Science.gov

Sample records for analogue study sites

  1. Analogue Study of Actinide Transport at Sites in Russia

    SciTech Connect

    Novikov, A P; Simmons, A M; Halsey, W G

    2003-02-12

    The U. S. Department of Energy (DOE) and the Russian Academy of Sciences (RAS) are engaged in a three-year cooperative study to observe the behavior of actinides in the natural environment at selected disposal sites and/or contamination sites in Russia. The purpose is to develop experimental data and models for actinide speciation, mobilization and transport processes in support of geologic repository design, safety and performance analyses. Currently at the mid-point of the study, the accomplishments to date include: evaluation of existing data and data needs, site screening and selection, initial data acquisition, and development of preliminary conceptual models.

  2. Understanding Rubredoxin Redox Sites by Density Functional Theory Studies of Analogues

    SciTech Connect

    Luo, Yan; Niu, Shuqiang; Ichiye, Toshiko

    2012-09-06

    Determining the redox energetics of redox site analogues of metalloproteins is essential in unraveling the various contributions to electron transfer properties of these proteins. Since studies of the [4Fe-4S] analogues show that the energies are dependent on the ligand dihedral angles, broken symmetry density functional theory (BS-DFT) with the B3LYP functional and double-ζ basis sets calculations of optimized geometries and electron detachment energies of [1Fe] rubredoxin analogues are compared to crystal structures and gas-phase photoelectron spectroscopy data, respectively, for [Fe(SCH3)4]0/1-/2-, [Fe(S2-o-xyl)2]0/1-/2-, and Na+[Fe(S2-oxyl) 2]1-/2- in different conformations. In particular, the study of Na+[Fe(S2-o-xyl)2]1-/2- is the only direct comparison of calculated and experimental gas phase detachment energies for the 1-/2- couple found in the rubredoxins. These results show that variations in the inner sphere energetics by up to ~0.4 eV can be caused by differences in the ligand dihedral angles in either or both redox states. Moreover, these results indicate that the protein stabilizes the conformation that favors reduction. In addition, the free energies and reorganization energies of oxidation and reduction as well as electrostatic potential charges are calculated, which can be used as estimates in continuum electrostatic calculations of electron transfer properties of [1Fe] proteins.

  3. Uranium mineral - groundwater equilibration at the Palmottu natural analogue study site, Finland

    SciTech Connect

    Ahonen, L.; Ruskeeniemi, T.; Blomqvist, R.; Ervanne, H.; Jaakkola, T.

    1993-12-31

    The redox-potential, pH, chemical composition of fracture waters, and uraninite alteration associated with the Palmottu uranium mineralization, have been studied. The data have been interpreted by means of thermodynamic calculations. The results indicate equilibrium between uraninite, ferric hydroxide and groundwater in the bedrock of the study site. Partially oxidized uraninite (UO{sub 2.33}) and ferric hydroxide are in equilibrium with the fresh, slightly acidic and oxidized water type, while primary uraninite is stable with deeper waters that have a higher pH and lower Eh. Measured Eh-pH values of groundwater cluster within a relatively narrow range indicating buffering by heterogeneous redox-processes. A good consistency between measured Eh and analyzed uranium oxidation states was observed.

  4. Modelling in-situ matrix diffusion at Palmottu natural analogue study site in SW Finland

    SciTech Connect

    Rasilainen, K.; Suksi, J.

    1993-12-31

    Radioactive disequilibria, between U-238, U-234, and Th-230, in crystalline rock adjacent to a fracture, indicates mass transfer of U and Th between water in the fracture and the rock. The matrix diffusion theory was used to interpret the observed profiles of mobilized nuclides around the natural fracture. The interpretation of the profiles was based on the use of uranium series disequilibrium code, URSE, and migration code FTRANS. The model system was characterized using all available site-specific data, and the system evolution was outlined using the geology of the Palmottu site. The simulated concentration profiles, as a function of depth from the fracture surface, indicate that measured profiles can be modelled by matrix diffusion, assuming realistic initial and boundary conditions and diffusion times of 300,000 years.

  5. 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.

  6. Gamma-ray characterization of uranium-series nuclides and its application to the study of the Pena Blanca natural analogue site, Chihuahua, Mexico

    NASA Astrophysics Data System (ADS)

    Wong, Virgina

    Two natural analogue sites located in the Pena Blanca Uranium District, Chihuahua, Mexico were characterized for radionuclide mobility. Analogue I is used to assess the long-term behavior of uranium-series nuclides in a host rock and geochemical environment that is similar to the proposed high-level waste repository at Yucca Mountain, Nevada. Analogue II represents a former dump site to assess short-term radionuclide mobility. Gamma-ray spectroscopy analysis was used to measure radioactivity of the U-series nuclides. Samples analyzed from Analogue I consist of: (1) fracture-infillings associated with different alteration assemblages collected within and outside the breccia pipe from various levels of the deposit and (2) fracture-infillings collected along an east-west trending fracture which intersects the breccia pipe and extends into the host rock. Alteration mineralogy, established via X-ray diffraction analysis, consists of pure kaolinite, a mixture of Fe-oxyhydroxide (goethite, hematite) With inclusions of jarosite and alunite, and carbonates. Results from activity ratios of 230Th/238U versus 226Ra/230Th indicate that majority of the Fe-oxyhydroxides from the breccia zone show a slight disequilibrium with respect to Ra enrichment and U depletion. This observation is modeled as requiring a multiple-event history of U mobility. An amorphous Fe sample distal to the breccia zone shows similar behavior but to a greater extent. This extreme behavior is ascribed to initially low U content and greater late-stage U removal. Two Fe-oxyhydroxide samples from Within the breccia pipe also display multiple-event stages but exhibit both Ra and U leaching. This behavior is shared by Fe-oxyhydroxide samples collected inside and peripheral to the breccia zone from the east-west trending fracture. Finally, three samples, two Fe phase samples outside the breccia zone and a kaolinite inside the breccia zone, show Ra and U enrichment. Also, a distal Fe-oxyhydroxide sample from the

  7. An analogue study of intrusions.

    PubMed

    Laposa, Judith M; Alden, Lynn E

    2006-07-01

    According to cognitive theorists, intrusive trauma memories have their origin in how information during the event is processed. Two studies investigated functional cognitive strategies during medical crises that might protect against intrusions. In Study 1, interviews with health-care professionals were used to identify cognitive strategies judged to be effective in controlling emotions and dealing with medical crises. Study 2 systematically manipulated the use of those strategies in a trauma analogue film paradigm. Experimental participants reported fewer intrusions, and less fear and avoidance of film-related stimuli during the subsequent week than controls. The manipulation did not affect anxiety during the film or memory disorganization. Implications for cognitive theories of intrusion development are discussed. PMID:16125135

  8. 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

  9. 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

  10. 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.

  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. 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.

  13. Carbon storage at defect sites in mantle mineral analogues

    NASA Astrophysics Data System (ADS)

    Wu, Jun; Buseck, Peter R.

    2013-10-01

    A significant fraction of Earth's carbon resides in the mantle, but the mode of carbon storage presents a long-standing problem. The mantle contains fluids rich in carbon dioxide and methane, carbonate-bearing melts, carbonate minerals, graphite, diamond and carbides, as well as dissolved carbon atoms in metals. However, it is uncertain whether these can sufficiently account for the total amount of carbon thought to be stored in the mantle and the volume of carbon degassed from the mantle at volcanoes. Moreover, such carbon hosts should significantly affect the physical and chemical behaviour of the mantle, including its melting temperature, electrical conductivity and oxidation state. Here we use in situ transmission electron microscopy to measure the storage of carbon within common mantle mineral analogues--nickel-doped lanthanum chromate perovskite and titanium dioxide--in laboratory experiments at high pressure and temperature. We detect elevated carbon concentrations at defect sites in the nanocrystals, maintained at high pressures within annealed carbon nanocages. Specifically, our experiments show that small stacking faults within the mantle analogue materials are effective carbon sinks at mantle conditions, potentially providing an efficient mechanism for carbon storage in the mantle. Furthermore, this carbon can be readily released under lower pressure conditions, and may therefore help to explain carbon release in volcanic eruptions.

  14. VARIABLE ACTIVE SITE LOOP CONFORMATIONS ACCOMMODATE THE BINDING OF MACROCYCLIC LARGAZOLE ANALOGUES TO HDAC8

    PubMed Central

    Decroos, Christophe; Clausen, Dane J.; Haines, Brandon E.; Wiest, Olaf; Williams, Robert M.; Christianson, David W.

    2015-01-01

    The macrocyclic depsipeptide Largazole is a potent inhibitor of metal-dependent histone deacetylases (HDACs), some of which are drug targets for cancer chemotherapy. Indeed, Largazole partially resembles Romidepsin (FK228), a macrocyclic depsipeptide already approved for clinical use. Each inhibitor contains a pendant side chain thiol that coordinates to the active site Zn2+ ion, as observed in the X-ray crystal structure of the HDAC8–Largazole complex [Cole, K. E.; Dowling, D. P.; Boone, M. A.; Phillips, A. J.; Christianson, D. W. J. Am. Chem. Soc. 2011, 133, 12474]. Here, we report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage. In two of these analogues, a 6-membered pyridine ring is also substituted (with two different orientations) for the 5-membered thiazole ring in the macrocycle skeleton. The side chain thiol group of each analogue coordinates to the active site Zn2+ ion with nearly ideal geometry, thereby preserving the hallmark structural feature of inhibition by Largazole. Surprisingly, in comparison with the binding of Largazole, these analogues trigger alternative conformational changes in the L1 and L2 loops flanking the active site. However, despite these structural differences, inhibitory potency is generally comparable to, or just moderately less than, the inhibitory potency of Largazole. Thus, this study reveals important new structure-affinity relationships for the binding of macrocyclic inhibitors to HDAC8. PMID:25793284

  15. 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

  16. 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.

  17. 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

  18. Insights into the role of the aromatic residue in galactose-binding sites: MP2/6-311G++** study on galactose- and glucose-aromatic residue analogue complexes.

    PubMed

    Sujatha, Mannargudi S; Sasidhar, Yellamraju U; Balaji, Petety V

    2005-06-14

    The presence of an aromatic residue (Trp, Phe, Tyr) facing the nonpolar face of galactose is a common feature of galactose-specific lectins. The interactions such as those between the C-H groups of galactose and the pi-electron cloud of aromatic residues have been characterized as weak hydrogen bonds between soft acids and soft bases, largely governed by dispersive and charge transfer interactions. An analysis of the binding sites of several galactose-specific lectins revealed that the spatial position-orientation of galactose relative to the binding site aromatic residue varies substantially. The effect of variations in position-orientations of galactose on the interaction energies of galactose-aromatic residue complexes has not been determined so far. In view of this, MP2/6-311G++** calculations were performed on galactose- and glucose-aromatic residue analogue complexes in eight position-orientations. The results show that the strength of the C-H...pi interactions in galactose-aromatic residue complexes is comparable to that of a hydrogen bond. Rather than the type of aromatic residue, the position-orientation of the saccharide appears to be more critical in determining the strength of their interactions. Earlier studies have found the binding site aromatic residue to be critical, but its role was not clear. This study shows that the aromatic residue is important for discriminating galactose from glucose, in addition to its contribution to binding energy. PMID:15938646

  19. 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.

  20. Structure-activity studies on the potentiation of benzodiazepine receptor binding by ethylenediamine analogues and derivatives.

    PubMed Central

    Morgan, P. F.; Stone, T. W.

    1983-01-01

    The effect of ethylenediamine analogues on in vitro binding of [3H]-diazepam to crude cerebral cortical synaptosomal membranes in the rat was studied. Ethylenediamine significantly increased [3H]-diazepam binding to a maximum potentiation of 154% control (EC50 = 1.8 X 10(-4) M) and was the most active compound studied in terms of both potency and the maximum potentiation observed. Potentiation of [3H]-diazepam binding by ethylenediamine analogues is dependent on carbon-chain length, appears to require two terminal amino groups, and is not observed in the rigid analogues studied. Potentiation of [3H]-diazepam binding by ethylenediamine analogues is mediated largely by a change in receptor number and not receptor affinity. Results are discussed in terms of the possible nature of the ethylenediamine binding site. PMID:6317124

  1. Probing the steric requirements of the γ-aminobutyric acid aminotransferase active site with fluorinated analogues of vigabatrin

    PubMed Central

    Juncosa, Jose I.; Groves, Andrew P.; Xia, Guoyao; Silverman, Richard B.

    2012-01-01

    We have synthesized three analogues of 4-amino-5-fluorohexanoic acids as potential inactivators of γ-aminobutyric acid aminotransferase (GABA-AT), which were designed to combine the potency of their shorter chain analogue, 4-amino-5-fluoropentanoic acid (AFPA), with the greater enzyme selectivity of the antiepileptic vigabatrin (Sabril®). Unexpectedly, these compounds failed to inactivate or inhibit the enzyme, even at high concentrations. On the basis of molecular modeling studies, we propose that the GABA-AT active site has an accessory binding pocket that accommodates the vinyl group of vigabatrin and the fluoromethyl group of AFPA, but is too narrow to support the extra width of one distal methyl group in the synthesized analogues. PMID:23306054

  2. 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 (55°53'N; 63°18'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

  3. High affinity ATP/ADP analogues as new tools for studying CFTR gating.

    PubMed

    Zhou, Zhen; Wang, Xiaohui; Li, Min; Sohma, Yoshiro; Zou, Xiaoqin; Hwang, Tzyh-Chang

    2005-12-01

    Previous studies using non-hydrolysable ATP analogues and hydrolysis-deficient cystic fibrosis transmembrane conductance regulator (CFTR) mutants have indicated that ATP hydrolysis precedes channel closing. Our recent data suggest that ATP binding is also important in modulating the closing rate. This latter hypothesis predicts that ATP analogues with higher binding affinities should stabilize the open state more than ATP. Here we explore the possibility of using N6-modified ATP/ADP analogues as high-affinity ligands for CFTR gating, since these analogues have been shown to be more potent than native ATP/ADP in other ATP-binding proteins. Among the three N6-modified ATP analogues tested, N6-(2-phenylethyl)-ATP (P-ATP) was the most potent, with a K(1/2) of 1.6 +/- 0.4 microm (>50-fold more potent than ATP). The maximal open probability (P(o)) in the presence of P-ATP was approximately 30% higher than that of ATP, indicating that P-ATP also has a higher efficacy than ATP. Single-channel kinetic analysis showed that as [P-ATP] was increased, the opening rate increased, whereas the closing rate decreased. The fact that these two kinetic parameters have different sensitivities to changes of [P-ATP] suggests an involvement of two different ATP-binding sites, a high-affinity site modulating channel closing and a low affinity site controlling channel opening. The effect of P-ATP on the stability of open states was more evident when ATP hydrolysis was abolished, either by mutating the nucleotide-binding domain 2 (NBD2) Walker B glutamate (i.e. E1371) or by using the non-hydrolysable ATP analogue AMP-PNP. Similar strategies to develop nucleotide analogues with a modified adenine ring could be valuable for future studies of CFTR gating. PMID:16223764

  4. High affinity ATP/ADP analogues as new tools for studying CFTR gating

    PubMed Central

    Zhou, Zhen; Wang, Xiaohui; Li, Min; Sohma, Yoshiro; Zou, Xiaoqin; Hwang, Tzyh-Chang

    2005-01-01

    Previous studies using non-hydrolysable ATP analogues and hydrolysis-deficient cystic fibrosis transmembrane conductance regulator (CFTR) mutants have indicated that ATP hydrolysis precedes channel closing. Our recent data suggest that ATP binding is also important in modulating the closing rate. This latter hypothesis predicts that ATP analogues with higher binding affinities should stabilize the open state more than ATP. Here we explore the possibility of using N6-modified ATP/ADP analogues as high-affinity ligands for CFTR gating, since these analogues have been shown to be more potent than native ATP/ADP in other ATP-binding proteins. Among the three N6-modified ATP analogues tested, N6-(2-phenylethyl)-ATP (P-ATP) was the most potent, with a K½ of 1.6 ± 0.4 μm (>50-fold more potent than ATP). The maximal open probability (Po) in the presence of P-ATP was ∼30% higher than that of ATP, indicating that P-ATP also has a higher efficacy than ATP. Single-channel kinetic analysis showed that as [P-ATP] was increased, the opening rate increased, whereas the closing rate decreased. The fact that these two kinetic parameters have different sensitivities to changes of [P-ATP] suggests an involvement of two different ATP-binding sites, a high-affinity site modulating channel closing and a low affinity site controlling channel opening. The effect of P-ATP on the stability of open states was more evident when ATP hydrolysis was abolished, either by mutating the nucleotide-binding domain 2 (NBD2) Walker B glutamate (i.e. E1371) or by using the non-hydrolysable ATP analogue AMP-PNP. Similar strategies to develop nucleotide analogues with a modified adenine ring could be valuable for future studies of CFTR gating. PMID:16223764

  5. Analogue sites for Mars missions: NASA's Mars Science Laboratory and beyond - Overview of an international workshop held at The Woodlands, Texas, on March 5-6, 2011

    NASA Astrophysics Data System (ADS)

    Hipkin, V. J.; Voytek, M. A.; Meyer, M. A.; Léveillé, R.; Domagal-Goldman, S. D.

    2013-06-01

    Recent research results from analogue sites, with a strong focus on astrobiology-related investigations, are presented in this special issue on 'Analogue sites for Mars missions'. In addition, this article describes workshop discussions and a resulting improved framework for reporting, evaluating, and comparing analogue sites. Developed through consideration of a broad range of sites, including many of those described in this special issue, this framework comprises an analogue site abstract, a rubric for the scientific evaluation of analogue sites, and a rubric for logistical information. An overview of the Mars Analogues Workshop is provided, and the rubrics are presented for further discussion.

  6. Synthesis of Cross-Linked DNA Containing Oxidized Abasic Site Analogues

    PubMed Central

    2015-01-01

    DNA interstrand cross-links are an important family of DNA damage that block replication and transcription. Recently, it was discovered that oxidized abasic sites react with the opposing strand of DNA to produce interstrand cross-links. Some of the cross-links between 2′-deoxyadenosine and the oxidized abasic sites, 5′-(2-phosphoryl-1,4-dioxobutane) (DOB) and the C4-hydroxylated abasic site (C4-AP), are formed reversibly. Chemical instability hinders biochemical, structural, and physicochemical characterization of these cross-linked duplexes. To overcome these limitations, we developed methods for preparing stabilized analogues of DOB and C4-AP cross-links via solid-phase oligonucleotide synthesis. Oligonucleotides of any sequence are attainable by synthesizing phosphoramidites in which the hydroxyl groups of the cross-linked product were orthogonally protected using photochemically labile and hydrazine labile groups. Selective unmasking of a single hydroxyl group precedes solid-phase synthesis of one arm of the cross-linked DNA. The method is compatible with commercially available phosphoramidites and other oligonucleotide synthesis reagents. Cross-linked duplexes containing as many as 54 nt were synthesized on solid-phase supports. Subsequent enzyme ligation of one cross-link product provided a 60 bp duplex, which is suitable for nucleotide excision repair studies. PMID:24949656

  7. 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

  8. Present-day serpentinization in the Tablelands, Gros Morne National Park, Newfoundland: a Mars Analogue Site

    NASA Astrophysics Data System (ADS)

    Szponar, N.; Morrill, P. L.; Brazelton, W. J.; Schrenk, M. O.; Bower, D. M.; Steele, A.

    2010-12-01

    Serpentinization - a reaction between water and ultramafic rock (derived from the mantle) - is suspected to be a source of hydrocarbons such as methane on Mars. Through the hydration of ultramafic rock, this reaction produces hydrogen (H2) gas and reducing conditions necessary for abiogenic hydrocarbon synthesis, while also producing conditions amendable for the production of methane through microbial chemoautotrophic pathways. Mars analogue sites of present-day serpentinization can be used to determine what geochemical measurements are required for determining the reactions responsible for the methane in the Martian atmosphere. On Earth few locations that are known to exhibit active serpentinization are easily accessible. One such location is found in the Tablelands at Gros Morne National Park, Newfoundland. Peridotite rocks similar to those found on Mars dominate the Tablelands thus making the Tablelands an important analogue site for potential ecosystems on Mars. Present-day serpentinization is evidenced by fluid seeps characterized by highly alkaline (pH 11 to 12) and highly reducing (as low as -820 mV) conditions, travertine and the presence of dissolved methane. These fluids contain high concentrations of Ca2+ (~5.00x104ppb) compared to freshwater inputs (~ 1.00x103) and react at the surface with atmospheric CO2 producing travertine deposits (as CaCO3 precipitate). Dissolved H2 gas produced abiogenically through the serpentinization reaction also provides copious geofuels, which can be used for chemosynthesis. Preliminary data has shown that microbial life lives in the high pH springs of the Tablelands. Ongoing studies of targeted compounds including phospholipid fatty acids and ether-linked lipids are being used to determine the microbial community compositions and verify the occurrence of Bacteria and Archaea in these fluids. An important question is also the source of the serpentinized fluid seeps. Hydrogen (δ2H) and oxygen (δ18O) isotopes of these

  9. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2014-07-01

    Dynamics of crystal water in Prussian blue (PB), Fe(III)4[Fe(II)(CN)6]3.14H2O and its analogue Prussian green (PG), ferriferricynaide, Fe(III)4[Fe(III)(CN)6]4.16H2O 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)6 units. However, PG does not have any such vacant N or Fe(CN)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.

  11. 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.

  12. 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.; Mäder, 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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, Ákos; Váczi, Tamás; 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

  17. 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.; Chirié, 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

  18. 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

  19. 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 an analytical 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 0.01 mg/mL. Eight common Raman peaks (△υ = 620, 1003, 1030, 1159, 1181, 1205, 1454, 1603 cm(-1)) were extracted experimentally and statistically to characterize the common feature of ephedrine analogues. A TLC-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 and can 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

  20. 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.

  1. 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.

  2. 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

  3. Multicomponent reactive transport in discrete fractures. II: Infiltration of hyperalkaline groundwater at Maqarin, Jordan, a natural analogue site

    NASA Astrophysics Data System (ADS)

    Steefel, C. I.; Lichtner, P. C.

    1998-08-01

    A numerical multicomponent reactive transport model described fully in Steefel and Lichtner (1998)[Steefel, C.I., Lichtner, P.C., 1998. Multicomponent reactive transport in discrete fractures, I. Controls on reaction front geometry. J. Hydrol. (in press)] is used to simulate the infiltration of hyperalkaline groundwater along discrete fractures at Maqarin, Jordan, a site considered as a natural analogue to cement-bearing nuclear waste repositories. In the Eastern Springs area at Maqarin, two prominent sets of sub-parallel fractures trending NW-SE are approximately perpendicular to the local water table contours, with the slope of the water table indicating north-westward flow. Extensive mineralogic investigations [Alexander W.R. (Ed.), 1992. A natural analogue study of cement-buffered, hyperalkaline groundwaters and their interaction with a sedimentary host rock. NAgrA Technical Report (NTB 91-10), Wettingen, Switzerland; Milodowski, A.E., Hyslop, E.K., Pearce, J.M., Wetton, P.D., Kemp, S.J., Longworth, G., Hodginson, E., and Hughes, C.R., 1998. Mineralogy and geochemistry of the western springs area. In: Smellie, J.A.T. (ed.), 1998: Maqarin Natural Analogue Study: Phase III. SKB Technical Report TR98-04, Stockholm, Sweden] indicate that the width of intense rock alteration zone bordering the fractures changes from about 4 mm at one locality (the M1 sampling site) to approximately 1 mm 100 m to the north-west in the flow direction (the M2 site), suggesting a lessening of alteration intensity in that direction. Using this information, the dimensionless parameter δ v/φ D' (φ=porosity, D'=effective diffusion coefficient in rock matrix, δ=fracture aperture, and v=fluid velocity in the fracture) and measurements of the local hydraulic head gradient and effective diffusion coefficient in the rock matrix, a mean fracture aperture of 0.194 mm is calculated assuming the cubic law applies. This information, in combination with measured groundwater compositions at the

  4. Affinity labeling of hepatitis C virus replicase with a nucleotide analogue: identification of binding site.

    PubMed

    Manvar, Dinesh; Singh, Kamlendra; Pandey, Virendra N

    2013-01-15

    We have used an ATP analogue 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSBA) to modify HCV replicase in order to identify the ATP binding site in the enzyme. FSBA inactivates HCV replicase activity in a concentration-dependent manner with a binding stoichiometry of 2 moles of FSBA per mole of enzyme. The enzyme activity is protected from FSBA in the presence of rNTP substrates or double-stranded RNA template primers that do not support ATP as the incoming nucleotide but not in the presence of polyrU.rA(26). HPLC analysis of tryptic peptides of FSBA-modified enzyme revealed the presence of two distinct peptides eluted at 23 and 36 min; these were absent in the control. Further we noted that both peptides were protected from FSBA modification in the presence of Mg·ATP. The LC/MS/MS analysis of the affinity-labeled tryptic peptides purified from HPLC, identified two major modification sites at positions 382 (Tyr), and 491 (Lys) and a minor site at position 38 (Tyr). To validate the functional significance of Tyr38, Tyr382, and Lys491 in catalysis, we individually substituted these residues by alanine and examined their ability to catalyze RdRp activity. We found that both Y382A and K491A mutants were significantly affected in their ability to catalyze RdRp activity while Y38A remained unaffected. We further observed that both Y382A and K491A mutants were not affected in their ability to bind template primer but were significantly affected in their ability to photo-cross-link ATP in the absence or presence of template primer. PMID:23268692

  5. Stability studies of a somatostatin analogue in biodegradable implants.

    PubMed

    Rothen-Weinhold, A; Besseghir, K; Vuaridel, E; Sublet, E; Oudry, N; Gurny, R

    1999-02-15

    In recent years, peptides and proteins have received much attention as drug candidates. For many polypeptides, particularly hormones, it is desirable to release the drug continuously at a controlled rate over a period of weeks or even months, and thus a controlled release system is needed. Polylactic acid (PLA) is a biocompatible and biodegradable material with wide utility for many applications, including the design of controlled release systems for pharmaceutical agents. Pharmaceutical development of these delivery systems presents new problems in the area of stability assessment, especially for peptide drugs. In this study, we aimed to investigate the influence of different steps, during the manufacturing of an implant, on peptide stability in the polymeric matrix. Polylactic acid implants containing vapreotide, a somatostatin analogue, were prepared by extrusion. The effects of time, extrusion and temperature on the peptide stability were studied. The influence of various gamma sterilization doses, as well as the conditions under which the implants were irradiated, were also investigated. Peptide stability in the polymeric matrix was evaluated at various temperatures and at various time intervals up to 9 months. PMID:10205641

  6. Computational study of Met-Car analogue heterofullerenes

    NASA Astrophysics Data System (ADS)

    Domingos, H. S.

    2006-06-01

    Structural, chemical and electronic properties of a number of Met-Car analogue heterofullerenes were investigated using a combination of ab initio and semi-empirical quantum mechanical calculations.Met-Car clusters of known structure and chemistry were studied together with some new hypothetical configurations. In particular, the stability of clusters of the form Y8C12 (Y = Al, S, Si, Ti, As, Bi, Sb, P, N, B, Sn, Sc, Cr, V), XY7C12 (X, Y = B, N, Si) and Y8Z12 (Y, Z = N, B, Si) were investigated based on computed binding energies, Mulliken charges, bond orders and ionization potentials. The results indicate that some novel clusters are due for observation. Clusters of this type are known to form the building blocks of new polymerized solids and may exhibit some novel dielectric, magnetic and superconducting properties. Isomers of D3d symmetry, which are possible global energy minima for Cr, V and Sc carbide clusters, were also identified.

  7. 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.

  8. 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.

  9. Synthesis, Receptor Binding, and CNS Pharmacological Studies of New Thyrotropin-Releasing Hormone (TRH) Analogues

    PubMed Central

    Monga, Vikramdeep; Meena, Chhuttan L.; Rajput, Satyendra; Pawar, Chandrashekhar; Sharma, Shyam S.; Lu, Xinping; Gershengorn, Marvin C.

