilling and hydrologic testing are scheduled prior to other subsurface activity at the Exploratory Shaft Facility to establish ground-water baseline conditions. The Technical Field Services Contractor is responsible for conducting the field program of drilling and testing. Samples and data will be handled and reported in accordance with established Salt Repository Project procedures. A quality assurance program will be utilized to assure that activities affecting quality are performed correctly and that the appropriate documentation is maintained. 45 refs., 11 figs., 4 tabs.

  16. Summary of 1990 eolian characterization studies, Hanford Site, Washington

    SciTech Connect

    Gaylord, D.R.; Stetler, L.D.; Smith, G.D.; Mars, R.W.

    1993-12-01

    A study of eolian activity was initiated to improve understanding of past climate change and the likely effect of wind on engineered protective barriers at the Hanford Site. Eolian features from a Holocene sand dune field located in the southeastern portion of the Hanford Site were investigated using a variety of field and laboratory techniques including stratigraphic examinations of hand-dug pits, textural and compositional analyses of dune sand and potential source detritus, and air photo interpretations. These investigations were undertaken to evaluate the provenance and eolian dynamics of the sand dunes. Interpretations of sand dune migration using archival air photo stereopairs document a 20% reduction in the volume of active sand dunes (measured from an approximate 15-km{sup 2} test area) between 1948 and 1987. Changes in annual precipitation appear to have influenced active dune migration strongly.

  17. Synthesis and biological evaluation of novel 4,5-disubstituted 2H-1,2,3-triazoles as cis-constrained analogues of combretastatin A-4.

    PubMed

    Madadi, Nikhil R; Penthala, Narsimha R; Howk, Kevin; Ketkar, Amit; Eoff, Robert L; Borrelli, Michael J; Crooks, Peter A

    2015-10-20

    A series of combretastatin A-4 (CA-4) analogues have been prepared from (Z)-substituted diarylacrylonitriles (1a-1p) obtained in a two-step synthesis from appropriate arylaldehydes and acrylonitriles. The resulting 4,5-disubstituted 2H-1,2,3-triazoles were evaluated for their anti-cancer activities against a panel of 60 human cancer cell lines. The diarylacrylonitrile analogue 2l exhibited the most potent anti-cancer activity in the screening studies, with GI₅₀ values of <10 nM against almost all the cell lines in the human cancer cell panel and TGI values of <10 nM against cancer cell lines SF-539, MDA-MB-435, OVCAR-3 and A498. Furthermore, in silico docking studies of compounds 2l, 2e and 2h within the active site of tubulin were carried out in order to rationalize the mechanism of the anti-cancer properties of these compounds. From the in silico studies, compound 2e was predicted to have better affinity for the colchicine binding site on tubulin compared to compounds 2l and 2h. Analogue 2e was also evaluated for its anti-cancer activity by colony formation assay against 9LSF rat gliosarcoma cells and afforded an LD₅₀ of 7.5 nM. A cell cycle redistribution assay using analogue 2e was conducted to further understand the mechanism of action of these CA-4 analogues. From this study, analogues 2e and 2l were the most potent anti-cancer agents in this structural class, and were considered lead compounds for further development as anti-cancer drugs. PMID:26352674

  18. Polyamine Analogues Bind Human Serum Albumin

    PubMed Central

    Beauchemin, R.; Nsoukpo-Kossi, C. N.; Thomas, T. J.; Thomas, T.; Carpentier, R.; Tajmir-Riahi, H. A.

    2008-01-01

    Polyamine analogues show antitumor activity in experimental models and their ability to alter activity of cytotoxic chemotherapeutic agents in breast cancer is well documented. Association of polyamines with nucleic acids and protein is included in their mechanism of action. The aim of this study was to examine the interaction of human serum albumin (HSA) with several polyamine analogues such as 1,11-diamino-4,8-diazaundecane (333), 3,7,11,15-tetrazaheptadecane.4HCl (BE-333) and 3,7,11,15,19-pentazahenicosane.5HCl (BE-3333) in aqueous solution at physiological conditions, using a constant protein concentration and various polyamine contents (?M to mM). FTIR, UV-visible and CD spectroscopic methods were used to determine the polyamine binding mode and the effects of polyamine complexation on protein stability and secondary structure. Structural analysis showed that polyamines bind non-specifically (H-bonding) via polypeptide polar groups with binding constants of K333 = 9.30 103 M?1, KBE-333 = 5.63 102 M?1 and KBE-3333 = 3.66 102 M?1. The protein secondary structure showed major alterations with reduction of ?-helix from 55% (free protein) to 4350% and increase of ?-sheet from 17% (free protein) to 2936% in the 333-, BE-333- and BE-3333 complexes, indicating a partial protein unfolding upon polyamine interaction. HSA structure was less perturbed by polyamine analogues than those of the biogenic polyamines. PMID:17887793

  19. Thymidine analogues for tracking DNA synthesis.

    PubMed

    Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B

    2011-01-01

    Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored. PMID:21921870

  20. [Paleoclimatology studies for Yucca Mountain site characterization]. Final report

    SciTech Connect

    1996-05-03

    This report consists of two separate papers: Fernley Basin studies; and Influence of sediment supply and climate change on late Quaternary eolian accumulation patterns in the Mojave Desert. The first study involved geologic mapping of late Quaternary sediments and lacustrine features combined with precise control of elevations and descriptions of sediments for each of the major sedimentary units. The second paper documents the response of a major eolian sediment transport system in the east-central Mojave Desert: that which feeds the Kelso Dune field. Information from geomorphic, stratigraphic, and sedimentologic studies of eolian deposits and landforms is combined with luminescence dating of these deposits to develop a chronology of periods of eolian deposition. Both studies are related to site characterization studies of Yucca Mountain and the forecasting of rainfall patterns possible for the high-level radioactive waste repository lifetime.

  1. Synthetic studies on glycosphingolipids from Protostomia phyla: synthesis of amphoteric glycolipid analogues containing a phosphocholine residue from the earthworm Pheretima hilgendorfi.

    PubMed

    Hada, N; Sato, K; Sakushima, J I; Goda, Y; Sugita, M; Takeda, T

    2001-11-01

    Two kinds of amphoteric glycosphingolipid analogues from the earthworm Pheretima hilgendorfi were synthesized as follows: The key reaction is a coupling of a phosphocholine group at the position C-6 of 1 and 6 which was attempted using 2-chloro-2-oxo-1,3,2-dioxaphospholane, followed by reaction of the resulting cyclic phosphate intermediate with anhydrous trimethylamine to give 2 and 7. Subsequent debenzylation afforded target compounds (3, 8). Their ability to inhibit the histamine release in vitro was examined. PMID:11724239

  2. Analogue Missions on Earth, a New Approach to Prepare Future Missions on the Moon

    NASA Astrophysics Data System (ADS)

    Lebeuf, Martin

    Human exploration of the Moon is a target by 2020 with an initial lunar outpost planned in polar regions. Current architectures maintain a capability for sorties to other latitudes for science activities. In the early stages of design of lunar outpost infrastructure and science activity planning, it has been recognized that analogue missions could play a major role in Moon mission design. Analogue missions, as high fidelity simulations of human and robotic surface operations, can help field scientists and engineers develop and test strategies as well as user requirements, as they provide opportunities to groundtruth measurements, and for the team to share understanding of key science needs and key engineering trades. These types of missions also provide direct training in planning science operations, and in team building and communication. The Canadian Space Agency's Exploration Core Program targets the development of technology infrastructure elements in key areas of science, technology and robotics in preparation for its role in the future exploration of the Moon and Mars. Within this Program, Analogue Missions specifically target the operations requirements and lessons learned that will reduce costs and lower the risk of planetary surface missions. Analogue missions are simulations of planetary surface operations that take place at analogue sites on Earth. A terrestrial analogue site resembles in some key way: eg. geomorphologically or geochemically, a surface environment of another planet. An analogue mission can, therefore, be defined as an integrated set of activities that represent (or simulate) entire mission designs or narrowly focus on specific aspects of planned or potential future planetary exploration missions. Within the CSA's Exploration Core Program, Analogue Missions facilitate the maturation of science instruments and mission concepts by integrating ongoing space instrument and technology development programs with science and analogue elements. As well as using analogue missions to meet agency programmatic needs, the Canadian Space Agency encourages scientists and engineers to make use of opportunities presented by analogue missions to further their own research objectives. Specific objectives of Analogue Missions are to (1) foster a multidisciplinary approach to planning, data acquisition, processing and interpretation, calibration of instruments, and telemetry during mission operations; (2) integrate new science with emerging technologies; and (3) develop an expertise on exploration architecture design from projects carried out at terrestrial analogue sites. Within Analogue Missions, teams develop planning tools, use mission-specific software and technology, and communicate results as well as lessons learned during tactical operations. The expertise gained through Analogue Missions will contribute to inform on all aspects of exploration architectures, including planetary mobility requirements and astronaut training.

  3. Ecosystem studies at the Los Medanos site, Eddy County, New Mexico. Volume I

    SciTech Connect

    Hart, J.S.

    1981-05-01

    This report summarizes the results of biological studies conducted during 1980 at the Los Medanos site in southeastern New Mexico. The studies include: (1) densities and species composition of the avifauna of the Los Medanos site; (2) aquatic ecosystems of the lower Pecos drainage; (3) floristic studies at the Los Medanos site; (4) plant successional, grazing, trampling, and salt studies on the Los Medanos site; (5) soil and vegetation studies at the Los Medanos site; (6) arthropod and decomposition studies at the WIPP site; (7) amphibians, reptiles and mammals at the Los Medanos site; (8) vertebrate ecology at the Los Medanos site; and (9) statistical analysis and data management. 7 refs. (ACR)

  4. Outcrop analogue study of Permocarboniferous geothermal sandstone reservoir formations (northern Upper Rhine Graben, Germany): impact of mineral content, depositional environment and diagenesis on petrophysical properties

    NASA Astrophysics Data System (ADS)

    Aretz, Achim; Bär, Kristian; Götz, Annette E.; Sass, Ingo

    2015-11-01

    The Permocarboniferous siliciclastic formations represent the largest hydrothermal reservoir in the northern Upper Rhine Graben in SW Germany and have so far been investigated in large-scale studies only. The Cenozoic Upper Rhine Graben crosses the Permocarboniferous Saar-Nahe Basin, a Variscan intramontane molasse basin. Due to the subsidence in this graben structure, the top of the up to 2-km-thick Permocarboniferous is located at a depth of 600-2900 m and is overlain by Tertiary and Quaternary sediments. At this depth, the reservoir temperatures exceed 150 °C, which are sufficient for geothermal electricity generation with binary power plants. To further assess the potential of this geothermal reservoir, detailed information on thermophysical and hydraulic properties of the different lithostratigraphical units and their depositional environment is essential. Here, we present an integrated study of outcrop analogues and drill core material. In total, 850 outcrop samples were analyzed, measuring porosity, permeability, thermal conductivity and thermal diffusivity. Furthermore, 62 plugs were taken from drillings that encountered or intersected the Permocarboniferous at depths between 1800 and 2900 m. Petrographic analysis of 155 thin sections of outcrop samples and samples taken from reservoir depth was conducted to quantify the mineral composition, sorting and rounding of grains and the kind of cementation. Its influence on porosity, permeability, the degree of compaction and illitization was quantified. Three parameters influencing the reservoir properties of the Permocarboniferous were detected. The strongest and most destructive influence on reservoir quality is related to late diagenetic processes. An illitic and kaolinitic cementation and impregnation of bitumina document CO2- and CH4-rich acidic pore water conditions, which are interpreted as fluids that migrated along a hydraulic contact from an underlying Carboniferous hydrocarbon source rock. Migrating oil and acidic waters led to the dissolution of haematite cements in the lower Permocarboniferous formations. During the Eocene, subsidence of the Upper Rhine Graben porosities and permeabilities of the sandstones of these formations were strongly reduced to 2.5 % and 3.2 × 10-18 m2. The second important influence on reservoir quality is the distinct depositional environment and its influence on early diagenetic processes. In early stage diagenesis, the best influence on reservoir properties exhibits a haematite cementation. It typically occurs in eolian sandstones of the Kreuznach Formation (Upper Permocarboniferous) and is characterized by grain covering haematite coatings, which are interpreted to inhibit cementation, compaction and illitization of pore space during burial. Eolian sandstones taken from outcrops and reservoir depths exhibit the highest porosities (16.4; 12.3 %) and permeabilities (2.0 × 10-15; 8.4 × 10-16 m2). A third important influence on reservoir quality is the general mineral composition and the quartz content which is the highest in the Kreuznach Formation with 73.8 %. Based on the integrated study of depositional environments and diagenetic processes, reservoir properties of the different Permocarboniferous formations within the northern Upper Rhine Graben and their changes with burial depth can be predicted with satisfactory accuracy. This leads to a better understanding of the reservoir quality and enables an appropriate well design for exploration and exploitation of these geothermal resources.

  5. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    It is always exciting when developments in one branch of physics turn out to have relevance in a quite different branch. It would be hard to find two branches farther apart in terms of energy scales than early-universe cosmology and low-temperature condensed matter physics. Nevertheless ideas about the formation of topological defects during rapid phase transitions that originated in the context of the very early universe have proved remarkably fruitful when applied to a variety of condensed matter systems. The mathematical frameworks for describing these systems can be very similar. This interconnection has led to a deeper understanding of the phenomena in condensed matter systems utilizing ideas from cosmology. At the same time, one can view these condensed matter analogues as providing, at least in a limited sense, experimental access to the phenomena of the early universe for which no direct probe is possible. As this special issue well illustrates, this remains a dynamic and exciting field. The basic idea is that when a system goes through a rapid symmetry-breaking phase transition from a symmetric phase into one with spontaneously broken symmetry, the order parameter may make different choices in different regions, creating domains that when they meet can trap defects. The scale of those domains, and hence the density of defects, is constrained by the rate at which the system goes through the transition and the speed with which order parameter information propagates. This is what has come to be known as the Kibble-Zurek mechanism. The resultant scaling laws have now been tested in a considerable variety of different systems. The earliest experiments illustrating the analogy between cosmology and condensed matter were in liquid crystals, in particular on the isotropic-to-nematic transition, primarily because it is very easy to induce the phase transition (typically at room temperature) and to image precisely what is going on. This field remains one of the liveliest. A number of new experiments are reported here studying the dynamical evolution of domains and defects. Another phenomenon that played a key early role was the formation of vortices in the normal-to-superfluid transition in liquid helium-3. The complicated nature of the order parameter energy surface gives rise to a variety of intriguing effects. This too is still a vigorous field. Superconductivity is a special case because the symmetry that is broken is a gauge symmetry. This is also true in fundamental particle physics theories of relevance to cosmology, and for that reason experiments on superconductors are of particular interest to cosmologists. The situation in this case is more complicated because there are competing mechanisms of defect formation. Experiments in the field have not proved easy, either to perform or to interpret, but the papers in this collection show that good progress has been made of late. In recent years a new type of system has proved immensely fruitful, namely atomic Bose-Einstein or Fermi-gas condensates. Experiments on condensates with tunable parameters have in general provided broad support for the theory, and have also revealed a wide range of interesting and novel features, with intriguing possible analogues in cosmology (e.g. causal horizons and particle creation). The basic idea of the Kibble-Zurek mechanism has been shown to be relevant in this whole range of systems. But numerous complexities have also emerged, concerned for example with the role of inhomogeneity or the existence of composite defects. The field is still developing rapidly. Acknowledgments Finally, we would like to thank all the authors who have contributed to this issue, and the staff of Journal of Physics: Condensed Matter who have made it possible. Condensed matter analogues of cosmology contents Condensed matter analogues of cosmologyTom Kibble and Ajit Srivastava Symmetry breaking in nematic liquid crystals: analogy with cosmology and magnetismR Repnik, A Ranjkesh, V Simonka, M Ambrozic, Z Bradac and S Kralj Morphogenesis of defects and tactoids during isotropic-nematic phase transition in self-assembled lyotropic chromonic liquid crystalsYoung-Ki Kim, Sergij V Shiyanovskii and Oleg D Lavrentovich Annihilation dynamics of stringlike topological defects in a nematic lyotropic liquid crystalR R Guimares, R S Mendes, P R G Fernandes and H Mukai Duality between the dynamics of line-like brushes of point defects in 2D and strings in 3D in liquid crystalsSanatan Digal, Rajarshi Ray, P S Saumia and Ajit M Srivastava The multiuniverse transition in superfluid 3HeYury Bunkov Coherent topological defect dynamics and collective modes in superconductors and electronic crystalsD Mihailovic, T Mertelj, V V Kabanov and S Brazovskii Gaussianity revisited: exploring the Kibble-Zurek mechanism with superconducting ringsD J Weir, R Monaco, V P Koshelets, J Mygind and R J Rivers The Kibble-Zurek mechanism in a subcritical bifurcationM A Miranda, D Laroze and W Gonzlez-Vias Topological relics of symmetry breaking: winding numbers and scaling tilts from random vortex-antivortex pairsW H Zurek Causality and non-equilibrium second-order phase transitions in inhomogeneous systemsA del Campo, T W B Kibble and W H Zurek The role of causality in tunable Fermi gas condensatesJen-Tsung Hsiang, Chi-Yong Lin, Da-Shin Lee and Ray J Rivers Kibble-Zurek mechanism in a trapped ferromagnetic Bose-Einstein condensateHiroki Saito, Yuki Kawaguchi and Masahito Ueda D-brane solitons and boojums in field theory and Bose-Einstein condensatesKenichi Kasamatsu, Hiromitsu Takeuchi and Muneto Nitta Kibble-Zurek scaling and string-net coarsening in topologically ordered systemsAnushya Chandran, F J Burnell, Vedika Khemani and S L Sondhi Universal frozen spectra after time-dependent symmetry restoring phase transitionsFriedemann Queisser, Patrick Navez and Ralf Schtzhold Microscopic theory of non-adiabatic response in real and imaginary timeC De Grandi, A Polkovnikov and A W Sandvik

  6. Theoretical and structural analysis of the active site of the transcriptional regulators LasR and TraR, using molecular docking methodology for identifying potential analogues of acyl homoserine lactones (AHLs) with anti-quorum sensing activity.