    2012-01-01

    As part of our search for selective and CNS-active thyrotropin-releasing hormone (TRH) analogues, we synthesized a set of 44 new analogues in which His and pGlu residues were modified or replaced. The analogues were evaluated as agonists at TRH-R1 and TRH-R2 in cells in vitro, and in vivo in mice for analeptic and anticonvulsant activities. Several analogues bound to TRH-R1 and TRH-R2 with good to moderate affinities, and are full agonists at both receptor subtypes. Specifically, analogue 21 a (R = CH3) exhibited binding affinities (Ki values) of 0.17 μM for TRH-R1 and 0.016 μM for TRH-R2; it is 10-fold less potent than TRH in binding to TRH-R1 and equipotent with TRH in binding to TRH-R2. Compound 21 a, the most selective agonist, activated TRH-R2 with a potency (EC50 value) of 0.0021 μM, but activated TRH-R1 at EC50 = 0.05 μM, and exhibited 24-fold selectivity for TRH-R2 over TRH-R1. The newly synthesized TRH analogues were also evaluated in vivo to assess their potencies in antagonism of barbiturate-induced sleeping time, and several analogues displayed potent analeptic activity. Specifically, analogues 21 a,b and 22 a,b decreased sleeping time by nearly 50 % more than TRH. These analogues also displayed potent anticonvulsant activity and provided significant protection against PTZ-induced seizures, but failed to provide any protection in MES-induced seizures at 10 μmol kg−1. The results of this study provide evidence that TRH analogues that show selectivity for TRH-R2 over TRH-R1 possess potent CNS activity. PMID:21302359

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

    NASA Astrophysics Data System (ADS)

    Dobson, Patrick F.; Ghezzehei, Teamrat A.; Cook, Paul J.; Rodríguez-Pineda, J. Alfredo; Villalba, Lourdes; de La Garza, Rodrigo

    2012-02-01

    A study of seepage occurring in an adit at the Nopal I uranium mine in Chihuahua, Mexico, was conducted as part of an integrated natural analogue study to evaluate the effects of infiltration and seepage on the mobilization and transport of radionuclides. An instrumented seepage collection system and local automated weather station permit direct correlation between local precipitation events and seepage. Field observations recorded between April 2005 and December 2006 indicate that seepage is highly heterogeneous with respect to time, location, and quantity. Seepage, precipitation, and fracture data were used to test two hypotheses: (1) that fast flow seepage is triggered by large precipitation events, and (2) that an increased abundance of fractures and/or fracture intersections leads to higher seepage volumes. A few zones in the back adit recorded elevated seepage volumes immediately following large (>20 mm/day) precipitation events, with transit times of less than 4 h through the 8-m thick rock mass. In most locations, there is a 1-6 month time lag between the onset of the rainy season and seepage, with longer times observed for the front adit. There is a less clear-cut relation between fracture abundance and seepage volume; processes such as evaporation and surface flow along the ceiling may also influence seepage.

  11. 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

  12. 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].

  13. 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

  14. 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

  15. Lithic microbial communities from a Mars analogue site in Utah desert

    NASA Astrophysics Data System (ADS)

    Rodrigues, L.; Foing, B. H.; Davies, G. R.; Stoker, C.; Clarke, J.; Correia, A.; Alves, A.

    2012-09-01

    Several rock samples have been collected as part of a Mars field analogue campaign (NASA DOMEXILEWG EuroMoonMars) at Mars Desert Research Station (MDRS) area (Utah Desert, USA), and were analyzed with respect to the microbial diversity they support; a culture-independent approach resulted in DGGE band profiles descriptive of the composition of the 3 domains, Bacteria, Archaea and Eukarya.

  16. Synthesis and study of new paramagnetic resveratrol analogues.

    PubMed

    Kálai, Tamás; Borza, Erzsébet; Antus, Csenge; Radnai, Balázs; Gulyás-Fekete, Gergely; Fehér, Andrea; Sümegi, Balázs; Hideg, Kálmán

    2011-12-15

    New resveratrol analogues containing five- and six-membered nitroxides and isoindoline nitroxides were synthesized. These new compounds were compared to resveratrol based on their ABTS radical scavenging ability as well on their capacity to suppress inflammatory process in macrophages induced by lipopolysaccharides. The ABTS and ROS scavenging activities of new molecules were the same or weaker than that of resveratrol, but some of paramagnetic resveratrol derivatives suppressed nitrite and TNFα production more efficiently than resveratrol. Based on these results the new nitroxide and phenol containing hybrid molecules can be considered as new antioxidant and anti-inflammatory agents. PMID:22088309

  17. Sorption aspects for in situ matrix diffusion modeling at Palmottu natural analogue site, SW Finland

    SciTech Connect

    Rasilainen, K.; Suksi, J.; Hakanen, M.; Olin, M.

    1995-12-31

    Concentration profiles in rock matrix around water-carrying fissures were measured at Palmottu U deposit. The profiles were interpreted by the classical matrix diffusion concept. Site-specific sorption studies were performed for U using standard batch experiments and surface complexation modeling; the response of sorption isotherms was also tested. Site-specific matrix properties as well as initial and boundary conditions were used in simulations. The results indicate that matrix diffusion alone cannot explain the observed enrichment of U and its daughters in the rock matrix.

  18. A computational study of open-chain epothilone analogue

    NASA Astrophysics Data System (ADS)

    Kamel, Karol; Rusinska-Roszak, Danuta

    Molecular mechanics (MM/Ambers) calculations were applied to probe the conformational profile of open-chain epothilone analogue [Org Lett 2006, 8, 685], cytotoxic against some cell lines. Geometries of the most stable conformers were optimized at DFT level using the B3LYP functional and then compared to known both experimental and virtual conformers of epothilone. One of the most stable structures is III (1.47 kcal/mol above global minimum) which represents high similarity to the appropriate fragment of the Taylor's model of epothilone A, but two other conformers: XIV and XX, although they have almost the same conformation as the mother structure, are very unstable (6.7 and 12.4 kcal/mol above the global minimum).0

  19. Synthesis and pharmacological studies of new pyrazole analogues of podophyllotoxin.

    PubMed

    Umesha, B; Basavarajuk, Y B

    2014-01-01

    The pyrazole analogues of podophyllotoxin were synthesized by the chalcone route. This route attracts the attention because of its simple operating conditions and easy availability ofthe chemicals. Initially, benzylide-neacetophenones (chalcones) were prepared in high yields by Claisen-Schmidt reaction of acetophenones with 4-(methylthio)benzaldehyde. The cyclopropyl ketones were prepared in good yields by the reaction of chalcones with trimethylsulfoxonium iodide. Tetralones were prepared in good yields by the Friedel-Craft's intramolecular cyclization reaction of cyclopropyle ketones in the presence of anhyd. stannic chloride and acetic anhydride. The tetralones on formylation to give substituted hydroxylmethylene tetralones. Condensation of substituted hydroxylmethylene tetralones with hydrazine hydrate afforded target compounds. The structures of the synthesized compounds were confirmed by IR, 'H-NMR and Mass spectral technique. The title compounds were screened for their antimitotic and antimicrobial activities. Among the synthesized compounds cyclopropyl ketones and pyrazole analogues of podophyllotoxin, compound 7-(Methytthio)-5-(4-(methylthio)phe- nyl)-4,5.-dihydro-2H-benzo[g]indazole is more active than 5-(4-(Methylthio)phenyl)-4,5-dihydro-2H-ben- zo[g]indazole, 7-Methyl-5-(4-(methylthio)phenyl)-4,5-dihydro-2H-benzo[g]indazole, 7-Methoxy-5-(4-(meth- ylthio)phenyl)-4,5-dihydro-2H-benzo[g]indazole and the key intermediate tetralones in 100, 200 and 400 ppm at 12, 18 and 24 hrs and also showed very good activity against screened bacteria and fungi compared to their standard. PMID:25898761

  20. 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

  1. Synthesis and Cytotoxicity Studies of Titanocene C Analogues

    PubMed Central

    Hogan, Megan; Claffey, James; Fitzpatrick, Eoin; Hickey, Thomas; Pampillón, Clara; Tacke, Matthias

    2008-01-01

    From the carbolithiation of 6-N,N-dimethylamino fulvene (3) and 2,4[bis(N,N-dimethylamino)methyl]-N-methylpyrrolyl lithium (2a), N-(N′,N′-dimethylaminomethyl)benzimidazolyl lithium (2b), or p-(N,N-dimethylamino)methylphenyl lithium (2c), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4' resulting in N,N-dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against a pig kidney epithelial cell line (LLC-PK), the IC50 values obtained were of 23, and 52  μM for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene in this paper, 5c with an IC50 value of 13 μM, was found to be approximately two times less cytotoxic than its analogue Titanocene C (IC50=5.5 μM) and almost four times less cytotoxic than cisplatin, which showed an IC50 value of 3.3 μM when tested on the LLC-PK cell line. PMID:18274663

  2. 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.

  3. 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.

  4. 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.

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

    PubMed Central

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

    2014-01-01

    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. PMID:25286859

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

    PubMed

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

    2014-10-01

    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. PMID:25286859

  7. 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 (β) 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 Young’s 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 – 8.01×10-4/mmHg (AAA in vivo: 1.8 – 9.4×10-4/mmHg)). The necks of our AAA models had similar stiffness to healthy aortas (20.44 – 29.83 (healthy aortas in vivo: 17.5±5.5)). 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

  8. Structure activity relationship study of curcumin analogues toward the amyloid-beta aggregation inhibitor.

    PubMed

    Endo, Hitoshi; Nikaido, Yuri; Nakadate, Mamiko; Ise, Satomi; Konno, Hiroyuki

    2014-12-15

    Inhibition of the amyloid β aggregation process could possibly prevent the onset of Alzheimer's disease. In this article, we report a structure-activity relationship study of curcumin analogues for anti amyloid β aggregation activity. Compound 7, the ideal amyloid β aggregation inhibitor in vitro among synthesized curcumin analogues, has not only potent anti amyloid β aggregation effects, but also water solubility more than 160 times that of curcumin. In addition, new approaches to improve water solubility of curcumin-type compounds are proposed. PMID:25467149

  9. 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 μM. 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 μM 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

  10. 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.

  11. 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…

  12. 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...

  13. Nonhydrolyzable ATP analogues as selective inhibitors of human NPP1: a combined computational/experimental study.

    PubMed

    Lecka, Joanna; Ben-David, Gal; Simhaev, Luba; Eliahu, Shay; Oscar, Jocelyn; Luyindula, Patrick; Pelletier, Julie; Fischer, Bilha; Senderowitz, Hanoch; Sévigny, Jean

    2013-11-14

    Elevated nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) activity is implicated in health disorders including pathological calcification. Specific NPP1 inhibitors would therefore be valuable for studying this enzyme and as potential therapeutic agents. Here we present a combined computational/experimental study characterizing 13 nonhydrolyzable ATP analogues as selective human NPP1 inhibitors. All analogues at 100 μM inhibited (66-99%) the hydrolysis of pnp-TMP by both recombinant NPP1 and cell surface NPP1 activity of osteocarcinoma (HTB-85) cells. These analogues only slightly altered the activity of other ectonucleotidases, NPP3 and NTPDases. The Ki,app values of the seven most potent and selective inhibitors were in the range of 0.5-56 μM, all with mixed type inhibition, predominantly competitive. Those molecules were docked into a newly developed homology model of human NPP1. All adopted ATP-like binding modes, suggesting competitive inhibition with the endogenous ligand. NPP1 selectivity versus NPP3 could be explained in terms of the electrostatic potential of the two proteins that of NPP1 favoring negatively charged ligands. Inhibitor 2 that had the lowest Ki,app (0.5 μM) was also inactive toward P2Y receptors. Overall, analogue 2 is the most potent and selective NPP1 inhibitor described so far. PMID:24083941

  14. 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.

  15. Aminopeptidase p mediated detoxification of organophosphonate analogues of sarin: mechanistic and stereochemical study at the phosphorus atom of the substrate.

    PubMed

    Huang, Li-Fang; Su, Benson; Jao, Shu-Chuan; Liu, Kwang-Ting; Li, Wen-Shan

    2006-03-01

    The activity of the aminopeptidase P from Escherichia coli in hydrolyzing a series of organophosphonate sarin analogues (1-6) was evaluated. The enzymatic rates of hydrolysis for methylphosphonate 1 with a methoxy group attached to the phosphorus center were 7- to 15-fold higher than those for the corresponding analogues 2-6. Double mutant R153W/R370L was able to hydrolyze the S(p) enantiomer of racemic 1 at a considerable rate. This mutant allowed the preparation of the R(p) isomer of the sarin analogue 1. All the mutants, R370L, R153A, W88L, R153L/R370L, and R153W/R370L, preferred the formation of (S(p))-8 to that of the corresponding (R(p))-8 enantiomer and displayed a better enantiomeric excess of products, by 1.4- to 2-fold as compared to the wild-type enzyme. Enzymatic hydrolysis of O,O-diisopropyl-p-nitrophenyl phosphate (9) in H(2) (18)O led to the formation of the (18)O-labeled O,O-diisopropyl phosphate product and confirmed that the catalytic reaction starts with cleavage of the P--O bond. From chemical and kinetic studies, the utilization of an optically pure S(p) enantiomer of O-methyl-p-nitrophenyl methylphosphonothioate (S(p))-MNMPT, 7) has demonstrated that the enzymatic reaction proceeds through a displacement mechanism and generates a chiral product in situ with an inversion of stereochemical configuration at the phosphorus atom. The results also lead to the conclusion that alteration of the active site through site-directed mutagenesis can result in a preference for (S(p))-MNMPT (7) rather than the R(p) isomer. PMID:16470765

  16. 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.

  17. 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

  18. Assessment of radionuclide retardation: uses and abuses of natural analogue studies

    NASA Astrophysics Data System (ADS)

    McKinley, Ian G.; Russell Alexander, W.

    1993-06-01

    Various techniques which have been reported for the in situ determination of radionuclide sorption or retardation as part of natural analogue studies have been critically assessed. In particular cases, the tacit assumptions used to derive retardation data from field observations can be shown to be questionable or, indeed, totally incorrect. Some problems identified are due to ambiguous or inconsistent use of terminology, but a fundamental error which commonly arises is the failure to distinguish between sorption and precipitation — processes which are treated quite differently in transport models. Natural analogue studies can be used to test radionuclide migration models and their associated databases, but considerable efforts are required to adequately characterise the geochemical process occurring. Without such extensive studies, the general applicability of data produced is limited and claims to derive parameters usable in repository performance assessment should be treated with considerable caution.

  19. 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.

  20. 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

  1. Life detection at a Mars analogue site of present-day serpentinization in the Tablelands Ophiolite of Newfoundland (Invited)

    NASA Astrophysics Data System (ADS)

    Morrill, P. L.; Szponar, N.; Brazelton, W. J.; Woodruff, Q.; Schrenk, M. O.; Bower, D. M.; Steele, A.

    2010-12-01

    The Tableland Ophiolite was created during the collision of Laurentia and Gondwana continents ca. 470 million years ago. Ultramafic mantle rocks, from the ancient sea bed that once separated these continents, were thrusted westward onto the old continental margin, which is now Western Newfoundland. Weathering due to recent glaciations has left large areas of ultramafic rock at the surface and created fissures for fluid flow. As a result serpentinization is occurring as fresh water penetrates the unaltered ultramafic rock. Serpentinization is of particular interest because, through hydration of ultramafic rock, this reaction produces H2 and the reducing conditions necessary for abiogenic hydrocarbon synthesis, while also producing conditions amenable for chemolithotrophic life. Therefore sites of active serpentinization can be the source of either abiogenic or biogenic organics, or both. Serpentinization is a suspected (past or present) source of (detected or putative) hydrocarbons on Mars, Titan and Europa, hence these astrobodies may be potentially habitable or once habitable environments. The Tablelands Ophiolite is an analogue site that is ideal for testing methods of life detection in an extreme environment of high pH and low microbial biomass characteristic of sites of serpentinization. Multiple ultrabasic reducing springs characteristic of present-day serpentinization have been identified and characterized based on their geochemistry and microbiology. Field-based instruments were deployed for the detection of microbial activity (ATP), microbial cell wall material, and mineralogy, in yet untested high pH and low biomass environment. In this talk I will give an overview of the in situ measurements of life detection and put these measurements in context of geochemistry, microbiology, carbon source and reaction pathways, and I will discuss what we have learned that will help us plan for future mission measurements.

  2. 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.

  3. Biological and quantitative-SAR evaluations, and docking studies of (E)-N -benzylidenebenzohydrazide analogues as potential antibacterial agents

    PubMed Central

    Alam, Mohammad Sayed; Jebin, Sefat; Rahman, M. Mostafizur; Bari, Md. Latiful; Lee, Dong-Ung

    2016-01-01

    A series of 15 (E)-N'-benzylidenebenzohydrazide analogues were evaluated for their antimicrobial activities against eleven pathogenic and food-borne microbes, namely, S. aureus (G+), L. monocytogenes (G+), B. subtilis (G+), K. pneumonia (G¯), C. sakazakii (G¯), C. freundii (G¯), S. enterica (G¯), S. enteritidis (G¯), E. coli (G¯), Y. pestis (G¯), and P. aeruginosa (G¯). Most of the compounds exhibited selective activity against some Gram-negative bacterial strains. Of the compounds tested (3a-o), 3b and 3g were most active against C. freundii (MIC = ~19 µg mL-1). Whereas, compounds 3d, 3i, 3k and 3n exhibited MIC values ranging from 37.5 to 75 μg mL-1 against C. freundii, and compounds 3e, 3l and 3n had MIC values of ~75 μg mL-1 against K. pneumonia. Quantitative structure-antibacterial activity relationships were studied using physicochemical parameters and a good correlation was found between calculated octanol-water partition coefficients (clogP; a lipophilic parameter) and antibacterial activities. In silico screening was also performed by docking high (3b and 3g) and low (3n) activity compounds on the active site of E. coli FabH receptor, which is an important therapeutic target. The findings of these in silico screening studies provide a theoretical basis for the design and synthesis of novel benzylidenebenzohydrazide analogues that inhibit bacterial FabH. PMID:27540348

  4. Biological and quantitative-SAR evaluations, and docking studies of (E)-N -benzylidenebenzohydrazide analogues as potential antibacterial agents.

    PubMed

    Alam, Mohammad Sayed; Jebin, Sefat; Rahman, M Mostafizur; Bari, Md Latiful; Lee, Dong-Ung

    2016-01-01

    A series of 15 (E)-N'-benzylidenebenzohydrazide analogues were evaluated for their antimicrobial activities against eleven pathogenic and food-borne microbes, namely, S. aureus (G(+)), L. monocytogenes (G(+)), B. subtilis (G(+)), K. pneumonia (G¯), C. sakazakii (G¯), C. freundii (G¯), S. enterica (G¯), S. enteritidis (G¯), E. coli (G¯), Y. pestis (G¯), and P. aeruginosa (G¯). Most of the compounds exhibited selective activity against some Gram-negative bacterial strains. Of the compounds tested (3a-o), 3b and 3g were most active against C. freundii (MIC = ~19 µg mL(-1)). Whereas, compounds 3d, 3i, 3k and 3n exhibited MIC values ranging from 37.5 to 75 μg mL(-1) against C. freundii, and compounds 3e, 3l and 3n had MIC values of ~75 μg mL(-1) against K. pneumonia. Quantitative structure-antibacterial activity relationships were studied using physicochemical parameters and a good correlation was found between calculated octanol-water partition coefficients (clogP; a lipophilic parameter) and antibacterial activities. In silico screening was also performed by docking high (3b and 3g) and low (3n) activity compounds on the active site of E. coli FabH receptor, which is an important therapeutic target. The findings of these in silico screening studies provide a theoretical basis for the design and synthesis of novel benzylidenebenzohydrazide analogues that inhibit bacterial FabH. PMID:27540348

  5. Synthesis and Comparative Study of Anti-Adenoviral Activity of 6-Azacytidine and Its Analogues.

    PubMed

    Alexeeva, Inna; Nosach, Lydia; Palchykovska, Larisa; Usenko, Lyubov; Povnitsa, Olga

    2015-01-01

    This paper presents the results of synthesis and study of cytotoxicity and the anti-adenoviral activity of new N4-derivatives of 6-azacytidine and its α-L-glycopyranosyl analogues obtained by the simplified one-pot version of the silyl condensation method. The resulting acylated 4-methylmercapto-1,2,4-triazin-3(2Н)-one glycosides then underwent the amination and/or ammonolysis to provide 6-azacytidine glycoside analogues (2-6, 12, 15, 17) and compounds with modifications at both base and sugar fragments (11, 15). The evaluation of cytotoxicity and antiviral activity of new compounds against AdV5 showed high selectivity indexes for N4-methyl-6-azacytidine (2) and N,O-tetraacetyl-6-azacytidine (8). High anti-adenoviral activity of N4-methyl-6-azacytidine as well as very low cytotoxicity may suggest its further investigation as potential compound for the therapy of AdV infection. PMID:26167665

  6. QM/MM Study of Dehydro and Dihydro β-Ionone Retinal Analogues in Squid and Bovine Rhodopsins: Implications for Vision in Salamander Rhodopsin

    PubMed Central

    Sekharan, Sivakumar; Altun, Ahmet; Morokuma, Keiji

    2010-01-01

    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, 3,4-dehydro-5,6-dihydro-PSB11, 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 to be rigid and stiff. On the basis of these studies, a tentative model of salamander rhodopsin binding site is also proposed. PMID:20964383

  7. Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues

    SciTech Connect

    Pereira, Jose H.; Petchprayoon, Chutima; Hoepker, Alexander C.; Moriarty, Nigel W.; Fink, Sarah J.; Cecere, Giuseppe; Paterson, Ian; Adams, Paul D.; Marriott, Gerard

    2014-07-22

    The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13) nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region to the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. In conclusion, structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.

  8. Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues

    DOE PAGESBeta

    Pereira, Jose H.; Petchprayoon, Chutima; Hoepker, Alexander C.; Moriarty, Nigel W.; Fink, Sarah J.; Cecere, Giuseppe; Paterson, Ian; Adams, Paul D.; Marriott, Gerard

    2014-07-22

    The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13) nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region tomore » the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. In conclusion, structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.« less

  9. FMR thermomagnetic studies up to 900 C of lunar soils and potential magnetic analogues. [Ferromagnetic Resonance studies

    NASA Technical Reports Server (NTRS)

    Morris, R. V.; Gibbons, R. V.; Hoerz, F.

    1975-01-01

    Using a recently developed furnace, ferromagnetic resonance (FMR) thermomagnetic studies up to 900 C were employed to measure the Curie points of the superparamagnetic (SP) and single domain (SD) particles in lunar soils and potential magnetic analogue materials. Based on measured Curie points of 775 C, the SP and SD particles in lunar soils 10084-853, 12070-29, 14161-46, and 67010-4 are essentially pure metallic Fe. Synthetic and terrestrial samples containing magnetite, titanomaghemites, and magnetite-like particles have measured Curie points below 600 C are thus not magnetic analogues of lunar soils.

  10. 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

  11. Combined QM/MM study of thyroid and steroid hormone analogue interactions with αvβ3 integrin.

    PubMed

    Freindorf, Marek; Furlani, Thomas R; Kong, Jing; Cody, Vivian; Davis, Faith B; Davis, Paul J

    2012-01-01

    Recent biochemical studies have identified a cell surface receptor for thyroid and steroid hormones that bind near the arginine-glycine-aspartate (RGD) recognition site on the heterodimeric αvβ3 integrin. To further characterize the intermolecular interactions for a series of hormone analogues, combined quantum mechanical and molecular mechanical (QM/MM) methods were used to calculate their interaction energies. All calculations were performed in the presence of either calcium (Ca(2+)) or magnesium (Mg(2+)) ions. These data reveal that 3,5'-triiodothyronine (T(3)) and 3,5,3',5'-tetraiodothyroacetic acid (T(4)ac) bound in two different modes, occupying two alternate sites, one of which is along the Arg side chain of the RGD cyclic peptide site. These orientations differ from those of the other ligands whose alternate binding modes placed the ligands deeper within the RGD binding pocket. These observations are consistent with biological data that indicate the presence of two discrete binding sites that control distinct downstream signal transduction pathways for T(3). PMID:22547930

  12. THE USE OF PANAX GINSENG AND ITS ANALOGUES AMONG PHARMACY CUSTOMERS IN ESTONIA: A CROSS-SECTIONAL STUDY.

    PubMed

    Volmer, Dasy; Raal, Ain; Kalle, Raivo; Sõukand, Renata

    2016-01-01

    The aim of the cross-sectional study was to evaluate the pattern of complementary self-treatment with P. ginseng and its analogues amongst pharmacy customers in Estonia. The study instrument consisted of multiple-choice items related to personal knowledge about and experience with the use of P. ginseng and its analogues. In total, 1233 customers participated in the study. Of study participants, 18.1% reported the use of P. ginseng and its analogues in their lives. P. ginseng preparations were used mostly according to the well- known indications (tiredness, weakness and decreased mental and physical capacity). Of P. ginseng users 44.3% reported positive treatment effects and 12.0% had experienced different side effects. With increase of age (p < 0.01) and at lower levels of education (p = 0.04), the use of ginseng or its analogues decreased. The better the users evaluated their health, the better they perceived the effect of P. ginseng preparations (p < 0.01). This study reported rather frequent use of P. ginseng and its analogues. P. ginseng could be seen in the treatment of conditions, where the use of local medicinal plants has not been established. Further research is needed to learn more about public knowledge and experiences about efficacy and safety of P. ginseng and its analogues. PMID:27476299

  13. Biological and chemical study of fused tri- and tetracyclic indazoles and analogues with important antiparasitic activity

    NASA Astrophysics Data System (ADS)

    Díaz-Urrutia, Christian A.; Olea-Azar, Claudio A.; Zapata, Gerald A.; Lapier, Michel; Mura, Francisco; Aguilera-Venegas, Benjamín; Arán, Vicente J.; López-Múñoz, Rodrigo A.; Maya, Juan D.

    A series of fused tri- and tetracyclic indazoles and analogues compounds (NID) with potential antiparasitic effects were studied using voltamperometric and spectroscopic techniques. Nitroanion radicals generated by cyclic voltammetry were characterized by electron spin resonance spectroscopy (ESR) and their spectral lines were explained and analyzed using simulated spectra. In addition, we examined the interaction between radical species generated from nitroindazole derivatives and glutathione (GSH). Biological assays such as activity against Trypanosoma cruzi and cytotoxicity against macrophages were carried out. Finally, spin trapping and molecular modeling studies were also done in order to elucidate the potentials action mechanisms involved in the trypanocidal activity.

  14. 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

  15. 1H/15N HSQC NMR studies of ligand carboxylate group interactions with arginine residues in complexes of brodimoprim analogues and Lactobacillus casei dihydrofolate reductase.

    PubMed

    Morgan, W D; Birdsall, B; Nieto, P M; Gargaro, A R; Feeney, J

    1999-02-16

    1H and 15N NMR studies have been undertaken on complexes of Lactobacillus casei dihydrofolate reductase (DHFR) formed with analogues of the antibacterial drug brodimoprim (2,4-diamino-5-(3', 5'-dimethoxy-4'-bromobenzyl)pyrimidine) in order to monitor interactions between carboxylate groups on the ligands and basic residues in the protein. These analogues had been designed by computer modeling with carboxylated alkyl chains introduced at the 3'-O position in order to improve their binding properties by making additional interactions with basic groups in the protein. Specific interactions between ligand carboxylate groups and the conserved Arg57 residue have been detected in studies of 1H/15N HSQC spectra of complexes of DHFR with both the 4-carboxylate and the 4, 6-dicarboxylate brodimoprim analogues. The spectra from both complexes showed four resolved signals for the four NHeta protons of the guanidino group of Arg57, and this is consistent with hindered rotation in the guanidino group resulting from interactions with the 4-carboxylate group in each analogue. In the spectra of each complex, one of the protons from each of the two NH2 groups and both nitrogens are considerably deshielded compared to the shielding values normally observed for such nuclei. This pattern of deshielding is that expected for a symmetrical end-on interaction of the carboxylate oxygens with the NHeta12 and NHeta22 guanidino protons. The differences in the degree of deshielding between the complexes of the two structurally similar brodimoprim analogues and the methotrexate indicates that the shielding is very sensitive to geometry, most probably to hydrogen bond lengths. The 1H/15N HSQC spectrum of the DHFR complex with the brodimoprim-6-carboxylate analogue does not feature any deshielded Arg NHeta protons and this argues against a similar interaction with the Arg57 in this case. It has not proved possible to determine whether the 6-carboxylate in this analogue is interacting directly with

  16. Studies on the interaction of fluorescein isothiocyanate and its sugar analogues with cetyltrimethylammonium bromide

    NASA Astrophysics Data System (ADS)

    Ghosh, Sujit Kumar; Ali, Mohammed; Chatterjee, Hirak

    2013-03-01

    The interaction of fluorescein isothiocyanate (FITC) and its two sugar analogues (viz., FITC-Dextran 40S and FITC-Dextran 2000S) with cetyltrimethylammonium bromide has been elucidated by absorption, fluorescence, Fourier transform infrared spectroscopy and fluorescence microscopic studies. It is seen that the emission of the probe molecules is uniquely sensitive to the changes in surfactant concentrations at a particular regime due to the formation of dye-surfactant supramolecular assembly. The formation of supramolecular assembly becomes effective at a lower surfactant concentration with increasing dextran size as a consequence of definite dye-surfactant interaction and could pave a facile strategy for designing hierarchical superstructures.

  17. Analogue experiments applied to active tectonics studies: the case of seismogenic normal faults

    NASA Astrophysics Data System (ADS)

    Seno, S.; Bonini, L.; Toscani, G.

    2010-12-01

    Lithosphere can be divided into three main zones as a function of increasing depth: an aseismic updip zone, the seismogenic zone and a deep aseismic zone. Identifying the location of these zones is a key goal to understand how a specific seismogenic fault works. The evaluation of the seismogenic structures potential in tectonically active regions needs an accurate knowledge of the geometries and kinematic of the faults. In many cases, large seismogenic faults are not clearly and unambiguously expressed at the surface, whereas in other regions with higher deformation rates a clear geological surface evidence is often associated with large earthquakes. Therefore, the characterization of the seismogenic faults and of their mutual interactions it is not always straightforward; in this case, analogue modeling can provide an independent and useful tool for the interpretation of the surface geological data. Analogue modeling applied to earthquake geology is a quite innovative technique: when combined with other datasets (e.g.: seismic tomography, seismic profiles, well-logging data, field geology, morphotectonic and palaeo-seismological data) it can provide significant insights on the long term (i.e. Quaternary) evolution of a seismogenic fault. We carried out a set of analogue models at 1 : 100,000 scale that reproduce in 2D a normal fault with a relatively low dip angle (45°-50°). In our experimental approach different materials have been used to simulate the three main zones in which the lithosphere is separated. Dry sand and wet clay simulate different mechanical behaviour of rocks during seismic cycle. The dry sand, with its negligible cohesion and ductility, represents brittle rocks that deformed by localized faulting during earthquakes. Wet clay, with its slightly greater cohesion and ductility, mimics aseismic updip zone. Glass microbeads simulate aseismic plastic zone. Preliminary results are highlighting a mutual control among the three analogue materials

  18. Biological evaluation and 3D-QSAR studies of curcumin analogues as aldehyde dehydrogenase 1 inhibitors.

    PubMed

    Wang, Hui; Du, Zhiyun; Zhang, Changyuan; Tang, Zhikai; He, Yan; Zhang, Qiuyan; Zhao, Jun; Zheng, Xi

    2014-01-01

    Aldehyde dehydrogenase 1 (ALDH1) is reported as a biomarker for identifying some cancer stem cells, and down-regulation or inhibition of the enzyme can be effective in anti-drug resistance and a potent therapeutic for some tumours. In this paper, the inhibitory activity, mechanism mode, molecular docking and 3D-QSAR (three-dimensional quantitative structure activity relationship) of curcumin analogues (CAs) against ALDH1 were studied. Results demonstrated that curcumin and CAs possessed potent inhibitory activity against ALDH1, and the CAs compound with ortho di-hydroxyl groups showed the most potent inhibitory activity. This study indicates that CAs may represent a new class of ALDH1 inhibitor. PMID:24840575

  19. Polarization studies of fluffy cometary analogues with the PROGRA2 experiment

    NASA Astrophysics Data System (ADS)

    Hadamcik, E.; Renard, J.-B.; Levasseur-Regourd, A.-C.; Worms, J.-C.

    Various observation and modelling results (infrared spectroscopy, dynamics of the particles, linear polarization of the scattered light), suggest the presence of fluffy aggregates in cometary comae. The solar light scattered by the dust is partially linearly polarized. The phase curve has a positive branch at phase angles higher than 20 degrees (with a maximum value of 30 percent in the visible domain at about 90 degrees phase angle) and a negative branch for smaller phase angles. For the positive branch, the polarization increases with wavelength. Laboratory scattering measurements with the PROGRA2 experiment (in A300-CNES and ESA dedicated microgravity flights or in ground based configurations) offer an alternative to models for exploring the scattering properties of aggregates particularly for structures too large or too complex to be handled easily by computer simulations. High porosity aggregates have been previously studied in levitation on single materials (pyrogenic oxides or carbon blacks). Their constituent grains size range is 10-100 nm; these grains are linked in aggregates with sizes in the 10 microns range. The levitating particles studied in the experiment are agglomerates of these aggregates with sizes between 10 microns and 500 microns (the size distribution is determined during the experiment by the imaging polarization technique). Their polarization phase curves have shapes that are approximately similar to those obtained for comets between 20 and 160 degrees phase angles. For grains in the 100 nm size range, the maximum value of polarization is smaller than 40 percent. Cometary particles are made of various materials (silicates and carbonaceous compounds). Mixtures of oxides (silica) and carbon blacks are currently studied to better understand the physical properties of these particles, which can become good analogues for cometary comae. The polarization phase curves obtained in two wavelengths for some of these mixtures and for silicates

  20. Probing the leucyl/phenylalanyl tRNA protein transferase active site with tRNA substrate analogues.

    PubMed

    Fung, Angela Wai Shan; Ebhardt, H Alexander; Krishnakumar, Kollappillil S; Moore, Jack; Xu, Zhizhong; Strazewski, Peter; Fahlman, Richard P

    2014-07-01

    Aminoacyl-tRNA protein transferases post-translationally conjugate an amino acid from an aminoacyl-tRNA onto the N-terminus of a target polypeptide. The eubacterial aminoacyl-tRNA protein transferase, L/F transferase, utilizes both leucyl-tRNA(Leu) and phenylalanyl-tRNA(Phe) as substrates. X-ray crystal structures with substrate analogues, the minimal substrate phenylalanyl adenosine (rA-Phe) and inhibitor puromycin, have been used to characterize tRNA recognition by L/F transferase. However analyses of these two X-ray crystal structures reveal significant differences in binding. Through structural analyses, mutagenesis, and enzymatic activity assays, we rationalize and demonstrate that the substrate analogues bind to L/F transferase with similar binding affinities using a series of different interactions by the various chemical groups of the analogues. Our data also demonstrates that enlarging the hydrophobic pocket of L/F transferase selectively enhances puromycin inhibition and may aid in the development of improved inhibitors for this class of enzymes. PMID:24521222

  1. Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

    PubMed

    Dowlat, H A; Kuhlmann, M K; Khatami, H; Ampudia-Blasco, F J

    2016-08-01

    Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included. PMID:27097592

  2. 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…

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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.; Gómez, 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

  8. 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 β-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

  9. Differential furanose selection in the active sites of archaeal DNA polymerases probed by fixed-conformation nucleotide analogues.

    PubMed

    Ketkar, Amit; Zafar, Maroof K; Banerjee, Surajit; Marquez, Victor E; Egli, Martin; Eoff, Robert L

    2012-11-13

    DNA polymerases select for the incorporation of deoxyribonucleotide triphosphates (dNTPs) using amino acid side-chains that act as a "steric-gate" to bar improper incorporation of rNTPs. An additional factor in the selection of nucleotide substrates resides in the preferred geometry for the furanose moiety of the incoming nucleotide triphosphate. We have probed the role of sugar geometry during nucleotide selection by model DNA polymerases from Sulfolobus solfataricus using fixed conformation nucleotide analogues. North-methanocarba-dATP (N-MC-dATP) locks the central ring into a RNA-type (C2'-exo, North) conformation near a C3'-endo pucker, and South-methanocarba-dATP (S-MC-dATP) locks the central ring system into a (C3'-exo, South) conformation near a C2'-endo pucker. Dpo4 preferentially inserts N-MC-dATP and in the crystal structure of Dpo4 in complex with N-MC-dAMP, the nucleotide analogue superimposes almost perfectly with Dpo4 bound to unmodified dATP. Biochemical assays indicate that the S. solfataricus B-family DNA polymerase Dpo1 can insert and extend from both N-MC-dATP and S-MC-dATP. In this respect, Dpo1 is unexpectedly more tolerant of substrate conformation than Dpo4. The crystal structure of Dpo4 bound to S-MC-dADP shows that poor incorporation of the Southern pucker by the Y-family polymerase results from a hydrogen bond between the 3'-OH group of the nucleotide analogue and the OH group of the steric gate residue, Tyr12, shifting the S-MC-dADP molecule away from the dNTP binding pocket and distorting the base pair at the primer-template junction. These results provide insights into substrate specificity of DNA polymerases, as well as molecular mechanisms that act as a barrier against insertion of rNTPs. PMID:23050956

  10. 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.

  11. Synthesis, in vitro binding studies and docking of long-chain arylpiperazine nitroquipazine analogues, as potential serotonin transporter inhibitors.

    PubMed

    Jarończyk, Małgorzata; Wołosewicz, Karol; Gabrielsen, Mari; Nowak, Gabriel; Kufareva, Irina; Mazurek, Aleksander P; Ravna, Aina W; Abagyan, Ruben; Bojarski, Andrzej J; Sylte, Ingebrigt; Chilmonczyk, Zdzisław

    2012-03-01

    It is well known that 6-nitroquipazine exhibits about 150-fold higher affinity for the serotonin transporter (SERT) than quipazine and recently we showed quipazine buspirone analogues with high to moderate SERT affinity. Now we have designed and synthesized several 6-nitroquipazine buspirone derivatives. Unexpectedly, their SERT binding affinities were moderate, and much lower than that of the previously studied quipazine buspirone analogues. To explain these findings, docking studies of both groups of compounds into two different homology models of human SERT was performed using a flexible target-ligand docking approach (4D docking). The crystal structures of leucine transporter from Aquifex aeolicus in complex with leucine and with tryptophan were used as templates for the SERT models in closed and outward-facing conformations, respectively. We found that the latter conformation represents the most reliable model for binding of buspirone analogues. Docking into that model showed that the nitrated compounds acquire a rod like shape in the binding pocket with polar groups (nitro- and imido-) at the ends of the rod. 6-Nitro substituents gave steric clashes with amino acids located at the extracellular loop 4, which may explain their lower affinity than corresponding quipazine buspirone analogues. The results from the present study may suggest chemical design strategies to improve the SERT modulators. PMID:22309909

  12. Structural insights into the interactions of xpt riboswitch with novel guanine analogues: a molecular dynamics simulation study.

    PubMed

    Jain, Swapan S; Sonavane, Uddhavesh B; Uppuladinne, Mallikarjunachari V N; McLaughlin, Emily C; Wang, Weiqing; Black, Sheneil; Joshi, Rajendra R

    2015-01-01

    Ligand recognition in purine riboswitches is a complex process requiring different levels of conformational changes. Recent efforts in the area of purine riboswitch research have focused on ligand analogue binding studies. In the case of the guanine xanthine phosphoribosyl transferase (xpt) riboswitch, synthetic analogues that resemble guanine have the potential to tightly bind and subsequently influence the genetic expression of xpt mRNA in prokaryotes. We have carried out 25 ns Molecular Dynamics (MD) simulation studies of the aptamer domain of the xpt G-riboswitch in four different states: guanine riboswitch in free form, riboswitch bound with its cognate ligand guanine, and with two guanine analogues SJ1 and SJ2. Our work reveals novel interactions of SJ1 and SJ2 ligands with the binding core residues of the riboswitch. The ligands proposed in this work bind to the riboswitch with greater overall stability and lower root mean square deviations and fluctuations compared to guanine ligand. Reporter gene assay data demonstrate that the ligand analogues, upon binding to the RNA, lower the genetic expression of the guanine riboswitch. Our work has important implications for future ligand design and binding studies in the exciting field of riboswitches. PMID:24404773

  13. 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

  14. Improved thrombin binding aptamer analogues containing inversion of polarity sites: structural effects of extra-residues at the ends.

    PubMed

    Virgilio, A; Amato, T; Petraccone, L; Filosa, R; Varra, M; Mayol, L; Esposito, V; Galeone, A

    2016-08-10

    In this paper, we report the investigations, based on NMR, molecular modelling, CD measurements and electrophoresis, of thrombin binding aptamer (TBA) analogues containing an extra-residue at the 3'-end or at both the ends of the original TBA sequence, linked through 3'-3' or 5'-5' phosphodiester bonds. The data indicate that most of the modified aptamers investigated adopt chair-like G-quadruplex structures very similar to that of the TBA and that stacking interactions occur between the 3'-3' or 5'-5' extra residues and the deoxyguanosines of the upper G-tetrad. A comparison of the thermodynamic data of TBA-A and TBA-T containing a 3'-3' extra residue and their canonical versions clearly indicates that the 3'-3' phosphodiester bond is fundamental in endowing the modified aptamers with remarkably higher thermal stabilities than the original TBA. PMID:27461474

  15. 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

  16. 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 β-lactam antibiotics. IPNS converts the tripeptide δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine (ACV) to isopenicillin N while reducing molecular oxygen to water. The substrate analogue δ-(L-α-aminoadipoyl)-L-cysteinyl-O-methyl-D-threonine (ACmT) is not turned over by IPNS. Epimeric δ-(L-α-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 β-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

  17. Constrained H-Phe-Phe-NH2 analogues with high affinity to the substance P 1-7 binding site and with improved metabolic stability and cell permeability.

    PubMed

    Fransson, Rebecca; Sköld, Christian; Kratz, Jadel M; Svensson, Richard; Artursson, Per; Nyberg, Fred; Hallberg, Mathias; Sandström, Anja

    2013-06-27

    We recently reported the discovery of H-Phe-Phe-NH2 as a small and high affinity ligand for the substance P 1-7 (SP(1-7), H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) specific binding site and its intriguing ability to reduce neuropathic pain. With the overall aim to develop stable and orally bioavailable SP(1-7) mimetics, the dipeptide was chosen as a lead compound. Herein the structure-activity relationship (SAR) of a set of modified H-Phe-Phe-NH2 analogues is presented together with their potential active uptake by PEPT1 transporter, intestinal permeability, and metabolic stability. Local constraints via peptide backbone methylation or preparation of cyclized analogues based on pyrrolidine were evaluated and were shown to significantly improve the in vitro pharmacokinetic properties. The SAR was rationalized by deriving a plausible binding pose for the high affinity ligands. Rigidification using a 3-phenylpyrrolidine moiety in the C-terminal of H-Phe-Phe-NH2 resulted in high affinity and improved intrinsic clearance and intestinal epithelial permeability. PMID:23735006

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

    PubMed Central

    López-Munguía, Agustín; Hernández-Romero, Yanet; Pedraza-Chaverri, José; Miranda-Molina, Alfonso; Regla, Ignacio; Martínez, 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 β-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

  19. XAFS and XEOL of tetramesityldigermene - An electronic structure study of a heavy group 14 ethylene analogue

    SciTech Connect

    Ward, Matthew J.; Rupar, Paul A.; Murphy, Michael W.; Yiu, Yun-Mui; Baines, Kim M.; Sham, Tsun-Kong

    2013-05-29

    Digermene, the germanium analogue of ethylene, has a multiple bonding motif that differs greatly from that of alkenes and exhibits no pure σ or π type bonds. The electronic structure of digermenes is difficult to study experimentally due to their reactivity, and is computationally challenging because of their shallow potential energy surfaces. Using X-ray absorption near edge structures at both the germanium K and L edges we have been able to directly probe the unoccupied electronic states, or the lowest unoccupied molecular orbital (LUMO), and LUMO+ etc. in the Ge=Ge bond of tetramesityldigermene. We have demonstrated that the LUMO, LUMO+, etc. are composed of hybrid Ge 4s and 4p orbitals. Additionally, our data suggest that the LUMO exhibits relatively more Ge 4s character, whereas the LUMO+ and LUMO+2 exhibit relatively more Ge 4p character. An X-ray excited optical luminescence study of Ge2Mes4 revealed one broad optical emission band at 620 nm, which is significantly red shifted compared to the known energy gap of this molecular germanium compound.

  20. Production and Study of Titan's Aerosols Analogues with A RF Low Pressure Plasma Discharge

    NASA Astrophysics Data System (ADS)

    Szopa, C.; Cernogora, G.; Correia, J. J.; Boufendi, L.; Jolly, A.

    2005-10-01

    The atmosphere of Titan, the biggest satellite of Saturn, contains aerosols produced by the organic chemistry induced by the photochemistry of N2 and CH4, the major gaseous atmospheric compounds. In spite of their importance for the properties of the Titan's atmosphere, and for organic chemistry, only few direct information are available about them because of the limitations of the observational techniques, and their processes of formation and growth are not understood. In order to bring answers to these questions, we developed a new type of laboratory simulation to produce analogues of Titan's aerosols (known as tholins) with a low pressure Radio Frequency plasma discharge. The main originality of this experiment (named PAMPRE) comes from its ability to produce particles in volume, as they are maintained in levitation by electrostatic forces compensating gravity, whereas the other experiments produce tholins on the reactors walls or a substrate. We initiated our investigations by a study of the properties of the produced particles as a function of the plasma operating conditions (i.e. amount of CH4 in N2, injected RF power, pressure, and gas flow). We here present the results of this study.

  1. The development of amine substituted analogues of MPTP as unique tools for the study of MPTP toxicity and Parkinson's disease.

    PubMed

    Johannessen, J N; Savitt, J M; Markey, C J; Bacon, J P; Weisz, A; Hanselman, D S; Markey, S P

    1987-02-23

    We are currently developing amino-substituted MPTP analogues as useful probes for understanding the mechanism of MPTP toxicity and Parkinson's disease. One analogue, 4'-amino MPTP, induces a loss of striatal dopamine and is thus a suitable substitute for MPTP. This probe will be used as a histologically fixable MPTP which can be used to answer detailed anatomical questions concerning the sites of MPTP, MPP+ uptake and storage. In addition, antibodies have been raised against MPTP and MPP+ in rabbits using diazo-linked bovine serum albumin conjugates. The antibodies have been characterized with regard to their recognition of relevant structural analogues using an enzymelinked immunoassay (ELISA) procedure. Antibodies to MPTP detected MPTP in mouse brain extracts derived from as little as 5 micrograms of tissue. The antibodies will be used for immunohistochemical localization of 4'-NH2-MPTP and 4'-NH2-MPP+ in brain, as well as probes for the screening of parkinsonian brain tissue for any MPTP- or MPP+-like materials which might exist. PMID:2433563

  2. A Numerical and Analogue Study of Dike Ascent in Asymmetric Continental Rift Zones

    NASA Astrophysics Data System (ADS)

    Schierjott, J.; Maccaferri, F.; Acocella, V.; Rivalta, E.

    2015-12-01

    In continental rift zones, tectonic extension generates deep topographic depressions, typically graben or half-graben structures, confined 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 the position of the magma source along the cross section of the rift and its spatial extent and the asymmetry of the graben cross section are the most important factors controlling one-sided volcanic activity at surface. For dikes starting beneath the rift's center, the more asymmetric the rift structure the more likely is asymmetric volcanic activity. Dikes are deflected to the shallow rift side and no volcanism develops on the deep side or only focused in one spot. However, if the position of the magma ponding region is offset towards the deep side of the graben, the dikes tend to emerge on the rift shoulder adjacent to such deep side. To a minor extent, also the starting depth of the dikes, any topographic loading on the graben flanks due to flank uplift and the background tectonic stress impact the surface distribution of volcanism

  3. Discrete and analogue quantity processing in the parietal lobe: a functional MRI study.

    PubMed

    Castelli, Fulvia; Glaser, Daniel E; Butterworth, Brian

    2006-03-21

    The human intraparietal sulcus (IPS) is implicated in processing symbolic number information and possibly in nonsymbolic number information. Specific IPS activity for discrete quantities (numerosities) as compared with continuous, analogue quantity has not been demonstrated. Here we use a stimulus-driven paradigm to distinguish automatic estimation of "how many things" from "how much" and "how long." The discrete analogue response task (DART) uses the perception of hues which can change either abruptly (discrete, numerous stimuli) or smoothly (analogue, nonnumerous stimuli) in space or in time. Subjects decide whether they saw more green or more blue. A conjunction analysis of spatial and temporal conditions revealed that bilateral IPS was significantly more active during the processing of discrete stimuli than during analogue stimuli, as was a parietal-occipital transition zone. We suggest that processing numerosity is a distinct process from processing analogue quantity, whether extended in space or time, and that an intraparietal network connects objects' segmentation to the estimation of their numerosity. PMID:16537401

  4. 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.

  5. An experimental analogue study into the role of abstract thinking in trauma-related rumination.

    PubMed

    Ehring, Thomas; Szeimies, Anna-Kristina; Schaffrick, Christina

    2009-04-01

    Trauma-related rumination has been shown to predict the maintenance of posttraumatic stress disorder (PTSD). However, it is still unclear how rumination can be distinguished from functional forms of thinking about traumatic events. The current study used an analogue design to experimentally test the hypothesis that the abstractness of thinking is responsible for the dysfunctional effects of trauma-related rumination. Eighty-three healthy university students first watched a distressing video and were then randomly assigned to abstract ruminative thinking, concrete thinking or distraction. Abstract thinking was found to lead to a significantly longer maintenance of negative mood and arousal than both concrete thinking and distraction. These results are in line with earlier findings in the context of excessive worry and depressive rumination and support the view that abstractness is a critical factor for the dysfunctional effects of trauma-related rumination. However, results regarding intrusive memories were not supportive of the hypotheses. Unexpectedly, the distraction group showed the highest number of intrusions, whereas the abstract and concrete conditions did not significantly differ. Implications for theoretical models of trauma-related rumination and possible clinical implications are discussed. PMID:19200947

  6. In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt1-DALDA Analogues

    PubMed Central

    2014-01-01

    In this study the μ opioid receptor (MOR) ligands DALDA (Tyr-d-Arg-Phe-Lys-NH2) and Dmt1-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 (δ 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 Dmt1-DALDA 1, compounds 4–7 are mixed MOR/DOR agonists, expected to produce reduced opioid-related side effects. PMID:24839540

  7. Treatment-limiting toxicities associated withnucleoside analogue reverse transcriptase inhibitor therapy: A prospective, observational study**

    PubMed Central

    Palacios, Rosario; Santos, Jesús; Camino, Xavier; Arazo, Piedad; Torres Perea, Rafael; Echevarrfa, Santiago; Ribera, Esteban; Sánchez de la Rosa, Rainel; Moreno Guillen, Santiago

    2005-01-01

    Background: The Recover Study is an ongoing, prospective study designed 10 to assess toxicity associated with the use of nucleoside analogue reverse transcriptase inhibitors (NRTIs) (stavudine, zidovudine, lamivudine, didanosine, abacavir) in HIV-1-infected patients receiving highly active antiretroviral therapy (HAART) in routine clinical practice. This project is being conducted at 120 HIV units at teaching hospitals across Spain. Objective: The aim of this study was to identify the most common treatment-limiting 10 moderate to severe clinical and laboratory adverse effects (AEs), and the individual NRTIs involved in the development of these effects, in HIV-1-infected patients receiving HAART who discontinued use of an NRTI in the Recover Study. Methods: Patients eligible for participation in the Recover Study are aged10 ≥18 years; have virologically documented HIV-1 infection; have sustained viral suppression (viral load <200 cells/mL or stable, heavily experienced [ie, have received ≥3 antiretroviral regimens] patients with viral load <5000 cells/mL) for ≥6 months; are receiving HAART; are undergoing active follow-up; and have developed 2:1 NRTI-associated AE that, in the opinion of a study investigator and under the conditions of routine clinical practice, justified discontinuation of treatment with the offending drug (principal AE/offending NRTI). The present study included patients recruited for the Recover Study between September 2002 and May 2003. Results: A total of 1391 patients were enrolled (966 men, 425 women; mean 1 age, 42 years [range, 18–67 years]). Five hundred six patients (36.4%) had been diagnosed with AIDS. The mean duration of treatment with the offending NRTI was 74 months (range, 6–156 months). Seven hundred nine patients (51.0%) were receiving fourth-line (or more) therapy. Eight hundred twenty-one patients (59.0%) were receiving nonnucleoside analogues, and 552 patients (39.7%), protease inhibitors, as components of their HAART

  8. 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.

  9. NMR studies of multiple conformations in complexes of Lactobacillus casei dihydrofolate reductase with analogues of pyrimethamine

    SciTech Connect

    Birdsall, B.; Tendler, S.J.B.; Feeney, J.; Carr, M.D. ); Arnold, J.R.P.; Thomas, J.A.; Roberts, G.C.K. ); Griffin, R.J.; Stevens, M.F.G. )

    1990-10-01

    {sup 1}H and {sup 19}F NMR signals from bound ligands have been assigned in one- and two-dimensional NMR spectra of complexes of Lactobacillus casei dihydrofolate reductase with various pyrimethamine analogues. The signals were identified mainly by correlating signals from bound and free ligands by using 2D exchange experiments. Analogues with symmetrically substituted phenyl rings give rise to {sup 1}H signals from four nonequivalent aromatic protons, clearly indicating the presence of hindered rotation about the pyrimidine-phenyl bond. Analogues with symmetrically substituted phenyl rings give rise to {sup 1}H signals from four nonequivalent aromatic protons, clearly indicating the presence of hindered rotation about the pyrimidine-phenyl bond. Analogues containing asymmetrically substituted aromatic rings exist as mixtures of two rotational isomers (an enantiomeric pair) because of this hindered rotation and the NMR spectra revealed that both isomers (forms A and B) bind to the enzyme with comparable, though unequal, binding energies. In this case two complete sets of bound proton signals were observed. The relative orientations of the two forms have been determined from NOE through-space connections between protons on the ligand and protein. Ternary complexes with NADP{sup {plus}} were also examined.

  10. Synthesis of selenium-containing amino acid analogues and their biological study.

    PubMed

    Abdel-Hafez, S H; Saad, H A; Aly, M R E

    2011-01-01

    Synthesis of selenium-containing amino acid analogues is described. These compounds were prepared in a concise and short synthetic route in good yields by nucleophilic substitution reaction of pyridineselenol and quinolineselenol derivatives with N-phthaloylglycyl chloride followed by hydrazinolysis. The newly synthesized compounds were screened against different strains of bacteria and fungi. PMID:21899043

  11. 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.

  12. Des analogues naturels de sites de stockage de déchets nucléaires vieux de 2 milliards d'années : les réacteurs de fission nucléaire naturels du Gabon (Afrique)

    NASA Astrophysics Data System (ADS)

    Gauthier-Lafaye, François

    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 Bangombé (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.

  13. Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic study of 11 cases.

    PubMed

    Din, Nasir Ud; Fatima, Saira; Kayani, Naila

    2016-06-01

    Mammary analogue secretory carcinoma (MASC) is a recently described tumor sharing the histologic, immunohistochemical, and molecular profile of secretory carcinoma of breast. We aimed to evaluate the morphologic and histochemical features needed/required for the diagnosis of MASC without adjunct of molecular analysis. Six retrospective cases suspicious for MASC and 5 prospective cases reported as MASC were included in the study. Molecular analysis of ETV6 by fluorescence in situ hybridization was performed at the University of Pittsburg, USA. The ages of the patients ranged from 9 to 60 years (mean, 27.5 years). Histologically, all tumors showed mixed growth patterns including microcystic, macrocystic, papillary, tubular, and solid, papillary the being most common pattern. The tumor cells showed round to oval vesicular nuclei with small nucleoli, and eosinophilic to vacuolated cytoplasm. All cases demonstrated luminal and cytoplasmic mucin on periodic acid-Schiff with and without diastase digestion and alcian blue stain. ETV6 fusion gene rearrangement by fluorescence in situ hybridization was detected in 10 of 11 tumors. Recurrences occurred in 3 patients, and 1 patient died of disease 5 years after surgery. In conclusion, MASC is a relatively rare salivary gland malignancy exhibiting distinct histologic and histochemical features which can help to differentiate it from other mimics. Histologically, papillary-cystic and microcystic patterns are the main clues to diagnosis. The follicular pattern of acinic cell carcinoma might represent MASC, as 4 cases in our series had this pattern. Two patients in our series were 9 and 9½ years old respectively, which are the youngest ages ever recorded for MASC. PMID:27180060

  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. Exploring an active hydrothermal system - An analogue study from the Swiss Alps

    NASA Astrophysics Data System (ADS)

    Egli, Daniel; Herwegh, Marco; Berger, Alfons; Baron, Ludovic

    2016-04-01

    Understanding the detailed flow paths in hydrothermal reservoirs is crucial for successful exploration of naturally porous and permeable rock masses for energy production. However, due to the common inaccessibility of active hydrothermal systems of suitable depth, e.g. in the northern Alpine foreland of the European Alps, direct observations are normally impossible and the knowledge about such systems is still insufficient. For that reason, a known fault-bound hydrothermal system in the crystalline basement of the Aar Massif serves as an analogue for potential geothermal reservoirs in the deep crystalline subsurface of the northern Alpine foreland. During summer 2015, a 125 m hole has been drilled across this active hydrothermal zone on the Grimsel Pass for in-situ characterization of its structural, petrophysical, mechanical as well as geophysical parameters. With this information, this project aims at improving the knowledge of natural hydrothermal systems as a potentially exploitable energy source. The investigated system is characterized by a central breccia zone surrounded by different types of cataclasites and localized high strain zones. The surrounding includes different altered and deformed granitoid host rocks. In this study, we focus on the ductile and brittle deformation (shear zones, fractures, joints) that provides the main fluid pathways. Their spatial distribution around a central water-bearing breccia zone as well as their continuity and permeability provide constraints on the water flow paths in such structurally controlled hydrothermal systems. The aim will be the connection of detailed structural data with petrophysical parameters such as porosities and permeabilities. The drillcore shows the high variability of deformation structures and related fluid pathways at different scales (millimeter-decameter) demonstrating the urgent need for an improved understanding of the link between mechanical evolution, associated deformation structures as well

  16. Experimental study of radon production and transport in an analogue for the Martian regolith

    NASA Astrophysics Data System (ADS)

    Meslin, P. Y.; Sabroux, J. C.; Bassot, S.; Chassefière, E.

    2011-05-01

    The suggestion that radon could be used as a radioactive tracer of regolith-atmosphere exchanges and as a proxy for subsurface water on Mars, as well as its indirect detection in the Martian atmosphere by the rover Opportunity, have raised the need for a better characterization of its production process and transport efficiency in the Martian soil. More specifically, a proper estimation of radon exhalation rate on Mars requires its emanation factor and diffusion length to be determined. The dependence of the emanation factor as a function of pore water content (at 267 and 293 K) and the dependence of the adsorption coefficient on temperature, specific surface area and nature of the carrier gas (He, He + CO 2) have been measured on a Martian soil analogue (Hawaiian palagonitized volcanic ash, JSC Mars-1), whose radiometric analysis has been performed. An estimation of radon diffusion lengths on Mars is provided and is used to derive a global average emanation factor (2-6.5%) that accounts for the exhalation rate inferred from the 210Po surface concentration detected on Martian dust and from the 214Bi signal measured by the Mars Odyssey Gamma Ray Spectrometer. It is found to be much larger than emanation factors characterizing lunar samples, but lower than the emanation factor of the palagonite samples obtained under dry conditions. This result probably reflects different degrees of aqueous alteration and could indicate that the emanation factor is also affected by the current presence of pore water in the Martian soil. The rationale of the "radon method" as a technique to probe subsurface water on Mars, and its sensitivity to soil parameters are discussed. These experimental data are useful to perform more detailed studies of radon transport in the Martian atmosphere using Global Climate Models and to interpret neutron and gamma data from Mars Odyssey Gamma Ray Spectrometer.