    PubMed

    Ahumedo, Maicol; Daz, Antonio; Vivas-Reyes, Ricardo

    2010-02-01

    In the present study the homology of transcriptional receptors LuxR type were evaluated using as point of reference the receptors TraR and LasR of the bacterial types Agrobacterium tumefaciens and Pseudomonas aureginosa respectively. A series of alignments were performed in order to demonstrate that the active site of the protein is conserved in wide range of gram negative bacteria. Moreover, some docking calculations were carried out for analogs of the acyl homoserin lactones (AHLs) and regulatory proteins LasR and TraR, to understand the complex microenvironment in which the ligands are exposed. The molecular alignments show clearly that there are preserved motifs in the residues (Y53, Y61, W57, D70, W85 to TraR, Y56, Y64, W60, D73, W88 to LasR) analyzed, which may serve as site-specific targets for the development of potential antagonists. In this study was found that the anti-quorum sensing activity of the AHLs molecular analogs appears to depend on; the structure of the lactone ring and on appropriate combination of absolute and relative stereochemistry of the carbonyl (C=O) and amide (NH(2)) groups of the side chain of these AHLs molecular analogs, in combination with the interactions with the conserved amino acids (D73, W60, Y56, S129 to LasR and D70, W57, Y53 to TraR) of the LuxR type protein family. PMID:19945196

  7. Yucca Mountain Site Characterization Project exploratory studies facilities construction status

    SciTech Connect

    Allan, J.N.; Leonard, T.M.

    1993-12-31

    This paper discusses the progress to date on the construction planning and development of the Yucca Mountain Site Characterization Project (YMP) Exploratory Studies Facilities (ESF). The purpose of the ESF is to determine early site suitability and to characterize the subsurface of the Yucca Mountain site to assess its suitability for a potential high level nuclear waste repository. The present ESF configuration concept is for two main ramps to be excavated by tunnel boring machines (TBM) from the surface to the Topopah Spring Member of the Paintbrush Tuff Formation. From the main ramps, slightly above Topopah Spring level, supplemental ramps will be penetrated to the Calico Hills formation below the potential repository. There will be exploratory development drifts driven on both levels with the Main Test Area being located on the Topopah Spring level, which is the level of the proposed repository. The Calico Hills formation lies below the Topopah Spring member and is expected to provide the main geo-hydrologic barrier between the potential repository and the underlying saturated zones in the Crater Flat Tuff.

  8. Antitumor Potential of Conjugable Valinomycins Bearing Hydroxyl Sites: In Vitro Studies

    PubMed Central

    2013-01-01

    Following our pioneering studies on the direct and efficient introduction of derivatizable hydroxyl handles into the valinomycin (VLM, 1) structure, a K+-ionophore with potent antitumor activity, the ensuing conjugable analogues (HyVLMs 2, 3, and 4) have herein been compared to the parent macrocycle for their potential antiproliferative effects on a panel of cancer cell lines, namely, human MCF-7, A2780, and HepG2, as well as rat C6 cells. On the basis of IC50 values, we find that hydroxyl analogues 3 and 4 are only moderately less active than 1, while analogue 2 experiences a heavily diminished activity. Cytofluorimetric analyses of MCF-7 cells treated with HyVLMs suggest that the latter depolarize mitochondria, thus retaining the typical VLM behavior. It is likely that C6 cells, for which the exceptionally potent cytotoxicity of VLM has never reported previously, follow the same fate, as evidenced by alteration of mitochondrial morphology upon incubation with each ionophore. PMID:24900628

  9. Hanford Site Annual Treatability Studies Report, Calendar Year 2002

    SciTech Connect

    Grohs, Eugene L.

    2003-02-28

    This report provides information required to be reported annually by the Washington Administrative Code (WAC) 173-303-071 (3)(r)(ii)(F) and (3)(s)(ix) on the treatability studies conducted on the Hanford Site in 2002. These studies were conducted as required by WAC 173-303-071, “Excluded Categories of Waste,” sections (3)(r) and (s). Unless otherwise noted, the waste samples were provided by and the treatability studies were performed for the U.S. Department of Energy, Richland Operations Office, P.O. Box 550, Richland, Washington 99352. The U.S. Environmental Protection Agency identification number for these studies is WA7890008967.

  10. Structure-activity relationship (SAR) studies of benzoxazinones, their degradation products, and analogues. Phytotoxicity on problematic weeds Avena fatua L. and Lolium rigidum Gaud.

    PubMed

    Macas, Francisco A; Marn, David; Oliveros-Bastidas, Alberto; Castellano, Diego; Simonet, Ana M; Molinillo, Jos M G

    2006-02-22

    Avena fatua L. (wild oat) and Lolium rigidum Gaud. (rigid ryegrass) are highly problematic weeds affecting a wide variety of cereal crops worldwide. The fact that both of these weeds have developed resistance to several herbicide groups made them optimal candidates as target organisms for ongoing research about the potential application of allelochemicals and analogue compounds as natural herbicide models. Benzoxazinones, a family of natural allelochemicals present in corn, wheat, and rye, including 2,4-dihydroxy-(2H)-1,4-benzoxazin-3(4H)-one and 2,4-dihydroxy-7-methoxy-(2H)-1,4-benzoxazin-3(4H)-one, together with some degradation products, found in crop soils as well as in other systems, and some synthetic analogues of them were tested on wild oat and rigid ryegrass seeds; the results were statistically treated, and some structure-activity relationships, useful in further development of natural herbicide models, were elucidated. The most active compounds were the synthetic benzoxazinone 2-acetoxy-(2H)-1,4-benzoxazin-3(4H)-one and the degradation product 2-aminophenoxazin-3-one, with highly significant inhibition on the development of both weeds. The ecological role of these compounds is discussed by considering both degradability and phytotoxicity. The bioactivity of aminophenoxazines has been correlated by their aqueous solubility-lipophilicity predicted by means of computational methods. PMID:16478215

  11. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    NASA Astrophysics Data System (ADS)

    Foing, Bernard

    2014-05-01

    We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International Journal of Astrobiology , IJA 2011, 10, vol. 3. 137-305 [1] Foing B. et al. (2011) Field astrobiology research at Moon-Mars analogue site: Instruments and methods, IJA 2011, 10 (3), 141;[2] Clarke, J., Stoker, C. Concretions in exhumed & inverted channels near Hanksville Utah: implications for Mars, (IJA 2011, 10 (3), 162;[3] Thiel et al., (2011) PCR-based analysis of microbial communities during the EuroGeoMars campaign at Mars Desert Research Station, Utah. (IJA 2011, 10 (3), 177;[4] Direito et al. (2011). A wide variety of putative extremophiles and large beta-diversity at the Mars Desert Research Station (Utah). (IJA 2011, 10 (3), 191;[5] Orzechowska, G. et al (20110 analysis of Mars Analog soils using solid Phase Microextraction, Organics solvent extraction and GCMS, (IJA 2011, 10 (3), 209; [6] Kotler et al. (2011). Analysis of mineral matrices of planetary soils analogs from the Utah Desert. (IJA 2011, 10 (3), 221; [7] Martins et al. (2011). Extraction of amino acids from soils close to the Mars Desert Research Station (MDRS), Utah. (IJA 2011, 10 (3), 231; [8] Ehrenfreund et al. (2011) Astrobiology and habitability studies in preparation for future Mars missions: trends from investigating minerals, organics and biota. (IJA 2011, 10 (3), 239; [9] Stoker C. et al (2011) Mineralogical, Chemical, Organic & Microbial Properties of Subsurface Soil Cores from Mars Desert Research Station, a Phyllosilicate and Sulfate Rich Mars Analog Site, IJA 2011, 10 (3), 269; [10] Rodrigues L. et al (2014, in preparation) Preventing biocontamination during sterile sampling; [11] Rodrigues L. et al (2014, in preparation) Microbial diversity in MDRS rocks and soils; [12] ILEWG EuroMoonMars Team, (2014, special issue in preparation) Results from ILEWG EuroMoonMars campaign 2013 **Acknowledgements: B.H.Foing (1, 2, 6), C. Stoker (3), P. Ehrenfreund (4, 5), I. Rammos (2), L. Rodrigues (2), A. Svendsen (2), D. Oltheten (2), K. Nebergall (6), M. Battler (6, 7), H. v't Houd (8), A. Bruneau (6,9), M. Cross (6,7), V. Maivald (10), C. Orgel (6), A. Elsaesser (4), S.O.L. Direito (2,4), W.F.M. Röling (2), G.R. Davies (2); EuroGeoMars2009 Team, DOMMEX-ILEWG EuroMoonMars 2010-2013 Teams (1) ESA/ ESTEC, Postbus 299, 2200 AG Noordwik, NL; (2) Vrije Universiteit, Amsterdam, NL; (3) NASA Ames Research Centre; US; (4) Leiden U. , NL; (5) Space Policy Institute, GWU, Washington D.C., USA; (6) ILEWG; (7) CPSX; (8) Cerberus Blackshore, ESIC Noordwijk, NL; (9) ENSC Bordeaux; (10) DLR, Bremen

  12. Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues

    PubMed Central

    2015-01-01

    2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, ()-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of ()-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of ()-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. PMID:24494745

  13. Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues.

    PubMed

    Okunola-Bakare, Oluyomi M; Cao, Jianjing; Kopajtic, Theresa; Katz, Jonathan L; Loland, Claus J; Shi, Lei; Newman, Amy Hauck

    2014-02-13

    2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, ()-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of ()-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of ()-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. PMID:24494745

  14. Adsorption on molecularly imprinted polymers of structural analogues of a template. Single-component adsorption isotherm data

    SciTech Connect

    Kim, Hyunjung; Guiochon, Georges A

    2005-10-01

    The equilibrium adsorption isotherms on two otherwise identical polymers, one imprinted with Fmoc-L-tryptophan (Fmoc-L-Trp) (MIP), the other nonimprinted (NIP), of compounds that are structural analogues of the template were acquired by frontal analysis (FA) in an acetonitrile/acetic acid (99/1 v/v) mobile phase, over a wide concentration range (from 0.005 to 50 mM). These analogues were Fmoc-L-tyrosine, Fmoc-L-serine, Fmoc-L-phenyalanine, Fmoc-glycine (Fmoc-Gly), Fmoc-L-tryptophan pentafluorophenyl ester (Fmoc-L-Trp(OPfp)), and their antipodes. These substrates have different numbers of functional groups able to interact with the 4-vinylpyridine groups of the polymer. For a given number of the functional groups, these substrates have different hydrophobicities of their side groups (as indicated by their partition coefficients (log P{sub ow}) in the octanol-water system (e.g., from 4.74 for Fmoc-Trp to 2.53 for Fmoc-Gly)). Statistical results from the fitting of the FA data to Langmuirian isotherm models, the calculation of the affinity energy distribution, and the comparison of calculated and experimental band profiles show that all these sets of FA data are best accounted for by a tri-Langmuir isotherm model, except for the data of Fmoc-L-Trp(OPfp) that are best modeled by a simple Langmuir isotherm. So, all compounds but Fmoc-L-Trp(OPfp) find three different types of adsorption sites on both the MIP and the NIP. The properties of these different types of sites were studied systematically. The results show that the affinity of the structural analogues for the NIP is controlled mostly by the number of the functional groups on the substrates and somewhat by the hydrophobicity of their side groups. These two factors control also the MIP affinity toward the enantiomers of the structural analogues that have a stereochemistry different from that of the template. In contrast, the affinity of the highest affinity sites of the MIP toward the enantiomers of these structural analogues that have the same stereochemistry as the template is highest for the imprinted molecule (Fmoc-L-Trp). The separation of the template from the substrates with the same stereochemistry is influenced by the number of the functional groups on the substrates that can interact with the highest affinity sites on the MIP. The separation of the enantiomers of the analogues of the substrates was also achieved on the MIP, and these enantiomeric separations are influenced by the hydrophobicity of the substrates.

  15. Toward a biorelevant structure of protein kinase C bound modulators: design, synthesis, and evaluation of labeled bryostatin analogues for analysis with rotational echo double resonance NMR spectroscopy.

    PubMed

    Loy, Brian A; Lesser, Adam B; Staveness, Daryl; Billingsley, Kelvin L; Cegelski, Lynette; Wender, Paul A

    2015-03-18

    Protein kinase C (PKC) modulators are currently of great importance in preclinical and clinical studies directed at cancer, immunotherapy, HIV eradication, and Alzheimer's disease. However, the bound conformation of PKC modulators in a membrane environment is not known. Rotational echo double resonance (REDOR) NMR spectroscopy could uniquely address this challenge. However, REDOR NMR requires strategically labeled, high affinity ligands to determine interlabel distances from which the conformation of the bound ligand in the PKC-ligand complex could be identified. Here we report the first computer-guided design and syntheses of three bryostatin analogues strategically labeled for REDOR NMR analysis. Extensive computer analyses of energetically accessible analogue conformations suggested preferred labeling sites for the identification of the PKC-bound conformers. Significantly, three labeled analogues were synthesized, and, as required for REDOR analysis, all proved highly potent with PKC affinities (?1 nM) on par with bryostatin. These potent and strategically labeled bryostatin analogues are new structural leads and provide the necessary starting point for projected efforts to determine the PKC-bound conformation of such analogues in a membrane environment, as needed to design new PKC modulators and understand PKC-ligand-membrane structure and dynamics. PMID:25710634

  16. SHRINE: Enabling Nationally Scalable Multi-Site Disease Studies

    PubMed Central

    McMurry, Andrew J.; Murphy, Shawn N.; MacFadden, Douglas; Weber, Griffin; Simons, William W.; Orechia, John; Bickel, Jonathan; Wattanasin, Nich; Gilbert, Clint; Trevvett, Philip; Churchill, Susanne; Kohane, Isaac S.

    2013-01-01

    Results of medical research studies are often contradictory or cannot be reproduced. One reason is that there may not be enough patient subjects available for observation for a long enough time period. Another reason is that patient populations may vary considerably with respect to geographic and demographic boundaries thus limiting how broadly the results apply. Even when similar patient populations are pooled together from multiple locations, differences in medical treatment and record systems can limit which outcome measures can be commonly analyzed. In total, these differences in medical research settings can lead to differing conclusions or can even prevent some studies from starting. We thus sought to create a patient research system that could aggregate as many patient observations as possible from a large number of hospitals in a uniform way. We call this system the ‘Shared Health Research Information Network’, with the following properties: (1) reuse electronic health data from everyday clinical care for research purposes, (2) respect patient privacy and hospital autonomy, (3) aggregate patient populations across many hospitals to achieve statistically significant sample sizes that can be validated independently of a single research setting, (4) harmonize the observation facts recorded at each institution such that queries can be made across many hospitals in parallel, (5) scale to regional and national collaborations. The purpose of this report is to provide open source software for multi-site clinical studies and to report on early uses of this application. At this time SHRINE implementations have been used for multi-site studies of autism co-morbidity, juvenile idiopathic arthritis, peripartum cardiomyopathy, colorectal cancer, diabetes, and others. The wide range of study objectives and growing adoption suggest that SHRINE may be applicable beyond the research uses and participating hospitals named in this report. PMID:23533569

  17. Evaluation Of Microdosing Strategies For Studies In Preclinical Drug Development: Demonstration Of Linear Pharmacokinetics In Dogs Of A Nucleoside Analogue Over A 50-Fold Dose Range

    SciTech Connect

    Sandhu, P; Vogel, J S; Rose, M J; Ubick, E A; Brunner, J E; Wallace, M A; Adelsberger, J K; Baker, M P; Henderson, P T; Pearson, P G; Baillie, T A

    2004-04-22

    The technique of accelerator mass spectrometry (AMS) was validated successfully and utilized to study the pharmacokinetics and disposition in dogs of a preclinical drug candidate (Compound A), after oral and intravenous administration. The primary objective of this study was to examine whether Compound A displayed linear kinetics across sub-pharmacological (microdose) and pharmacological dose ranges in an animal model, prior to initiation of a human microdose study. The AMS-derived disposition properties of Compound A were comparable to data obtained via conventional techniques such as LC-MS/MS and liquid scintillation counting analyses. Thus, Compound A displayed multiphasic kinetics and possessed low plasma clearance (4.4 mL/min/kg), a long terminal elimination half-life (19.4 hr) and high oral bioavailability (82%). Currently there are no published comparisons of the kinetics of a pharmaceutical compound at pharmacological versus sub-pharmacological doses employing microdosing strategies. The present study thus provides the first description of the pharmacokinetics of a drug candidate assessed under these two dosing regimens. The data demonstrated that the pharmacokinetic properties of Compound A were similar following dosing at 0.02 mg/kg as at 1 mg/kg, indicating that in the case of Compound A, the kinetics of absorption, distribution and elimination in the dog appear to be linear across this 50-fold dose range. Moreover, the exceptional sensitivity of AMS provided a pharmacokinetic profile of Compound A, even following a microdose, which revealed aspects of the disposition of this agent that were inaccessible by conventional techniques. The applications of accelerator mass spectrometry (AMS) are broad ranging and vary from studying environmental and ecological issues such as the isotopic composition of the atmosphere, soil and water (Hughen et al., 2000; Beck et al., 2001; Keith-Roach et al., 2001; Mironov et al., 2002), to archaeology and volcanology (Stafford et al., 1984; Vogel et al., 1990; Smith et al., 1999) to its use as a bioanalytical tool for nutritional research (Buchholz et al., 1999; Deuker et al., 2000; Weaver and Liebman, 2002). Biomedical applications of AMS and its use in the arena of pharmaceutical research also have been detailed in review articles (Barker and Garner, 1999; Garner, 2000; Turteltaub and Vogel, 2000). To date, most studies on the metabolism and disposition of xenobiotics by AMS have focused on how carcinogens bind to DNA and proteins to form adducts (Turteltaub et al., 1990, 1997; Frantz et al., 1995; Dingley et al., 1999; Li et al., 2003). Its application to the field of pharmaceutical sciences has been limited to a few studies (Kaye et al., 1997; Young et al., 2001; Garner et al., 2002). However, the pharmaceutical industry is becoming increasingly aware of the potential benefits that may accrue from the ultra high sensitivity afforded by AMS in terms of evaluating the pharmacokinetics of lead drug candidates in early development. Specifically, AMS allows administration of sub-pharmacological doses (microdoses) of carbon-14 or tritium-labeled investigational drugs to animals or humans at radiologically insignificant levels with the goal of obtaining preliminary information regarding the absorption, distribution, metabolism, and excretion of test compounds (Turteltaub and Vogel, 2000). An unresolved issue, however, is whether the pharmacokinetics determined following a microdose are representative of those following a conventional (pharmacological) dose (Lappin and Garner, 2003). This paper examines the linearity of kinetics of an antiviral nucleoside analogue, Compound A, across sub-pharmacological and pharmacological dose ranges in the dog prior to initiation of a human microdose study. The specific objectives of this study, therefore, were (1) to assess the pharmacokinetics of Compound A in dogs by a conventional dosing approach utilizing LC-MS/MS for sample analysis, (2) to assess the pharmacokinetics of Compound A in dogs by the microdose approach utilizing AMS for sample analysis, (3) to compare the pharmacokinetics of Compound A at a microdose versus a pharmacological dose, and (4) to validate AMS for this application and to compare the sensitivity of AMS to that of LC-MS/MS.