  17. 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.

  18. Reactivity Study of a Pyridyl-1-azaallylgermanium(I) Dimer: Synthesis of Heavier Ether and Ester Analogues of Germanium.

    PubMed

    Leung, Wing-Por; Chan, Yuk-Chi; So, Cheuk-Wai; Mak, Thomas C W

    2016-04-01

    The reactivity study of a pyridyl-1-azaallylgermanium(I) dimer LGe-GeL [1; L = N(SiMe3)C(Ph)C(SiMe3)(C5H4N-2)] with different stoichiometric ratios of elemental selenium and tellurium is described. The reactions of 1 with 1 equiv of selenium and tellurium afforded the first examples of heavier ether analogues of germanium, bis(germylene) selenide and telluride LGe(μ-E)GeL [E = Se (2) and Te (3)], respectively. Meanwhile, the reactions of 1 with 2 equiv of selenium and tellurium gave the heavier ester analogues LGe═E(μ-E)GeL [E = Se (4) and (5)]. All compounds have been characterized by X-ray crystallography and multinuclear NMR spectroscopy. PMID:26991426

  19. 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

  20. Pharmacophore modeling, 3D-QSAR, and docking study of pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues as PDE4 selective inhibitors.

    PubMed

    Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal

    2015-11-01

    Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study pharmacophore and atom based 3D-QSAR studies were carried out for pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues. A five point pharmacophore model was developed using 52 molecules having pIC50 values ranging from 9.959 to 3.939. The best predictive pharmacophoric hypothesis AHHRR.3 was characterized by survival score (2.944), cross validated (r(2) = 0.8147), regression coefficient (R(2) = 0.9545) and Fisher ratio (F =173) with 4 component PLS factor. Results explained that one hydrogen bond acceptor, two aromatic rings and two hydrophobic groups are crucial for the PDE4 inhibition. The docking studies of all selected inhibitors in the active site of PDE4 showed crucial hydrogen bond interactions with Asp392, Asn395 Tyr233, and Gln443 residues. The pharmacophoric features R15 and R16 exhibited π-π stacking with His234, Phe414, and Phe446 residues. The generated model was further validated by carrying out the decoy test. The binding free energies of these inhibitors in the catalytic domain of 1XMU were calculated by the molecular mechanics/generalized Born surface area VSGB 2.0 method. The results of molecular dynamics simulation confirmed the extra precision docking-predicted priority for binding sites, the accuracy of docking, and the reliability of active conformations. Pyrozolo[1,5-a]pyridine/4,4-dimethylpyrazolone analogues in this study showed lower binding affinity toward PDE3A in comparison to PDE4. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity. Graphical Abstract Pyrozolo[1,5-a]pyridines/4,4-dimethylpyrazolones. PMID:26499496

  1. Hysteroscopic myomectomy outcomes after 3-month treatment with either Ulipristal Acetate or GnRH analogues: a retrospective comparative study.

    PubMed

    Sancho, Javier Monleón; Delgado, Verónica Serrano de la Cruz; Valero, Maria José Nuñez; Soteras, Marta Gurrea; Amate, Vicente Payá; Carrascosa, Antonio Abad

    2016-03-01

    Ulipristal Acetate (UPA) modifies the endometrium, as well as fibroids, and therefore it might make hysteroscopic surgery more difficult. To confirm that pre-treatment with UPA is as safe and effective an option as pre-treatment with GnRH analogues, considered the gold standard. We present the first series of 26 hysteroscopic myomectomies after 3 months treatment with UPA and we compare the results with a series of 24 cases pretreated with GnRH analogues. This was a retrospective cohort study between July 2013 and May 2015. We analyszed patients with submucous myomas >2.5 in diameter. Hysteroscopic myomectomy was performed after 3 months of treatment with either UPA (5mg daily) or the GnRH agonist (3.75mg/month). Both groups were similar in age, myoma initial size and classification. There were no significant differences between UPA and GnRHa treated groups in terms of percentage of myomas resected (93% vs 98%), duration of surgery (38 vs 37min), fluid deficit (200 vs 350ml) and complications. In the surgeon's subjective opinion, UPA treatment was associated with an easier resection. Based on our experience, previous treatment with UPA does not difficult Hhysteroscopic myomectomy. Endometrial changes have no impact on surgery. Safety and feasibility are comparable to hysteroscopic myomectomies with previous treatment with GnRH analogues. This allows us to take advantage of the reduction in size of fibroids before surgery with less side effects. PMID:26871272

  2. 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.

  3. 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.

  4. CANTON CAFO FIELD SITE STUDY - SITE CHARACTERIZATION AND CONTAMINANT IMPACTS

    EPA Science Inventory

    This presentation of CAFO research concerning the Canton CAFO field site study, including its characterization and contaminant impacts, was given at a NRMRL program review discussion of the CAFO Research Program.

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

    PubMed

    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 (Logβ11n) 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 Al(3+) at pH 7.4, in water. Moreover, TAME5OX can distinguish Al(3+) from Fe(3+) and Cr(3+) via two different sensing mechanisms: photoinduced electron transfer (PET) for Al(3+) and internal charge transfer (ICT) for Fe(3+) and Cr(3+). 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

  6. 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.

  7. Identification of proteolytic cleavage sites within the gag-analogue protein of Ty1 virus-like particles.

    PubMed

    Martin-Rendon, E; Hurd, D W; Marfany, G; Kingsman, S M; Kingsman, A J

    1996-12-01

    Like retroviruses, the yeast retrotransposon Ty1 produces its proteins as precursors that are subsequently cleaved by a protease encoded by the element. These cleavage events are essential for transposition as they release the active reverse transcriptase and integrase and they modify the structure of the virus-like particles in a way that is analogous to the morphological changes that occur during retrovirus core maturation. Using a combination of epitope tagging, amino acid analysis and mutagenesis, we have identified the major cleavage sites for the Ty1 protease within the particle-forming protein, p1, at 407S/408N. In addition, we present evidence indicating that the Ty1 protease may be a 17 kDa protein. PMID:8971723

  8. Bisphenol A and Its Analogues Activate Human Pregnane X Receptor

    PubMed Central

    Sui, Yipeng; Ai, Ni; Park, Se-Hyung; Rios-Pilier, Jennifer; Perkins, Jordan T.; Welsh, William J.

    2012-01-01

    Background: Bisphenol A (BPA) is a base chemical used extensively in many consumer products. BPA and its analogues are present in environmental and human samples. Many endocrine-disrupting chemicals, including BPA, have been shown to activate the pregnane X receptor (PXR), a nuclear receptor that functions as a master regulator of xenobiotic metabolism. However, the detailed mechanism by which these chemicals activate PXR remains unknown. Objective: We investigated the mechanism by which BPA interacts with and activates PXR and examined selected BPA analogues to determine whether they bind to and activate PXR. Methods: Cell-based reporter assays, in silico ligand–PXR docking studies, and site-directed mutagenesis were combined to study the interaction between BPA and PXR. We also investigated the influence of BPA and its analogues on the regulation of PXR target genes in human LS180 cells. Results: We found that BPA and several of its analogues are potent agonists for human PXR (hPXR) but do not affect mouse PXR activity. We identified key residues within hPXR’s ligand-binding pocket that constitute points of interaction with BPA. We also deduced the structural requirements of BPA analogues that activate hPXR. BPA and its analogues can also induce PXR target gene expression in human LS180 cells. Conclusions: The present study advances our understanding of the mechanism by which BPA interacts with and activates human PXR. Activation of PXR by BPA may explain some of the adverse effects of BPA in humans. PMID:22214767

  9. 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...

  10. Design and Synthesis of 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (Citalopram) Analogues as Novel Probes for the Serotonin Transporter S1 and S2 Binding Sites

    PubMed Central

    Banala, Ashwini K.; Zhang, Peng; Plenge, Per; Cyriac, George; Kopajtic, Theresa; Katz, Jonathan L.; Loland, Claus Juul; Newman, Amy Hauck

    2013-01-01

    The serotonin transporter (SERT) is the primary target for antidepressant drugs. The existence of a high affinity primary orthosteric binding site (S1) and a low affinity secondary site (S2) has been described and their relation to antidepressant pharmacology has been debated. Herein, structural modifications to the N-, 4, 5, and 4’-positions of (±)citalopram (1) are reported. All of the analogues were SERT-selective and demonstrated that steric bulk was tolerated at the SERT S1 site, including two dimeric ligands (15 and 51.) In addition, 8 analogues were identified with similar potencies to S-1 for decreasing the dissociation of [3H]S-1 from the S1 site, via allosteric modulation at S2. Both dimeric compounds had similar affinities for the SERT S1 site (Ki=19.7 and 30.2 nM, respectively), whereas only the N-substituted analogue, 51, was as effective as S-1 in allosterically modulating the binding of [3H]S-1 via S2. PMID:24237160

  11. Phosphonate analogues of aminoacyl adenylates.

    PubMed Central

    Southgate, C C; Dixon, H B

    1978-01-01

    Phosphonomethyl analogues of glycyl phosphate and valyl phosphate, i.e. NH2-CHR-CO-CH2-PO(OH)2, were synthesized and esterified with adenosine to give analogues of aminoacyl adenylates. The interaction of these adenylate analogues with valyl-tRNA synthetase from Escherichia coli was studied by fluorescence titration. The analogue of valyl phosphate has an affinity for the enzyme comparable with that of valine, but that of valyl adenylate is bound much less tightly than either valyl adenylate or corresponding derivative of valinol. The affinity of the analogue of glycyl adenylate was too low to be measured. We conclude that this enzyme interacts specifically with both the side chain and the anhydride linkage of the adenylate intermediate. PMID:743207

  12. 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.

  13. Copper inhibits activated protein C: protective effect of human albumin and an analogue of its high-affinity copper-binding site, d-DAHK.

    PubMed

    Bar-Or, David; Rael, Leonard T; Winkler, James V; Yukl, Richard L; Thomas, Gregory W; Shimonkevitz, Richard P

    2002-02-01

    Activated protein C (APC) is useful in the treatment of sepsis. Ischemia and acidosis, which often accompany sepsis, cause the release of copper from loosely bound sites. We investigated (i) whether physiological concentrations of copper inhibit APC anticoagulant activity and (ii) if any copper-induced APC inhibition is reversible by human serum albumin (HSA) or a high-affinity copper-binding analogue of the human albumin N-terminus, d-Asp-d-Ala-d-His-d-Lys (d-DAHK). APC activity after 30 min of incubation with CuCl2 (10 microM) was decreased 26% below baseline. HSA, both alone and when combined with various ratios of CuCl2, increased APC activity significantly above baseline. d-DAHK alone and 2:1 and 4:1 ratios of d-DAHK:CuCl2 also increased APC activity. APC contained 1.4 microM copper, which helps explain the increased APC activity with HSA and d-DAHK alone. These in vitro results indicate that copper inhibits APC activity and that albumin and d-DAHK reverse the copper-induced APC deactivation. PMID:11820775

  14. In vitro pharmacological evaluation of the radiolabeled C-terminal substance P analogue Lys-Phe-Phe-Gly-Leu-Met-NH2: Does a specific binding site exist?

    PubMed

    Tomczyszyn, Aleksandra; Csibrany, Balazs; Keresztes, Attila; Mallareddy, Jayapal Reddy; Dyniewicz, Jolanta; Misicka, Aleksandra; Toth, Geza; Lipkowski, Andrzej W

    2014-01-01

    In the present paper, we report the synthesis, radiolabeling and comprehensive pharmacological evaluation of a C-terminally truncated tachykinin derivative, 3H-KFFGLM-NH2. The C-terminal fragments of endogenous tachykinins are pharmacophores responsible for interaction with the tachykinin receptors NK1, NK2 and NK3. The N-terminal fragments are responsible for modulation of receptor selectivity and interactions with other receptor systems. To evaluate and separate the function of an NK-pharmacophore from the activity of its parent neurokinin, KFFGLM-NH2 was synthesized in both tritiated and unlabeled forms. It has been proposed that the obtained NK-binding profiles of specific reference ligands and KFFGLM-NH2 differentiate monomeric and dimeric forms of NK receptors. We hypothesize that dimers of NK receptors could be specific receptor(s) for C-terminal fragments of all neurokinins as well as their C-terminal fragments, including H-KFFGLM-NH2. Dissociation of dimers into monomers opens access to additional allosteric binding sites. Fully elongated undecapeptide substance P interacts with both the "tachykinin pocket" and the "allosteric pocket" on the monomeric NK1 receptor, resulting in high and selective activation. However, C-terminal hexapeptide fragment analogues, recognizing only the "tachykinin pocket", may have less specific interactions with all tachykinin receptors in both monomeric and dimeric forms. PMID:25574743

  15. 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.

  16. 2,14-Dithiacalix[4]arene and its homooxa analogues: synthesis and dynamic NMR study of conformational behaviour.

    PubMed

    Hucko, Michal; Dvoráková, Hana; Eigner, Václav; Lhoták, 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

  17. 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…

  18. Interactions of vasopressin and oxytocin receptors with vasopressin analogues substituted in position 2 with 3,3'-diphenylalanine--a molecular docking study.

    PubMed

    Slusarz, Magdalena J; Sikorska, Emilia; Slusarz, Rafał

    2013-02-01

    Vasopressin and oxytocin receptors belong to the superfamily of G protein-coupled receptors and play an important role in many physiological functions. They are also involved in a number of pathological conditions being important drug targets. In this work, four vasopressin analogues substituted at position 2 with 3,3'-diphenylalanine have been docked into partially flexible vasopressin and oxytocin receptors. The bulky residue at position 2 acts as a structural restraint much stronger in the oxytocin receptor (OTR) than in the vasopressin V2 receptor (V2R), resulting in a different location of the analogues in these receptors. This explains the different, either agonistic or antagonistic, activities of the analogues in V2R and OTR, respectively. In all complexes, the conserved polar residues serve as anchor points for the ligand both in OTR and V2R. Strong interactions of the C-terminus of analogue II ([Mpa(1) ,d-Dpa(2) ,Val(4) ,d-Arg(8) ]VP) with extracellular loop 3 may be responsible for its highest activity at V2R. It also appears that V2R adapts more readily to the docking analogues by conformational changes in the aromatic side chains triggering receptor activation. A weak activity at V1a vasopressin receptor appears to be caused by weak receptor-ligand interactions. Results of this study may facilitate a rational design of new analogues with the highest activity/selectivity at vasopressin and OTRs. PMID:23303737

  19. Studying Z-DNA and B- to Z-DNA transitions using a cytosine analogue FRET-pair.

    PubMed

    Dumat, Blaise; Larsen, Anders Foller; Wilhelmsson, L Marcus

    2016-06-20

    Herein, we report on the use of a tricyclic cytosine FRET pair, incorporated into DNA with different base pair separations, to study Z-DNA and B-Z DNA junctions. With its position inside the DNA structure, the FRET pair responds to a B- to Z-DNA transition with a distinct change in FRET efficiency for each donor/acceptor configuration allowing reliable structural probing. Moreover, we show how fluorescence spectroscopy and our cytosine analogues can be used to determine rate constants for the B- to Z-DNA transition mechanism. The modified cytosines have little influence on the transition and the FRET pair is thus an easily implemented and virtually non-perturbing fluorescence tool to study Z-DNA. This nucleobase analogue FRET pair represents a valuable addition to the limited number of fluorescence methods available to study Z-DNA and we suggest it will facilitate, for example, deciphering the B- to Z-DNA transition mechanism and investigating the interaction of DNA with Z-DNA binding proteins. PMID:26896804

  20. Studying Z-DNA and B- to Z-DNA transitions using a cytosine analogue FRET-pair

    PubMed Central

    Dumat, Blaise; Larsen, Anders Foller; Wilhelmsson, L. Marcus

    2016-01-01

    Herein, we report on the use of a tricyclic cytosine FRET pair, incorporated into DNA with different base pair separations, to study Z-DNA and B-Z DNA junctions. With its position inside the DNA structure, the FRET pair responds to a B- to Z-DNA transition with a distinct change in FRET efficiency for each donor/acceptor configuration allowing reliable structural probing. Moreover, we show how fluorescence spectroscopy and our cytosine analogues can be used to determine rate constants for the B- to Z-DNA transition mechanism. The modified cytosines have little influence on the transition and the FRET pair is thus an easily implemented and virtually non-perturbing fluorescence tool to study Z-DNA. This nucleobase analogue FRET pair represents a valuable addition to the limited number of fluorescence methods available to study Z-DNA and we suggest it will facilitate, for example, deciphering the B- to Z-DNA transition mechanism and investigating the interaction of DNA with Z-DNA binding proteins. PMID:26896804

  1. Analogue validation study of natural radionuclide migration in crystalline rocks using uranium-series disequilibrium studies

    SciTech Connect

    Smellie, J.A.T.; MacKenzie, A.B.; Scott, R.D.

    1986-01-01

    Concentrations and isotope ratios of natural decay series radionuclides have been studied in three contrasting crystalline rock drill core sections intersecting water-conducting fractures deep in the bedrock. Radioactive disequilibria resulting from rock-water interactions were observed in two of the cores. These indicated uranium migration along distances of 40 cm or more on a timescale of 10/sup 6/ years in conjunction with thorium immobility under the same conditions. Fracture surface minerals showed a high affinity for radionuclide retardation and a limit of about 3 cm is suggested for the migration of radionuclides from fracture fluids into the saturated rock. This limit may correspond to enhanced matrix porosities resulting from earlier hydrothermal activity along the same channels.

  2. A Computational Study of the Hydrolysis of dGTP Analogues with Halomethylene Modified Leaving Groups in Solution: Implications for the Mechanism of DNA Polymerases

    PubMed Central

    Kamerlin, Shina C. L.; McKenna, Charles E.; Goodman, Myron F.; Warshel, A.

    2009-01-01

    DNA polymerases are a family of enzymes responsible for regulating DNA replication and repair, which in turn maintains the integrity of the genome. However, despite intensive kinetic, crystallographic and computational studies, elucidation of the detailed enzymatic mechanism still presents a significant challenge. We recently developed an alternative strategy for exploring the fidelity and mechanism of DNA polymerases, by probing leaving group effects on nucleotidyl transfer using a series of dGTP bisphosphonate analogues in which the β, γ-bridging oxygen was replaced by a series of substituted methylene groups (X=CYZ, where Y,Z=H, halogen or other substituent). Pre-steady state kinetic measurements of DNA polymerase-catalyzed incorporation of correctly base paired (R) and mispaired (W) analogues demonstrated a strong linear free energy relationship (LFER) between the polymerase rate constant (kpol) and the highest pKa of the free bisphosphonic acid corresponding to the leaving group. However, unexpectedly, the data segregated into two distinctly different linear correlations depending on the nature of the substituent. The discrepancy between the two lines was considerably greater when the dGTP analogue formed an incorrect (G•T) rather than a correct (G•C) base pair, although the reason for this phenomenon remains unexplained. Here, we have evaluated the complete free energy surfaces for bisphosphonate hydrolysis in aqueous solution and evaluated the corresponding LFER. Our study, which employs several alternative solvation models, finds a split of the calculated LFER for the mono- and dihalogen compounds into two parallel lines, reflecting their behavior in the polymerase-catalyzed condensation reaction. We suggest that the division into two linear subsets may be a generalized solvation phenomenon involving the overall electrostatic interaction between the substrates and enzyme and would be observed in solution in the absence of the enzyme. In contrast, the

  3. 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.

  4. Synthesis and conformational studies of calixarene analogue chiral [3.3.1]metacyclophanes

    NASA Astrophysics Data System (ADS)

    Islam, Md Monarul; Hirotsugu, Tomiyasu; Thuery, Pierre; Matsumoto, Taisuke; Tanaka, Junji; Elsegood, Mark R. J.; Redshaw, Carl; Yamato, Takehiko

    2015-10-01

    Trihydroxy[3.3.1]metacyclophane, which can be regarded as an unsymmetrical or incomplete "homocalix[3]arene", has been prepared from trimethoxy[3.3.1]metacyclophane by demethylation with trimethylsilyl iodide in MeCN. Di-O-methylation at the lower rim of trihydroxy[3.3.1]metacyclophane in the presence of K2CO3 in acetone afforded a novel, inherently chiral calixarene-analogue, namely a macrocyclic [3.3.1]metacyclophane, possessing C1 symmetry. The inherent chirality of the two conformers was characterized by 1H NMR spectroscopy by addition of an excess of Pirkle's chiral shift reagent [(S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol], which caused a splitting of the OMe group and AB patterns corresponding to the methylene protons.

  5. [Theoretical study on fluorescence spectra of four kinds of p-substituted curcumin analogues].

    PubMed

    Jia, Fei-Yun; Su, Yu; Ran, Ming; Zhu, Jiang; Zhang, Bo

    2014-04-01

    Four kinds of p-substituted curcumin analogues were optimized at B3LYP/6-31G (d, p) level. On this basis, the excited states geometry structure was optimized by the CIS method, and finally the fluorescence emission spectra were calculated through the TD-DFT method. The results showed that: the four compounds, a large conjugated system, is preferably coplanar structure. Because of introducing hydroxyl and halogen atom on the benzene ring, the molecular pi-electron conjugation is relatively larger, emission wavelength is relatively longer, and fluorescence spectra show different degrees of red shift. As the electron donating group is hydroxy, the fluorescence phenomenon is more obviously red shifted. PMID:25007617

  6. Laboratory simulation and modeling of size, shape distributed interstellar graphite dust analogues: A comparative study

    NASA Astrophysics Data System (ADS)

    Boruah, Manash J.; Gogoi, Ankur; Ahmed, Gazi A.

    2016-06-01

    The computation of the light scattering properties of size and shape distributed interstellar graphite dust analogues using discrete dipole approximation (DDA) is presented. The light scattering properties of dust particles of arbitrary shapes having sizes ranging from 0.5 to 5.0 μm were computed using DDSCAT 7.3.0 software package and an indigenously developed post-processing tool for size and shape averaging. In order to model realistic samples of graphite dust and compute their light scattering properties using DDA, different target geometries were generated to represent the graphite particle composition in terms of surface smoothness, surface roughness and aggregation or their combination, for using as the target for DDSCAT calculations. A comparison of the theoretical volume scattering function at 543.5 nm and 632.8 nm incident wavelengths with laboratory simulation is also presented in this paper.

  7. Preparation and Magnetic Studies of Mn Substituted Analogues of BiFeO3

    NASA Astrophysics Data System (ADS)

    Choudhary, B. L.; Kumar, Sudhish; Krishnamurthy, Anjali; Srivastava, Bipin K.

    2011-11-01

    Manganese substituted samples (for iron) in the multiferroic BiFeO3 have been prepared using solid state ceramic route. It has been possible to prepare a sample with the highest 40% Mn content. Reitveld analysis of the X-ray diffraction patterns shows that the substituted analogues crystallize in rhombohedral symmetry in R-3¯c space group. Effort to prepare 50 atomic% Mn substituted sample did not succeed. Magnetization measurements have been made in the temperature range 20K-300K and in fields upto 8 kOe. Magnetic nature of the 40 atomic% Mn substituted sample is alike that of 30 atomic% Mn substituted one. Mn induces weak ferromagnetism with the average magnetic moment increasing with its concentration.

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

    PubMed

    Ahmad, Syed Usman; Szilvási, 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

  9. Distribution and geochemical characterization of coalbed gases at excavation fields at natural analogue site area Velenje Basin, Slovenia

    NASA Astrophysics Data System (ADS)

    Kanduč, Tjaša; Žigon, Stojan; Grassa, Fausto; Sedlar, Jerneja; Zadnik, Ivo; Zavšek, Simon

    2016-04-01

    Unconventional gas resources, including coal bed methane and shale gas, are a growing part of the global energy mix, which has changed the economic and strategic picture for gas consuming and producing countries, including the USA, China and Australia that, together are responsible for around half the currently recoverable unconventional gas resources. However, CBM production was often hindered by low permeability and mineralization in cleats and fractures, necessitating the development of cost effective horizontal drilling and completion techniques. Geochemical and isotopic monitoring of coalbed gases at excavation fields in Velenje Basin started in year 2000, with the aim to obtain better insights into the origin of coalbed gases. Results from active excavation fields in the mining areas Pesje and Preloge in the year period 2014-2015 are presented in this study. Composition and isotopic composition of coalbed gases were determined with mass - spectrometric methods. The chemical (methane, carbon dioxide, nitrogen) and isotopic composition of carbon in methane and carbon dioxide in the Velenje Basin vary and depend on the composition of the source of coalbed gas before excavation, advancement of the working face, depth of the longwall face, pre-mining activity and newly mined activity. The basic gas components determined in excavation fields are carbon dioxide and methane. Knowledge of the stable isotope geochemistry of coal bed and shale gas and the related production water is essential to determine not only gas origins but also the dominant methanogenic pathway in the case of microbial gas. Concentrations of methane at active excavation fields are changing from 1.8 to 63.9 %, concentrations of carbon dioxide are changing from 36.1 to 98.2% and CDMI (Carbon Dioxide Methane Index) index from 0.2 to 100 %. Isotopic composition of carbon dioxide is changing from -11.0 to -1.9‰ , isotopic composition of methane from -71.8 to -43.3‰ , isotopic composition of

  10. 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 350 mmol L(-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 175 mmol L(-1) with osmotic compensation by 175 mmol L(-1) mannitol. However, when the urea analogues thiourea or acetamide were present in the perfusate at concentrations equimolar (175 mmol L(-1)) to those of urea (175 mmol L(-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

  11. Evidence for Radical-Mediated Catalysis by HppE – A Study Using Cyclopropyl and Methylenecyclopropyl Substrate Analogues

    PubMed Central

    Huang, Hui; Chang, Wei-chen; Pai, Pei-Jing; Romo, Anthony; Mansoorabadi, Steven O.; Russell, David H.; Liu, Hung-wen

    2012-01-01

    (S)-2-Hydroxypropylphosphonic acid epoxidase (HppE) is an unusual mononuclear iron enzyme that catalyzes the oxidative epoxidation of (S)-2-hydroxypropylphosphonic acid ((S)-HPP) in the biosynthesis of the antibiotic fosfomycin. HppE also recognizes (R)-2-hydroxypropylphosphonic acid ((R)-HPP) as a substrate and converts it to 2-oxo-propylphosphonic acid. To probe the mechanisms of these HppE-catalyzed oxidations, cyclopropyl- and methylenecyclopropyl-containing compounds were synthesized and studied as radical clock substrate analogues. Enzymatic assays indicated that the (S)- and (R)-isomers of the cyclopropyl-containing analogues were efficiently converted to epoxide and ketone products by HppE, respectively. In contrast, the ultrafast methylenecyclopropyl-containing probe inactivated HppE, consistent with a rapid radical-triggered ring-opening process that leads to enzyme inactivation. Taken together, these findings provide, for the first time, experimental evidence for the involvement of a C2-centered radical intermediate with a lifetime on the order of nanoseconds in the HppE-catalyzed oxidation of (R)-HPP. PMID:23006053

  12. 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.

  13. 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.

  14. Theoretical Study of the Photophysics of 8-Vinylguanine, an Isomorphic Fluorescent Analogue of Guanine.

    PubMed

    Kochman, Michał A; Pola, Martina; Miller, R J Dwayne

    2016-08-11

    Paving the way for the application of the algebraic-diagrammatic construction scheme of second-order (ADC(2)) to systems based on the guanine chromophore, we demonstrate the this excited-state electronic structure method provides a realistic description of the photochemistry of 9H-guanine, in close agreement with the benchmark provided by the CASPT2 method. We then proceed to apply the ADC(2) method to the photochemistry of 8-vinylguanine (8vG), a minimally modified analogue of guanine which, unlike the naturally occurring nucleobase, displays intense fluorescence, indicative of a much longer-lived excited electronic state. The emissive electronic state of 8vG is identified as an ππ*-type intramolecular charge transfer (ICT) state, in which a charge of roughly -0.2 e is transferred from the guanine moiety onto the vinyl substituent. The main radiationless deactivation pathway competing with fluorescence is predicted to involve the molecule leaving the minimum on the ICT ππ* state, and reaching a region of the S1 adiabatic state where it resembles the La ππ* state of unmodified 9H-guanine. The topology of the La ππ* region of the S1 state favors subsequent internal conversion at a crossing seam with the ground electronic state. The sensitivity of this process to environment polarity may explain the experimentally observed fluorescence quenching of 8vG upon incorporation in single- and double-stranded DNA. PMID:27427772

  15. A 4D Analogue Modeling Study Assessing the Effects of Transtension and Inherited Structures on Rift Interaction

    NASA Astrophysics Data System (ADS)

    Zwaan, F.; Schreurs, G.; Naliboff, J.; Buiter, S. J.