  18. Geomorphological and Spectrophotometric Study of Philae Landing Site A

    NASA Astrophysics Data System (ADS)

    Pajola, M.; La Forgia, F.; Giacomini, L.; Oklay, N.; Massironi, M.; Bertini, I.; Simioni, E.; Marzari, F.; Barbieri, C.; Naletto, G.; Groussin, O.; Lazzarin, M.; Scholten, F.; Preusker, F.; Fornasier, S.; Vincent, J. B.; Sierks, H.

    2015-10-01

    On August 6, 2014, the European Space Agency's Rosetta spacecraft started orbiting the Jupiter family comet 67P/Churyumov-Gerasimenko (hereafter 67P). Afterwards, the OSIRIS instrument (Optical, Spectroscopic and Infrared Remote Imaging System [1]), got the highest-resolution-ever images of a cometary nucleus, reaching the unprecedented scale of 50 cm/px. A brief description of OSIRIS early analysis on the nucleus structure and activity of 67P is available in [2]. Despite its small dimensions, #4 km diameter, 67P shows a morphological diversity that is still puzzling the cometary community: boulders [3], highreflectivity particle clusters [4], local fracturing [5], pits [6], as well as dust covered terrains [7], are only few examples that can be found on 67P. Since the Rosetta arrival, an extremely detailed analysis of 67P surface has been performed to select five different landing sites candidates for the lander Philae. By using the OSIRIS images the comet shape model [8] has been produced to study the slope constraints, as well as the identification and measurements of boulders and production of hazard maps of the landing spots [3]. A final landing site, called Agilkia and located on the smaller lobe of the comet, was announced on October 15, 2014. Here, Philae, on November 12, 2014, made its historic comet touchdown [9]. Despite its unique scientific potential, one of the five finalists, called "site A", was avoided due to higher risks with respect to Agilkia, during both the landing phase and the surface operations. This area is located on the bigger lobe of the comet, on the Seth region [10] facing the Hathor cliff. Site A (Fig. 1) is close to the 'neck' region, i.e. the connecting bridge between the two lobes, where the main dust jet activity has been observed since the Rosetta arrival. This area is the biggest terrace of Seth region, delimited in the upper part by a steep wall showing multiple niches, strata heads and smaller terraces. Moreover, between the 5 finalists, this site has the unique value to provide detailed analysis of the multiple fractures present on its cliff and on the neighboring Hathor. Figure 1: Site A as imaged by the OSIRIS NAC camera on 6 August 2014 at 02:20:12 UT. The distance from the comet center is 117.24 km, the scale is 2.17 m/px. EPSC Abstracts Vol. 10, EPSC2015-526, 2015 European Planetary Science Congress 2015 c Author(s) 2015 EPSC European Planetary Science Congress We here present the geomorphological map coupled with the size-frequency distributions of boulders # 2 m located on the different types of terrains here identified, such as outcropping layered terrains, gravitational accumulation deposits, taluses and fine particle deposits. Gravitational slopes, derived through the 67P shape model by assuming uniform density, have been used to characterize and better interpret the various terrains. Moreover, we show the spectrophotometric properties of the area, studied through images taken by OSIRIS NAC with a scale of 50 cm/px. Albedo maps, as well as surface reflectance spectra have been obtained by taking advantage of the shape model and DTM in order to correct for the illumination and observing conditions of the terrain. This multidisciplinary analysis highlights that different types of deposits show different photometric properties.

  19. BIOREMEDIATION TREATABILITY STUDIES OF CONTAMINATED SOILS AT WOOD PRESERVING SITES

    EPA Science Inventory

    Bioremediationis used frequently at sites contaminated with organic hazardous chemical where releases from processing vessels and the mismanagement of reagents and generated waste have contributed to significant impairment of the environment. At wood treater sites, process reagen...

  20. Synthetic studies on glycosphingolipids from protostomia phyla: synthesis of neogala-series glycolipid analogues containing a mannose residue from the earthworm Pheretima hilgendorfi.

    PubMed

    Hada, N; Matsusaki, A; Sugita, M; Takeda, T

    1999-09-01

    Two kinds of glycosphingolipid analogues from the earthworm Pheretima hilgendorfi were synthesized as follows: the trisaccharide 2-(tetradecyl)hexadecyl alpha-D-mannopyranosyl-(1-->4)-beta-D-galactopyranosyl-(1-->6)-beta-D- galactopyranoside (13) and the tetrasaccharide 2-(tetradecyl) hexadecyl alpha-D-galactopyranosyl-(1-->6)-[alpha-D-mannopyranosyl-(1-->4)]-beta-D - galactopyranosyl-(1-->6)-beta-D-galactopyranoside (20) were synthesized by stepwise condensation of suitably protected monosaccharide units. A 2-(trimethylsilyl)ethyl 2,3,4-tri-O-benzoyl-beta-D-galactopyranoside derivative (5) was used as the glycosyl acceptor and thiophenyl derivatives of D-galactose and D-mannose were used as donors respectively. PMID:10517007

  1. Structural and spectroscopic studies of the copper site of stellacyanin.

    PubMed

    Strange, R W; Reinhammar, B; Murphy, L M; Hasnain, S S

    1995-01-10

    The structure of the copper site in oxidized and reduced Rhus vernicifera stellacyanin has been studied by X-ray absorption (XAFS) spectroscopy at different pH values. Data for the oxidized protein are consistent with the fourth ligand being an O- or N-donating ligand rather than a cysteine from the disulfide bridge. The fourth ligand is not present in the inner coordination sphere, but makes a more distant interaction 2.7 A from the copper atom. Only minor changes in the details of the Cu(II) coordination occur when the pH is varied. Direct structural information on reduced stellacyanin is provided. Upon reduction, one of the histidine ligands moves away from the copper atom by at least 0.2 A. A low-Z (O or N) scatterer is present approximately 2.4 A from the Cu(I) atom in the protein at low pH, and this ligand is lost at high pH. There is no evidence for an S-donating fourth ligand in the reduced protein. The XAFS results are presented in relation to the spectroscopic and structural information available for some methionine-121 mutants of azurin. The data reveal that there are spectroscopic similarities between stellacyanin and some of the mutant proteins, but distinct structural differences exist that preclude these proteins as suitable models for the copper site of stellacyanin. PMID:7819200

  2. Photoaffinity analogues of methotrexate as folate antagonist binding probes. 2. Transport studies, photoaffinity labeling, and identification of the membrane carrier protein for methotrexate from murine L1210 cells

    SciTech Connect

    Price, E.M.; Freisheim, J.H.

    1987-07-28

    A membrane-derived component of the methotrexate/one-carbon-reduced folate transport system in murine L1210 cells has been identified by using a photoaffinity analogue of methotrexate. The compound, a radioiodinated 4-azidosalicylyl derivative of the lysine analogue of methotrexate, is transported into murine L1210 cells in a temperature-dependent, sulfhydryl reagent inhibitable manner with a K/sub t/ of 506 +/- 79 nM and a V/sub max/ of 17.9 +/- 4.2 pmol min/sup -1/ (mg of total cellular protein)/sup -1/. Uptake of the iodinated compound at 200 nM is inhibited by low amounts of methotrexate. The parent compounds of the iodinated photoprobe inhibit (/sup 3/H)methotrexate uptake, with the uniodinated 4-azidosalicylyl derivative exhibiting a K/sub i/ of 66 +/- 21 nM. UV irradiation, at 4 /sup 0/C, of a cell suspension that had been incubated with the probe results in the covalent modification of a 46K-48K protein. This can be demonstrated when the plasma membranes from the labeled cells are analyzed via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Labeling of this protein occurs half-maximally at a reagent concentration that correlates with the K/sub t/ for transport of the iodinated compound. Protection against labeling of this protein by increasing amounts of methotrexate parallels the concentration dependence of inhibition of photoprobe uptake by methotrexate. Evidence that, in the absence of irradiation and at 37/sup 0/C, the iodinated probe is actually internalized is demonstrated by the labeling of two soluble proteins (M/sub r/ 38K and 21K) derived from the cell homogenate supernatant.

  3. The ratio between tetrahydrobiopterin and oxidized tetrahydrobiopterin analogues controls superoxide release from endothelial nitric oxide synthase: an EPR spin trapping study.

    PubMed Central

    Vásquez-Vivar, Jeannette; Martásek, Pavel; Whitsett, Jennifer; Joseph, Joy; Kalyanaraman, Balaraman

    2002-01-01

    Augmentation of superoxide levels has been linked to impaired relaxation in hypertension, diabetes and hypercholesterolaemia. Purified endothelial nitric oxide synthase (eNOS) generates superoxide under limited availability of 5,6,7,8-tetrahydrobiopterin (BH(4)). Thus alterations in endothelial BH(4) levels have been postulated to stimulate superoxide production from eNOS. This possibility was examined by determining the concentration-dependent effects of BH(4), and its analogues, on superoxide formation by eNOS. Superoxide was quantified by EPR spin trapping, which is the only available technique to quantify superoxide from eNOS. Using 5-ethoxycarbonyl-5-methyl-pyrroline N-oxide, we show that only fully reduced BH(4) diminished superoxide release from eNOS, with efficiency BH(4)>6-methyl-BH(4)>5-methyl-BH(4). In contrast, partially oxidized BH(4) analogues, 7,8-dihydrobiopterin (7,8-BH(2)) and sepiapterin had no effect. Neither l-arginine nor N(G)-nitro-l-arginine methyl ester (l-NAME) abolished superoxide formation. Together, BH(4) and l-arginine stimulated .NO production at maximal rates of 148 nmol/min per mg of protein. These results indicate that BH(4) acts as a "redox switch", decreasing superoxide release and enhancing .NO formation. This role was verified by adding 7,8-BH(2) or sepiapterin to fully active eNOS. Both 7,8-BH(2) and sepiapterin enhanced superoxide release while inhibiting (.)NO formation. Collectively, these results indicate that the ratio between oxidized and reduced BH(4) metabolites tightly regulates superoxide formation from eNOS. The pathological significance of this scenario is discussed. PMID:11879202

  4. The ?,?-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase-Dependent Signal Transduction in Vitro, and In Living Cells

    PubMed Central

    Panigrahi, Kaushik; Eggen, MariJean; Maeng, Jun-Ho; Shen, Quanrong; Berkowitz, David B.

    2009-01-01

    SUMMARY This overview focuses on the (?,?-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction pathways of great interest to drug development. The most versatile modes of access to these chemical biological tools are discussed, organized by method of PCF2-C bond. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a constitutive phosphorylation phenotype, and is seen to support native protein-protein interactions that depend upon serine phosphorylation. Signal transduction pathways studied with this chemical biological approach include the regulation of p53 tumor suppressor protein activity, and of melatonin production. Given these successes, the future is bright for the use of such teflon phospho-amino acid mimics to map kinase-based signaling pathways. PMID:19778720

  5. Tetragonal Lysozyme Interactions Studied by Site Directed Mutagenesis

    NASA Technical Reports Server (NTRS)

    Crawford, Lisa; Karr, Laurel; Pusey, Marc

    1998-01-01

    A number of recent experimental and theoretical studies have indicated that tetragonal lysozyme crystal growth proceeds by the addition of aggregates, formed by reversible self association of the solute molecules in the bulk'solution. Periodic bond chain and atomic force microscopy studies have indicated that the probable growth unit is at minimum a 43 tetramer, and most likely an octamer composed of two complete turns about the 4(sub 3) axis. If these results are correct, then there are intermolecular interactions which are only formed in the solution and others only formed at the joining of the growth unit to the crystal surface. We have set out to study these interactions, and the correctness of this hypothesis, using site directed mutagenesis of specific amino acid residues involved in the different bonds. We had initially expressed wild type lysozyme in S. cervasiae with yields of approximately 5 mg/L, which were eventually raised to approximately 40 mg/L. We are now moving the expression to the Pichia system, with anticipated yields of 300 to greater than 500 mg/L, comparable to what can be obtained from egg whites. An additional advantage of using recombinant protein is the greater genetic homogeneity of the material obtained and the absence of any other contaminating egg proteins. The first mutation experiments are TYR 23 yields PHE or ALA and ASN 113 yields ALA or ASP. Both TYR 23 and ASN 113 form part of the postulated dimerization intermolecular binding site which lead to the formation of the 4(sub 3) helix. Tyrosine also participates in an intermolecular hydrogen bond with ARG 114. The results of these and subsequent experiments will be discussed.

  6. Tetragonal Lysozyme Interactions Studied by Site Directed Mutagenesis

    NASA Technical Reports Server (NTRS)

    Crawford, Lisa; Karr, Laurel J.; Nadarajah, Arunan; Pusey, Marc

    1999-01-01

    A number of recent experimental and theoretical studies have indicated that tetragonal lysozyme crystal growth proceeds by the addition of aggregates, formed by reversible self association of the solute molecules in the bulk solution. Periodic bond chain and atomic force microscopy studies have indicated that the probable growth unit is at minimum a 43 tetramer, and most likely an octamer composed of two complete turns about the 43 axis. If these results are correct, then there are intermolecular interactions which are only formed in the solution and others only formed at the joining of the growth unit to the crystal surface. We have set out to study these interactions, and the correctness of this hypothesis, using site directed mutagenesis of specific amino acid residues involved in the different bonds. We had initially expressed wild type lysozyme in S. cervasiae with yields of approximately 5 mg/L, which were eventually raised to approximately 40 mg/L. We are now moving the expression to the Pichia system, with anticipated yields of 300 to (3)500 mg/L, comparable to what can be obtained from egg whites. An additional advantage of using recombinant protein is the greater genetic homogeneity of the material obtained and the absence of any other contaminating egg proteins. The first mutation experiments are TYR 23 (Registered) PHE or ALA and ASN 113 (Registered) ALA or ASP. Both TYR 23 and ASN 113 form part of the postulated dimerization intermolecular binding site which lead to the formation of the 43 helix. Tyrosine also participates in an intermolecular hydrogen bond with ARG 114. The results of these and subsequent experiments will be discussed.

  7. Solution structures of purine base analogues 9-deazaguanine and 9-deazahypoxanthine.

    PubMed

    Karnawat, Vishakha; Puranik, Mrinalini

    2016-03-01

    Deaza analogues of nucleobases are potential drugs against infectious diseases caused by parasites. A caveat is that apart from binding their target parasite enzymes, they also bind and inhibit enzymes of the host. In order to design derivatives of deaza analogues which specifically bind target enzymes, knowledge of their molecular structure, protonation state, and predominant tautomers at physiological conditions is essential. We have employed resonance Raman spectroscopy at an excitation wavelength of 260nm, to decipher solution structure of 9-deazaguanine (9DAG) and 9-deazahypoxanthine (9DAH). These are analogues of guanine and hypoxanthine, respectively, and have been exploited to study static complexes of nucleobase binding enzymes. Such enzymes are known to perturb pKa of their ligands, and thus, we also determined solution structures of these analogues at two, acidic and alkaline, pH. Structure of each possible protonation state and tautomer was computed using density functional theoretical calculations. Species at various pHs were identified based on isotopic shifts in experimental wavenumbers and by comparing these shifts with corresponding computed isotopic shifts. Our results show that at physiological pH, N1 of pyrimidine ring in 9DAG and 9DAH bears a proton. At lower pH, N3 is place of protonation, and at higher pH, deprotonation occurs at N1 position. The proton at N7 of purine ring remains intact even at pH 12.5. We have further compared these results with naturally occurring nucleotides. Our results identify key vibrational modes which can report on hydrogen bonding interactions, protonation and deprotonation in purine rings upon binding to the active site of enzymes. PMID:25894214

  8. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G. Saulnier and W. Statham

    2006-04-16

    The Nopal I uranium mine in the Sierra Pena Blanca, Chihuahua, Mexico serves as a natural analogue to the Yucca Mountain repository. The Pena Blanca Natural Analogue Performance Assessment Model simulates the mobilization and transport of radionuclides that are released from the mine and transported to the saturated zone. The Pena Blanca Natural Analogue Performance Assessment Model uses probabilistic simulations of hydrogeologic processes that are analogous to the processes that occur at the Yucca Mountain site. The Nopal I uranium deposit lies in fractured, welded, and altered rhyolitic ash-flow tuffs that overlie carbonate rocks, a setting analogous to the geologic formations at the Yucca Mountain site. The Nopal I mine site has the following analogous characteristics as compared to the Yucca Mountain repository site: (1) Analogous source--UO{sub 2} uranium ore deposit = spent nuclear fuel in the repository; (2) Analogous geology--(i.e. fractured, welded, and altered rhyolitic ash-flow tuffs); (3) Analogous climate--Semiarid to arid; (4) Analogous setting--Volcanic tuffs overlie carbonate rocks; and (5) Analogous geochemistry--Oxidizing conditions Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table.

  9. 64Cu-labeled somatostatin analogues conjugated with cross-bridged phosphonate-based chelators via strain-promoted click chemistry for PET imaging: in silico through in vivo studies.

    PubMed

    Cai, Zhengxin; Ouyang, Qin; Zeng, Dexing; Nguyen, Kim N; Modi, Jalpa; Wang, Lirong; White, Alexander G; Rogers, Buck E; Xie, Xiang-Qun; Anderson, Carolyn J

    2014-07-24

    Somatostatin receptor subtype 2 (sstr2) is a G-protein-coupled receptor (GPCR) that is overexpressed in neuroendocrine tumors. The homology model of sstr2 was built and was used to aid the design of new somatostatin analogues modified with phosphonate-containing cross-bridged chelators for evaluation of using them as PET imaging radiopharmaceuticals. The new generation chelators were conjugated to Tyr3-octreotate (Y3-TATE) through bioorthogonal, strain-promoted alkyne azide cycloaddition (SPAAC) to form CB-TE1A1P-DBCO-Y3-TATE (AP) and CB-TE1K1P-PEG4-DBCO-Y3-TATE (KP) in improved yields compared to standard direct conjugation methods of amide bond formation. Consistent with docking studies, the clicked bioconjugates showed high binding affinities to sstr2, with Kd values ranging from 0.6 to 2.3 nM. Selected isomers of the clicked products were used in biodistribution and PET/CT imaging. Introduction of the bulky dibenzocyclooctyne group in AP decreased clearance rates from circulation. However, the additional carboxylate group and PEG linker from the KP conjugate significantly improved labeling conditions and in vivo stability of the copper complex and ameliorated the slower pharmacokinetics of the clicked somatostatin analogues. PMID:24983404

  10. Improved selectivity for Pb(II) by sulfur, selenium and tellurium analogues of 1,8-anthraquinone-18-crown-5: synthesis, spectroscopy, X-ray crystallography and computational studies.

    PubMed

    Mariappan, Kadarkaraisamy; Alaparthi, Madhubabu; Hoffman, Mariah; Rama, Myriam Alcantar; Balasubramanian, Vinothini; John, Danielle M; Sykes, Andrew G

    2015-07-14

    We report here a series of heteroatom-substituted macrocycles containing an anthraquinone moiety as a fluorescent signaling unit and a cyclic polyheteroether chain as the receptor. Sulfur, selenium, and tellurium derivatives of 1,8-anthraquinone-18-crown-5 (1) were synthesized by reacting sodium sulfide (Na2S), sodium selenide (Na2Se) and sodium telluride (Na2Te) with 1,8-bis(2-bromoethylethyleneoxy)anthracene-9,10-dione in a 1 : 1 ratio. The optical properties of the new compounds are examined and the sulfur and selenium analogues produce an intense green emission enhancement upon association with Pb(II) in acetonitrile. Selectivity for Pb(II) is markedly improved as compared to the oxygen analogue 1 which was also competitive for Ca(II) ion. UV-Visible and luminescence titrations reveal that 2 and 3 form 1 : 1 complexes with Pb(II), confirmed by single-crystal X-ray studies where Pb(II) is complexed within the macrocycle through coordinate covalent bonds to neighboring carbonyl, ether and heteroether donor atoms. Cyclic voltammetry of 2-8 showed classical, irreversible oxidation potentials for sulfur, selenium and tellurium heteroethers in addition to two one-electron reductions for the anthraquinone carbonyl groups. DFT calculations were also conducted on 1, 2, 3, 6, 6 + Pb(II) and 6 + Mg(II) to determine the trend in energies of the HOMO and the LUMO levels along the series. PMID:26051600

  11. Fungicidal activity of beta-thujaplicin analogues.

    PubMed

    Baya, M; Soulounganga, P; Gelhaye, E; Grardin, P

    2001-09-01

    The fungicidal activity of analogues of beta-thujaplicin, a natural product responsible for the durability of heartwood of several cupressaceous trees, was investigated in vitro on the growth of different white and brown rot fungi involved in wood biodegradation, Coriolus versicolor, Phanerochaete chrysosporium, Poria placenta and Gloephyllum trabeum. The study shows that 2-hydroxycyclohepta-2,4,6-trienone (tropolone), easily prepared according to a literature procedure, possesses interesting fungicidal activity when compared to beta-thujaplicin, azaconazole, tebuconazole and copper oxine, which suggests this compound should be examined further as a potential biocide for wood preservation. PMID:11561410

  12. Site contamination health risk assessment case study involving tenant relocation from a former gasworks site.

    PubMed

    Turczynowicz, Len; Fitzgerald, D James; Nitschke, Monika; Mangas, Sam; McLean, Angela

    2007-10-01

    An Adelaide suburban public-housing residential site with 16 apartments was investigated after complaints of odor in some yard areas. A distinct 0.5-m layer of dark, odorous (tarry), contaminant material, which in some areas had been covered with plastic sheeting, was subsequently found beneath the topsoil across most of the site. This material appeared to extend beneath the apartments. Analysis indicated high levels of cyanide and polycyclic aromatic hydrocarbons (PAHs), consistent with gasworks waste. Historical investigation revealed that the site was originally owned by a gas company and that a large gasometer (gas-storage tank) existed in one corner of the site. This finding of significant soil contamination precipitated a decision by the health and housing authorities to notify tenants immediately and to plan for their relocation. In addition to tending to the consequent personal disruption and logistical difficulties this posed, a detailed risk assessment process was developed. Urine samples were collected before and after relocation and analyzed for 1-hydroxypyrene (1-OHP), a biomarker for polycyclic aromatic hydrocarbon (PAH) exposure. In addition, samples of tap water, indoor and outdoor air, indoor and ceiling dust, carpets, and soil from tillage areas were analyzed for PAHs. Data indicated a low health risk associated with tenancy on the site. This report presents details of the health risk assessment process undertaken and discusses vindicative reasons for tenant relocation. PMID:17763082

  13. In Vitro Structure-Activity Relationship of Re-cyclized Octreotide Analogues

    PubMed Central

    Dannoon, Shorouk F.; Bigott-Hennkens, Heather M.; Ma, Lixin; Gallazzi, Fabio; Lewis, Michael R.; Jurisson, Silvia S.

    2010-01-01

    Introduction Development of radiolabeled octreotide analogues is of interest for targeting somatostatin receptor-positive tumors for diagnostic and therapeutic purposes. We are investigating a direct labeling approach for incorporation of a Re ion into octreotide analogues, where the peptide sequences are cyclized via coordination to Re rather than through a disulfide bridge. Methods Various octreotide analogue sequences and coordination systems (e.g., S2N2 and S3N) were synthesized and cyclized with non-radioactive Re. In vitro competitive binding assays with 111In-DOTA-Tyr3-octreotide in AR42J rat pancreatic tumor cells yielded IC50 values as a measure of somatostatin receptor affinity of the Re-cyclized analogues. Three-dimensional structures of Re-cyclized Tyr3-octreotate and its disulfide-bridged analogue were calculated from two-dimensional NMR experiments to visualize the effect of metal cyclization on the analogues pharmacophore. Results Only two of the eleven Re-cyclized analogues investigated showed moderate in vitro binding affinity toward somatostatin subtype 2 receptors. Three-dimensional molecular structures of Re- and disulfide-cyclized Tyr3-octreotate were calculated, and both of their pharmacophore turns appear to be very similar with minor differences due to metal coordination to the amide nitrogen of one of the pharmacophore amino acids. Conclusions Various Re-cyclized analogues were developed and analogue 4 had moderate affinity toward somatostatin subtype 2 receptors. In vitro stable studies that are in progress showed stable radiometal-cyclization of octreotide analogues via NS3 and N2S2 coordination forming 5- and 6- membered chelate rings. In vivo biodistribution studies are underway of 99m Tc- cyclized analogue 4. PMID:20610157

  14. Bivalent Tin Analogues of Carbenes

    NASA Astrophysics Data System (ADS)

    Shiryaev, Vladimir I.; Mironov, Vladimir F.

    1983-02-01

    The structure and certain chemical and physicochemical properties of bivalent tin compounds (stannylenes) are examined and the electronic, structural and chemical similarity between these compounds and carbenes and their analogues bivalent compounds of Group IVB elements is demonstrated. The possibilities of stannylenes in the synthesis of organotin (IV) compounds as well as complexes in which stannylenes are electron-donating ligands, like carbenes, are analysed. The bibliography includes 457 references.

  15. Emerald Lake Watershed study: Introduction and site description

    SciTech Connect

    Tonnessen, K.A. )

    1991-07-01

    The Emerald Lake Watershed study was organized to investigate the effects of acidic deposition on high-elevation watersheds and surface waters of the Sierra Nevada, California. Some of the results of this comprehensive study of aquatic and terrestrial ecosystems at a small, headwater basin are presented in four papers in this series. The watershed study site is in Sequoia National Park, on the western slope of the Sierra Nevada. This glacial cirque is located in the upper Marble Fork of the Kaweah River. This 120-ha watershed ranges from Alta Peak (3,416 m) down to Emerald Lake (2,400 m). Most of the watershed surface area is exposed granite and granodiorite rocks, with limited coverage (about 20%) by thin, acidic soils. The hydrology of the basin is dominated by snowmelt runoff during March-June. Emerald Lake, a glacial tarn, is 2.72 ha in area, with a maximum depth of 10.5 m. Surface waters are poorly buffered and dominated by calcium and bicarbonate. Most of the yearly precipitation falls as dilute snow (pH5.2-5.4), with acidic rain storms sampled during May-October.

  16. FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors

    PubMed Central

    Makala, Levi; Di Maro, Salvatore; Lou, Tzu-Fang; Sivanand, Sharanya; Ahn, Jung-Mo; Pace, Betty S.

    2012-01-01

    Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD. PMID:22655179

  17. Heat generation during implant site preparation: an in vitro study.

    PubMed

    Cordioli, G; Majzoub, Z

    1997-01-01

    Thermal changes elicited during drilling and tapping procedures used in site preparation for screw-shaped and cylindrical implants were measured in vitro in blocks of bovine cortical femur bone. Heat-sensitive thermocouples were placed in the bone specimens at 4- and 8-mm depths and at a constant distance from the periphery of the drilling site; this distance was preset for each type of bur used. Rotary cutting was performed with 10-mm-long twist drills (2- and 3-mm diameter) and triflute drills (3.3- and 4-mm diameter) running at 1,500 rpm with external irrigation. A special guide drill was used to ensure unidirectional continuous drilling with a load of 2,000 g. In addition, the effect of irrigation was evaluated during tapping procedures with 10-mm-long taps used at 20 rpm. The greatest temperature increase was observed with the 2-mm twist drill at both 4- and 8-mm depths. Significantly greater temperature increase was noted at the 8-mm depth versus the 4-mm depth with the twist drills. Such significant difference between temperature rise at the two different drilling depths was not observed with the triflute burs. The time interval required for the maximum temperature reached during rotary cutting to return to baseline values was two times longer for the 2-mm twist drill than for the 3.3-mm triflute bur at both drilling depths. No statistically significant differences could be found between the maximum temperatures generated when tapping was performed with and without irrigation at both 4- and 8-mm depths. It can be suggested that the geometry of triflute burs combines cutting efficacy with greater heat dissipation capabilities than twist drills at the drilling depths of 4 and 8 mm used in this study. PMID:9109268

  18. Substrate analogues for isoprenoid enzymes

    SciTech Connect

    Stremler, K.E.

    1987-01-01

    Diphosphonate analogues of geranyl diphosphate, resistant to degradation by phosphatases, were found to be alternate substrates for the reaction with farnesyl diphosphate synthetase isolated from avian liver. The difluoromethane analogue was shown to be the better alternate substrate, in agreement with solvolysis results which indicate that the electronegativity of the difluoromethylene unit more closely approximates that of the normal bridging oxygen. The usefulness of the C/sub 10/ difluoro analogue, for detecting low levels of isoprenoid enzymes in the presence of high levels of phosphatase activity, was demonstrated with a cell-free preparation from lemon peel. A series of C/sub 5/ through C/sub 15/ homoallylic and allylic diphosphonates, as well as two 5'-nucleotide diphosphonates, was prepared in high overall yield using the activation-displacement sequence. Radiolabeled samples of several of the allylic diphosphonates were prepared with tritium located at C1. A series of geraniols, stereospecifically deuterated at C1, was prepared. The enantiomeric purities and absolute configurations were determined by derivatization as the mandelate esters for analysis by /sup 1/H NMR. The stereochemistry of the activation-displacement sequence was examined using C1-deuterated substrates.

  19. Inhibition of angiotensinogen production by angiotensin II analogues in human hepatoma cell line

    SciTech Connect

    Coezy, E.; Darby, I.; Mizrahi, J.; Cantau, B.; Donnadieu, M.H.; Nussberger, J.; Escher, E.; Chapnick, B.; Corvol, P. )

    1989-11-01

    The aim of this study was to examine in Hep G2, a human hepatoma-derived cell line, the presence of angiotensin II (ANG II) receptors and the effect of ANG II and its analogues on angiotensinogen production. The presence of ANG II receptors was demonstrated using a long-acting ANG II analogue, 125I-labeled (Sar1)ANG II. A single class of specific binding sites was identified in these cells with a dissociation constant (Kd) of 2 nM. The number and affinity of these binding sites were not changed by (Sar1)ANG II treatment over 24 h. ANG II showed an inhibitory effect on angiotensinogen production. (Sar1)ANG II also exhibited a similar inhibitory effect as that of ANG II but to a greater extent and therefore was used throughout these studies. (Sar1)ANG II inhibited angiotensinogen production in a dose-dependent manner, exhibiting a half-maximal inhibitory concentration (IC50) of 2 nM. Other ANG II analogues showed similar effects on angiotensinogen production. In order of decreasing ability, they were (Sar1)ANG II greater than (Sar1-Ala8)ANG II greater than (Sar1-Val8)ANG II greater than (Sar1-Val5-(Br5)-Phe8)ANG II greater than (Sar1-Val5-DPhe8)ANG II. Results of these studies show that the Hep G2 cell possesses specific ANG II receptors and that (Sar1)ANG II induces a dose-dependent inhibition of angiotensinogen production in this system.

  20. Comparison of the inhibitory action of synthetic capsaicin analogues with various NADH-ubiquinone oxidoreductases.

    PubMed

    Satoh, T; Miyoshi, H; Sakamoto, K; Iwamura, H

    1996-01-11

    Capsaicin is a new naturally occurring inhibitor of proton-pumping NADH-ubiquinone oxidoreductase (NDH-1), that competitively acts against ubiquinone. A series of capsaicin analogues was synthesized to examine the structural factors required for the inhibitory action and to probe the structural property of the ubiquinone catalytic site of various NADH-ubiquinone reductases, including non-proton-pumping enzyme (NDH-2), from bovine heart mitochondria, potato tuber (Solanum tuberosum, L) mitochondria and Escherichia coli (GR 19N) plasma membranes. Some synthetic capsaicins were fairly potent inhibitors of each of the three NDH-1 compared with the potent rotenone and piericidin A. Synthetic capsaicin analogues inhibited all three NDH-1 activities in a competitive manner against an exogenous quinone. The modification both of the substitution pattern and of the number of methoxy groups on the benzene ring, which may be superimposable on the quinone ring of ubiquinone, did not drastically affect the inhibitory potency. In addition, alteration of the position of dipolar amide bond unit in the molecule and chemical modifications of this unit did not change the inhibitory potency, particularly with bovine heart and potato tuber NDH-1. These results might be explained assuming that the ubiquinone catalytic site of NDH-1 is spacious enough to accommodate a variety of structurally different capsaicin analogues in a dissimilar manner. Regarding the moiety corresponding to the alkyl side chain, a rigid diphenyl ether structure was more inhibitory than a flexible alkyl chain. Structure-activity studies and molecular orbital calculations suggested that a bent form is the active conformation of capsaicin analogues. On the other hand, poor correlations between the inhibitory potencies determined with the three NDH-1 suggested that the structural similarity of the ubiquinone catalytic sites of these enzymes is rather poor. The sensitivity to the inhibition by synthetic capsaicins remarkably differed between NDH-1 and NDH-2, supporting the notion that the sensitivity against capsaicin inhibition correlates well with the presence of an energy coupling site in the enzyme (Yagi, T. (1990) Arch. Biochem. Biophys. 281, 305-311). It is noteworthy that several synthetic capsaicins discriminated between NDH-1 and NDH-2 much better than natural capsaicin. PMID:8573592

  1. Site sampling and treatability studies for demonstration of WasteChem's asphalt encapsulation technology under EPA's SITE program

    SciTech Connect

    Hubbard, J.; Tsadwa, S.; Wills, N.; Evans, M.

    1990-10-01

    This paper presents a sampling approach that was used to determine whether there were adequate quantities and concentrations of wastes at the Woodland Township Route 532 Site for demonstration of the asphalt encapsulation technology. This paper also presents the result of a bench-scale treatability study on wastes from this site. The preliminary sampling and analysis confirmed most of the types of organic and inorganic contaminants found at the Woodland Township Route 532 site during the remedial investigation (RI). However, the contamination levels varied over relatively short distances across the site from some contaminants. The bench-scale treatability study indicated that, when compared with concentrations in the untreated waste, WasteChem's asphalt encapsulation technology reduced semivolatile organic compound concentrations in the toxicity characteristic leaching procedure extracts of treated wastes. The study also indicated that metals concentrations in the TCLP extracts were lower in the treated wastes than the untreated wastes in some samples and higher in others.

  2. Synthesis of a des-B-Ring Bryostatin Analogue Leads to an Unexpected Ring Expansion of the Bryolactone Core

    PubMed Central

    2015-01-01

    A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues. PMID:25207434

  3. Synthesis of a des-B-ring bryostatin analogue leads to an unexpected ring expansion of the bryolactone core.

    PubMed

    Kraft, Matthew B; Poudel, Yam B; Kedei, Noemi; Lewin, Nancy E; Peach, Megan L; Blumberg, Peter M; Keck, Gary E

    2014-09-24

    A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues. PMID:25207434

  4. SITE CHARACTERIZATION AND THERMAL REMEDIATION TREATABILITY STUDIES FOR TWO WOOD TREATER SITES

    EPA Science Inventory

    Assessment of the applicability of thermal remediation at two wood treater sites is ongoing. The two wood treaters had been in operation for 50 to 80 years, and a variety of wood treating chemicals had been employed, including creosote, pentachlorophenol, and various metal prepa...