    2015-12-01

    The interaction of individual rift segments determines the evolution of a rift system and subsequent continental break-up. Inherited heterogeneities control where initial rifts will form and since these are often not properly aligned, rift segments form separately and need to interact. Another important factor affecting rift-segment interaction is the obliquity of plate divergence (transtension), which also promotes eventual continent break-up (Brune et al., 2012). Both analogue and numerical techniques have been used to model rift interaction (e.g. Acocella et al., 1999; Allken et al., 2012) but transtension has never been applied. Here we present a first-order analogue study that elaborates upon earlier studies by assessing the effects of (1) transtension, (2) rift offset and (3) presence and geometry of inherited weak zones that link rift segments. An improved analogue set-up allows more freedom in inherited structure geometry and model analysis with X-Ray Computer Tomography (CT) techniques reveals internal structures with time (Fig. 2 and 3). Our experiments yield the following conclusions: Increasing the degree of transtension (decreasing angle α in Fig. 1) controls general rift structures: from wide rifts in orthogonal divergence settings to narrower rifts with oblique internal structures under transtensional conditions to narrow strike-slip dominated systems towards the strike-slip domain; Rift linkage through transfer zones (hard linkage) is generally promoted by 1) decreasing rift offset and 2) increasing the degree of transtension. However, initial rift linkage might involve relay ramps (soft linkage) due to the interplay of divergence direction and rift offset; Inherited rift-linking weak zones have little effect on rift interaction unless they are oriented ca. perpendicular to the divergence direction; Since the orthogonal divergence models resemble natural examples (Fig. 3), our transtension models might predict what structures can be expected in

  16. Opto-electronic properties of low band gap fused-ring thieno[3,4-b]pyrazine analogues - A theoretical study

    NASA Astrophysics Data System (ADS)

    Saranya, G.; Kolandaivel, P.; Senthilkumar, K.

    2013-10-01

    The structural, optical and ionic properties of thieno[3,4-b]pyrazine (TP) analogues have been studied using quantum chemical methods. The density functional theory (DFT) and time-dependent density functional theory (TD-DFT) methods were employed to optimise the ground- and excited-state geometries of TP analogues. Based on the ground- and excited-state geometries, the absorption and emission spectra have been calculated by using TD-DFT method with 6-311G(d,p) basis set. All the calculations were carried out in gas phase and in acetonitrile and chloroform medium. The solvent-phase calculations were performed using the polarisable continuum model (PCM). It has been observed that the effect of medium on the calculated absorption and emission spectra of these analogues is negligible. The calculated absorption and emission spectra are in good agreement with the available experimental results. This theoretical investigation shows that the fused-ring thieno[3,4-b]pyrazine analogues dibenzo[f,h]thieno[3,4-b]quinoxalines and thieno[3‧,4‧:5,6]pyrazino[2,3-f][1,10] phenanthroline have lower band gap than the thieno[3,4-b]pyrazine. Hence, these analogues can be used for the production of low band gap conjugated polymers.

  17. Stadium Site Utilization Study. University of Cincinnati.

    ERIC Educational Resources Information Center

    Caudill, Rowlett, and Scott, New York, NY.

    An evaluative study of the University of Cincinnati stadium site shows its potential with relation to the existing campus. Conclusions and recommendations concerning its future utilization are presented, based upon consideration of the following--(1) basic university planning policies, (2) assets and liabilities of the site, (3) the decision to…

  18. 3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide

    PubMed Central

    Li, Shun-Lai; He, Mao-Yu; Du, Hong-Guang

    2011-01-01

    The active metabolite of the novel immunosuppressive agent leflunomide has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. Self-organizing molecular field analysis (SOMFA), a simple three-dimensional quantitative structure-activity relationship (3D-QSAR) method is used to study the correlation between the molecular properties and the biological activities of a series of analogues of the active metabolite. The statistical results, cross-validated rCV2 (0.664) and non cross-validated r2 (0.687), show a good predictive ability. The final SOMFA model provides a better understanding of DHODH inhibitor-enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme. PMID:21686163

  19. Conformational studies of synthetic lipid A analogues and partial structures by infrared spectroscopy.

    PubMed

    Brandenburg, K; Kusumoto, S; Seydel, U

    1997-10-01

    Synthetic lipid A analogues and partial structures were analyzed and compared with natural hexaacyl lipid A from E. coli applying Fourier transform infrared spectroscopy. The investigations comprised (i) the measurement of the beta <=> alpha phase transition of the acyl chains via monitoring of the symmetric stretching vibration of the methylene groups, (ii) an estimation of the supramolecular aggregate structures evaluating vibrations from the interface like ester carbonyl and applying theoretical calculations (iii) a determination of the inter- and intramolecular conformations monitoring functional groups from the interface and the diglucosamine backbone (ester carbonyl, phosphate). The phase transition temperature Tc was found to be nearly a linear function of the number of acyl chains for most bisphosphoryl compounds indicating comparable packing density, whereas the deviating behaviour of some samples indicated a higher packing density. From the determination of the supramolecular aggregate structures (cubic, HII) of natural hexaacyl lipid A by X-ray small-angle diffraction, the existence of the same aggregate structures also for the synthetic hexaacyl lipid A was deduced from the nearly identical thermotropism of the ester carbonyl band. From this, a good approximation of the supramolecular structures of all synthetic samples was possible on the basis of the theory of Israelachvili. The analysis of the main phosphate band, together with that of the Tc data and former colorimetric results, allowed the establishment of a model of the intermolecular conformations of neighbouring lipid A/LPS molecules. The biological relevance of the findings is discussed in terms of the strongly varying biological activity (between high and no activity) of the samples. PMID:9370256

  20. Mass spectrometric studies of cocaine disposition in animals and humans using stable isotope-labeled analogues.

    PubMed

    Jindal, S P; Lutz, T

    1989-12-01

    Ion cluster technique in conjunction with gas chromatography-mass spectrometry (GC-MS) was used for the identification and quantitation of major metabolites of cocaine (1a) in rat and humans. In a typical experiment, a female rat weighing 250 gm was intraperitoneally administered a 20-mg/kg mixture of 1a, NCD3-cocaine (1b), OCD3-cocaine (1c), and 4T2-cocaine (1d). The urine was collected, extracted with organic solvents, and separated into several fractions using TLC and HPLC techniques. Tritium radioactivity in a metabolically stable position in 1d was useful in the separation of metabolites, while the deuterium labeled 1(b + c), creating an artificial isotopic cluster, provided specific identification of metabolites by mass spectrometric interpretation. Norcocaine (2), benzoylnorecgonine (3), N-hydroxynorcocaine (4), methylecgonidine (5), benzoylecgonine (11), ecgonine methyl ester (9), hydroxycocaine (7), hydroxymethoxycocaine (10), and dimethoxyhydroxycocaine (6) were found to be the major metabolites of 1a in the rat urine as well as in plasma. The whole brain analysis showed significant amounts of unmetabolized 1a and 2, and minor concentrations of 9, 5, 7, and 10, and traces of 6. Some of these metabolites have been reported earlier by us as well as other investigators and are unequivocally confirmed in this work. Unmetabolized 1a, its pharmacologically active metabolite 2, and other major metabolites were quantitated in the rat brain, plasma, and urine using stable isotope-labeled analogues as internal standards and selected ion monitoring (SIM) mass spectrometry. The pharmacokinetic profiles of 1a and 2 indicate half-lives of less than 20 min in the brain and plasma. These data are in good agreement with widely reported short-lived behavioral effects of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2614690

  1. Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

    PubMed Central

    Penthala, Narsimha Reddy; Zong, Hongliang; Ketkar, Amit; Madadi, Nikhil Reddy; Janganati, Venumadav; Eoff, Robert L.; Guzman, Monica L.; Crooks, Peter A.

    2015-01-01

    A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stablized by van der Waals’ interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs. PMID:25557492

  2. 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 C–H deprotonation adjacent to the sulfone, with concomitant opening by β-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

  3. 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.

  4. 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

  5. Total Synthesis and Biological Studies of TMC-205 and Analogues as Anticancer Agents and Activators of SV40 Promoter

    PubMed Central

    2014-01-01

    TMC-205 is a natural fungal metabolite with antiproliferative activity against cancer cell lines. The light- and air-sensitivity prevented in-depth exploitation of this novel indole derivative. Herein, we report the first synthesis of TMC-205. On the basis of its reactivity with reactive oxygen species, we developed air-stable analogues of TMC-205. These analogues are 2–8-fold more cytotoxic than TMC-205 against HCT-116 colon cancer cell line. Importantly, at noncytotoxic dose levels, these analogues activated the transcription of luciferase reporter gene driven by simian virus 40 promoter (SV40). Further, these small molecules also inhibit firefly luciferase, presumably by direct interaction. PMID:25147604

  6. Dilazep analogues for the study of equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2).

    PubMed

    Playa, Hilaire; Lewis, Timothy A; Ting, Amal; Suh, Byung-Chul; Muñoz, Benito; Matuza, Robert; Passer, Brent J; Schreiber, Stuart L; Buolamwini, John K

    2014-12-15

    As ENT inhibitors including dilazep have shown efficacy improving oHSV1 targeted oncolytic cancer therapy, a series of dilazep analogues was synthesized and biologically evaluated to examine both ENT1 and ENT2 inhibition. The central diamine core, alkyl chains, ester linkage and substituents on the phenyl ring were all varied. Compounds were screened against ENT1 and ENT2 using a radio-ligand cell-based assay. Dilazep and analogues with minor structural changes are potent and selective ENT1 inhibitors. No selective ENT2 inhibitors were found, although some analogues were more potent against ENT2 than the parent dilazep. PMID:25454272

  7. Structural Analogues of Selfotel.

    PubMed

    Dziuganowska, Zofia A; Ślepokura, Katarzyna; Volle, Jean-Noël; Virieux, David; Pirat, Jean-Luc; Kafarski, Paweł

    2016-06-17

    A small library of phosphonopiperidylcarboxylic acids, analogues of NMDA antagonist selfotel (CGS 19755), was synthesized. First, the series of aromatic esters was obtained via a palladium-catalyzed cross-coupling reaction (Hirao coupling) of dialkyl phosphites with bromopyridinecarboxylates, followed by their hydrolysis. Then, hydrogenation of the resulting phosphonopyridylcarboxylic acids over PtO2 yielded the desired phosphonopiperidylcarboxylic acids. NMR studies indicated that the hydrogenation reaction proceeds predominantly by cis addition. Several compounds were obtained as monocrystal structures. Preliminary biological studies performed on cultures of neurons suggest that the obtained compounds possess promising activity toward NMDA receptors. PMID:27187758

  8. The chemical synthesis and preliminary biological studies of phosphodiester and phosphorothioate analogues of 2-methoxy-lysophosphatidylethanolamine.

    PubMed

    Sowińska, Agata; Rytczak, Przemysław; Gendaszewska-Darmach, Edyta; Drzazga, Anna; Koziołkiewicz, Maria; Okruszek, Andrzej

    2016-08-01

    The chemical synthesis of phosphorothioate/phosphodiester analogues of 2-methoxy-lysophosphatidylethanolamine has been described. For the preparation of phosphorothioate derivatives oxathiaphospholane approach has been employed. The phosphodiester compounds were prepared by OXONE® oxidation of corresponding phosphorothioates. Each lysophospholipid analogue was synthesized as a series of four compounds, bearing different fatty acid residues both saturated (14:0, 16:0, 18:0) and unsaturated (18:1). The methylation of glycerol 2-hydroxyl function was applied in order to increase the stability of prepared analogues by preventing 1→2 acyl migration. The cytotoxicity of newly synthesized 2-methoxy-lysophosphatidylethanolamine derivatives was evaluated with resazurin-based method in prostate cancer PC3 cell line. The highest reduction of cell viability was noted for LPE analogues containing myristoyl acyl chain. PMID:27268697

  9. Assessing the bioequivalence of analogues of endogenous substances (‘endogenous drugs’): considerations to optimize study design

    PubMed Central

    Dissanayake, Sanjeeva

    2010-01-01

    BACKGROUND Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed. AIMS To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs. METHODS A literature search of the EMBASE and PubMed databases was performed. RESULTS The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ‘substance-deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra-therapeutic drug doses. CONCLUSIONS On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so-called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed. PMID:20233194

  10. Pre-clinical and Clinical Safety Studies of CMX-2043: A Cytoprotective Lipoic Acid Analogue for Ischaemia–Reperfusion Injury

    PubMed Central

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

    2014-01-01

    CMX-2043 is an α-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 μg/mL (10 μM). 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 >10 mg/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

  11. 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

  12. Utility of the Neurobehavioral Symptom Inventory Validity-10 index to detect symptom exaggeration: An analogue simulation study.

    PubMed

    Sullivan, Karen A; Lange, Rael T; Edmed, Shannon L

    2016-01-01

    The Neurobehavioral Symptom Inventory (NSI) has been recommended by the interagency Traumatic Brain Injury (TBI) Outcome Workgroup as an outcome measure for TBI research. A new symptom exaggeration index-the NSI Validity-10-can be calculated from its items, but its utility has not been evaluated in a malingering simulation study. Data from a prior analogue study were reanalyzed to examine the NSI Validity-10 test properties. The data were from a sample of 85 Australian undergraduate students. A battery of measures was completed under 1 of 3 experimental conditions: control (i.e., honest responding, n = 24), feign postconcussional disorder (PCD; n = 29), and feign posttraumatic stress disorder (PTSD; n = 32). Participants who feigned PTSD or PCD had significantly higher scores on the NSI Validity-10 compared with controls. There were minimal differences between the 2 feigning groups. Using the combined data from the feigning groups and assuming a 35% symptom exaggeration base rate, the optimal NSI Validity-10 cutoff score was ≥10. This cutoff score identified "probable exaggeration" (sensitivity = .75, specificity = 1.0, positive predictive power = 1.0, negative predictive power = .88). Diagnostic efficiency statistics for 25% and 45% base rates were also generated. The cutoff score identified in this study is lower than previously reported. Its properties are promising, but its usage requires careful consideration. PMID:26943718

  13. Asymmetric Synthesis and Binding Study of New Long-Chain HPA-12 Analogues as Potent Ligands of the Ceramide Transfer Protein CERT.

    PubMed

    Ďuriš, Andrej; Daïch, Adam; Santos, Cécile; Fleury, Laurence; Ausseil, Frédéric; Rodriguez, Frédéric; Ballereau, Stéphanie; Génisson, Yves; Berkeš, Dušan

    2016-05-01

    A series of 12 analogues of the Cer transfer protein (CERT) antagonist HPA-12 with long aliphatic chains were prepared as their (1R,3S)-syn and (1R,3R)-anti stereoisomers from pivotal chiral oxoamino acids. The enantioselective access to these intermediates as well as their ensuing transformation relied on a practical crystallization-induced asymmetric transformation (CIAT) process. Sonogashira coupling followed by triple bond reduction and thiophene ring hydrodesulfurization (HDS) into the corresponding alkane moieties was then implemented to complete the synthetic routes delivering the targeted HPA-12 analogues in concise 4- to 6-step reaction sequences. Ten compounds were evaluated regarding their ability to bind to the CERT START domain by using the recently developed time-resolved FRET-based homogeneous (HTR-FRET) binding assay. The introduction of a lipophilic appendage on the phenyl moiety led to an overall 10- to 1000-fold enhancement of the protein binding, with the highest effect being observed for a n-hexyl residue in the meta position. The importance of the phenyl ring for the activity was indicated by the reduced potency of the 3-deoxyphytoceramide aliphatic analogues. The 1,3-syn stereoisomers were systematically more potent than their 1,3-anti analogues. In silico studies were used to rationalized these trends, leading to a model of protein recognition coherent with the stronger binding of (1R,3S)-syn HPAs. PMID:27031925

  14. 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.

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

    PubMed

    Fairén, 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

  16. 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

  17. Experimental and computational studies on the formation of three para-benzyne analogues in the gas phase.

    PubMed

    Kirkpatrick, Lindsey M; Vinueza, Nelson R; Jankiewicz, Bartłomiej J; Gallardo, Vanessa A; Archibold, Enada F; Nash, John J; Kenttämaa, Hilkka I

    2013-07-01

    Experimental and computational studies on the formation of three gaseous, positively-charged para-benzyne analogues in a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer are reported. The structures of the cations were examined by isolating them and allowing them to react with various neutral reagents whose reactions with aromatic carbon-centered σ-type mono- and biradicals are well understood. Cleavage of two iodine-carbon bonds in N-deuterated 1,4-diiodoisoquinolinium cation by collision-activated dissociation (CAD) produced a long-lived cation that showed nonradical reactivity, which was unexpected for a para-benzyne. However, the reactivity closely resembles that of an isomeric enediyne, N-deuterated 2-ethynylbenzonitrilium cation. A theoretical study on possible rearrangement reactions occurring during CAD revealed that the cation formed upon the first iodine atom loss undergoes ring-opening before the second iodine atom loss to form an enediyne instead of a para-benzyne. Similar results were obtained for the 5,8-didehydroisoquinolinium cation and the 2,5-didehydropyridinium cation. The findings for the 5,8-didehydroisoquinolinium cation are in contradiction with an earlier report on this cation. The cation described in the literature was regenerated by using the literature method and demonstrated to be the isomeric 5,7-didehydro-isoquinolinium cation and not the expected 5,8-isomer. PMID:23703949

  18. 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

  19. 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…

  20. Upper Ottawa street landfill site health study

    SciTech Connect

    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.

  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 λmax=538 nm, Macrolampis sp2 λmax=564 nm; pH-insensitive, Phrixotrix hirtus λmax=623 nm, Phrixotrix vivianii λmax=546 nm, and Pyrearinus termitilluminans λmax=534 nm), a luciferase-like enzyme (Tenebrionidae, Zophobas morio λmax=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

  2. 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 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

  3. Crystallinity and motional dynamics study of a series of poly(arylene ether sulfone) segmented copolymer analogues.

    PubMed

    Zhang, Bin; Spano, Justin; Chen, Ying; Turner, Richard; Wi, Sungsool

    2012-07-12

    Solid-state NMR spectroscopy was utilized to study the crystallinity and its correlation to the motional dynamics of a series of biphenol based poly(arylene ether sulfone) (PAES) copolymer analogues obtained by incorporating flexible aliphatic blocks. Introduction of a series of conformationally flexible aliphatic blocks into the rigid aromatic PAES blocks in the copolymer sequence had increased the crystallinity of the polymer matrix because the copolymer system with aliphatic blocks provided a decrease in the glass transition temperature (Tg) while maintaining a nonvariant melting temperature (Tm). Modified PAES copolymer systems with aliphatic blocks had yielded shorter (1)H T1 relaxation times and longer (1)H T1ρ relaxation times relative to the neat aromatic PAES copolymer. Trends observed in (1)H T1ρ and T1 data had demonstrated direct correlations to the observed ΔT (= Tm - Tg) and thus to the amount of crystallinity in the polymer matrix. Slow segmental reorientations of PAES blocks in a few milliseconds range also became slightly faster as the size of an aliphatic, segmented block became larger. Additionally, the local electronic environments of aromatic PAES blocks were invariant to the incorporation of aliphatic segments in the copolymer sequence. PMID:22697501

  4. Vitamin E analogue Trolox C. E.s.r. and pulse-radiolysis studies of free-radical reactions.

    PubMed Central

    Davies, M J; Forni, L G; Willson, R L

    1988-01-01

    The reactions between Trolox C, a water-soluble vitamin E analogue, and several oxidizing free radicals including the hydroxyl radical and various peroxy radicals were examined by using the pulse-radiolysis technique. The results demonstrate that Trolox C may undergo rapid one-electron-transfer reactions as well as hydrogen-transfer processes; the resulting phenoxyl radical is shown to be relatively stable, in common with the phenoxyl radical derived from vitamin E. The reactions between the Trolox C phenoxyl radical and a variety of biologically relevant reducing compounds were examined by using both pulse radiolysis and e.s.r. The results demonstrate that the Trolox C phenoxyl radical is readily repaired by ascorbate (k = 8.3 x 10(6) dm3.mol-1.s-1) and certain thiols (k less than 10(5) dm3.mol-1.s-1) but not by urate, NADH or propyl gallate. Evidence from e.s.r. studies indicates that thiol-containing compounds may also enter into similar repair reactions with the alpha-tocopherol phenoxyl radical. Kinetic evidence is presented that suggests that Trolox C may 'repair' proteins that have been oxidized by free radicals. PMID:2849418

  5. 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.

  6. Attachment Anxiety, Verbal Immediacy, and Blood Pressure: Results from a Laboratory-Analogue Study Following Marital Separation

    PubMed Central

    Lee, Lauren A.; Sbarra, David A.; Mason, Ashley E.; Law, Rita W.

    2011-01-01

    Marital separation and divorce increase risk for all-cause morbidity and mortality. Using a laboratory analogue paradigm, the present study examined attachment anxiety, language use, and blood pressure (BP) reactivity among 119 (n = 43 men, 76 women) recently separated adults who were asked to mentally reflect on their relationship history and separation experience. We created a language use composite of verbal immediacy from participants’ stream-of-consciousness recordings about their separation experience as a behavioral index of attachment-related hyperactivation. Verbal immediacy moderated the association between attachment anxiety and BP at the beginning of a divorce-specific activation task. Participants reporting high attachment anxiety who discussed their separation in a first-person, present-oriented and highly engaged manner evidenced the highest levels of BP at the start of the divorce-specific task. Results provide a deeper understanding of the association between marital dissolution and health and suggest that verbal immediacy may be a useful behavioral index of hyperactivating coping strategies. PMID:21647240

  7. Web vulnerability study of online pharmacy sites.

    PubMed

    Kuzma, Joanne

    2011-01-01

    Consumers are increasingly using online pharmacies, but these sites may not provide an adequate level of security with the consumers' personal data. There is a gap in this research addressing the problems of security vulnerabilities in this industry. The objective is to identify the level of web application security vulnerabilities in online pharmacies and the common types of flaws, thus expanding on prior studies. Technical, managerial and legal recommendations on how to mitigate security issues are presented. The proposed four-step method first consists of choosing an online testing tool. The next steps involve choosing a list of 60 online pharmacy sites to test, and then running the software analysis to compile a list of flaws. Finally, an in-depth analysis is performed on the types of web application vulnerabilities. The majority of sites had serious vulnerabilities, with the majority of flaws being cross-site scripting or old versions of software that have not been updated. A method is proposed for the securing of web pharmacy sites, using a multi-phased approach of technical and managerial techniques together with a thorough understanding of national legal requirements for securing systems. PMID:21208091

  8. Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study.

    PubMed

    Rana, Sandeep; Blowers, Elizabeth C; Tebbe, Calvin; Contreras, Jacob I; Radhakrishnan, Prakash; Kizhake, Smitha; Zhou, Tian; Rajule, Rajkumar N; Arnst, Jamie L; Munkarah, Adnan R; Rattan, Ramandeep; Natarajan, Amarnath

    2016-05-26

    Design, synthesis, and evaluation of α-methylene-γ-butyrolactone analogues and their evaluation as anticancer agents is described. SAR identified a spirocyclic analogue 19 that inhibited TNFα-induced NF-κB activity, cancer cell growth and tumor growth in an ovarian cancer model. A second iteration of synthesis and screening identified 29 which inhibited cancer cell growth with low-μM potency. Our data suggest that an isatin-derived spirocyclic α-methylene-γ-butyrolactone is a suitable core for optimization to identify novel anticancer agents. PMID:27077228

  9. Comparison of GLP-1 Analogues versus Sitagliptin in the Management of Type 2 Diabetes: Systematic Review and Meta-Analysis of Head-to-Head Studies

    PubMed Central

    Wang, Tiansheng; Gou, Zhuoyue; Wang, Fei; Ma, Manling; Zhai, Suo-di

    2014-01-01

    Background Incretin–based therapies which include glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are recommended by several practice guidelines as second-line agents for add-on therapy to metformin in patients with type 2 diabetes (T2DM) who do not achieve glycemic control with metformin plus lifestyle interventions alone. The purpose of this study is to perform a systematic review with meta-analysis of existing head to head studies to compare the efficacy and safety of GLP-1 analogues with DPP-4 inhibitors. Methods We performed a systematic review and meta-analysis of head-to-head studies to compare GLP-1 analogues with DPP-4 inhibitors in the management of type 2 diabetes. A random effects model was selected to perform the meta-analyses, results were expressed as weighted mean differences for continuous outcomes and relative risks for dichotomous outcomes, both with 95% confidence intervals, and with I2 values and P values as markers of heterogeneity. Results Four head-to-head randomized controlled studies with 1755 patients were included. Compared to sitagliptin, GLP-1 analogues are more effective in reducing HbA1C (weight mean difference −0.41%, 95% CI −0.51 to −0.31) and body weight (weight mean difference −1.55 kg, 95% CI −1.98 to −1.12). Conversely, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events compared to sitagliptin: nausea (relative risk 3.14, 95% CI 2.15 to 4.59), vomiting (relative risk 2.60, 95% CI 1.48 to 4.56), diarrhea (relative risk 1.82, 95% CI 1.24 to 2.69), and constipation (relative risk 2.50, 95% CI 1.33 to 4.70). Conclusions The result of this meta-analysis demonstrates that compared to sitagliptin, GLP-1 analogues are more effective for glycemic control and weight loss, but have similar efficacy in reducing blood pressure and lipid parameters, however, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse

  10. Arabinose 5-phosphate isomerase as a target for antibacterial design: studies with substrate analogues and inhibitors.

    PubMed

    Gabrielli, Luca; Merlo, Silvia; Airoldi, Cristina; Sperandeo, Paola; Gianera, Serena; Polissi, Alessandra; Nicotra, Francesco; Holler, Tod P; Woodard, Ronald W; Cipolla, Laura

    2014-04-15

    Structural requirements of D-arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Pseudomonas aeruginosa were analysed in detail using advanced NMR techniques. We performed epitope mapping studies of the binding between the enzyme and the most potent KdsD inhibitors found to date, together with studies of a set of newly synthesised arabinose 5-phosphate (A5P) mimetics. We report here the first experimental evidence that KdsD may bind the furanose form of A5P, suggesting that catalysis of ring opening may be an important part of KdsD catalysis. PMID:24680056

  11. 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…

  12. Inter-year repeatability study of volatile organic compounds from surface decomposition of human analogues.

    PubMed

    Stadler, Sonja; Desaulniers, Jean-Paul; Forbes, Shari L

    2015-05-01

    Decomposition odour and volatile organic compounds (VOCs) have gained considerable attention recently due to their use by insects and scent detection canines to locate remains. However, a comprehensive and accurate profile of decomposition odour is yet to be confirmed. This is, in part, due to the geographical diversity in the studies conducted and the variation in the methodology and compounds being reported. To date, no repeatability studies of decomposition odour have been conducted in the same environment. In order to address this current gap in the scientific literature, this study conducted three replicate trials in order to evaluate the inter-year repeatability of the decomposition VOC profile in a southern Canadian environment. Surface decomposition trials were conducted during the spring and summer months and the VOCs were analysed by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). This study was able to demonstrate that decomposition VOCs are produced consistently during their characteristic stages and that this relationship is maintained under varying environmental factors which influence the rate of decomposition. This consistent production of decomposition VOCs can lead to a better understanding of the mechanisms of soft tissue decomposition and their sources of variation, and it could potentially lead to improved applications of these compounds for the detection of decomposed remains. PMID:24867182

  13. CO2 Capture with Enzyme Synthetic Analogue

    SciTech Connect

    Cordatos, Harry

    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.

  14. A Functionalized Sphingolipid Analogue for Studying Redistribution during Activation in Living T Cells.

    PubMed

    Collenburg, Lena; Walter, Tim; Burgert, Anne; Müller, Nora; Seibel, Jürgen; Japtok, Lukasz; Kleuser, Burkhard; Sauer, Markus; Schneider-Schaulies, Sibylle

    2016-05-01

    Sphingolipids are major components of the plasma membrane. In particular, ceramide serves as an essential building hub for complex sphingolipids, but also as an organizer of membrane domains segregating receptors and signalosomes. Sphingomyelin breakdown as a result of sphingomyelinase activation after ligation of a variety of receptors is the predominant source of ceramides released at the plasma membrane. This especially applies to T lymphocytes where formation of ceramide-enriched membrane microdomains modulates TCR signaling. Because ceramide release and redistribution occur very rapidly in response to receptor ligation, novel tools to further study these processes in living T cells are urgently needed. To meet this demand, we synthesized nontoxic, azido-functionalized ceramides allowing for bio-orthogonal click-reactions to fluorescently label incorporated ceramides, and thus investigate formation of ceramide-enriched domains. Azido-functionalized C6-ceramides were incorporated into and localized within plasma membrane microdomains and proximal vesicles in T cells. They segregated into clusters after TCR, and especially CD28 ligation, indicating efficient sorting into plasma membrane domains associated with T cell activation; this was abolished upon sphingomyelinase inhibition. Importantly, T cell activation was not abrogated upon incorporation of the compound, which was efficiently excluded from the immune synapse center as has previously been seen in Ab-based studies using fixed cells. Therefore, the functionalized ceramides are novel, highly potent tools to study the subcellular redistribution of ceramides in the course of T cell activation. Moreover, they will certainly also be generally applicable to studies addressing rapid stimulation-mediated ceramide release in living cells. PMID:27036914

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. Hydrolysis theory for cisplatin and its analogues based on density functional studies.