  5. Remediation case studies: On-site incineration. Volume 12

    SciTech Connect

    1998-09-01

    The case studies present available cost and performance information of full-scale remediation efforts and several large-scale demonstration projects. They are meant to serve as primary reference sources, and contain information on site background and setting, contaminants and media treated, technology, cost and performance, and points of contact for the technology application. The case studies in this volume describe a wide variety of incinerators, including rotary kiln (13), horizontal liquid injection (1), submerged quench (1), and infrared (1). Air pollution controls include secondary combustion chambers (SCC), quench towers, baghouses, cyclone separators, wet scrubbing systems, gas conditioners, mist eliminators, and cooling towers. Contaminants treated by the incinerators included dioxins, volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs), pesticides, and explosives and propellants. Relatively small and large incineration projects are included, with the quantity of material treated ranging from 4,660 to 496,000 tons of solid material (soil, sludge, and debris) and from 213,000 to 350,000,000 gallons of liquids.

  6. Observational study of contracts processing at 29 CTSA sites.

    PubMed

    Kiriakis, James; Gaich, Nicholas; Johnston, S Claiborne; Kitterman, Darlene; Rosenblum, Daniel; Salberg, Libby; Rifkind, Adam

    2013-08-01

    We measured contracts final negotiation (FN) and full execution (FE) times using shared definitions in a prospective observational study of management of contracts for clinical trials at 29 CTSA institutions. Median FN and FE times were reached in 39 and 91 days, respectively; mean times for FN and FE were 55 and 103 days, respectively. Individual site medians ranged from 3 to 116 days for FN and 34 to 197 days for FE. The use of master agreements (MAs) and previously negotiated terms (PNTs) was associated with significant reduction of FN times by a mean of 33 days (p < 0) and 22 days (p < 0.001), respectively. PNTs, but not MAs, were associated with significantly reduced FE time (22 days, p < 0.007). Gap analysis revealed a gap of 22 days between contracts negotiation and Institutional Review Board (IRB) review and intervals of 33 days (contracts) and 48 days (IRB review) during which the process steps were being conducted alone, suggesting a potential benefit with parallel processing. These baseline data support a plan to investigate root causes of prolonged study start-up time by examining causes of variation and outliers. PMID:23919362

  7. How Analogue Research Can Advance Descriptive Evaluation Theory: Understanding (and Improving) Stakeholder Dialogue

    ERIC Educational Resources Information Center

    Campbell, Bernadette; Mark, Melvin M.

    2015-01-01

    Evaluation theories can be tested in various ways. One approach, the experimental analogue study, is described and illustrated in this article. The approach is presented as a method worthy to use in the pursuit of what Alkin and others have called descriptive evaluation theory. Drawing on analogue studies conducted by the first author, we…

  8. How Analogue Research Can Advance Descriptive Evaluation Theory: Understanding (and Improving) Stakeholder Dialogue

    ERIC Educational Resources Information Center

    Campbell, Bernadette; Mark, Melvin M.

    2015-01-01

    Evaluation theories can be tested in various ways. One approach, the experimental analogue study, is described and illustrated in this article. The approach is presented as a method worthy to use in the pursuit of what Alkin and others have called descriptive evaluation theory. Drawing on analogue studies conducted by the first author, we

  9. Enhanced Television Strategy Models: A Study of TV Web Sites.

    ERIC Educational Resources Information Center

    Ha, Louisa

    2002-01-01

    Compares the use of enhanced television features and television commerce features on the Web sites of cable and broadcast television networks. Shows differences in strategies and site usability; proposes three enhanced television strategy models; and discusses implications on television revenue and viewership. (Author/LRW)

  10. A somatostatin analogue induces translocation of Ku 86 autoantigen from the cytosol to the nucleus in colon tumour cells.

    PubMed

    Tvri, J; Szende, B; Bocsi, J; Falaschi, A; Simoncsits, A; Pongor, S; Erchegyi, J; Stetk, A; Kri, G

    1998-04-01

    Flow cytometric and electron microscopic immunocytochemical studies have been performed in HT-29 human colon tumour cells in vitro, to determine and localise p86 Ku protein, which is a regulatory subunit of DNA-dependent kinase and a specific binding site for somatostatin. We have demonstrated that HT-29 cells contain p86 Ku and that the distribution between the cytoplasm and the nucleus is even. After administration of the somatostatin analogues Sandostatin and TT-232 to HT-29 cells, the p86 Ku content of the cytoplasmic compartment decreased in the first 4 h. An increase in the content of this protein in the nuclear compartment was observed at hour 1 followed by a decrease at hour 4 after treatment. Quantitative differences between the two analogues have been observed in this respect. The practical significance of these findings is discussed. PMID:9617485

  11. Transition States and transition state analogue interactions with enzymes.

    PubMed

    Schramm, Vern L

    2015-04-21

    Enzymatic transition states have lifetimes of a few femtoseconds (fs). Computational analysis of enzyme motions leading to transition state formation suggests that local catalytic site motions on the fs time scale provide the mechanism to locate transition states. An experimental test of protein fs motion and its relation to transition state formation can be provided by isotopically heavy proteins. Heavy enzymes have predictable mass-altered bond vibration states without altered electrostatic properties, according to the Born-Oppenheimer approximation. On-enzyme chemistry is slowed in most heavy proteins, consistent with altered protein bond frequencies slowing the search for the transition state. In other heavy enzymes, structural changes involved in reactant binding and release are also influenced. Slow protein motions associated with substrate binding and catalytic site preorganization are essential to allow the subsequent fs motions to locate the transition state and to facilitate the efficient release of products. In the catalytically competent geometry, local groups move in stochastic atomic motion on the fs time scale, within transition state-accessible conformations created by slower protein motions. The fs time scale for the transition state motions does not permit thermodynamic equilibrium between the transition state and stable enzyme states. Isotopically heavy enzymes provide a diagnostic tool for fast coupled protein motions to transition state formation and mass-dependent conformational changes. The binding of transition state analogue inhibitors is the opposite in catalytic time scale to formation of the transition state but is related by similar geometries of the enzyme-transition state and enzyme-inhibitor interactions. While enzymatic transition states have lifetimes as short as 10(-15) s, transition state analogues can bind tightly to enzymes with release rates greater than 10(3) s. Tight-binding transition state analogues stabilize the rare but evolved enzymatic geometry to form the transition state. Evolution to efficient catalysis optimized this geometry and its stabilization by a transition state mimic results in tight binding. Release rates of transition state analogues are orders of magnitude slower than product release in normal catalytic function. During catalysis, product release is facilitated by altered chemistry. Compared to the weak associations found in Michaelis complexes, transition state analogues involve strong interactions related to those in the transition state. Optimum binding of transition state analogues occurs when the complex retains the system motions intrinsic to transition state formation. Conserved dynamic motion retains the entropic components of inhibitor complexes, improving the thermodynamics of analogue binding. PMID:25848811

  12. Earth Desert Analogues for Titan's Large Linear Dunes

    NASA Astrophysics Data System (ADS)

    Radebaugh, J.; Lorenz, R. D.; Barnes, J. W.; Hayes, A. G.; Farr, T. G.; Heggy, E.; Wall, S. D.; Aharonson, O.

    2013-09-01

    Large seas of linear dunes on Titan have analogues in the Saharan, SW African, Australian and Arabian deserts of Earth. Analogue field studies of these more accessible terrestrial locations can provide insight into the formation of linear dunes in general and of surface, wind and climate conditions on Titan. Initial studies in these remote desert regions using various methods have revealed that linear dune systems have dynamic surfaces subject to continual reworking by recent winds. Given similar morphologies on Titan, similar conditions may prevail.

  13. The unsaturated acyclic nucleoside analogues bearing a sterically constrained (Z)-4'-benzamido-2'-butenyl moiety: Synthesis, X-ray crystal structure study, cytostatic and antiviral activity evaluations.

    PubMed

    Benci, Kresimir; Wittine, Karlo; Radan, Malajka; Cetina, Mario; Sedi?, Mirela; Kraljevi? Paveli?, Sandra; Paveli?, Kresimir; Clercq, Erik De; Mintas, Mladen

    2010-09-01

    A series of the novel acyclic unsaturated pyrimidine (1-12) and adenine (13) nucleoside analogues bearing conformationally restricted (Z)-2'-butenyl moiety were synthesized and evaluated for their antiviral and cytostatic activity potency against malignant tumor cell lines and normal human fibroblast (WI38). The N-1 and/or N-3 acyclic side chain substitution in pyrimidine ring in N-3 substituted 5-trifluoromethyluracil derivative (11), N-1, N-3 disubstituted 5-fluorouracil derivative (12) and adenine derivative (13) was deduced from their (1)H and (13)C NMR spectra and confirmed by single crystal X-ray structure analysis. The X-ray crystal structure analysis 11-13 revealed also supramolecular self-assemblies, in which infinite chains or dimers built two- and three-dimensional networks. The results of the in vitro cytostatic activity evaluations of 1-13 indicate that the majority of the compounds tested exhibited a non-specific and moderate antiproliferative effect at the highest concentration (100 microM). Of all evaluated compounds on the cell lines tested only the N-1 4''-fluoro-substituted-benzamide uracil derivative (7) showed rather marked and selective inhibitory activity against the growth of MCF-7 cells at a concentration of 2.7 microM and no cytotoxic effect on normal fibroblasts WI38. This compound can be therefore considered as a potential antitumor lead compound for further synthetic structure modification. PMID:20696582

  14. Soft x-ray absorption spectroscopy study of Prussian blue analogue ACo[Fe(CN)6]H2O nano-particles (A=Na, K)

    NASA Astrophysics Data System (ADS)

    Lee, Eunsook; Kim, D. H.; Hwang, Jihoon; Kang, J.-S.; Van Minh, Nguyen; Yang, In-Sang; Ueno, T.; Sawada, M.

    2013-06-01

    The electronic structures of Prussian blue analogue ACo[Fe(CN)6]H2O (A=Na, K) nano-size particles has been investigated by employing soft X-ray absorption spectroscopy (XAS) at the Fe and Co L edges. Both Fe and Co ions are found to be Fe2+-Fe3+ and Co2+-Co3+ mixed-valent, with the average valence of v(Fe)˜ 2.36 and v(Co)˜ 2.41. This finding suggests that the mechanism of the photo-induced spin transition in ACo[Fe(CN)6]H2O (A=Na, K) is not a simple spin-state transition of Fe2+-Co3+ → Fe3+-Co2+. The Fe ions in ACo[Fe(CN)6]H2O are also found to have a strong covalent bonding to (CN)- ligands, but a very weak bonding to O(H2O), while Co ions have a stronger bonding to O(H2O) than to (CN)- ligands.

  15. A 1H NMR Study of Host/Guest Supramolecular Complexes of a Curcumin Analogue with ?-Cyclodextrin and a ?-Cyclodextrin-Conjugated Gemini Surfactant.

    PubMed

    Poorghorban, Masoomeh; Karoyo, Abdalla H; Grochulski, Pawel; Verrall, Ronald E; Wilson, Lee D; Badea, Ildiko

    2015-08-01

    Host systems based on ?-cyclodextrin (?CD) were employed as pharmaceutical carriers to encapsulate a poorly soluble drug, curcumin analogue (NC 2067), in order to increase its water solubility. ?CD was chemically conjugated with an amphiphilic gemini surfactant with the ability to self-assemble and to form nanoscale supramolecular structures. The conjugated molecule, ?CDgemini surfactant (?CDg), was shown to be a promising drug delivery agent. In this report, its physicochemical properties were assessed in aqueous solution using 1D and 2D 1H NMR spectroscopy. The results showed that the apolar hydrocarbon domain of the gemini surfactant was self-included within the ?CD internal cavity. The host/guest complexes composed of native ?CD or ?CDg with NC 2067 were examined using 1D/2D ROESY NMR methods. The stoichiometry of ?CD/NC 2067 complex was estimated using Job's method via 1H NMR spectroscopy. The binding geometry of NC 2067 within ?CD was proposed using molecular docking and further supported by 1D and 2D ROESY NMR results. Addition of NC 2067 to ?CDg revealed minimal changes to the overall structure of the ?CDg system, in agreement with the formation of a ?CDg/NC 2067 ternary complex. PMID:26083126

  16. SUPERFUND TREATABILITY CLEARINGHOUSE: SOIL STABILIZATION PILOT STUDY, UNITED CHROME NPL SITE PILOT STUDY AND HEALTH AND SAFETY PROGRAM, UNITED CHROME NPL SITE PILOT STUDY

    EPA Science Inventory

    This document is a project plan for a pilot study at the United Chrome NPL site, Corvallis, Oregon and includes the health and safety and quality assurance/quality control plans. The plan reports results of a bench-scale study of the treatment process as iieasured by the ...

  17. Preliminary study on calcium aluminosilicate glass as a potential host matrix for radioactive 90Sr--an approach based on natural analogue study.

    PubMed

    Sengupta, Pranesh; Fanara, Sara; Chakraborty, Sumit

    2011-06-15

    Given the environmental-, safety- and security risks associated with sealed radioactive sources it is important to identify suitable host matrices for (90)Sr that is used for various peaceful applications. As SrO promotes phase separation within borosilicate melt, aluminosilicate bulk compositions belonging to anorthite-wollastonite-gehlenite stability field are studied in this work. Tests for their homogeneity, microstructural characteristics and resistance to phase separation narrowed the choice down to the composition CAS11 (CaO=35 wt%, Al(2)O(3)=20 wt%, SiO(2)=45 wt%). We find that up to 30 wt% SrO can be loaded in this glass without phase separation (into Ca, Sr-rich and Sr-poor, Si-rich domains). Leaching behaviour of the glasses differs depending on the content and distribution of Sr. In general, the elemental leach rates determined from conventional PCT experimental procedure yield values better than 10(-7)gcm(-2)day(-1) for both CAS11 base glass as well as SrO doped glass. It was noted that leach rates calculated on the basis of Ca(2+) and Sr(2+) were of the same order and bit higher compared to those calculated on the basis of Si(4+) and Al(3+). During accelerated leaching tests, zeolite and zeolite+epidote were found to have developed on CAS11 base glass and SrO doped glasses respectively. The Sr bulk diffusion coefficients is found to vary from ∼ 10(-15) to 10(-13)cm(2)/s at temperature intervals as high as 725-850°C. Based on the experimental observations, it is suggested that CAS11 glass can be used as host matrix of (90)Sr for various applications of radioactive Sr-pencils. PMID:21477923

  18. Pyrazolo[1,5-a]quinazoline scaffold as 5-deaza analogue of pyrazolo[5,1-c][1,2,4]benzotriazine system: synthesis of new derivatives, biological activity on GABAA receptor subtype and molecular dynamic study.

    PubMed

    Guerrini, Gabriella; Ciciani, Giovanna; Ciattini, Samuele; Crocetti, Letizia; Daniele, Simona; Martini, Claudia; Melani, Fabrizio; Vergelli, Claudia; Giovannoni, Maria Paola

    2016-04-01

    To investigate the binding affinity of GABAA receptor subtype, new pyrazolo [1,5-a]quinazolines were designed, synthesized, and in vitro evaluated. These compounds, 5-deaza analogues of pyrazolo[5,1-c][1,2,4]benzotriazine derivatives which were already studied in our research group, permit us to evaluate the relevance of the nitrogen or the oxygen atom at 5-position of the tricyclic scaffold. Molecular dynamic study was done on a set of the new and known ligands to rationalize and to explain the lack of affinity on the 4- or 5-substituted new derivative. In fact, from biological results, it can be found that the only 5-unsubstituted new derivative, compound 15, has receptor recognition (Ki?=?834.7?nM). PMID:25792503

  19. Mammalian folylpoly-. gamma. -glutamate synthetase. 3. Specificity for folate analogues

    SciTech Connect

    George, S.; Cichowicz, D.J.; Shane, B.

    1987-01-27

    A variety of folate analogues were synthesized to explore the specificity of the folate binding site of hog liver folypolyglutamate synthetase and the requirements for catalysis. Modifications of the internal and terminal glutamate moieties of folate cause large drops in on rates and/or affinity for the protein. The only exceptions are glutamine, homocysteate, and ornithine analogues, indicating a less stringent specificity around the delta-carbon of glutamate. It is proposed that initial folate binding to the enzyme involves low-affinity interactions at a pterin and a glutamate site and that the first glutamate bound is the internal residue adjacent to the benzoyl group. Processive movement of the polyglutamate chain through the glutamate site and a possible conformational change in the protein when the terminal residue is bound would result in tight binding and would position the ..gamma..-carboxyl of the terminal glutamate in the correct position for catalysis. The 4-amino substitution of folate increases the on rate for monoglutamate derivatives but severely impairs catalysis with diglutamate derivatives. Pteroylornithine derivatives are the first potent and specific inhibitors of folylpolyglutamate synthetase to be identified and may act as analogues of reaction intermediates. Other folate derivatives with tetrahedral chemistry replacing the peptide bond, such as pteroyl-..gamma..-glutamyl-(psi,CH/sub 2/-NH)-glutamate, retain affinity for the protein but are considerably less effective inhibitors than the ornithine derivatives. Enzyme activity was assayed using (/sup 14/C)glutamate.