    PubMed

    Zhang, Y; Guo, Z; You, X Z

    2001-09-26

    Hydrolysis of cisplatin, the most widely used anticancer drug in the world, is believed to be the key activation step before the drug reaching its intracellular target DNA. To obtain an accurate hydrolysis theory for this important class of square-planar Pt(II) complexes, three typical reactions, i.e., the first and second hydrolyses of cisplatin and the hydrolysis of [Pt(dien)Cl](+) (dien = diethylenetriamine), were studied at the experimental temperature with the solvent effect using mPW1PW91/SDD from a comprehensive methodological study on the Hartree-Fock (HF) ab initio method, electron correlation methods, pure density functional theory (DFT) methods, and hybrid HF-DFT methods with several basis sets. The true five stationary states in the second-order nucleophilic substitution (S(N)2) pathway for the hydrolysis process, namely, reactant (R) --> intermediate 1 (I1) --> TS --> intermediate 2 (I2) --> product (P) were obtained and characterized theoretically for the first time. The most remarkable structural variations and the associated atomic charge variations in the hydrolysis process were found to occur in the equatorial plane of the five-coordinate trigonal-bipyramidal (TBP)-like structures of I1, TS, and I2. The reaction with the TS structure of smaller L-M-E angle and more lengthened M-L and M-E bonds was found to have a smaller Gibbs free energy change and accordingly the better hydrolysis yield. It is found that the sum of the three concentric angles in the TBP's equator is near 360 degrees in I1 and I2 and is almost 360 degrees in TS in each reaction. The associated energy profiles again demonstrated a typical S(N)2 reaction curve. The computed forward and backward reaction enthalpy (Delta H(++)) and reaction entropy (Delta S(++)) in the rate-determining step I1 --> TS --> I2 are in good agreement with the experiments. Natural bonding orbital population analysis shows that the charge-separating extent follows the same order of Delta G in studied

  1. Analogue Study of Peer Influence on Risk-Taking Behavior in Older Adolescents

    PubMed Central

    Reynolds, Elizabeth K.; MacPherson, Laura; Schwartz, Sarah; Fox, Nathan A.; Lejuez, C. W.

    2013-01-01

    This experimental study aimed to examine whether adolescents act in a riskier manner in the presence of peers and whether peer presence alone influences risk behavior or if a direct influence process is necessary. Utilizing a behavioral task assessing risk-taking, 183 older adolescents (18–20 year olds) came to the laboratory alone once and then were randomized to one of three conditions: alone, peers present, peers encouraging. An interaction was found such that at baseline there were no significant differences between the three conditions but at the experimental session there was a significant increase in risk task scores particularly for the encouraging condition. These findings challenge proposed models of the interaction between peer influence and risk taking by providing evidence that adolescents take more risks when being encouraged by peers but that the presence of peers on its own does not lead to more risks than when completing the task alone. PMID:24122411

  2. Transport modelling in the natural analogue study of the Cigar Lake uranium deposit (Saskatchewan, Canada)

    NASA Astrophysics Data System (ADS)

    Liu, Jinson; Yu, Ji-Wei; Neretnieks, Ivars

    1996-02-01

    A near-field release model is developed both conceptually and mathematically. The model is tested against known helium release from the Cigar Lake uranium ore deposit. The release and transport of various aqueous species (including some radionuclides) in the deposit are studied by using this model. The uranium release rate predicted by the model is extremely low, which is consistent with field observations. In modelling the release of three other radionuclides ( 3H, 14C and 36Cl), the in situ generation and decay are taken into account. The measured concentration gradients of hydrogen was used to estimate the net rate of radiolysis. The simultaneously formed oxidising species are found in sulphates formed by oxidation of sulphides. There is a good agreement of the estimated rate of formation of the reducing component hydrogen and the oxidising component as found in the sulphate.

  3. Mineral-chemical and isotopic studies of Namaqualand granulites, South Africa: A grenville analogue

    NASA Astrophysics Data System (ADS)

    Clifford, Tom N.; Stumpfl, Eugen F.; Burger, Alwyn J.; McCarthy, Terence S.; Rex, David C.

    1981-10-01

    The northwestern part of South Africa and southern South-West Africa/Namibia is amongst the most extensive granulite terranes in Africa. This work reports the results of electron microprobe studies of minerals from two-pyroxene, cordieriteorthopyroxene (-gedrite) (-sapphirine) and garnet and/or cordierite parageneses from Namaqualand, in the N.W. Cape Province of South Africa. Determined PT conditions of prograde metamorphism based on thermodynamic calculations are 800°-900° C and ca. 6-7 Kb; and it is argued that rocks of unusual composition, notably cordierite-orthopyroxene rocks, are restites after the extraction of granitic liquid from former argillites. This interpretation is consistent with previously published data on similar rocks, and with McCarthy's (1976) suggestion of extensive partial melting in the quartzofeldspathic rocks in the area. U-Pb isotopic studies of some 50 zircon fractions have been carried out and confirm an age of 1,200 m.y. for the high-grade regional metamorphism; but certain zircon populations record inherited ages greater than 1,700 m.y. Garnet-sillimanite rocks that contain retrograde kyanite reflect PT conditions of 550°-650° C and ca. 7-8 Kb; and constituent biotite has yielded a K-Ar age of ca. 950 m.y. These data, the regional stratigraphy and structure, and the mineralisation are compared with data from the Grenville Province of Canada. Notable similarities are the possible basement-cover relationships, and the calendar of tectonothermal events, while differences include the important stratiform base-metal mineralisation in the supracrustal sequence in Namaqualand, and the Cu-mineralisation in hypersthenebearing intrusives, emplaced some 1,100 m.y. ago, that are areally, and believed to be genetically, related to the granulite facies metamorphic regime.

  4. 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

  5. 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

  6. 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

  7. 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…

  8. Recent advances in topoisomerase I-targeting agents, camptothecin analogues.

    PubMed

    Kim, Dae-Kee; Lee, Namkyu

    2002-12-01

    The present review concentrates on camptothecin (CPT) analogues, the most extensively studied topoisomerase I (topo I) inhibitors, and provides concise information on the structural features of human topo I enzyme, mechanisms of interaction of CPT with topo I, structure-activity relationship study of CPT analogues including the influence of lactone stability on antitumor activity, and recent updates of valuable CPT analogues. PMID:12370044

  9. The structure-AChE inhibitory activity relationships study in a series of pyridazine analogues.

    PubMed

    Saracoglu, M; Kandemirli, F

    2009-07-01

    The structure-activity relationships (SAR) are investigated by means of the Electronic-Topological Method (ETM) followed by the Neural Networks application (ETM-NN) for a class of anti-cholinesterase inhibitors (AChE, 53 molecules) being pyridazine derivatives. AChE activities of the series were measured in IC(50) units, and relative to the activity levels, the series was partitioned into classes of active and inactive compounds. Based on pharmacophores and antipharmacophores calculated by the ETM-software as sub-matrices containing important spatial and electronic characteristics, a system for the activity prognostication is developed. Input data for the ETM were taken as the results of conformational and quantum-mechanics calculations. To predict the activity, we used one of the most well known neural networks, namely, the feed-forward neural networks (FFNNs) trained with the back propagation algorithm. The supervised learning was performed using a variant of FFNN known as the Associative Neural Networks (ASNN). The result of the testing revealed that the high ETM's ability of predicting both activity and inactivity of potential AChE inhibitors. Analysis of HOMOs for the compounds containing Ph1 and APh1 has shown that atoms with the highest values of the atomic orbital coefficients are mainly those atoms that enter into the pharmacophores. Thus, the set of pharmacophores and antipharmacophores found as the result of this study forms a basis for a system of the anti-cholinesterase activity prediction. PMID:19689389

  10. 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.

  11. 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

  12. 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.

  13. 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

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

    PubMed

    Maćczak, Aneta; Bukowska, Bożena; Michałowicz, 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 500μg/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

  15. 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

  16. 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

  17. 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

  18. Global profiling and rapid matching of natural products using diagnostic product ion network and in silico analogue database: Gastrodia elata as a case study.

    PubMed

    Lai, Chang-Jiang-Sheng; Zha, Liangping; Liu, Da-Hui; Kang, Liping; Ma, Xiaojing; Zhan, Zhi-Lai; Nan, Tie-Gui; Yang, Jian; Li, Fajie; Yuan, Yuan; Huang, Lu-Qi

    2016-07-22

    Rapid discovery of novel compounds of a traditional herbal medicine is of vital significance for pharmaceutical industry and plant metabolic pathway analysis. However, discovery of unknown or trace natural products is an ongoing challenge. This study presents a universal targeted data-independent acquisition and mining strategy to globally profile and effectively match novel natural product analogues from an herbal extract. The famous medical plant Gastrodia elata was selected as an example. This strategy consists of three steps: (i) acquisition of accurate parent and adduct ions (PAIs) and the product ions data of all eluting compounds by untargeted full-scan MS(E) mode; (ii) rapid compound screening using diagnostic product ions (DPIs) network and in silico analogue database with SUMPRODUCT function to find novel candidates; and (iii) identification and isomerism discrimination of multiple types of compounds using ClogP and ions fragment behavior analyses. Using above data mining methods, a total of 152 compounds were characterized, and 70 were discovered for the first time, including series of phospholipids and novel gastroxyl derivatives. Furthermore, a number of gastronucleosides and phase II metabolites of gastrodin and parishins were discovered, including glutathionylated, cysteinylglycinated and cysteinated compounds, and phosphatidylserine analogues. This study extended the application of classical DPIs filter strategy and developed a structure-based screening approach with the potential for significant increase of efficiency for discovery and identification of trace novel natural products. PMID:27318507

  19. Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site.

    PubMed

    Liu, Yan-Na; Wang, Jing-Jing; Ji, Ya-Ting; Zhao, Guo-Dong; Tang, Long-Qian; Zhang, Cheng-Mei; Guo, Xiu-Li; Liu, Zhao-Peng

    2016-06-01

    By targeting a new binding region at the interface between αβ-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent. PMID:27172319

  20. 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.

  1. 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.

  2. 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

  3. 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

  4. Antimicrobial Peptide from the Wild Bee Hylaeus signatus Venom and Its Analogues: Structure-Activity Study and Synergistic Effect with Antibiotics.

    PubMed

    Nešuta, Ondřej; Hexnerová, Rozálie; Buděšínský, Miloš; Slaninová, Jiřina; Bednárová, Lucie; Hadravová, Romana; Straka, Jakub; Veverka, Václav; Čeřovský, Václav

    2016-04-22

    Venoms of hymenopteran insects have attracted considerable interest as a source of cationic antimicrobial peptides (AMPs). In the venom of the solitary bee Hylaeus signatus (Hymenoptera: Colletidae), we identified a new hexadecapeptide of sequence Gly-Ile-Met-Ser-Ser-Leu-Met-Lys-Lys-Leu-Ala-Ala-His-Ile-Ala-Lys-NH2. Named HYL, it belongs to the category of α-helical amphipathic AMPs. HYL exhibited weak antimicrobial activity against several strains of pathogenic bacteria and moderate activity against Candida albicans, but its hemolytic activity against human red blood cells was low. We prepared a set of HYL analogues to evaluate the effects of structural modifications on its biological activity and to increase its potency against pathogenic bacteria. This produced several analogues exhibiting significantly greater activity compared to HYL against strains of both Staphylococcus aureus and Pseudomonas aeruginosa even as their hemolytic activity remained low. Studying synergism of HYL peptides and conventional antibiotics showed the peptides act synergistically and preferentially in combination with rifampicin. Fluorescent dye propidium iodide uptake showed the tested peptides were able to facilitate entrance of antibiotics into the cytoplasm by permeabilization of the outer and inner bacterial cell membrane of P. aeruginosa. Transmission electron microscopy revealed that treatment of P. aeruginosa with one of the HYL analogues caused total disintegration of bacterial cells. NMR spectroscopy was used to elucidate the structure-activity relationship for the effect of amino acid residue substitution in HYL. PMID:26998557

  5. Structure-Activity Studies of Brassinosteroids and the Search for Novel Analogues and Mimetics with Improved Bioactivity.

    PubMed

    Back, Thomas G.; Pharis, Richard P.

    2003-12-01

    A number of novel brassinosteroid analogues were synthesized and subjected to the rice leaf lamina inclination bioassay. Modified B-ring analogues included lactam, thiolactone, cyclic ether, ketone, hydroxyl, and exocyclic methylene derivatives of brassinolide. Those derivatives containing polar functional groups retained considerable bioactivity, whereas the exocyclic methylene compounds were devoid of activity. Analogues containing normal alkyl and cycloalkyl substituents at C-24 (in place of the isopropyl group of brassinolide) showed an inverse relationship between activity and chain length or ring size, respectively. The corresponding cyclopropyl and cyclobutyl derivatives were significantly more active than brassinolide and appear to be the most potent brassinosteroids reported to date. When synergized with the auxin indole-3-acetic acid (IAA), their bioactivity can be further enhanced by 1-2 orders of magnitude. The cyclopropyl derivative, when coapplied with the auxin naphthaleneacetic acid, gave a significant increase in yield of wheat in a field trial. Certain 25- and 26-hydroxy derivatives are known metabolites of brassinosteroids. All of the C-25 stereoisomers of 25-hydroxy, 26-hydroxy, and 25,26-dihydroxy derivatives of brassinolide were prepared and shown to be much less active than brassinolide. This indicates that they are likely metabolic deactivation products of the parent phytohormone. A series of methyl ethers of brassinolide was synthesized to block deactivation by glucosylation of the free hydroxyl groups. The most significant finding was that the compound where three of the four hydroxyl groups (at C-3, C-22, and C-23) had been converted to methyl ethers retained substantial bioactivity. This type of modification could, in theory, allow brassinolide or 24-epibrassinolide to resist deactivation and thus offer greater persistence in field applications. A series of nonsteroidal mimetics of brassinolide was designed and synthesized. Two of the

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

    PubMed

    Pérez, 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 μg/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

  7. Blue copper proteins: Synthesis, spectra, and structures of CuIN3(SR) and CuIIN3(SR) active site analogues

    PubMed Central

    Thompson, Jeffery S.; Marks, Tobin J.; Ibers, James A.

    1977-01-01

    The reaction of Cu(SR) or [Cu(SR)][ClO4] derivatives (SR = p-nitrobenzenethiolate or O-ethylcysteinate) with potassium hydrotris(3,5-dimethyl-1-pyrazolyl)borate produces redox pairs of the stoichiometry CuIN3(SR) and CuIIN3(SR). These complexes are well-defined synthetic approximations to the proposed N3S binding sites of blue (type 1) copper electron transfer proteins. The compounds were investigated by a variety of chemical and spectral (optical, resonance Raman, and electron paramagnetic resonance) techniques; the complex K[Cu(hydrotris(3,5-dimethyl-1-pyrazolyl)borate)(p- NO2C6H4S]-2 acetone was also studied by single-crystal x-ray diffraction methods. The spectrochemical characteristics of the CuIIN3(SR) species are in large part similar to the native system and thus provide some perspective regarding the origin of the unique type 1 spectral parameters and electron transfer properties. PMID:16592426

  8. Western Maryland Power Plant Siting Study: discussion of licensing issues and site boundary considerations at three candidate sites. Final report

    SciTech Connect

    Klauda, R.J.; Portner, E.M.

    1984-10-01

    This document is one of a series of technical reports prepared for the Western Maryland Power Plant Siting Study. Selected licensing issues for the three remaining candidate sites are discussed and related to site boundary considerations. None of the four licensing issues evaluated (noise, fugitive dust, solid waste disposal, point source water discharges) would eliminate any of the three candidate sites from the comparison study. All three sites could likely comply with the air quality standards applicable to fugitive dust emissions. Compliance could be periodically complicated by levels of airborne coal dust at WP-26 during high wind episodes. Noise and fugitive dust level predictions suggested that the original site boundaries could be further refined. Final site boundaries will not be established until after the preferred site is selected.

  9. Plant volatile analogues strengthen attractiveness to insect.

    PubMed

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

    2014-01-01

    Green leaf bug Apolygus lucorum (Meyer-Dür) 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 β-ionone and benzaldehyde. The stabilities of β-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 β-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 β-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

  10. 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-Dür) 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 β-ionone and benzaldehyde. The stabilities of β-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 β-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 β-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

  11. 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 δ13C 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 δ13C 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 δ13CTDIC, 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 μS/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 δ13CTDIC 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 δ13CTDIC 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 δ13CTDIC values are 0 and -3 hours, respectively; the pH change occurs simultaneously with the change of δ13CTDIC, 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).

  12. 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 3.0×106 and 1.8×107 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.

  13. 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

    2016-02-01

    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

  14. 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.

  15. Synthesis and in vitro evaluation of novel triazine analogues as anticancer agents and their interaction studies with bovine serum albumin.

    PubMed

    Singla, Prinka; Luxami, Vijay; Paul, Kamaldeep

    2016-07-19

    A novel series of triazine-benzimidazole analogs has been designed and synthesized for their in vitro anticancer activities. Four compounds (6, 16, 17 and 20) were identified as highly potent anticancer agents against 60 human cancer cell lines with GI50 in the nanomolar range. To improve the drug applications toward cancer cells, there is a need to couple these compounds to some carrier macromolecules. Following this approach, the interaction between triazine-benzimidazole analogues and bovine serum albumin (BSA) has been investigated with UV-Visible and fluorescence spectroscopic methods under physiological conditions. The observed fluorescence quenching indicates that these compounds could efficiently bind with BSA and be transported to the target site. PMID:27089212

  16. Alligator rivers analogue project an OECD/NEA international project

    SciTech Connect

    Duerden, P.; Airey, P.; Pescatore, C.

    1994-12-31

    The Koongarra uranium deposit in the Alligator Rivers Region of the Northern Territory of Australia was studied as a natural analogue of the far field behaviour of high level waste repositories following groundwater ingress. A number of mathematical modelling approaches were developed for processes as diverse as groundwater transport, host rock weathering, radionuclide sorption, evolution of the uranium dispersion fan and the distribution of uranium series nuclides between mineral assemblages in weathered host rock. Some of these models are relevant to performance assessment at the level of individual processes and subsystem performance. Through the project, new insights into the application of the natural analogue approach to the assessment of potential waste repository sites were obtained.

  17. Muscarinic interactions of bisindolylmaleimide analogues.

    PubMed

    Lazareno, S; Popham, A; Birdsall, N J

    1998-11-01

    We have used radioligand binding studies to determine the affinities of seven bisindolylmaleimide analogues, six of which are selective inhibitors of protein kinase C, at human muscarinic M1-M4 receptors. The compounds were most potent at M1 receptors, and Ro-31-8220 was the most potent analogue, with a Kd of 0.6 microM at M1 receptors. The weakest compounds, bisindolylmaleimide IV and bisindolylmaleimide V, had Kd values of 100 microM. If it is necessary to use protein kinase C inhibitors at concentrations of 10 microM or more in studies involving muscarinic receptors then bisindolylmaleimide IV may be the most appropriate inhibitor to use. PMID:9851596

  18. Mapping general anesthetic binding site(s) in human α1β3 γ-aminobutyric acid type A receptors with [³H]TDBzl-etomidate, a photoreactive etomidate analogue.

    PubMed

    Chiara, David C; Dostalova, Zuzana; Jayakar, Selwyn S; Zhou, Xiaojuan; Miller, Keith W; Cohen, Jonathan B

    2012-01-31

    The γ-aminobutyric acid type A receptor (GABA(A)R) is a target for general anesthetics of diverse chemical structures, which act as positive allosteric modulators at clinical doses. Previously, in a heterogeneous mixture of GABA(A)Rs purified from bovine brain, [³H]azietomidate photolabeling of αMet-236 and βMet-286 in the αM1 and βM3 transmembrane helices identified an etomidate binding site in the GABA(A)R transmembrane domain at the interface between the β and α subunits [Li, G. D., et.al. (2006) J. Neurosci. 26, 11599-11605]. To further define GABA(A)R etomidate binding sites, we now use [³H]TDBzl-etomidate, an aryl diazirine with broader amino acid side chain reactivity than azietomidate, to photolabel purified human FLAG-α1β3 GABA(A)Rs and more extensively identify photolabeled GABA(A)R amino acids. [³H]TDBzl-etomidate photolabeled in an etomidate-inhibitable manner β3Val-290, in the β3M3 transmembrane helix, as well as α1Met-236 in α1M1, a residue photolabeled by [³H]azietomidate, while no photolabeling of amino acids in the αM2 and βM2 helices that also border the etomidate binding site was detected. The location of these photolabeled amino acids in GABA(A)R homology models derived from the recently determined structures of prokaryote (GLIC) or invertebrate (GluCl) homologues and the results of computational docking studies predict the orientation of [³H]TDBzl-etomidate bound in that site and the other amino acids contributing to this GABA(A)R intersubunit etomidate binding site. Etomidate-inhibitable photolabeling of β3Met-227 in βM1 by [³H]TDBzl-etomidate and [³H]azietomidate also provides evidence of a homologous etomidate binding site at the β3-β3 subunit interface in the α1β3 GABA(A)R. PMID:22243422

  19. Oxidation and reaction of trolox c, a tocopherol analogue, in aqueous solution. A pulse-radiolysis study

    SciTech Connect

    Thomas, M.J. ); Bielski, B.H.J. )

    1989-04-26

    Trolox c, 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid, 1, a water-soluble {alpha}-tocopherol analogue, was oxidized with Br{sub 2}{sup {minus}} to give the phenoxyl radical 2. These radicals disproportionate by a second-order, pH-dependent process to give 1 and an unstable intermediate 3, identified as 4,5-dihydro-3,6,8,9-tetramethyl-2H-3,9a-epoxy-1-benzoxepin-2,7(3H)-dione, which has a strong UV absorption at 235 nm. The disproportionation rate constant decreases with increasing pH, the greatest change occurring between pH 2 and 9, where it decreased by 10{sup 4}. The rate constant versus pH plot is consistent with a scheme that involves three reactions of the protonated and the unprotonated forms of 2. Intermediate 3 undergoes slow pH-dependent decomposition to 2-hydroxy-2-methyl-4-(2,5,6-trimethyl-2,4-dioxo-2,5-cyclohexadienyl)butanoic acid, 4. The same first-order rate constant was found for the decay of 3 and the appearance of 4. Simultaneous intramolecular cyclization during disproportionation is unique to 2 and similar derivatives, but would not occur in analogues that have hydrocarbon chains instead of a carboxyl moiety.

  20. Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties.

    PubMed

    Sears, Justin E; Boger, Dale L

    2015-03-17

    Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure-function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach. PMID:25586069

  1. 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

  2. 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 δ18O values correspond to meteoric waters. The δ13C (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

  3. 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 Central

    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

  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. Site characterization studies in high plateau of Tibet

    NASA Astrophysics Data System (ADS)

    Yao, Yongqiang; Wang, Hongshuai; Liu, Liyong; Wang, Yiping; Qian, Xuan; Yin, Jia

    2012-09-01

    The site survey in western China has been carried out since 2003. Remote studies and local surveys are performed, and Oma site, Ali area in southwest Tibet, has been selected in 2005 to make site testing measurements. The monitoring results show that Ali area can be the best choice for astronomical observations over the East Asian regions. A new site in Ali has been identified and begun construction in 2010 for small telescopes and detailed site characterization. This paper reviews the long term site survey, presents site characteristics in Tibet, and introduces current status of the new Ali observatory.

  7. 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

    2016-01-01

    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 GI(50) (10.47, 7.24 and 14.12 µM. respectively), and are nearly 1.5-3.0-fold more potent compared with the positive control 5-FU with mean GI50, 22.60 µM. 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

  8. 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

  9. Design, Synthesis, EPR-Studies and Conformational Bias of Novel Spin-Labeled DCC-Analogues for the Highly Regioselective Labeling of Aliphatic and Aromatic Carboxylic Acids.

    PubMed

    Gölz, Jan Philipp; NejatyJahromy, Yaser; Bauer, Mirko; Muhammad, Ashraf; Schnakenburg, Gregor; Grimme, Stefan; Schiemann, Olav; Menche, Dirk

    2016-07-01

    Novel types of spin-labeled N,N'-dicyclohexylcarbodiimides (DCC) are reported that bear a 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) residue on one side and different aromatic and aliphatic cyclohexyl analogues on the other side of the diimide core. These readily available novel reagents add efficiently to aliphatic and aromatic carboxylic acids, forming two possible spin-labeled amide derivatives with different radical distances of the resulting amide. The addition of aromatic DCC analogues proceeds with excellent selectivity, giving amides where the carboxylic acid is exclusively connected to the aromatic residue, while little or no selectivity was observed for the aliphatic congeners. The usefulness of these adducts in structural studies was demonstrated by EPR (electron paramagnetic resonance) measurements of biradical adducts of biphenyl-4,4'-dicarboxylic acids. These analyses also reveal high degrees of conformational bias for aromatic DCC derivatives, which further underlines the powerfulness of these novel reagents. This observation was further corroborated by quantum chemical calculations, giving a detailed understanding of the structural dynamics, while detailed information on the solid state structure of all novel reagents was obtained by X-ray structure analyses. PMID:27272435

  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. 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

  12. 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.

  13. Characterisation of ATP analogues to cross-link and label P2X receptors

    PubMed Central

    Agboh, Kelvin C.; Powell, Andrew J.; Evans, Richard J.

    2009-01-01

    P2X receptors are a distinct family of ATP-gated ion channels with a number of physiological roles ranging from smooth muscle contractility to the regulation of blood clotting. In this study we determined whether the UV light-reactive ATP analogues 2-azido ATP, ATP azidoanilide (ATP-AA) and 2′,3′-O-(4-benzoylbenzoyl)-ATP (BzATP) can be used to label the ATP binding site of P2X1 receptors. These analogues were agonists, and in patch clamp studies evoked inward currents from HEK293 cells stably expressing the P2X1 receptor. Following irradiation in the presence of these compounds subsequent responses to an EC50 concentration of ATP were reduced by >65%. These effects were partially reversed by co-application of ATP or suramin with the photo-reactive ATP analogue at the time of irradiation. In autoradiographic studies radiolabelled 2-azido [γ32P] ATP and ATP-AA-[γ32P] cross-linked to P2X1 receptors and this binding was reduced by co-incubation with ATP. These studies demonstrate that photo-reactive ATP analogues can be used to label P2X receptor and may prove useful in elucidating the ATP binding site at this novel class of ATP binding proteins. PMID:18599093

  14. Effective strand invasion ODN incorporating a new bicyclic nucleoside analogue (WNA).

    PubMed

    Aoki, Eriko; Taniguchi, Yosuke; Sasaki, Shigeki

    2007-01-01

    Efficient and specific targeting of DNA sequences by synthetic ligands is a major goal in chemical biology. Triplex-forming oligonucleotides (TFOs) are sequence-specific DNA-binding agents, but are limited to homopurine/homopyrimidine target sequences. We have previously reported two useful analogues (WNA: W-shaped nucleoside analogues), WNA-bT and WNAbC, which recognize a TA and a CG interrupting site forming triplexes with high stability and selectivity, respectively. However, their ability to form triplexes depended on their neighbouring bases in the TFO. Subsequent studies have shown that the sequence-dependency of the WNA analogues, for the formation of triplexes, has been partially solved by use of a WNA analogue bearing a substituted aromatic ring. Investigations into the effects of the substituted aromatic ring of WNA derivatives on the stability of triplexes led to the discovery of strand invasion by the TFO incorporating the new WNA analogue to form a highly stable duplex. PMID:18029683

  15. 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

  16. 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

  17. Picosecond time-resolved fluorescence of ribonuclease T1. A pH and substrate analogue binding study.

    PubMed Central

    Chen, L X; Longworth, J W; Fleming, G R

    1987-01-01

    The tryptophyl fluorescence of ribonuclease T1 decays monoexponentially at pH 5.5, tau = 4.04 ns but on increasing pH, a second short-lived component of 1.5 ns appears with a midpoint between pH 6.5 and 7.0. Both components have the same fluorescence spectrum. Acrylamide quenches both fluorescence components, and the short-lived component is quenched fivefold faster than the predominant long component. Binding of the substrate analogue 2'-guanylic acid at pH 5.5 quenches the fluorescence by 20% and introduces a second decay component, tau = 1.16 ns. Acrylamide quenches both tryptophyl decay components, with similar quenching rates. The fluorescence anisotropy decay of ribonuclease T1 was consistent with a molecule the size of ribonuclease T1 surrounded by a single layer of water at pH 7.4, even though the anisotropy decay at pH 5.5 deviated from Stokes-Einstein behavior. The fluorescence data were interpreted with a model where the tryptophyl residue exists in two conformations, remaining in a hydrophobic pocket. The acrylamide quenching is interpreted with electron transfer theory and suggests that one conformer has the nearest atom approximately 3 A from the protein surface, and the other, approximately 2 A. PMID:3038204

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

    NASA Astrophysics Data System (ADS)

    Wysokiński, Rafał; 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.

  19. Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-D-glucopyranosylamine and N-trifluoroacetyl-beta-D-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase.

    PubMed

    Anagnostou, Eleni; Kosmopoulou, Magda N; Chrysina, Evangelia D; Leonidas, Demetres D; Hadjiloi, Theodoros; Tiraidis, Costantinos; Zographos, Spyros E; Györgydeák, Zoltán; Somsák, László; Docsa, Tibor; Gergely, Pál; Kolisis, Fragiskos N; Oikonomakos, Nikos G

    2006-01-01

    Structure-based inhibitor design has led to the discovery of a number of potent inhibitors of glycogen phosphorylase b (GPb), N-acyl derivatives of beta-D-glucopyranosylamine, that bind at the catalytic site of the enzyme. The first good inhibitor in this class of compounds, N-acetyl-beta-D-glucopyranosylamine (NAG) (K(i) = 32 microM), has been previously characterized by biochemical, biological and crystallographic experiments at 2.3 angstroms resolution. Bioisosteric replacement of the acetyl group by trifluoroacetyl group resulted in an inhibitor, N-trifluoroacetyl-beta-D-glucopyranosylamine (NFAG), with a K(i) = 75 microM. To elucidate the structural basis of its reduced potency, we determined the ligand structure in complex with GPb at 1.8 angstroms resolution. To compare the binding mode of N-trifluoroacetyl derivative with that of the lead molecule, we also determined the structure of GPb-NAG complex at a higher resolution (1.9 angstroms). NFAG can be accommodated in the catalytic site of T-state GPb at approximately the same position as that of NAG and stabilize the T-state conformation of the 280 s loop by making several favourable contacts to Asn284 of this loop. The difference observed in the K(i) values of the two analogues can be interpreted in terms of subtle conformational changes of protein residues and shifts of water molecules in the vicinity of the catalytic site, variations in van der Waals interaction, and desolvation effects. PMID:16213146

  20. 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 < 0.005). Conclusions High-viscosity cement injected using vertebroplasty delivers more cement volume before cement leakage and fills the vertebral body more uniformly when compared with balloon kyphoplasty in osteoporotic vertebrae with

  1. Synthetic Analogues of the Active Site of the A-cluster of Acetyl Coenzyme A Synthase/CO Dehydrogenase: Syntheses, Structures, and Reactions with CO

    PubMed Central

    Harrop, Todd C.; Olmstead, Marilyn M.; Mascharak, Pradip K.

    2016-01-01

    Two metallosynthons, namely (Et4N)2[Ni(NpPepS)] (1) and (Et4N)2[Ni(PhPepS)] (2) containing carboxamido-N and thiolato-S as donors have been used to model the bimetallic Mp-Nid subsite of the A-cluster of the enzyme ACS/CODH. A series of sulfurbridged Ni/Cu dinuclear and trinuclear complexes (3-10) have been synthesized to explore their redox properties and affinity of the metal centers toward CO. The structures of (Et4N)2[Ni(PhPepS)] (2), (Et4N)[Cu(neo)Ni(NpPepS)]•0.5Et2O•0.5H2O (3•0.5Et2O•0.5H2O), (Et4N)[Cu(neo)Ni(PhPepS)]•H2O (4•H2O), (Et4N)2[Ni{Ni(NpPepS)}2]•DMF (5•DMF), (Et4N)2[Ni(DMF)2{Ni(NpPepS)}2]•3DMF (6•3DMF), (Et4N)2[Ni(DMF)2{Ni(PhPepS)}2] (8), and [Ni(dppe)Ni(PhPepS)]•CH2Cl2 (10•CH2Cl2) have been determined by crystallography. The Nid mimics 1 and 2 resist reduction and exhibit no affinity toward CO. In contrast, the sulfur-bridged Ni center (designated NiC) in the trinuclear models 5–8 are amenable to reduction and binds CO in the Ni(I) state. Also, the sulfur-bridged NiC center can be removed from the trimers (5–8) by treatment with 1,10-phenanthroline much like the “labile Ni” from the enzyme. The dinuclear Ni-Ni models 9 and 10 resemble the Nip-Nid subsite of the A-cluster more closely and only the modeled Nip site of the dimers can be reduced. The Ni(I)-Ni(II) species display EPR spectra typical of a Ni(I) center in distorted trigonal bipyramidal and distorted tetrahedral geometries for 9red and 10red, respectively. Both species bind CO and the CO-adducts 9red-CO and 10red-CO display strong νco at 2044 and 1997 cm-1, respectively. The reduction of 10 is reversible. The CO-affinity of 10 in the reduced state and the νco value of 10red-CO closely resemble the CO-bound reduced A-cluster (νco = 1996 cm-1). PMID:16602803

  2. Study on reactivity and protection of the alpha-hydroxyphosphonate moiety in 5'-nucleotide analogues: formation of the 3'-O-P-C(OH)-C4' internucleotide linkage.

    PubMed

    Králíková, Sárka; Masojídková, Milena; Budĕsínský, Milos; Rosenberg, Ivan

    2003-03-01

    The recently described epimeric nucleosidyl-5'-C-phosphonates (alpha-hydroxyphosphonates) represent novel nucleotide analogues that can be incorporated into chimeric oligonucleotides by the phosphotriester condensation method. In order to prepare suitable protected monomer(s) we have studied condensation reaction between protected 2'-deoxythymidine and 2'-deoxythymidinyl-5'-C-phosphonate, both as model compounds, in dependence on the nature of the 5'-hydroxyl protecting group. We have found that the O-acetyl group is unstable in the presence of TPSCl or MSNT used as condensing agents for activation of the phosphorus moiety. This instability negatively influences the scope of the condensation process. On the other hand, introduction of the O-methoxycarbonyl group gave excellent results. The O-methoxycarbonyl group does not participate in the condensation process, and its quantitative introduction into the nucleotide analo gues is accomplished using a novel acylating agent, methoxycarbonyl tetrazole. PMID:12816391

  3. [Comparative distribution study of 14C labeled amino acids, glucose-analogue and precursor of nuclei acid, as tumor seeking agents].

    PubMed

    Shiba, K; Mori, H; Hisada, K

    1984-08-01

    As tumor-seeking agents, glucose analogues, natural amino acids, synthetic nonmetabolized amino acids, and precursor of nucleic acids, etc., labeled with positron emitter, such as 11C and 18F have been recently investigated. However, there are very few reports concerning comparative study of tumor uptake and tissue distribution of these agents. This preliminary paper describes comparative distribution and whole-body autoradiography of these agents. 14C labeled deoxy-2-fluoro-D-glucose (FDG), L-, DL-leucine, 1-aminocyclopentane carboxylic acid (ACPC), alpha-amino isobutyric acid (alpha-AIB), and thymidine were intravenously injected through tail vein into separate groups of the experimental animals. As the experimental animals, the mice with Ehrlich tumor and the rats with Hepatoma AH109A were used. Within 30 min after injection, FDG had the highest tumor uptake and tumor to tissue ratios, although FDG was inferior to ACPC and thymidine in related to tumor to heart, lung and brain ratios. However, the time course study indicated that tumor uptake of ACPC, alpha-AIB and D-leucine increased with time, whereas those of other agents decreased with time or reached a plateau. Thus, at 120 min after injection, ACPC had the highest tumor uptake and tumor to tissue ratios, although ACPC was inferior to FDG in related to tumor to blood, liver and pancreas ratios. Autoradiogram of ACPC showed very clear tumor image as well as that of FDG. The above data suggest that synthetic nonmetabolized amino acids, such as ACPC may be promising as tumor-seeking agents, when used with a single photon emission computed tomography, while glucose analogue such as FDG, are the best tumor-seeking agent, when used with a positron emission computed tomography. PMID:6505304

  4. A Transition State Analogue for an RNA-Editing Reaction

    PubMed Central

    Haudenschild, Brittany L.; Maydanovych, Olena; Véliz, Eduardo A.; Macbeth, Mark R.; Bass, Brenda L.; Beal, Peter A.

    2007-01-01

    Deamination at C6 of adenosine in RNA catalyzed by the ADAR enzymes generates inosine at the corresponding position. Because inosine is decoded as guanosine during translation, this modification can lead to codon changes in messenger RNA. Hydration of 8-azanebularine across the C6–N1 double bond generates an excellent mimic of the transition state proposed for the hydrolytic deamination reaction catalyzed by ADARs. Here, we report the synthesis of a phosphoramidite of 8-azanebularine and its use in the preparation of RNAs mimicking the secondary structure found at a known editing site in the glutamate receptor B subunit pre-mRNA. The binding properties of analogue-containing RNAs indicate that a tight binding ligand for an ADAR can be generated by incorporation of 8-azanebularine. The observed high-affinity binding is dependent on a functional active site, the presence of one, but not the other, of ADAR2’s two double-stranded RNA-binding motifs (dsRBMs), and the correct placement of the nucleoside analogue into the sequence/structural context of a known editing site. These results advance our understanding of substrate recognition during ADAR-catalyzed RNA editing and are important for structural studies of ADAR· RNA complexes. PMID:15355102

  5. Imidazoline binding sites (IBS) profile modulation: key role of the bridge in determining I1-IBS or I2-IBS selectivity within a series of 2-phenoxymethylimidazoline analogues.

    PubMed

    Gentili, Francesco; Bousquet, Pascal; Brasili, Livio; Dontenwill, Monique; Feldman, Josiane; Ghelfi, Francesca; Giannella, Mario; Piergentili, Alessandro; Quaglia, Wilma; Pigini, Maria

    2003-05-22

    The alpha- and beta-methyl derivatives of 2-phenylethylimidazoline (compounds 7 and 8) and the corresponding enantiomers were prepared and tested with the purpose of studying the role played by the ethylene bridge in modulating I(1)- and I(2)-IBS selectivity. The alpha-methylation appeared to be extremely critical regarding the affinity and selectivity for the I1-IBS subtypes (I1/I2 = 186 for imidazoline 7) and the stereospecificity of interaction (eudismic ratio (S)-(-)-7/(R)-(+)-7 = 5888). Instead, even if in a more limited fashion, the -methylation tended toward I2-IBS selectivity (I2/I1 = 50 for imidazoline 8). The unsubstituted compound 4 (I2/I1 = 1479) proved to be considerably more potent and selective with respect to I2-IBS subtypes. PMID:12747788

  6. A prospective randomised cross-over study of the effect of insulin analogues and human insulin on the frequency of severe hypoglycaemia in patients with type 1 diabetes and recurrent hypoglycaemia (the HypoAna trial): study rationale and design

    PubMed Central

    2012-01-01

    Background Severe hypoglycaemia still represents a significant problem in insulin-treated diabetes. Most patients do not experience severe hypoglycaemia often. However, 20% of patients with type 1 diabetes experience recurrent severe hypoglycaemia corresponding to at least two episodes per year. The effect of insulin analogues on glycaemic control has been documented in large trials, while their effect on the frequency of severe hypoglycaemia is less clear, especially in patients with recurrent severe hypoglycaemia. The HypoAna Trial is designed to investigate whether short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing the occurrence of severe hypoglycaemic episodes in patients with recurrent hypoglycaemia. This paper reports the study design of the HypoAna Trial. Methods/design The study is a Danish two-year investigator-initiated, prospective, randomised, open, blinded endpoint (PROBE), multicentre, cross-over trial investigating the effect of insulin analogues versus human insulin on the frequency of severe hypoglycaemia in subjects with type 1 diabetes. Patients are randomised to treatment with basal-bolus therapy with insulin detemir / insulin aspart or human NPH insulin / human regular insulin in random order. The major inclusion criterion is history of two or more episodes of severe hypoglycaemia in the preceding year. Discussion In contrast to almost all other studies in this field the HypoAna Trial includes only patients with major problems with hypoglycaemia. The HypoAna Trial will elucidate whether basal-bolus regimen with short-acting and long-acting insulin analogues in comparison with human insulin are superior in reducing occurrence of severe hypoglycaemic episodes in hypoglycaemia prone patients with type 1 diabetes. http://www.clinicaltrials.gov: NCT00346996. PMID:22727048

  7. Direct observation of adsorbed H{sub 2}-framework interactions in the Prussian Blue analogue Mn{sup II}{sub 3} [CO{sup III}(CN){sub 6}]{sub 2} : the relative importance of accessible coordination sites and Van Der Waals interactions.

    SciTech Connect

    Chapman, K. W.; Chupas, P. J.; Maxey, E. R.; Richardson, J. W.

    2006-01-01

    Selective recovery of the guest-framework interactions for H{sub 2} adsorbed in a nanoporous Prussian Blue analogue, through differential X-ray and neutron pair distribution function analysis at ca. 77 K, suggests that the H{sub 2} molecule is disordered about a single position at the centre of the pore, (1/4, 1/4, 1/4), without binding at accessible Mn{sup II} sites.

  8. 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.

  9. An experimental NEXAFS and computational TDDFT and ΔDFT study of the gas-phase core excitation spectra of nitroxide free radical TEMPO and its analogues.

    PubMed

    Ljubić, Ivan; Kivimäki, Antti; Coreno, Marcello

    2016-04-21

    Core-hole spectroscopy adds to the fundamental understanding of the electronic structure of stable nitroxide free radicals thus paving way for a sensible design of new analogues with desired functionalities. We study the gas-phase C 1s, N 1s and O 1s excitation spectra of three nitroxide free radicals - TEMPO and two of its amide-substituted analogues - using the experimental NEXAFS technique and the theoretical TDDFT and ΔDFT methods in the unrestricted setting. The short-range corrected SRC1-BLYP and SRC2-BLYP exchange-correlation functionals are used with TDDFT, and the standard B3LYP functional with ΔDFT. The TDDFT-based detailed spectral assignment includes the valence, mixed valence-Rydberg and Rydberg portions of the spectra from the onset of absorptions to the vicinity of the core-ionization thresholds. The relative overlaps between the experimental and TDDFT-modelled spectra are reasonably good, in the range of 0.7-0.8, 0.6-0.8, and 0.7-0.8 for the C 1s, N 1s, and O 1s spectra, respectively. The extent of spin contamination within the unrestricted framework and its effect on the accuracy of the calculated excitation energies and dipole intensities are discussed in detail. It is concluded that, despite the sizeable spin contamination, the presently used methods are capable of predicting the core-excitation spectra of comparatively large free radical species fairly reliably over a wide spectral range. PMID:27020039

  10. 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.

  11. 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.

  12. 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.

  13. Nutrient and dissolved oxygen studies at OTEC sites

    SciTech Connect

    Quinby-Hunt, M.S.; Fanning, K.; Ziemann, D.; Walsh, T.W.; Knauer, G.A.

    1981-07-01

    In order to adequately assess the impact of artificial upwelling and other possible ecological impacts of OTEC operations on the chemistry of the water column at OTEC sites, studies were initiated at several potential sites. At most sites,hydrocasts were taken at approximately noon and midnight to a depth of about 100 m; samples were collected from about 15 depths to be analyzed for nitrates, nitrites, reactive phosphate, silicate and dissolved oxygen. At some sites, samples were analyzed for various other parameters including ammonia, total organic phosphorus and carbonate alkalinity. Preliminary data on nitrates, phosphates, silicates and dissolved oxygen from several potential sites - off Hawaii, Oahu, Peurto Rico, and the Virgin Islands - are presented and compared. Significant differences between nutrient concentrations have been found at the Caribbean and Hawaiian sites. There is also evidence of seasonal variation at the Oahu site. (LEW)

  14. Convergent syntheses of LeX analogues

    PubMed Central

    Wang, An; Hendel, Jenifer

    2010-01-01

    Summary The synthesis of three Lex derivatives from one common protected trisaccharide is reported. These analogues will be used respectively for competitive binding experiments, conjugation to carrier proteins and immobilization on gold. An N-acetylglucosamine monosaccharide acceptor was first glycosylated at O-4 with a galactosyl imidate. This coupling was performed at 40 °C under excess of BF3·OEt2 activation and proceeded best if the acceptor carried a 6-chlorohexyl rather than a 6-azidohexyl aglycon. The 6-chlorohexyl disaccharide was then converted to an acceptor and submitted to fucosylation yielding the corresponding protected 6-chlorohexyl Lex trisaccharide. This protected trisaccharide was used as a precursor to the 6-azidohexyl, 6-acetylthiohexyl and 6-benzylthiohexyl trisaccharide analogues which were obtained in excellent yields (70–95%). In turn, we describe the deprotection of these intermediates in one single step using dissolving metal conditions. Under these conditions, the 6-chlorohexyl and 6-azidohexyl intermediates led respectively to the n-hexyl and 6-aminohexyl trisaccharide targets. Unexpectedly, the 6-acetylthiohexyl analogue underwent desulfurization and gave the n-hexyl glycoside product, whereas the 6-benzylthiohexyl analogue gave the desired disulfide trisaccharide dimer. This study constitutes a particularly efficient and convergent preparation of these three Lex analogues. PMID:20485599

  15. 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

  16. 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.

  17. A study on the flexibility of enzyme active sites

    PubMed Central

    2011-01-01

    Background A common assumption about enzyme active sites is that their structures are highly conserved to specifically distinguish between closely similar compounds. However, with the discovery of distinct enzymes with similar reaction chemistries, more and more studies discussing the structural flexibility of the active site have been conducted. Results Most of the existing works on the flexibility of active sites focuses on a set of pre-selected active sites that were already known to be flexible. This study, on the other hand, proposes an analysis framework composed of a new data collecting strategy, a local structure alignment tool and several physicochemical measures derived from the alignments. The method proposed to identify flexible active sites is highly automated and robust so that more extensive studies will be feasible in the future. The experimental results show the proposed method is (a) consistent with previous works based on manually identified flexible active sites and (b) capable of identifying potentially new flexible active sites. Conclusions This proposed analysis framework and the former analyses on flexibility have their own advantages and disadvantage, depending on the cause of the flexibility. In this regard, this study proposes an alternative that complements previous studies and helps to construct a more comprehensive view of the flexibility of enzyme active sites. PMID:21342563

  18. 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

  19. Analogue-to-Digital and Digital-to-Analogue Conversion.

    ERIC Educational Resources Information Center

    Gregory, Martin

    1997-01-01

    Discusses circuits for three-bit and four-bit analogue digital converters and digital analogue converters. These circuits feature slow operating speeds that enable the circuitry to be used to demonstrate the mode of operation using oscilloscopes and signal generators. (DDR)

  20. 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)

    Bakker, E.; Hangx, S.; Spiers, C. J.

    2012-12-01

    CO2 capture followed by storage in depleted oil and gas reservoirs is currently seen as one of the most promising CO2-mitigation strategies. An important issue in relation to long-term CO2 storage is the prediction of the effects of fluid-rock interaction on the mechanical integrity and sealing capacity of the reservoir-seal system, on timescales of the order of 103 or 104 years. However, the assumed chemical interactions in the rock/CO2/brine system are slow, so that their long-term effects on rock composition, microstructure, mechanical properties and transport properties cannot be reproduced in laboratory experiments. One way to address this is to study the effects of reactions in natural CO2 reservoirs, using a so-called natural analogue approach. We tackled the question of how reactions characterizing natural CO2 fields affect fault friction, fault reactivation potential and seismic vs. aseismic slip stability, as well as transmissivity evolution during and after fault reactivation. Simulated fault gouges were prepared by crushing material obtained from surface outcrops of the Entrada Sandstone, a locally CO2-bearing formation forming an analogue field under the Colorado Plateau, Utah, USA . We used three types of starting material: 1) CO2 unaffected (unbleached) samples consisting mainly of quartz and feldspar, 2) "bleached" samples, and 3) heavily cemented/altered fault rock containing a high percentage of carbonates (> 40 wt%). The latter two were altered as a result of interaction with CO2-rich fluids over geological time. We performed triaxial direct shear experiments on these materials at room temperature under nominally dry conditions, at normal stresses up to 90 MPa and shear velocities of 0.22 -10.9 μm/s. The results of the experiments yielded friction coefficients (μ= τ/σn) of 0.55-0.85 for unbleached sandstone gouge and 0.45-0.80 for bleached material, while the fault material showed systematically higher friction coefficients (0.60-0.95). All

  1. Universal Access in Heritage Sites: A Case Study on Historic Sites in Jaipur, India.

    PubMed

    Vardia, Shweta; Khare, Rachna; Khare, Ajay

    2016-01-01

    A nation is recognized by a range of its significant historical, cultural and natural properties. These properties are generally preserved and maintained either by national administration or by private owners and charitable trusts due to higher value of their cultural inheritance and termed globally as heritage or historic sites. Heritage sites are a significant asset, a unique and irreplaceable resource which reflects a rich and diverse expression of past societies and forms an integral part of local, regional and national cultural identity. Today, heritage sites also play an important role in communication and knowledge exchange. Thus the rapidly increasing heritage tourism industry faces several challenges too. One of the challenges is that there is a segment of society who is not yet able to equally enjoy the visit to historic structures/sites and attractions, facilities and services. This paper aims to study the experience and develop understanding regarding the heritage structures/sites approached and interacted by diverse users. This study is an outcome of a hands on workshop conducted with diverse users at various historic sites in the city of Jaipur viz. at The City Palace Complex, Jaipur, Jaigarh Fort and the Haveli at Kanota near to Jaipur India. PMID:27534337

  2. 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; Öberg, 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], 0.27–1.97; 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, 0.89–4.32; 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, 0.20–0.98; 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

  3. Monochromatic excimer light versus combination of topical steroid with vitamin D3 analogue in the treatment of nonsegmental vitiligo: a randomized blinded comparative study.

    PubMed

    Abdel Latif, Azmy Ahmed; Ibrahim, Shady Mahmoud Attia

    2015-01-01

    Vitiligo is a difficult disease to treat, socially stigmatizing its patients. Monochromatic excimer light (MEL) was developed for use in dermatology and adapted for the treatment of vitiligo. Comparing the efficacy of MEL versus topical combination therapy of vitamin D3 analogue and steroid in the treatment of nonsegmental vitiligo. Forty-four patients with localized and stable nonsegmental vitiligo participated in the present study. In each patient, two lesions were selected and divided randomly into two groups, group A was treated with daily topical combination of calcipotriol and betamethasone and group B was treated with biweekly sessions of MEL for 3 months. Efficacy based on repigmentation percentages were blindly evaluated by two independent physicians and patient's satisfaction. There was significant improvement in both treatment modalities at the end of the study, but without significant differences in both groups. There was a significant difference between both groups regarding the onset of repigmentation (p-value < 0.05), whereas group B showed early sign of repigmentation in first 4 weeks of treatment in 16 patients versus 7 patients in group A. Both treatment modalities offered encouraging results and both are promising lines for the treatment of vitiligo. PMID:26358764

  4. 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.

  5. Readability of menopause web sites: a cross-sectional study.

    PubMed

    Charbonneau, Deborah H

    2012-01-01

    More women are frequently referring to the Internet for health information, yet the readability of information about menopause on the Internet has not been widely studied. To address this gap, this study examined the readability of information about menopause on 25 Internet Web sites. Findings included that information on the Web sites had a reading level higher than the recommended sixth-grade level, and culturally appropriate health information was lacking. Health educators and practitioners are in a pivotal role to help women understand information useful for healthcare decisions. Several criteria are discussed to help practitioners evaluate Web sites. PMID:23098043

  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. Circular dichroism study of the interaction between mutagens and bilirubin bound to different binding sites of serum albumins.

    PubMed

    Orlov, Sergey; Goncharova, Iryna; Urbanová, Marie

    2014-05-21

    Although recent investigations have shown that bilirubin not only has a negative role in the organism but also exhibits significant antimutagenic properties, the mechanisms of interactions between bilirubin and mutagens are not clear. In this study, interaction between bilirubin bound to different binding sites of mammalian serum albumins with structural analogues of the mutagens 2-aminofluorene, 2,7-diaminofluorene and mutagen 2,4,7-trinitrofluorenone were investigated by circular dichroism and absorption spectroscopy. Homological human and bovine serum albumins were used as chiral matrices, which preferentially bind different conformers of bilirubin in the primary binding sites and make it observable by circular dichroism. These molecular systems approximated a real system for the study of mutagens in blood serum. Differences between the interaction of bilirubin bound to primary and to secondary binding sites of serum albumins with mutagens were shown. For bilirubin bound to secondary binding sites with low affinity, partial displacement and the formation of self-associates were observed in all studied mutagens. The associates of bilirubin bound to primary binding sites of serum albumins are formed with 2-aminofluorene and 2,4,7-trinitrofluorenone. It was proposed that 2,7-diaminofluorene does not interact with bilirubin bound to primary sites of human and bovine serum albumins due to the spatial hindrance of the albumins binding domains. The spatial arrangement of the bilirubin bound to serum albumin along with the studied mutagens was modelled using ligand docking, which revealed a possibility of an arrangement of the both bilirubin and 2-aminofluorene and 2,4,7-trinitrofluorenone in the primary binding site of human serum albumin. PMID:24589992

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

    NASA Astrophysics Data System (ADS)

    Magyari, Enikő Katalin; Kuneš, Petr; Jakab, Gusztáv; Sümegi, Pál; Pelánková, Barbora; Schäbitz, Frank; Braun, Mihály; Chytrý, 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, Hippophaë rhamnoides, Populus, Salix and Alnus. The pollen

  9. A new approach for ovarian stimulation in IVF using Corifollitropin Alfa in combination with GnRH analogues to trigger final oocyte maturation. A pilot study

    PubMed Central

    Decleer, W.; Osmanagaoglu, K.; Meganck, G.; Devroey, P.

    2014-01-01

    A pilot study of 10 patients undergoing IVF stimulation, using the new combination of Corifollitropin Alfa with highly purified hMG and GnRH antagonists has been performed, whereas final oocyte maturation was induced by GnRH analogues. The hormonal profiles were analyzed, as well as the clinical outcome. All patients were recruited between March 1st 2013 and June 30th 2013. They were all younger than 38 years, had a normal BMI (between 18,0 and 32,0) and did not have more than three previous IVF stimulations. The combination of long acting FSH with hphMG, and under protection of GnRH antagonists against spontaneous LH-surge, provided a normal hormonal profile for estradiol, progesterone, LH, and FSH. The average oocyte quality and embryo quality were excellent, which resulted in four pregnancies out of ten. We conclude that the described combination is a safe, efficient, and patient friendly alternative for the classical IVF stimulation. PMID:25374659

  10. Synthesis and biological activity of tetralone abscisic acid analogues.

    PubMed

    Nyangulu, James M; Nelson, Ken M; Rose, Patricia A; Gai, Yuanzhu; Loewen, Mary; Lougheed, Brenda; Quail, J Wilson; Cutler, Adrian J; Abrams, Suzanne R

    2006-04-01

    Bicyclic analogues of the plant hormone abscisic acid (ABA) were designed to incorporate the structural elements and functional groups of the parent molecule that are required for biological activity. The resulting tetralone analogues were predicted to have enhanced biological activity in plants, in part because oxidized products would not cyclize to forms corresponding to the inactive catabolite phaseic acid. The tetralone analogues were synthesized in seven steps from 1-tetralone and a range of analogues were accessible through a second route starting with 2-methyl-1-naphthol. Tetralone ABA 8 was found to have greater activity than ABA in two bioassays. The absolute configuration of (+)-8 was established by X-ray crystallography of a RAMP hydrazone derivative. The hydroxymethyl compounds 10 and 11, analogues for studying the roles of 8- and 9-hydroxy ABA 3 and 6, were also synthesized and found to be active. PMID:16557330

  11. Which dressing do donor site wounds need?: study protocol for a randomized controlled trial

    PubMed Central

    2011-01-01

    Background Donor site wounds after split-skin grafting are rather 'standard' wounds. At present, lots of dressings and topical agents for donor site wounds are commercially available. This causes large variation in the local care of these wounds, while the optimum 'standard' dressing for local wound care is unclear. This protocol describes a trial in which we investigate the effectiveness of various treatment options for these donor site wounds. Methods A 14-center, six-armed randomized clinical trial is being carried out in the Netherlands. An a-priori power analysis and an anticipated dropout rate of 15% indicates that 50 patients per group are necessary, totaling 300 patients, to be able to detect a 25% quicker mean time to complete wound healing. Randomization has been computerized to ensure allocation concealment. Adult patients who need a split-skin grafting operation for any reason, leaving a donor site wound of at least 10 cm2 are included and receive one of the following dressings: hydrocolloid, alginate, film, hydrofiber, silicone dressing, or paraffin gauze. No combinations of products from other intervention groups in this trial are allowed. Optimum application and changes of these dressings are pursued according to the protocol as supplied by the dressing manufacturers. Primary outcomes are days to complete wound healing and pain (using a Visual Analogue Scale). Secondary outcomes are adverse effects, scarring, patient satisfaction, and costs. Outcome assessors unaware of the treatment allocation will assess whether or not an outcome has occurred. Results will be analyzed according to the intention to treat principle. The first patient was randomized October 1, 2009. Discussion This study will provide comprehensive data on the effectiveness of different treatment options for donor site wounds. The dressing(s) that will prevail in effectiveness, satisfaction and costs will be promoted among clinicians dealing with such patients. Thus, we aim to

  12. 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.

  13. 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.

  14. 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),…

  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. 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

  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. Design, Synthesis and Structure-Activity Relationship Studies of Novel 4 (1-adamantyl) Phenyl Analogues as HIF-1α Inhibitors.

    PubMed

    Xia, Yan; Duan, Qiong; Zhao, Bao-Hua; Li, Dong-Feng; Hou, Rui-Bin

    2016-01-01

    Hypoxia inducible factor-1 (HIF-1) is a key mediator during cancer cells to adapt tumor hypoxic condition. In this study, a series of adamantane-based compounds were synthesized and evaluated as potential inhibitors of HIF-1α. Examination of their structure-activity relationship (SAR) identified the adamantane-containing indole derivative 20a as a potent inhibitor of HIF-1α in Hep3B cell lines under tumor hypoxia (IC50 = 0.02 µM). The study herein may provide valuable information for the development of novel therapeutics against cancer and tumor angiogenesis. PMID:26548744

  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. 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.

  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. 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 (45a–c (PAT) vs 1 (SMART)). PMID:21557538

  5. Effects of gender-related domain violations and sexual orientation on perceptions of male and female targets: an analogue study.