  20. Engineering of Insulin Receptor Isoform-Selective Insulin Analogues

    PubMed Central

    Glendorf, Tine; Stidsen, Carsten E.; Norrman, Mathias; Nishimura, Erica; Srensen, Anders R.; Kjeldsen, Thomas

    2011-01-01

    Background The insulin receptor (IR) exists in two isoforms, A and B, and the isoform expression pattern is tissue-specific. The C-terminus of the insulin B chain is important for receptor binding and has been shown to contact the IR just adjacent to the region where the A and B isoforms differ. The aim of this study was to investigate the importance of the C-terminus of the B chain in IR isoform binding in order to explore the possibility of engineering tissue-specific/liver-specific insulin analogues. Methodology/Principal Findings Insulin analogue libraries were constructed by total amino acid scanning mutagenesis. The relative binding affinities for the A and B isoform of the IR were determined by competition assays using scintillation proximity assay technology. Structural information was obtained by X-ray crystallography. Introduction of B25A or B25N mutations resulted in analogues with a 2-fold preference for the B compared to the A isoform, whereas the opposite was observed with a B25Y substitution. An acidic amino acid residue at position B27 caused an additional 2-fold selective increase in affinity for the receptor B isoform for analogues bearing a B25N mutation. Furthermore, the combination of B25H with either B27D or B27E also resulted in B isoform-preferential analogues (2-fold preference) even though the corresponding single mutation analogues displayed no differences in relative isoform binding affinity. Conclusions/Significance We have discovered a new class of IR isoform-selective insulin analogues with 24-fold differences in relative binding affinities for either the A or the B isoform of the IR compared to human insulin. Our results demonstrate that a mutation at position B25 alone or in combination with a mutation at position B27 in the insulin molecule confers IR isoform selectivity. Isoform-preferential analogues may provide new opportunities for developing insulin analogues with improved clinical benefits. PMID:21625452

  1. The Effectiveness of Course Web Sites in Higher Education: An Exploratory Study.

    ERIC Educational Resources Information Center

    Comunale, Christie L.; Sexton, Thomas R.; Voss, Diana J. Pedagano

    2002-01-01

    Describes an exploratory study of the educational effectiveness of course Web sites among undergraduate accounting students and graduate students in business statistics. Measured Web site visit frequency, usefulness of each site feature, and the impacts of Web sites on perceived learning and course performance. (Author/LRW)

  2. 76 FR 81959 - Notice of Proposed Information Collection: Comment Request; Homelessness Prevention Study Site...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... URBAN DEVELOPMENT Notice of Proposed Information Collection: Comment Request; Homelessness Prevention... following information: Title of Proposal: Homelessness Prevention Study Site Visits. OMB Control Number, if... requirements associated with HUD's Homelessness Prevention Study Site Visits. This information...

  3. Report of the Fermilab Committee for Site Studies

    SciTech Connect

    Steve Holmes, Vic Kuchler et. al.

    2001-09-10

    Fermilab is the flagship laboratory of the U.S. high-energy physics program. The Fermilab accelerator complex has occupied the energy frontier nearly continuously since its construction in the early 1970s. It will remain at the frontier until the Large Hadron Collider at CERN begins operating in 2006-7. A healthy future for Fermilab will likely require construction of a new accelerator in the post-LHC era. The process of identifying, constructing and operating a future forefront facility will require the support of the world high-energy-physics community, the governments and funding agencies of many nations and the people of surrounding communities. This report explores options for construction of a new facility on or near the existing Fermilab site. We began the study that forms the basis of this report with the idea that Fermilab, and the surrounding area of northeastern Illinois, possesses attributes that make it an attractive candidate for a new accelerator construction project: excellent geology; a Fermilab staff and local contractors who are experienced in subsurface construction; abundant energy supplies; good access to transportation networks; the presence of local universities with strong interest and participation in the Fermilab research program; Fermilab's demonstrated ability to mount large accelerator construction projects and operate complex accelerator facilities; and a surrounding community that is largely supportive of Fermilab's presence. Our report largely confirms these perceptions.

  4. Variation effect on the insecticide activity of DDT analogues. A chemometric approach

    NASA Astrophysics Data System (ADS)

    Itoh, S.; Nagashima, U.

    2002-08-01

    We investigated a variation effect on the insecticide activity of DDT analogues by using the first principles electronic structure calculations and the neural network analysis. It has been found that the charge distribution at the specific atomic sites in the DDT molecule is related to their toxicity. This approach can contribute to designing a new insecticide and a new harmlessness process of the DDT analogues.

  5. NREL Studies Wind Farm Aerodynamics to Improve Siting (Fact Sheet)

    SciTech Connect

    Not Available

    2012-04-01

    NREL researchers have used high-tech instruments and high-performance computing to understand atmospheric turbulence and turbine wake behavior in order to improve wind turbine design and siting within wind farms.

  6. Evolving a polymerase for hydrophobic base analogues

    PubMed Central

    Loakes, David; Gallego, Jos; Pinheiro, Vitor B.; Kool, Eric T.; Holliger, Philipp

    2009-01-01

    Hydrophobic base analogues (HBAs) have shown great promise for the expansion of the chemical and coding potential of nucleic acids but are generally poor polymerase substrates. While extensive synthetic efforts have yielded examples of HBAs with favourable substrate properties, their discovery has remained challenging. Here we describe a complementary strategy for improving HBA substrate properties by directed evolution of a dedicated polymerase using compartmentalized self-replication (CSR) with the archetypal HBA 5-nitroindole (d5NI) and its derivative 5-nitroindole-3-carboxamide (d5NIC) as selection substrates. Starting from a repertoire of chimeric polymerases generated by molecular breeding of DNA polymerase genes from the genus Thermus, we isolated a polymerase (5D4) with a generically-enhanced ability to utilize HBAs after five rounds of CSR selection. 5D4 was able to form and extend d5NI and d5NIC (d5NI(C)) self-pairs as well as d5NI(C) heteropairs with all four bases with efficiencies approaching, or exceeding, those of the cognate Watson-Crick pairs, despite significant distortions caused by the intercalation of the d5NI(C) heterocycles into the opposing strand base stack, as shown by nuclear magnetic resonance spectroscopy (NMR). Unlike Taq polymerase, the selected polymerase 5D4 was also to extend HBA pairs such as Pyrene: ? (abasic site), d5NI: ?, and isocarbostyril (ICS): 7-azaindole (7AI), allowed bypass of a chemically diverse spectrum of HBAs and enabled PCR amplification with primers comprising multiple d5NI(C)-substitutions, while maintaining high levels of catalytic activity and fidelity. The selected polymerase 5D4 promises to expand the range of nucleobase analogues amenable to replication and should find numerous applications, including the synthesis and replication of nucleic acid polymers with expanded chemical and functional diversity. PMID:19778048

  7. Design of novel CSA analogues as potential safeners and fungicides.

    PubMed

    Zheng, Yang; Liu, Bin; Gou, Zhaopin; Li, Yao; Zhang, Xiao; Wang, Yanqing; Yu, Shujing; Li, Yonghong; Sun, Dequn

    2015-02-15

    Study of safeners has been seldom reported in literature. In this work, a series of novel acylsulfamoylbenzamide analogues was designed and synthesized with newly developed safener cyprosulfamide (CSA) as the leading compound. The activity assay against the herbicide thiencarbazone-methyl (TCM) on maize revealed that fifteen compounds showed better protective effect than CSA on the fresh weight of aerial parts, twelve compounds exhibited better activity on the dry weight of aerial parts. Remarkably, two compounds (6Ih, 7II) had protective effect on the four aspects of TCM treated maize. Further antifungal assay showed their excellent activity against Physollospora piricola. The structure-activity relationships of CSA analogues as safeners and fungicides were discussed and it might be valuable for further molecular modification of new CSA analogues. PMID:25582601

  8. Synthesis and Biological Evaluation of Carbocyclic Analogues of Pachastrissamine

    PubMed Central

    Kwon, Yongseok; Song, Jayoung; Bae, Hoon; Kim, Woo-Jung; Lee, Joo-Youn; Han, Geun-Hee; Lee, Sang Kook; Kim, Sanghee

    2015-01-01

    A series of carbocyclic analogues of naturally-occurring marine sphingolipid pachastrissamine were prepared and biologically evaluated. The analogues were efficiently synthesized via a tandem enyne/diene-ene metathesis reaction as a key step. We found that the analogue 4b exhibited comparable cytotoxicity and more potent inhibitory activity against sphingosine kinases, compared to pachastrissamine. Molecular modeling studies were conducted to provide more detailed insight into the binding mode of 4b in sphingosine kinase. In our docking model, pachastrissamine and 4b were able to effectively bind to the binding pocket of sphingosine kinase 1 as co-crystalized sphingosine. However, 4b showed a hydrophobic interaction with Phe192, which suggests that it contributes to its increased inhibitory activity against sphingosine kinase 1. PMID:25654428

  9. a New Framework for Geospatial Site Selection Using Artificial Neural Networks as Decision Rules: a Case Study on Landfill Sites

    NASA Astrophysics Data System (ADS)

    Abujayyab, S. K. M.; Ahamad, M. A. S.; Yahya, A. S.; Saad, A.-M. H. Y.

    2015-10-01

    This paper briefly introduced the theory and framework of geospatial site selection (GSS) and discussed the application and framework of artificial neural networks (ANNs). The related literature on the use of ANNs as decision rules in GSS is scarce from 2000 till 2015. As this study found, ANNs are not only adaptable to dynamic changes but also capable of improving the objectivity of acquisition in GSS, reducing time consumption, and providing high validation. ANNs make for a powerful tool for solving geospatial decision-making problems by enabling geospatial decision makers to implement their constraints and imprecise concepts. This tool offers a way to represent and handle uncertainty. Specifically, ANNs are decision rules implemented to enhance conventional GSS frameworks. The main assumption in implementing ANNs in GSS is that the current characteristics of existing sites are indicative of the degree of suitability of new locations with similar characteristics. GSS requires several input criteria that embody specific requirements and the desired site characteristics, which could contribute to geospatial sites. In this study, the proposed framework consists of four stages for implementing ANNs in GSS. A multilayer feed-forward network with a backpropagation algorithm was used to train the networks from prior sites to assess, generalize, and evaluate the outputs on the basis of the inputs for the new sites. Two metrics, namely, confusion matrix and receiver operating characteristic tests, were utilized to achieve high accuracy and validation. Results proved that ANNs provide reasonable and efficient results as an accurate and inexpensive quantitative technique for GSS.

  10. A new nonhydrolyzable reactive cGMP analogue, (Rp)-guanosine-3',5'-cyclic-S-(4-bromo-2,3-dioxobutyl)monophosphorothioate, which targets the cGMP binding site of human platelet PDE3A.

    PubMed

    Hung, Su H; Liu, Andy H; Pixley, Robin A; Francis, Penelope; Williams, LaTeeka D; Matsko, Christopher M; Barnes, Karine D; Sivendran, Sharmila; Colman, Roberta F; Colman, Robert W

    2008-06-01

    The amino acids involved in substrate (cAMP) binding to human platelet cGMP-inhibited cAMP phosphodiesterase (PDE3A) are identified. Less is known about the inhibitor (cGMP) binding site. We have now synthesized a nonhydrolyzable reactive cGMP analog, Rp-guanosine-3',5'-cyclic-S-(4-bromo-2, 3-dioxobutyl)monophosphorothioate (Rp-cGMPS-BDB). Rp-cGMPS-BDB irreversibly inactivates PDE3A (K(I)=43.4+/-7.2muM and k(cart)=0.007+/-0.0006 min(-1)). The effectiveness of protectants in decreasing the rate of inactivation by Rp-cGMPS-BDB is: Rp-cGMPS (K(d)=72 microM)>Sp-cGMPS (124), Sp-cAMPS (182)>GMP (1517), Rp-cAMPS (3762), AMP (4370 microM). NAD(+), neither a substrate nor an inhibitor of PDE3A, does not protect. Nonhydrolyzable cGMP analogs exhibit greater affinity than the cAMP analogs. These results indicate that Rp-cGMPS-BDB targets favorably the cGMP binding site consistent with a docking model of PDE3A-Rp-cGMPS-BDB active site. We conclude that Rp-cGMPS-BDB is an effective active site-directed affinity label for PDE3A with potential for other cGMP-dependent enzymes. PMID:18394675

  11. Long-term effects of CO2 on the mechanical behaviour of faults - a study of samples from a natural CO2 analogue (Entrada Sandstone, Utah, USA)

    NASA Astrophysics Data System (ADS)

    Hangx, S. J. T.; Bakker, E.; Spiers, C. J.

    2012-04-01

    In an attempt to reduce CO2 emissions, CO2 capture and storage in depleted oil and gas reservoirs is seen as one of the most important mitigation strategies. However, in order to achieve safe storage on geological timescales, it is key to maintain integrity of the caprock and any faults penetrating the seal. One of the largest uncertainties lies in the prediction of the effects of fluid-rock interaction on the mechanical integrity and sealing capacity of the reservoir-seal system in the very long term, i.e. on timescales of the order of 103 or 104 years. As chemical interactions in the rock/CO2/brine system are slow, their long-term effects on rock composition, microstructure, mechanical properties and transport properties cannot be properly reproduced in laboratory experiments. One way of addressing this issue is to conduct experiments on reservoir, caprock and fault rock samples taken from natural CO2 reservoir-seal systems, which can serve as natural analogues for CO2 storage fields. The transport and mechanical properties of these rock samples, which have reacted with CO2 over geological timescales, can then be compared with data obtained for laterally equivalent materials that are unaffected by CO2. The observed changes in rock properties can subsequently be used as input for numerical models aimed at assessing the long-term effects of CO2 on reservoir compaction, caprock damage, fault reactivation and fault permeability. We assessed the mechanical behaviour and transport properties of fault rocks. To this end, we performed triaxial direct shear experiments at room temperature under nominally dry conditions, at normal stresses up to 90 MPa and shear velocities of 0.22 -10.9 ?m/s. Simulated fault rocks were prepared by crushing material obtained from surface outcrops of the Entrada Sandstone, one of the CO2-bearing formations from an analogue field under the Colorado Plateau, Utah, USA. Three types of starting material were obtained: 1) red-coloured samples consisting mainly of quartz and feldspar, some minor clay minerals and hematite/goethite grain coatings, 2) yellow-coloured, (so-called) bleached samples additionally containing various amounts of kaolinite, calcite and dolomite, and 3) heavily cemented samples from the surface outcrop of the fault core of the Little Grand Wash Fault, containing a high percentage of carbonates (> 40 wt%). Previous work demonstrates that the bleached samples and the material from the fault were altered as a result of interaction with CO2-rich fluids. Over the experimental range investigated, we measured friction coefficients of 0.55-0.85 for unbleached material and 0.55-0.80 for bleached material, while the fault core material showed higher friction coefficients (0.60-0.95), all showing a minor decrease with decreasing shear velocity and normal stress. Almost all samples showed velocity-strengthening slip behaviour. Overall, the frictional behaviour of Entrada Sandstone does not seem to be strongly influenced by CO2/brine/rock interactions.

  12. Preliminary study on brominated dioxins/furans and hydroxylated/methoxylated PBDEs in Baltic cod (Gadus morhua) liver. Comparison to the levels of analogue chlorinated co-occurring pollutants.

    PubMed

    Roszko, Marek; Szymczyk, Krystyna; Rzepkowska, Ma?gorzata; J?drzejczak, Renata

    2015-07-15

    Low pg levels of PBDD/Fs in 0.8-38.9 pg g(-1) (fat) range (mean 14.2 pg g(-1)) observed in the tested cod liver samples were significantly lower than levels of their chlorinated analogues (25.1-95.9 range, 37.7 mean pg g(-1) fat). Brominated furans dominated the congener profile. Elevated levels of OH-/MeO-BDE were however observed with mean concentrations at 27691319 and 54412918 pg g(-1) (fat) respectively. The observed congener profiles with the predominance of 6-OH-BDE 47 and the relatively high proportion between the native and hydroxylated compounds indicate on natural origin of those compounds or at least presence of various exposure sources. A large fraction of studied samples did not comply with the currently standing EU regulations concerning PCBs and chlorinated dioxins (11%), especially as regards non-dioxin like PCBs (88%). PMID:26002098

  13. Andrographolide and analogues in cancer prevention.

    PubMed

    Mishra, Siddhartha Kumar; Tripathi, Swati; Shukla, Archana; Oh, Seung Hyun; Kim, Hwan Mook

    2015-01-01

    Andrographis paniculata is a medicinal plant traditionally used for treatment of cough and cold, fever, laryngitis, and several infectious diseases. Extracts of A. paniculata have shown versatile potency against various diseases including cancer. The active biomolecules of A. paniculata mainly are lactone and diterpene. Andrographolide and analogues have been widely used for prevention of different diseases. Andrographolides have shown potent antiinflammatory and anticancer activities. It showed potentials as chemopreventive agents by suppressing growth of cancer cells by inhibiting NF-kappaB, PI3K/AKT and other kinase pathways and by inducing apoptosis. Andrographolide induced both intrinsic and extrinsic apoptosis pathway in different cancer cells via expression of different anti-apoptotic protein like Bax, p53, and activated caspases. Andrographolide was successfully used as an antineoplastic drug in cancer chemotherapy. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide and analogues need to be subjected to further clinical and biomedical studies in cancer chemoprevention. Andrographolide could be potent anticancer agent when used in combination with other chemotherapeutic agents. PMID:25553378

  14. Scandium(iii) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with (44)Sc from cyclotron and from a (44)Ti/(44)Sc generator.

    PubMed

    Kerdjoudj, R; Pniok, M; Alliot, C; Kubíček, V; Havlíčková, J; Rösch, F; Hermann, P; Huclier-Markai, S

    2016-01-19

    The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine. PMID:26675416

  15. β Sheets Not Required: Combined Experimental and Computational Studies of Self-Assembly and Gelation of the Ester-Containing Analogue of an Fmoc-Dipeptide Hydrogelator

    PubMed Central

    2015-01-01

    In our work toward developing ester-containing self-assembling peptides as soft biomaterials, we have found that a fluorenylmethoxycarbonyl (Fmoc)-conjugated alanine-lactic acid (Ala-Lac) sequence self-assembles into nanostructures that gel in water. This process occurs despite Fmoc-Ala-Lac’s inability to interact with other Fmoc-Ala-Lac molecules via β-sheet-like amide–amide hydrogen bonding, a condition previously thought to be crucial to the self-assembly of Fmoc-conjugated peptides. Experimental comparisons of Fmoc-Ala-Lac to its self-assembling peptide sequence analogue Fmoc-Ala-Ala using a variety of microscopic, spectroscopic, and bulk characterization techniques demonstrate distinct features of the two systems and show that while angstrom-scale self-assembled structures are similar, their nanometer-scale size and morphological properties diverge and give rise to different bulk mechanical properties. Molecular dynamics simulations were performed to gain more insight into the differences between the two systems. An analysis of the hydrogen-bonding and solvent-surface interface properties of the simulated fibrils revealed that Fmoc-Ala-Lac fibrils are stronger and less hydrophilic than Fmoc-Ala-Ala fibrils. We propose that this difference in fibril amphiphilicity gives rise to differences in the higher-order assembly of fibrils into nanostructures seen in TEM. Importantly, we confirm experimentally that β-sheet-type hydrogen bonding is not crucial to the self-assembly of short, conjugated peptides, and we demonstrate computationally that the amide bond in such systems may act mainly to mediate the solvation of the self-assembled single fibrils and therefore regulate a more extensive higher-order aggregation of fibrils. This work provides a basic understanding for future research in designing highly degradable self-assembling materials with peptide-like bioactivity for biomedical applications. PMID:24786493

  16. High resolution 1H NMR-based metabonomic study of the auditory cortex analogue of developing chick (Gallus gallus domesticus) following prenatal chronic loud music and noise exposure.

    PubMed

    Kumar, Vivek; Nag, Tapas Chandra; Sharma, Uma; Mewar, Sujeet; Jagannathan, Naranamangalam R; Wadhwa, Shashi

    2014-10-01

    Proper functional development of the auditory cortex (ACx) critically depends on early relevant sensory experiences. Exposure to high intensity noise (industrial/traffic) and music, a current public health concern, may disrupt the proper development of the ACx and associated behavior. The biochemical mechanisms associated with such activity dependent changes during development are poorly understood. Here we report the effects of prenatal chronic (last 10 days of incubation), 110dB sound pressure level (SPL) music and noise exposure on metabolic profile of the auditory cortex analogue/field L (AuL) in domestic chicks. Perchloric acid extracts of AuL of post hatch day 1 chicks from control, music and noise groups were subjected to high resolution (700MHz) (1)H NMR spectroscopy. Multivariate regression analysis of the concentration data of 18 metabolites revealed a significant class separation between control and loud sound exposed groups, indicating a metabolic perturbation. Comparison of absolute concentration of metabolites showed that overstimulation with loud sound, independent of spectral characteristics (music or noise) led to extensive usage of major energy metabolites, e.g., glucose, β-hydroxybutyrate and ATP. On the other hand, high glutamine levels and sustained levels of neuromodulators and alternate energy sources, e.g., creatine, ascorbate and lactate indicated a systems restorative measure in a condition of neuronal hyperactivity. At the same time, decreased aspartate and taurine levels in the noise group suggested a differential impact of prenatal chronic loud noise over music exposure. Thus prenatal exposure to loud sound especially noise alters the metabolic activity in the AuL which in turn can affect the functional development and later auditory associated behaviour. PMID:25049174

  17. Tandem Friedel–Crafts Annulation to Novel Perylene Analogues

    PubMed Central

    Penick, Mark A.; Mahindaratne, Mathew P. D.; Gutierrez, Robert D.; Smith, Terrill D.; Tiekink, Edward R. T.

    2014-01-01

    Novel dialkyloxy- and dihydroxyoctahydroperylenes are regioselectively available via a new tandem Friedel–Crafts alkylation of tetrahydronaphthalene precursors followed by oxidative aromatization. Heating of 5-alkyloxy-1-tetralol with p-toluenesulfonic acid in sulfolane gave the corresponding octahydroperylenes in moderate yields. Studies with Lewis acids and tetralin-1,5-diol in acetonitrile at room temperature provided the 4,10-dihydroxy analogue cleanly, albeit in reduced yields. Examples of these new series of perylene analogues were partially oxidized to the corresponding contiguously aromatic, anthracene core products or fully aromatized to 3,9-dialkyloxyperylenes in good yields. PMID:18630879

  18. Non-natural acetogenin analogues as potent Trypanosoma brucei inhibitors

    PubMed Central

    Florence, Gordon J.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Menzies, Stefanie K.; Morris, Joanne C.; Tulloch, Lindsay B.; Smith, Terry K.

    2015-01-01

    A series of novel bis-tetrahydropyran 1,4-triazole analogues based on the acetogenin framework display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei, the causative agent of African sleeping sickness. A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4-triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure activity relationship studies. PMID:25145275

  19. Graphene analogues of layered metal selenides.

    PubMed

    Matte, H S S Ramakrishna; Plowman, Blake; Datta, Ranjan; Rao, C N R

    2011-10-28

    Graphene analogues of MoSe(2) and WSe(2) have been prepared by three different chemical methods and characterized by electron microscopy and other methods. Graphene analogues of these diselenides as well as of GaSe have also been obtained by liquid-phase exfoliation. Raman spectra of the graphene analogues show significant changes relative to those of the bulk samples. PMID:21776532

  20. FUNCTION GENERATOR FOR ANALOGUE COMPUTERS

    DOEpatents

    Skramstad, H.K.; Wright, J.H.; Taback, L.

    1961-12-12

    An improved analogue computer is designed which can be used to determine the final ground position of radioactive fallout particles in an atomic cloud. The computer determines the fallout pattern on the basis of known wind velocity and direction at various altitudes, and intensity of radioactivity in the mushroom cloud as a function of particle size and initial height in the cloud. The output is then displayed on a cathode-ray tube so that the average or total luminance of the tube screen at any point represents the intensity of radioactive fallout at the geographical location represented by that point. (AEC)

  1. Descriptions of research sites in the integrated forest study on effects of atmospheric deposition

    SciTech Connect

    Bondiette, E.A.

    1990-03-01

    This site descriptions report documents the site characteristics and site-specific measurement approaches of participating sites in the Integrated Forest Study on Effects of Atmospheric Deposition (IFS), a multiyear integrated research effort designed to improve our understanding of how chemicals which are deposited from the atmosphere influence the mineral nutrient cycles in forests. The research has been performed at a series of forested sites in the US, Canada, and Norway. 56 refs., 18 figs., 22 tabs.

  2. Site study plan for Deep Hydronest Test Wells, Deaf Smith County Site, Texas: Preliminary draft

    SciTech Connect

    Not Available

    1987-05-01

    Wells called Deep Hydronest Wells will be installed at six locations at the Deaf Smith County Site to characterize hydraulic parameters in the geologic column between the top of the San Andres Formation and the base of Pennsylvanian System. Three hydronests will be drilled during early stages of site characterization to provide data for performance assessment modeling. Four wells are proposed for each of these 3 nests. Results of drilling, testing, and preliminary modeling will direct drilling and testing activities at the last 3 nests. Two wells are proposed at each of the last 3 nests for a total of 18 wells. The Salt Repository Project (SRP) Networks specify the schedule under which this program will operate. Drilling and hydrologic testing of the first Deep Hydronest will begin early in the Surface Investigation Program. Drilling and testing of the first three Deep Hydronests will require about 18 months. After 12 months of evaluating and analyzing data from the first three hydronests, the remaining three hydronests will be drilled during a 12-month period. The Technical Field Services Contractor is responsible for conducting the field program. Samples and data will be handled and reported in accordance with established SRP procedures. A quality assurance program will be used to assure that activities affecting quality are performed correctly and that the appropriate documentation is maintained. 36 refs., 20 figs., 6 tabs.

  3. Technical procedures for implementation of aesthetics site studies, Deaf Smith County site, Texas: Environmental Field Program

    SciTech Connect

    Not Available

    1987-06-01

    This chapter introduces the purpose and scope of the visually affected areas determination, as well as definitions, interfaces, and concurrent data needs. This procedure provides a method for determining the extent of visibility of the project. This area is identified as the visually affected area, and becomes the area within which all visual analysis is conducted. The visually affected area analysis of the Deaf Smith County site will involve identifying and mapping the visibility of all major proposed project features. Baseline analysis will be conducted within the overall visually affected area; impact assessment will be conducted within the visually affected area of each major project feature. This procedure presents the guidelines for determining the visually affected area will be in computer data base construction; viewshed modeling, and site visit and verification of results. Computer data base construction will involve digitizing topographic and project facility data from available data source. The extent of the visible area from each major project feature will then be plotted. Finally, these computer-generated visibility plots will be verified in the field.

  4. A Fluorescent Adenosine Analogue as a Substrate for an A-to-I RNA Editing Enzyme.

    PubMed

    Mizrahi, Rena A; Shin, Dongwon; Sinkeldam, Renatus W; Phelps, Kelly J; Fin, Andrea; Tantillo, Dean J; Tor, Yitzhak; Beal, Peter A

    2015-07-20

    Adenosine to inosine RNA editing catalyzed by ADAR enzymes is common in humans, and altered editing is associated with disease. Experiments using substrate RNAs with adenosine analogues at editing sites are useful for defining features of the ADAR reaction mechanism. The reactivity of ADAR2 was evaluated with RNA containing the emissive adenosine analogue thieno[3,4-d]-6-aminopyrimidine ((th)A). This nucleoside was incorporated into a mimic of the glutamate receptor B (GluR B) mRNA R/G editing site. We found that (th)A is recognized by AMV reverse transcriptase as A, and is deaminated rapidly by human ADAR2 to give (th)I. Importantly, ADAR reaction progress can be monitored by following the deamination-induced change in fluorescence of the (th)A-modified RNA. The observed high (th)A reactivity adds to our understanding of the structural features that are necessary for an efficient hADAR2 reaction. Furthermore, the new fluorescent assay is expected to accelerate mechanistic studies of ADARs. PMID:26095193

  5. The voluntary siting process, a case study in New Jersey.

    PubMed

    Stencel, Joseph R; Lee, Kenneth Y

    2004-02-01

    The Low-Level Radioactive Waste Policy Act of 1980 and its 1985 Amendments has not provided new disposal capacity within the United States; however, sufficient disposal capacity currently exists to handle today's disposal needs. Politics, opposition groups, and public mistrust in government have combined to limit the possibilities for establishing new disposal facilities. In 2000, New Jersey (NJ and Connecticut (CT), as members of the Northeast Compact for the disposal of low-level radioactive waste, admitted South Carolina (SC) to their compact, renaming it as the "Atlantic Compact." The advantage to SC is that they are able to prevent disposal of waste from outside the Compact. The advantage to NJ and CT is that they are guaranteed waste disposal for approximately the next 50 years, or until all currently operating nuclear power plants in the states are decommissioned. This paper details the process, much of it not following the scientific method, to try to site a low-level waste facility in NJ. With the formation of the NJ Siting Board in 1987, an effort was made to locate a site using deterministic criteria; however, in 1992, the Board shifted to a voluntary process. In 1998, the Board made the determination that there was adequate capacity for waste disposal and ended active siting. In 2000, the opportunity to form the Atlantic Compact ended siting through an out-of-state solution. While it is not clear that the voluntary process would have ultimately worked in NJ, it has worked in Canada and the process may be one of the few mechanisms for the siting of any type of hazardous material disposal facility. Also, other states still have to decide what they will do after 2008 when Barnwell is no longer open to them. PMID:14744073

  6. Reactions of site-differentiated [Fe4S4]2+, 1+ clusters with sulfonium cations: reactivity analogues of biotin synthase and other members of the S-adenosylmethionine enzyme family.

    PubMed

    Daley, Christopher J A; Holm, R H

    2003-11-01

    The first examples of reduced 3:1 site-differentiated Fe(4)S(4) clusters have been synthesized as [Fe(4)S(4)(LS(3))(SR')](3-) (R=Et, Ph) by chemical reduction of previously reported [Fe(4)S(4)(LS(3))(SR')](2-) clusters, and isolated as NBu(4)(+) salts. The reduced clusters were characterized by electrochemistry and EPR, 1H NMR, and Mössbauer spectroscopies. The reaction of oxidized clusters with the sulfonium ions [PhMeSCH(2)R](+) (R=COPh, p-C(6)H(4)CN) in acetonitrile results in electrophilic attack on coordinated thiolate and production of PhSMe and R'SCH(2)R when the reaction occurs at the unique cluster site. The reactions of reduced clusters with these substrates were examined in relation to the reductive cleavage of the cofactor S-adenosylmethionine, the first step in the catalytic cycle of biotin synthase. Product analysis indicated a approximately 4:1 ratio of reductive cleavage to electrophilic attack. The cleavage products are PhSMe, R'SCH(2)R, and RCH(3) for both clusters, and also PhMeS=CHR and RCH(2)CH(2)R from secondary reactions when the sulfonium cation is [PhMeSCH(2)COPh](+) and [PhMeSCH(2)-p-C(6)H(4)CN](+), respectively. Reaction schemes for reductive cleavage based on product distributions are presented. These results parallel those previously reported for homoleptic [Fe(4)S(4)(SR')(4)](2-,3-) clusters and demonstrate that site-differentiated clusters sustain a high percentage of reductive cleavage, a necessary result in the context of biotin synthase activity preceding an investigation of the mode of binding of sulfonium substrates and inhibitors at the unique iron site. [LS(3)=1,3,5-tris[(4,6-dimethyl-3-mercaptophenyl)thio]-2,4,6-tris(p-tolylthio)benzene(3-)]. PMID:14511891

  7. First generation analogues of the binuclear site in the Fe-only hydrogenases: Fe{sub 2}({mu}-SR){sub 2}(CO){sub 4}(CN){sub 2}{sup 2{minus}}

    SciTech Connect

    Schmidt, M.; Contakes, S.M.; Rauchfuss, T.B.

    1999-10-20

    Hydrogenase enzymes are utilized by numerous microorganisms to produce dihydrogen or to take up dihydrogen in support of their metabolic activities. The two families of metallo-hydrogenases feature FeM({mu}-SR){sub 2}(CO){sub n}(CN){sub n} cores. Having cyanide and CO coligands as well as metal-metal bonding, the hydrogenase active sites represent a link between the otherwise disparate realms of organometallic and biological Fe-S chemistry.

  8. Space Analogue Environments: Are the Populations Comparable?

    NASA Astrophysics Data System (ADS)

    Sandal, G. M.

    Background: Much of our present understanding about psychology in space is based on studies of groups operating in so-called analogue environments where personnel are exposed to many of the same stressors as those experienced by astronauts in space. One possible problem with extrapolating results is that personnel operating in various hazardous and confined environments might differ in characteristics influencing coping, interaction, and performance. The object of this study was to compare the psychological similarity of these populations in order to get a better understanding of whether this extrapolation is justifiable. The samples investigated include polar crossings (N= 22), personnel on Antarctic research stations (N= 183), several military occupations (N= 187), and participants in space simulation studies (N=20). Methods: Personnel in each of these environments were assessed using the Personality Characteristic Inventory (PCI) and Utrecht Coping List (UCL). The PCI is a multidimensional trait assessment battery that measures various aspects of achievement orientation and social competence. The UCL is a questionnaire designed to assess habitual coping strategies when encountering stressful or demanding situations. Results: Only minor differences in use of habitual coping strategies were evident across the different samples. In relation to personality scores, the military subjects and participants in space simulation studies indicated higher competitiveness and negative instrumentality compared to both the personnel on Antarctic research stations and participants in polar expedition. Among the personnel on Antarctic research stations, significant gender differences were found with women scoring lower on competitiveness, negative instrumentality and impatience/irritability. Compared to the other samples, the participants in polar expeditions were found to be more homogeneous in personality and no significant gender differences were evident on the traits that were assessed. Most of the polar expeditionners had the combination of high scores on positive expressivity and high achievement motivation- a profile which has sometimes been characterized as "the right stuff" for coping in confined and isolated settings. Conclusion: The findings from this study suggest that populations in various space-analogue environments differ in personality traits which might impact on the comparability of psychological findings obtained in different setting. Gender differences in personality also represent a potential source of variance that need to be addressed when generalizing results across space analogue environments.

  9. A Preliminary Case Study for Rectenna Sites in Indonesia

    NASA Astrophysics Data System (ADS)

    Purwanto, Y.; Collins, P.

    2004-12-01

    Electricity power generation using alternative energy sources in Indonesia has become an important policy. Until now, the contribution from alternative energy sources (especially from renewable energy sources) is very small, only about 1% of the total energy supply. It is expected that in the next 10 years this contribution will be raised to 20%. The development of renewable energy sources is primarily performed in remote areas, that are poor in infrastructure facilities. This is considered to be a good policy since there are many such remote areas in Indonesia that need development programs. The existence of Solar Power Satellite system will open a new horizon in alternative energy supply, including Indonesia, because of its higher efficiency compared to conventional terrestrial solar cells, with almost no influence from either climate or solar position. Like other countries in the world, Indonesia, although one of the largest mineral energy producers in the world (i.e. oil, coal, and natural gas), still gives attention to energy diversification programs, including solar energy utilization. SPS, being based on solar energy, could be a good choice. The Indonesian archipelago consists of thousands of islands (more than 13,000) and is the equatorial country with the longest equatorial extent (more than 5000 km). This condition is very good for energy reception from the SPS 2000 pilot plant since the energy transmitting system (spacetenna) will orbit above the equator. Along the equator there could be placed more than four receiving stations (rectenna), especially in remote areas. Thus, it is very important to consider the involvement of Indonesia in SPS energy reception research. This paper describes a preliminary study of the development possibilities in SPS energy reception in Indonesia. To define the rectenna sites and physical development aspect, this study considers some major aspects: environmental, technical, social, and economic aspects. Environmental aspects include the possibilities of environmental damage due to the high intensity electromagnetic energy from outer space. As is well known, most Indonesian land areas consist of tropical forest which is rich with flora and fauna; these may face risks from receiving such electromagnetic energy illumination. It is considered that rectenna location selection in the main islands (like Java, Sumatra, Kalimantan, Sulawesi, Irian, etc.) which are densely populated should be avoided. The same conditions should also be considered for the location in the forest, due to the flora and fauna damage possibilities during the physical development process. From this study it can be considered that the appropriate rectenna location should be placed on uninhabited small coral islands (atoll) sized about 5x5 km 2 , which are located along the equator. Such coral islands are vailable in the western and eastern parts of Indonesia. It is also considered that such coral islands should be located not too far from major inhabited islands, that is about 5-10 km offshore due to the convenience of physical rectenna development and electric energy distribution to the mainland. Such a coral island is to be considered to suffer minimal effects if the surface is illuminated by microwave energy. The same effect suffered by resident creatures like birds and reptiles should also be minimal. Because of the very limited infrastructure available on the mainland (and likely no facilities at all), a rectenna development study should consider all technical risks. For example, antenna installation and building of other support components should be done in such a location so that sea surface transportation can be easily performed. Communication system may be performed only by radio transceivers and satellite systems. The existence of human resources, that are needed to physically develop buildings, must be considered since the location is a remote island. There will also be no expert staff available, so that they will need to be recruited on the mainland (i.e. Java). From these considerations it can be seen that a good first rectenna location would be in North Moluccas, that is islands around Halmahera Island. As remote islands, Halmahera Island and the nearby Biang Island and Bacan Island do not have enough electric energy sources to support economic activities significantly. A rectenna site can be developed there to support SPS energy reception research and, as a benefit for the people, can support their electricity needs to improve their life quality. Educational research on SPS energy reception, as a most important aspect in this case, can be performed by local research institutions and universities in Ambon and Java in collaboration with international institutions. The previous study of SPS in Indonesia showed that many research institutions and universities in Indonesia offered their kind attention to involve their researchers in energy reception research. Furthermore, the political conditions and social safety in Indonesia now offer a conducive atmosphere for such research.

  10. Martian Habitability Studies in Two Field Earth Analogues: the Permafrost in the Imuruk Lake Basaltic Field (alaska) and the Atacama Desert

    NASA Astrophysics Data System (ADS)

    Gómez-Gómez, Felipe; Rodriguez-Manfredi, Jose-Antonio; Perez, Lidia; Prieto-Ballesteros, Olga; Amils, Ricardo; Gomez-Elvira, Javier

    We are developing a Universal Habitability Index for life prospection studies in space missions. Authors will present in this abstract the results of the application of the habitability index in two field case studies: Alaskan permafrost and Atacama Desert. We are using extreme envi-ronments as test facilities from an Astrobiological perspective, in order to reach three main objectives: 1) Define preservation patterns of biosignatures in extreme environments (cold, low water stress, high radiation. . . ) that may be used in future space exploration missions; 2) develop new instrumentation for detecting life in situ or remotely, and for new instrumenta-tion for detection and mapping of extreme niches where life (or biochemical tracers of past life) may be preserved and 3) develop an Universal Habitability Index for space astrobiolog-ical mission application (Mars or Europa life prospection). These aims will be achieved by selected site characterization using geophysical sounding and drilling, atmospheric characteri-zation by meteorological analysis, soil water and temperature profile analysis and, finally, by sampling different levels of the rock cores and analyzing their mineralogy, geochemistry and microbiology in laboratory. First case: studying the permafrost in the Imuruk lake volcanic field area (Alaska): In order to map the permafrost underground, electric tomography sounding was performed. Resulting tomographic data indicate that the permafrost of the studied area is at a mean depth of 0.50 meter from the surface, sometimes even shallower. Drilling points were selected depending on the permafrost depth known from the tomographic data analysis. Three perforations were done all along the hill. Samples were collected at several depths in the three holes for mineralogical, geochemical and biological analysis. They were in situ fixed with formaldehyde in order to be maintained till laboratory analysis was developed. Several growth fresh media were inoculated with samples from different depths in the field for microor-ganism's enrichment. First results report enrichment in several inoculated media including some specific for heterotrophic aerobic bacteria, anaerobic chemolithotrophic and methanogen bacteria. Two different molecular methods are being used for microbial determination: "In situ" hybridizitation (was used for microbial determination and cell counting also) and 16S rRNA genes amplification, cloning and sequencing. First results in cell counting determined a population density gradient vs. depth. Second case: studying Atacama Desert: Habitability studies in the Atacama Desert were developed by the selection of a 36 square meters area where an atmospheric station was installed. The following parameters were measured: UV radiation, atmosphere temperature, ground temperature at three different depths, wind direction. Sam-ples at the pre-selected depths were taken in order to develop microbiological studies in the laboratory. Interesting results that will be presented at the COSPAR session were obtained with decreasing levels of life presence along the core profile. Acknowledgments: Centro de Astrobiologia INTA/CSIC (Spain) supported the expedition to Imuruk Lake. The Atacama expedition was supported with the Grant ESP 2004-05008 "De-teccién de biomoléculas en exploracién planetaria" from the Spanish Government. Laboratory analysis was supported with the Grant ESP-2006/06640 "Desarrollo de Tecnologé para la ıa Identificacién de Vida de forma Automética (DTIVA)"

  11. Fuel quality/processing study. Volume 4: On site processing studies

    NASA Technical Reports Server (NTRS)

    Jones, G. E., Jr.; Cutrone, M.; Doering, H.; Hickey, J.

    1981-01-01

    Fuel treated at the turbine and the turbine exhaust gas processed at the turbine site are studied. Fuel treatments protect the turbine from contaminants or impurities either in the upgrading fuel as produced or picked up by the fuel during normal transportation. Exhaust gas treatments provide for the reduction of NOx and SOx to environmentally acceptable levels. The impact of fuel quality upon turbine maintenance and deterioration is considered. On site costs include not only the fuel treatment costs as such, but also incremental costs incurred by the turbine operator if a turbine fuel of low quality is not acceptably upgraded.

  12. The ketamine analogue methoxetamine and 3- and 4-methoxy analogues of phencyclidine are high affinity and selective ligands for the glutamate NMDA receptor.

    PubMed

    Roth, Bryan L; Gibbons, Simon; Arunotayanun, Warunya; Huang, Xi-Ping; Setola, Vincent; Treble, Ric; Iversen, Les

    2013-01-01

    In this paper we determined the pharmacological profiles of novel ketamine and phencyclidine analogues currently used as 'designer drugs' and compared them to the parent substances via the resources of the National Institute of Mental Health Psychoactive Drug Screening Program. The ketamine analogues methoxetamine ((RS)-2-(ethylamino)-2-(3-methoxyphenyl)cyclohexanone) and 3-MeO-PCE (N-ethyl-1-(3-methoxyphenyl)cyclohexanamine) and the 3- and 4-methoxy analogues of phencyclidine, (1-[1-(3-methoxyphenyl)cyclohexyl]piperidine and 1-[1-(4-methoxyphenyl)cyclohexyl]piperidine), were all high affinity ligands for the PCP-site on the glutamate NMDA receptor. In addition methoxetamine and PCP and its analogues displayed appreciable affinities for the serotonin transporter, whilst the PCP analogues exhibited high affinities for sigma receptors. Antagonism of the NMDA receptor is thought to be the key pharmacological feature underlying the actions of dissociative anaesthetics. The novel ketamine and PCP analogues had significant affinities for the NMDA receptor in radioligand binding assays, which may explain their psychotomimetic effects in human users. Additional actions on other targets could be important for delineating side-effects. PMID:23527166

  13. RESEARCH STUDIES AT THE GILT EDGE MINE SUPERFUND SITE

    EPA Science Inventory

    A collaborative effort is being implemented at the Gilt Edge Mine Superfund site near Lead, SD. The partnerships involves the Mine Waste Technology Program (MWTP) with the USEPA's NRMRL, Region VIII Superfund program, the DOE, MSE Technology Application, Inc (MSE) and CDM Federal...

  14. Spectroscopic studies of the active site of galactose oxidase

    SciTech Connect

    Knowles, P.F.; Brown, R.D. III; Koenig, S.H.

    1995-07-19

    X-ray absorption and EPR spectroscopy have been used to probe the copper site structure in galactose oxidase at pH 4.5 and 7.0. the results suggest that there are no major differences in the structure of the tetragonal Cu(II) site at these pH values. Analysis of the extended X-ray absorption fine structure (EXAFS) indicates that four N,O scatterers are present at approximately 2 {Angstrom}; these are presumably the equatorial ligands. In addition, the EXAFS data establish that oxidative activation to produce the active-site tyrosine radical does not cause major changes in the copper coordination environment. Therefore results obtained on the one-electron reduced enzyme, containing Cu(II) but not the tyrosine radical, probably also apply to the catalytically active Cu(II)/tyrosine radical state. Solvent water exchange, inhibitor binding, and substrate binding have been probed via nuclear magnetic relaxation dispersion (NMRD) measurements. The NMRD profile of galactose oxidase is quantitatively consistent with the rapid exchange of a single, equatorial water ligand with a Cu(II)-O separation of about 2.4 {Angstrom}. Azide and cyanide displace this coordinated water. The binding of azide and the substrate dihydroxyacetone produce very similar effects on the NMRD profile of galactose oxidase, indicating that substrates also bind to the active site Cu(II) in an equatorial position.

  15. CASE STUDY: SITE CONCEPTUAL MODEL FOR ENHANCED MNA OF ARSENIC

    EPA Science Inventory

    Field investigations have been conducted to understand the fate of arsenic in contaminated ground water during discharge into the Halls Brook Holding Area (HBHA) Pond at the Industri-Plex Superfund Site in Massachusetts. The ground water plume contains elevated levels of arsenic...

  16. Site study plan for utilities and solid waste, Deaf Smith County Site, Texas: Environmental Field Program: Preliminary draft

    SciTech Connect

    Not Available

    1987-06-01

    This site plan describes utilities and solid waste studies to be conducted during the characterization of the Deaf Smith County, Texas, site for the US Department of Energy's Salt Repository Project. After utilities and solid waste information needs derived from Federal, State, and local statutes and regulations and the project specifications are briefly described, the site study plan describes the study design and rationale, the field data collection procedures and equipment, and data analysis methods and application of results, the data management strategy, the schedule of field activities, the management of the study, and the study's quality assurance program. The field data collection activities are organized into programs to characterize electrical power, natural gas, communication, water, wastewater sludge, nonradiological solid waste, nonradiological hazardous waste, and low-level radiological waste. These programs include details for the collection of project needs, identification of utilities and solid waste disposal contractor capabilities, and verification of the obtained data. Utilities and solid waste field activities will begin approximately at the time of site access. Utilities and solid waste characterization will be completed within the first year of activity. 29 refs., 6 figs., 2 tabs.

  17. Variability in ultraplankton at the Porcupine Abyssal Plain study site

    NASA Astrophysics Data System (ADS)

    Martin, Adrian P.; Zubkov, Mikhail V.; Holland, Ross J.; Tarran, Glen; Burkill, Peter

    2010-08-01

    Observations of the ultraplankton (<5 μm) are presented from a 4 day mesoscale survey centred on the Porcupine Abyssal Plain (PAP) study site (49°00'N 16°30'W), in July 2006. The organisms enumerated include two groups of phytoplankton, Synechococcus cyanobacteria, heterotrophic bacteria, large viruses, and two size classes of heterotrophic protist. The dataset comprises over 400 samples from the mixed layer taken over a 100 × 100 km 2 area at a spatial resolution of typically 2-3 km. For phytoplankton and heterotrophic bacteria there is a clear bimodal structure to the histograms of abundance indicative of two distinct communities in the region. Using the strong bimodality of one of the phytoplankton groups' histogram as a basis, the dataset is split into two subsets, with roughly 200 points in each, corresponding to the two histogram peaks. Doing so provides evidence that Synechococcus and viruses may also have a bimodal structure. Correlations between all pairings of these five organisms (both phytoplankton groups, Synechococcus, heterotrophic bacteria and viruses) are positive and quite high (r>0.7). The two communities can therefore be characterised as high and low abundance. Although there is a coincidence of low abundances with high temperatures in the southwest corner of the region, where there was known to be an eddy present, the spatial distributions of these organisms over the whole region is poorly predicted by temperature (or salinity or density). Furthermore, the spatial distributions of heterotrophic protists are found to differ strongly from those of the other organisms, having a unimodal structure and no obvious large scale structure. The more random structure of the heterotrophs' spatial distribution compared to their prey is consistent with previous results from the continental shelf, but is demonstrated for the open ocean here for the first time. Spatial variability is a large potential source of error in point samples, such as those comprising time series or transect cruises, unless a sufficient number of samples are taken. This large dataset is further used to provide guidance on the number of samples that would be required to estimate the mean abundance for the organisms accurately in this spatially variable region. Even if the bimodal structure was known initially, many of the organisms would require 10 or more samples to estimate the mean with 25% accuracy.

  18. Synthesis of Oxadiazole-2-oxide Analogues as Potential Antischistosomal Agents

    PubMed Central

    Rai, Ganesha; Thomas, Craig J.; Leister, William; Maloney, David J.

    2009-01-01

    The synthesis of several 1,2,5-oxadiazole-2-oxide (Furoxan) analogues is described herein. These compounds were prepared in an effort to probe the SAR around the phenyl substituent and oxadiazole core for our studies toward thioredoxin-glutathione reductase (TGR) inhibition and anti-schistosomal activity. PMID:19802367

  19. Synthesis and anticancer activity of nordihydroguaiaretic acid (NDGA) and analogues.

    PubMed

    McDonald, R W; Bunjobpon, W; Liu, T; Fessler, S; Pardo, O E; Freer, I K; Glaser, M; Seckl, M J; Robins, D J

    2001-12-01

    Nordihydroguaiaretic acid (NDGA) 1 is a constituent of the creosote bush Larrea divaricata and is well known to be a selective inhibitor of lipoxygenases. NDGA can also inhibit the platelet derived growth factor receptor and the protein kinase C intracellular signalling family, which both play an important role in proliferation and survival of cancers. Moreover, NDGA induces apoptosis in tumour xenografts. Although it is likely to have several targets of action, NDGA is well tolerated in animals. These encouraging results have prompted interest in the compound for clinical study. However, high concentrations of NDGA are required for efficacy and more potent analogues are required. We have synthesized five analogues of NDGA with different lengths of carbon bridge between the two catechol moieties in order to establish the spacing required for optimum anticancer effect and to compare their activities with NDGA. In order to ascertain if the catechol moieties are essential for anticancer activity, we prepared five analogues of NDGA containing only one hydroxyl group on each aromatic ring. NDGA 1, its racemic form 2, the catechol derivatives 5, 6 with five or six carbon atom bridges and the phenol analogues 8-11 with bridges of three to six carbon atoms all showed similar activity, with IC50 values of approximately 3-5 microM against the H-69 small cell lung cancer cell line. Analogues with shorter (3) or longer bridges (7, 12) were much less active. The most potent analogue was the biscatechol with a four-carbon bridge 4 which was > 10 times more active than NDGA and therefore represents a new lead compound in this area. Surprisingly, the tetramethyl ether 14 of this compound was slightly more active than NDGA, but the trihydroxy analogue 13 was less active than NDGA. The conformationally restricted analogue 15 was also less active than NDGA. In summary, simplification of the structure of NDGA by removal of the methyl groups has produced a new lead compound 4, which is >10 times more potent than NDGA as a proliferative inhibitor of H-69 small cell lung cancer cells. PMID:12375879

  20. Triazole phosphohistidine analogues compatible with the Fmoc-strategy.

    PubMed

    McAllister, Tom E; Webb, Michael E

    2012-05-28

    Phosphorylation of histidine is essential for bacterial two-component signalling; its importance to modulation of eukaryotic protein function remains undefined. Until recently, no immunochemical probes of this post-translational modification existed, however triazole phosphonate analogues of this modified amino acid have now been applied to the generation of site-specific antibodies. The protecting group strategy used in the original report is incompatible with standard protocols for Fmoc-solid phase peptide synthesis. In this paper, we report the application of P(III) chemistry to generate the complementary dibenzyl and di-tert-butyl phosphonate esters. These forms of the triazole analogue are fully compatible with standard Fmoc-SPPS and are therefore ideal for wider application by the chemical and biochemical community. PMID:22505221

  1. Site study plan for intermediate hydrology clusters tests wells Deaf Smith County Site, Texas

    SciTech Connect

    Not Available

    1988-01-01

    To characterize the geologic, geochemical, and hydrologic characteristics of intermediate-depth formations at the proposed Deaf Smith County, Texas, repository site, wells called Intermediate Hydrology clusters will test the Dewey Lake, Alibates, Salado, Yates, Upper and Lower Seven Rivers, and Queen Grayburg Formations. Sixteen wells will be installed at six locations. One location will have four wills, two locations will have three wells, and three locations will have two wells for a total of 16 wells. Testing of the formations is to proceed from the bottom up, with 2-day pumping tests at the less permeable formations. Tracer tests and tests for verticall hydraulic properties will be designed and performed after other hydrologic tests are completed. After testing, selected wells are to be completed as single or possibly dual monitoring wells to observe water-level trends. To develop a hydrogeologic testing plan, the response of each formation to potential testing procedures was evaluated using design values and an assumend range for hydraulic parameters. These evaluations indicate that hydraulic properties of a sandy zone of the Dockum, the lower Sever Rivers, and possibly the Alibates and Queen/Grayburg can be determined by pumping tests. Standard of shut-in slug tests must be conducted in the remaining formations. Tests of very long duration would be required to determine the verticla properties of less permeable formations. Tracer tests would also require weeks or months. 61 figs., 34 refs., 4 tabs.

  2. Federated Search and the Library Web Site: A Study of Association of Research Libraries Member Web Sites

    ERIC Educational Resources Information Center

    Williams, Sarah C.

    2010-01-01

    The purpose of this study was to investigate how federated search engines are incorporated into the Web sites of libraries in the Association of Research Libraries. In 2009, information was gathered for each library in the Association of Research Libraries with a federated search engine. This included the name of the federated search service and…

  3. Federated Search and the Library Web Site: A Study of Association of Research Libraries Member Web Sites

    ERIC Educational Resources Information Center

    Williams, Sarah C.

    2010-01-01

    The purpose of this study was to investigate how federated search engines are incorporated into the Web sites of libraries in the Association of Research Libraries. In 2009, information was gathered for each library in the Association of Research Libraries with a federated search engine. This included the name of the federated search service and

  4. Natural analogues of nuclear waste glass corrosion.

    SciTech Connect

    Abrajano, T.A. Jr.; Ebert, W.L.; Luo, J.S.