    PubMed

    Blashill, Aaron J; Powlishta, Kimberly K

    2012-10-01

    The current study examined factors that influenced heterosexual male and female raters' evaluations of male and female targets who were gay or heterosexual, and who displayed varying gender roles (i.e., typical vs. atypical) in multiple domains (i.e., activities, traits, and appearance). Participants were 305 undergraduate students from a private, midwestern Jesuit institution who read vignettes describing one of 24 target types and then rated the target on possession of positive and negative characteristics, psychological adjustment, and on measures reflecting the participants' anticipated behavior toward or comfort with the target. Results showed that gender atypical appearance and activity attributes (but not traits) were viewed more negatively than their gender typical counterparts. It was also found that male participants in particular viewed gay male targets as less desirable than lesbian and heterosexual male targets. These findings suggest a nuanced approach for understanding sexual prejudice, which incorporates a complex relationship among sex, gender, sexual orientation, and domain of gendered attributes. PMID:22722956

  6. The effect of long-term fluid-rock interactions on the mechanical properties of reservoir rock - a case study of the Werkendam natural CO2 analogue field

    NASA Astrophysics Data System (ADS)

    Hangx, Suzanne; Bertier, Pieter; Bakker, Elisenda; Nover, Georg; Busch, Andreas

    2015-04-01

    Geological storage of CO2 is one of the most promising technologies to rapidly reduce anthropogenic emissions of carbon dioxide. During long-term geological storage of CO2, fluid-rock interactions, induced by the formation of carbonic acid, may affect the mineralogical composition of the reservoir rock. Commonly expected reactions include the dissolution of carbonate and/or sulphate cements, as well as the reaction of primary minerals (feldspars, clays, micas) to form new, secondary phases. In order to ensure storage integrity, it is important to understand the effect of such fluid-rock interactions on the mechanical behaviour of a CO2 storage complex. However, most of these reactions are very slow, which limits the ability to study coupled chemical-mechanical processes in the lab. A possible way to circumvent long reaction times is to investigate natural CO2 analogue fields, which experienced CO2-exposure for thousands of years. In this study, we looked at the Dutch Werkendam natural CO2 field and its unreacted counterpart (Röt Fringe Sandstone, Werkendam, the Netherlands). We focussed on CO2-induced mineralogical and porosity-permeability changes, and their effect on mechanical behaviour of intact rock. Overall, CO2-exposure did not lead to drastic mineralogical changes, though markedly different porosity-permeability relationships were found for the unreacted and exposed material. 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 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 were significantly weaker. Simple stress path calculations predict that reservoir failure due to depletion and injection is unlikely.

  7. Effects of tamoxifen and somatostatin analogue on growth of human medullary, follicular, and papillary thyroid carcinoma cell lines: tissue culture and nude mouse xenograft studies.

    PubMed

    Weber, C J; Marvin, M; Krekun, S; Koschitzky, T; Karp, F; Benson, M; Feind, C R

    1990-12-01

    The knowledge that (1) the normal thyroid contains somatostatin, (2) polypeptide growth factors influence thyroid cell function, and (3) thyroid cells contain steroid hormone receptors prompted us to add somatostatin analogue No. 201-995 (SMS) (5 ng/ml) and/or tamoxifen citrate (TAM) (5 mumol/L) to 7-day monolayer cultures (50,000 cells/well) of three separate human thyroid carcinoma cell lines: DR081 (medullary), WR082 (follicular), and NPA'87 (papillary). Results, tabulated as cell numbers/well (X10(5) on day 7, revealed that TAM inhibited growth of medullary and follicular cells and that TAM plus SMS inhibited growth of papillary cells. In vivo studies of subcutaneous tumor cell xenografts in nude mice have documented that TAM (5 mg subcutaneous pellet) significantly inhibits the growth of medullary implants. Flow cytometric DNA studies of medullary cell cultures demonstrated a reduced G2 + M phase with TAM treatment. For papillary cell implants, TAM plus SMS (5 micrograms subcutaneously, twice daily) did not suppress tumor growth. All three cell lines were negative for estrogen receptor; addition of estradiol (5 ng/ml) to medullary cell cultures neither stimulated replication nor reversed the inhibitory effects of TAM in vitro. We conclude that (1) TAM slowed the growth of a cell line of human medullary carcinoma, both in vitro and in vivo; (2) this effect was not reversed by estradiol; (3) TAM plus SMS inhibited replication of a papillary carcinoma cell line in vitro, but not in vivo; and (4) TAM alone and TAM plus SMS inhibited replication of cultures of a human follicular thyroid carcinoma cell line. TAM and SMS may be useful in treatment of some human thyroid carcinomas. PMID:1978945

  8. 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 (α-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 α-MSH peptide based imaging and therapeutic agents. Initially, the native α-MSH peptide was radiolabeled directly, but it suffered from low specific activity and poor stability. The addition of non-natural amino acids yielded α-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 α-MSH analogues was improved through the conjugation of metal chelators to the peptide’s N-terminus or lysine residues for radionuclide coordination. In vitro cell binding studies demonstrated that the radiolabeled α-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 α-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 α-MSH peptides for melanoma imaging and treatment of disseminated disease. PMID:20467398

  9. 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 ...

  10. A Patient Specific Biomechanical Analysis of Custom Root Analogue Implant Designs on Alveolar Bone Stress: A Finite Element Study

    PubMed Central

    2016-01-01

    Objectives. The aim of this study was to analyse by means of FEA the influence of 5 custom RAI designs on stress distribution of peri-implant bone and to evaluate the impact on microdisplacement for a specific patient case. Materials and Methods. A 3D surface model of a RAI for the upper right canine was constructed from the cone beam computed tomography data of one patient. Subsequently, five (targeted) press-fit design modification FE models with five congruent bone models were designed: “Standard,” “Prism,” “Fins,” “Plug,” and “Bulbs,” respectively. Preprocessor software was applied to mesh the models. Two loads were applied: an oblique force (300 N) and a vertical force (150 N). Analysis was performed to evaluate stress distributions and deformed contact separation at the peri-implant region. Results. The lowest von Mises stress levels were numerically observed for the Plug design. The lowest levels of contact separation were measured in the Fins model followed by the Bulbs design. Conclusions. Within the limitations of the applied methodology, adding targeted press-fit geometry to the RAI standard design will have a positive effect on stress distribution, lower concentration of bone stress, and will provide a better primary stability for this patient specific case. PMID:27274727

  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 Zeise’s 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 η2 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. Comparative study of midtrimester termination of pregnancy using hypertonic saline, ethacridine lactate, prostaglandin analogue and iodine-saline.

    PubMed

    Allahbadia, G

    1992-09-01

    The study consisted of terminations of 200 cases of second trimester pregnancies ranging from 14 weeks to 20 weeks. Out of these 200 cases, in 50 cases intra-amniotic instillation of 20% hypertonic saline (200 ml) was done after withdrawing 35-200 ml of amniotic fluid. Ethacridine lactate was instilled in 50 cases extra-amniotically. Prostaglandin F2 alpha was injected intramuscularly at regular intervals in 50 cases. Fifty cases of pregnancies were terminated with extra-amniotic instillation of 5% povidone-iodine solution mixed with normal saline. Comparison was made among all the methods regarding instillation-abortion interval, completeness of abortion, failure of the procedure and postoperative complications. Solution of 5% povidone-iodine in normal saline was found to be comparable in all aspects to other methods and above all a much cheaper alternative for poor patients. Success rate was highest with iodine-saline solution (100%) followed by ethacridine lactate (98%), hypertonic saline (96%) and lowest with prostaglandin F2 alpha (90%). PMID:1460314

  13. X-ray powder diffractometry and liquid chromatography studies of sibutramine and its analogues content in herbal dietary supplements.

    PubMed

    Stypułkowska, K; Błażewicz, A; Maurin, J; Sarna, K; Fijałek, 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

  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. 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 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

  16. 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

  17. Study of Functional and Allosteric Sites in Protein Superfamilies

    PubMed Central

    Suplatov, D.; Švedas, 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. Rat intestinal trehalase. Studies of the active site.

    PubMed

    Chen, C C; Guo, W J; Isselbacher, K J

    1987-11-01

    Rat intestinal trehalase was solubilized, purified and reconstituted into proteoliposomes. With octyl glucoside as the solubilizing detergent, the purified protein appeared as a single band on SDS/polyacrylamide-gel electrophoresis with an apparent molecular mass of 67 kDa. Kinetic studies indicated that the active site of this enzyme can be functionally divided into two adjacent regions, namely a binding site (with pKa 4.8) and a catalytic site (with pKa 7.2). Other findings suggested that the catalytic site contains a functional thiol group, which is sensitive to inhibition by N-ethylmaleimide, Hg2+ and iodoacetate. Substrate protection and iodoacetate labelling of the thiol group demonstrated that only a protein of 67 kDa was labelled. Furthermore, sucrose and phlorizin protected the thiol group, but Tris-like inhibitors did not. Structure-inhibition analysis of Tris-like inhibitors, the pH effect of Tris inhibition and Tris protection of 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide inactivation permitted characterization and location of a separate site containing a carboxy group for Tris binding, which may also be the binding region. On the basis of these findings, a possible structure for the active site of trehalase is proposed. PMID:3426558

  19. 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.

  20. 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, Maurício Temotheo; Pasqualoto, Kerly Fernanda Mesquita; de Azevedo, Ricardo Alexandre; Teixeira, Sarah Fernandes; Ferreira-Junior, Wilson Alves; Bertin, Ariane Matiello; de-Sá-Junior, Paulo Luiz; Barbuto, José Alexandre Marzagão; Figueiredo, Carlos Rogério; Cury, Yara; Damião, 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

  1. Theoretical study of 1,2-hydride shift associated with the isomerization of glyceraldehyde to dihydroxy acetone by Lewis acid active site models.

    PubMed

    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. PMID:21707087

  2. 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.

  3. 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.

  4. 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)

  5. Recent developments in naturally derived antimalarials: cryptolepine analogues.

    PubMed

    Wright, Colin W

    2007-06-01

    Increasing resistance of Plasmodium falciparum to commonly used antimalarial drugs has made the need for new agents increasingly urgent. In this paper, the potential of cryptolepine, an alkaloid from the West African shrub Cryptolepis sanguinolenta, as a lead towards new antimalarial agents is discussed. Several cryptolepine analogues have been synthesized that have promising in-vitro and in-vivo antimalarial activity. Studies on the antimalarial modes of action of these analogues indicate that they may have different or additional modes of action to the parent compound. Elucidation of the mode of action may facilitate the development of more potent antimalarial cryptolepine analogues. PMID:17637183

  6. Microbial studies of a selenium-contaminated mine site and potential for on-site remediation.

    PubMed

    Knotek-Smith, Heather M; Crawford, Don L; Möller, 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

  7. 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...

  8. Testing technologies and strategies for exploration in Australian Mars analogues: A review

    NASA Astrophysics Data System (ADS)

    West, Michael D.; D. A. Clarke, Jonathan; Laing, Jennifer H.; Willson, David; Waldie, James M. A.; Murphy, Guy M.; Thomas, Matilda; Mann, Graham A.

    2010-03-01

    Australia is an ideal testing ground in preparation for the robotic and human exploration of Mars. Numerous sites with landforms or processes analogous to those on Mars are present and the deserts of central Australia provide a range of locations for free-ranging Mars analogue mission simulations. The latest developments in testing technologies and strategies for exploration in Australian Mars analogues are reviewed. These include trials of analogue space suits based on mechanical counter pressure technology and the development of an analogue, crewed, pressurized rover for long-range exploration. Field science activities and instrumentation testing relevant to robotic and future crewed missions are discussed. Australian-led human factors research undertaken during expeditions to Mars analogue research stations and expeditions to Antarctica are also reviewed. Education and public outreach activities related to Mars analogue research in Australia are also detailed.

  9. sup 1 H and sup 31 P nuclear magnetic resonance and kinetic studies of the active site structure of chloroplast CF sub 1 ATP synthase

    SciTech Connect

    Devlin, C.C.; Grisham, C.M. )

    1990-07-03

    The interaction of nucleotides and nucleotide analogues and their complexes with Mn{sup 2+} bound to both the latent and dithiothreitol-activated CF{sub 1} ATP synthase has been examined by means of steady-state kinetics, water proton relaxation rate (PRR) measurements, and {sup 1}H and {sup 31}P nuclear relaxation measurements. Titration of both the latent and activated Mn{sup 2+}-CF{sub 1} complexes with ATP, ADP, P{sub i}, Co(NH{sub 3}){sub 4}ATP, Co(NH{sub 3}){sub 4}ADP, and Co(NH{sub 3}){sub 4}AMPPCP leads to increases in the water relaxation enhancement, consistent with enhanced metal binding and a high ternary complex enhancement. Steady-state kinetic studies are consistent with competitive inhibition of CF{sub 1} by Co(NH{sub 3}){sub 4}AMPPCP with respect to CaATP. {sup 1}H and {sup 31}P nuclear relaxation measurements in solutions of CF{sub 1} and Co(NH{sub 3}){sub 4}AMPPCP were used to determine the conformation of the bound substrate analogue and the arrangement with respect to this structure of high- and low-affinity sites for Mn{sup 2+}. The bound nucleotide analogue adopts a bent conformation, with the low-affinity sites for Mn{sup 2+}. The bound nucleotide analogue adopts a bent conformation, with the low-affinity Mn{sup 2+} site situated between the adenine and triphosphate moieties and the high-affinity metal site located on the far side of the triphosphate chain. The low-affinity metal forms a distorted inner-sphere complex with the {beta}-P and {gamma}-P of the substrate. The distances from Mn{sup 2+} to the triphosphate chain are too large for first coordination sphere complexes but are appropriate for second-sphere complexes involving, for example, intervening hydrogen-bonded water molecules or residues from the protein.

  10. 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.

  11. Design and synthesis of new fluconazole analogues.

    PubMed

    Pore, Vandana S; Agalave, Sandip G; Singh, Pratiksha; Shukla, Praveen K; Kumar, Vikash; Siddiqi, Mohammad I

    2015-06-21

    We have synthesized new fluconazole analogues containing two different 1,2,3-triazole units in the side chain. The synthesis of new amide analogues using a variety of acids is also described. All the compounds showed very good antifungal activity. A hemolysis study of the most active compounds 6e and 13j showed that both compounds did not cause any hemolysis at the dilutions tested. These compounds did not exhibit any toxicity to L929 cells at MIC and lower concentrations. In the docking study, the overall binding mode of 6e and 13j appeared to be reasonable and provided a good insight into the structural basis of inhibition of Candida albicans Cyp51 by these compounds. PMID:25975803

  12. 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.

  13. Studies of the potential genotoxic effects of furoxans: the case of CAS 1609 and of the water-soluble analogue of CHF 2363.

    PubMed

    Balbo, S; Lazzarato, L; Di Stilo, A; Fruttero, R; Lombaert, N; Kirsch-Volders, M

    2008-04-21

    CAS 1609 (compound 1) and CHF 2363 (compound 2) are two furoxan derivatives able to release nitric oxide (NO) under physiological conditions, and display typical NO-dependent vasodilator activity. The potential genotoxic effects of compound 1 and of the water-soluble analogue of CHF 2363 (compound 2a) were investigated. The results show that the two compounds induce genotoxic effects only at concentrations that significantly reduce cell viability. However, in the case of compound 1 this range of concentrations is one order of magnitude higher than the one leading to the beneficial effects, while in the case of compound 2a these ranges partially overlap. In both cases the release of NO plays a key role in the induction of the cytotoxic and genotoxic effects, since the non-NO-donating furazan analogues display a different toxicological profile, and since the effects were reduced in the presence of oxyhaemoglobin, a well-known NO-scavenger. PMID:18378101

  14. A photoaffinity analogue of discodermolide specifically labels a peptide in beta-tubulin.

    PubMed

    Xia, Shujun; Kenesky, Craig S; Rucker, Paul V; Smith, Amos B; Orr, George A; Horwitz, Susan Band

    2006-10-01

    Discodermolide is a potentially important antitumor agent that stabilizes microtubules and blocks cells at the G2/M phase of the cell cycle in a manner similar to that of Taxol. Discodermolide also has unique properties that distinguish it from Taxol. In the present study, photoaffinity-labeled discodermolide analogues are used to investigate their binding site in tubulin. Three photoaffinity-labeled discodermolide analogues were synthesized, all of which promoted microtubule polymerization in the absence of GTP. The analogue, C19-[4-(4-(3)H-benzoyl-phenyl)-carbamate]-discodermolide (C19-[3H]BPC-discodermolide), was selected for photolabeling studies because it had the highest extent of photoincorporation, approximately 1%, of the three radiolabeled discodermolide analogues explored. Although compared to discodermolide, C19-BPC-discodermolide revealed no hypernucleation effect in the in vitro microtubule polymerization assay, it was more cytotoxic than discodermolide, and, like discodermolide, demonstrated synergism with Taxol. These results suggest that the hypernucleation effect of discodermolide is not involved in its cytotoxic activity. Similar to discodermolide, C19-BPC-discodermolide can effectively displace [3H]Taxol from microtubules, but Taxol cannot effectively displace C19-[3H]BPC-discodermolide binding. Discodermolide can effectively displace C19-[3H]BPC-discodermolide binding. Formic acid hydrolysis, immunoprecipitation experiments, and subtilisin digestion indicate that C19-BPC-discodermolide labels amino acid residues 305-433 in beta-tubulin. Further digestion with Asp-N and Arg-C enzymes suggested that C19-BPC-discodermolide binds to amino acid residues, 355-359, in beta-tubulin, which is in close proximity to the Taxol binding site. Molecular modeling guided by the above evidence led to a putative binding model for C19-BPC-discodermolide in tubulin. PMID:17002277

  15. Cell-Cycle Analyses Using Thymidine Analogues in Fission Yeast

    PubMed Central

    Anda, Silje; Boye, Erik; Grallert, Beata

    2014-01-01

    Thymidine analogues are powerful tools when studying DNA synthesis including DNA replication, repair and recombination. However, these analogues have been reported to have severe effects on cell-cycle progression and growth, the very processes being investigated in most of these studies. Here, we have analyzed the effects of 5-ethynyl-2′-deoxyuridine (EdU) and 5-Chloro-2′-deoxyuridine (CldU) using fission yeast cells and optimized the labelling procedure. We find that both analogues affect the cell cycle, but that the effects can be mitigated by using the appropriate analogue, short pulses of labelling and low concentrations. In addition, we report sequential labelling of two consecutive S phases using EdU and 5-bromo-2′-deoxyuridine (BrdU). Furthermore, we show that detection of replicative DNA synthesis is much more sensitive than DNA-measurements by flow cytometry. PMID:24551125

  16. 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

  17. 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.

  18. Somatostatin Analogues for Receptor Targeted Photodynamic Therapy

    PubMed Central

    Kaščáková, Slávka; 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

  19. Farnesyl Diphosphate Analogues with Aryl Moieties are Efficient Alternate Substrates for Protein Farnesyltransferase

    PubMed Central

    Subramanian, Thangaiah; Pais, June E.; Liu, Suxia; Troutman, Jerry M.; Suzuki, Yuta; Subramanian, Karunai Leela; Fierke, Carol; Andres, Douglas A.; Spielmann, H. Peter

    2012-01-01

    Farnesylation is an important post-translational modification essential for proper localization and function of many proteins. Transfer of the farnesyl group from farnesyl diphosphate (FPP) to proteins is catalyzed by protein farnesyltransferase (FTase). We employed a library of FPP analogues with a range of aryl groups substituting for individual isoprene moieties to examine some of the structural and electronic properties of analogue transfer to peptide catalyzed by FTase. Analysis of steady-state kinetics for modification of peptide substrates revealed that the multiple turnover activity depends on the analogue structure. Analogues where the first isoprene is replaced by a benzyl group and an analogue where each isoprene is replaced by an aryl group are good substrates. In sharp contrast with the steady-state reaction, the single turnover rate constant for dansyl-GCVLS alkylation was found to be the same for all analogues, despite the increased chemical reactivity of the benzyl analogues and the increased steric bulk of other analogues. However, the single turnover rate constant for alkylation does depend on the Ca1a2X peptide sequence. These results suggest that the isoprenoid transition state conformation is preferred over the inactive E•FPP• Ca1a2X ternary complex conformation. Furthermore, these data suggest that the farnesyl binding site in the exit groove may be significantly more selective for the farnesyl diphosphate substrate than the active site binding pocket and therefore might be a useful site for design of novel inhibitors. PMID:22989235

  20. 76 FR 81959 - Notice of Proposed Information Collection: Comment Request; Homelessness Prevention Study Site...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-29

    ... Study Site Visits AGENCY: Office of the Chief Information Officer, HUD. ACTION: Notice. SUMMARY: The... 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...

  1. 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

  2. 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

  3. Substrate-induced conformational transition in human phenylalanine hydroxylase as studied by surface plasmon resonance analyses: the effect of terminal deletions, substrate analogues and phosphorylation.

    PubMed Central

    Stokka, Anne J; Flatmark, Torgeir

    2003-01-01

    The optical biosensor technique, based on the surface plasmon resonance (SPR) phenomenon, was used for real-time measurements of the slow conformational transition (isomerization) which occurs in human phenylalanine hydroxylase (hPAH) on the binding/dissociation of L-phenylalanine (L-Phe). The binding to immobilized tetrameric wt-hPAH resulted in a time-dependent increase in the refractive index (up to approx. 3 min at 25 degrees C) with an end point of approx. 75 RU (resonance units)/(pmol subunit/mm(2)). By contrast, the contribution of binding the substrate (165 Da) to its catalytic core enzyme [DeltaN(1-102)/DeltaC(428-452)-hPAH] was only approx. 2 RU/(pmol subunit/mm(2)). The binding isotherm for tetrameric and dimeric wt-hPAH revealed a [S](0.5)-value of 98+/-7 microM (h =1.0) and 158+/-11 microM, respectively, i.e. for the tetramer it is slightly lower than the value (145+/-5 microM) obtained for the co-operative binding (h =1.6+/-0.4) of L-Phe as measured by the change in intrinsic tryptophan fluorescence. The responses obtained by SPR and intrinsic tryptophan fluorescence are both considered to be related to the slow reversible conformational transition which occurs in the enzyme upon L-Phe binding, i.e. by the transition from a low-activity state ('T-state') to a relaxed high-activity state ('R-state') characteristic of this hysteretic enzyme, however, the two methods reflect different elements of the transition. Studies on the N- and C-terminal truncated forms revealed that the N-terminal regulatory domain (residues 1-117) plus catalytic domain (residues 118-411) were required for the full signal amplitude of the SPR response. Both the on- and off-rates for the conformational transition were biphasic, which is interpreted in terms of a difference in the energy barrier and the rate by which the two domains (catalytic and regulatory) undergo a conformational change. The substrate analogue 3-(2-thienyl)-L-alanine revealed an SPR response comparable with

  4. Design, synthesis, in silico and in vitro screening of 1,2,4-thiadiazole analogues as non-peptide inhibitors of beta-secretase.

    PubMed

    Gurjar, Archana S; Andrisano, Vincenza; Simone, Angela D; Velingkar, Vinay S

    2014-12-01

    Beta-secretase is the key enzyme involved in Alzheimer's disease thus; inhibition of the enzyme can lead to a potential anti-Alzheimer drug. In the search of an effective lead candidate, we have designed non-peptide inhibitor molecules based on amino aromatic heterocyclic motifs specifically, substituted 1,2,4-thiadiazole analogues. In silico modelling was employed to study interaction of the designed ligands in the enzyme active site using molecular docking approach as well as for Absorption, Distribution, Metabolism and Excretion studies. The synthesized analogues were pharmacologically screened using in vitro FRET technique. Overall results indicate that one of the analogues, compound 8 is the most promising one against beta secretase. PMID:25303313

  5. Geographic studies of pediatric cancer near hazardous waste sites.

    PubMed

    White, E; Aldrich, T E

    1999-01-01

    The incidence of pediatric (i.e., 0-17 y of age) cancers in North Carolina was studied for the years 1990-1993 in counties and ZIP-code areas that contained a National Priorities List hazardous-waste site. We analyzed the areas to determine if there was an excess incidence of cancer among the pediatric population. We used geographic information systems technology to address-match and map the cancer cases, along with county and National Priorities List hazardous waste-site location. No significantly elevated cancer incidence rates were found at the county level. Two ZIP-code areas had statistically significant elevations in cancer incidence (p < .05). Only 3 of the cancer cases we mapped resided within a 1.6-km (1 mi) buffer zone of a National Priorities List hazardous-waste site. These 3 cases were not in the ZIP-code areas that had increased incidence rates. The small numerators throughout the study led us to question the accuracy of the assessment of underlying rates. The general capabilities of the geographic information systems, as well as advantages and limitations of the system, are discussed. As an exploratory study, this study serves as a springboard into more in-depth environmental-health hypotheses and more-specific investigations of point sources of hazardous exposures. PMID:10634228

  6. 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

    (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

  7. Inhibition of ATP Synthase by Chlorinated Adenosine Analogue

    PubMed Central

    Chen, Lisa S.; Nowak, Billie J.; Ayres, Mary L.; Krett, Nancy L.; Rosen, Steven T.; Zhang, Shuxing; Gandhi, Varsha

    2009-01-01

    8-Chloroadenosine (8-Cl-Ado) is a ribonucleoside analogue that is currently in clinical trial for chronic lymphocytic leukemia. Based on the decline in cellular ATP pool following 8-Cl-Ado treatment, we hypothesized that 8-Cl-ADP and 8-Cl-ATP may interfere with ATP synthase, a key enzyme in ATP production. Mitochondrial ATP synthase is composed of two major parts; FO intermembrane base and F1 domain, containing α and β subunits. Crystal structures of both α and β subunits that bind to the substrate, ADP, are known in tight binding (αdpβdp) and loose binding (αtpβtp) states. Molecular docking demonstrated that 8-Cl-ADP/8-Cl-ATP occupied similar binding modes as ADP/ATP in the tight and loose binding sites of ATP synthase, respectively, suggesting that the chlorinated nucleotide metabolites may be functional substrates and inhibitors of the enzyme. The computational predictions were consistent with our whole cell biochemical results. Oligomycin, an established pharmacological inhibitor of ATP synthase, decreased both ATP and 8-Cl-ATP formation from exogenous substrates, however, did not affect pyrimidine nucleoside analogue triphosphate accumulation. Synthesis of ATP from ADP was inhibited in cells loaded with 8-Cl-ATP. These biochemical studies are in consent with the computational modeling; in the αtpβtp state 8-Cl-ATP occupies similar binding as ANP, a non-hydrolyzable ATP mimic that is a known inhibitor. Similarly, in the substrate binding site (αdpβdp) 8-Cl-ATP occupies a similar position as ATP mimic ADP-BeF3 −. Collectively, our current work suggests that 8-Cl-ADP may serve as a substrate and the 8-Cl-ATP may be an inhibitor of ATP synthase. PMID:19477165

  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

  9. 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.

  10. Antimicrobial activity of resveratrol analogues.

    PubMed

    Chalal, Malik; Klinguer, Agnès; 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

  11. Efficient total syntheses and biological activities of two teixobactin analogues.

    PubMed

    Parmar, Anish; Iyer, Abhishek; Vincent, Charlotte S; Van Lysebetten, Dorien; Prior, Stephen H; Madder, Annemieke; Taylor, Edward J; Singh, Ishwar

    2016-04-26

    The discovery of the new antibiotic teixobactin has been timely in the race for unearthing novel antibiotics wherein the emergence of drug resistant bacteria poses a serious threat worldwide. Herein, we present the total syntheses and biological activities of two teixobactin analogues. This approach is simple, efficient and has several advantages: it uses commercially available building blocks (except AllocHN-d-Thr-OH), has a single purification step and a good recovery (22%). By using this approach we have synthesised two teixobactin analogues and established that the d-amino acids are critical for the antimicrobial activity of these analogues. With continuing high expectations from teixobactin, this work can be regarded as a stepping stone towards an in depth study of teixobactin, its analogues and the quest for synthesising similar molecules. PMID:26984316

  12. From BPA to its analogues: Is it a safe journey?

    PubMed

    Usman, Afia; Ahmad, Masood

    2016-09-01

    Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful? PMID:27262103

  13. Structural analogues of diosgenyl saponins: synthesis and anticancer activity.

    PubMed

    Kaskiw, Matthew J; Tassotto, Mary Lynn; Mok, Mac; Tokar, Stacey L; Pycko, Roxanne; Th'ng, John; Jiang, Zi-Hua

    2009-11-15

    Saponins display various biological activities including anti-tumor activity. Recently intensive research has been focused on developing saponins for tumor therapies. The diosgenyl saponin dioscin is one of the most common steroidal saponins and exhibits potent anticancer activity in several human cancer cells through apoptosis-inducing pathways. In this paper, we describe the synthesis of several diosgenyl saponin analogues containing either a 2-amino-2-deoxy-beta-d-glucopyranosyl residue or an alpha-l-rhamnopyranosyl-(1-->4)-2-amino-2-deoxy-beta-d-glucopyranosyl residue with different acyl substituents on the amino group. The cytotoxic activity of these compounds was evaluated in MCF-7 breast cancer cells and HeLa cervical cancer cells. Structure-activity relationship studies show that the disaccharide saponin analogues are in general less active than their corresponding monosaccharide analogues. The incorporation of an aromatic nitro functionality into these saponin analogues does not exhibit significant effect on their cytotoxic activity. PMID:19819703

  14. Phosphonomethyl analogues of hexose phosphates.

    PubMed

    Webster, D; Jondorf, W R; Dixon, H B

    1976-05-01

    The analogue of fructose 1,6-bisphosphate in which the phosphate group, -O-PO3H2, on C-6 is replaced by the phosphonomethyl group, -CH2-PO3H2, was made enzymically from the corresponding analogue of 3-phosphoglycerate. It was a substrate for aldolase, which was used to form it, but not for fructose 1,6-bisphosphatase. It was hydrolysed chemically to yield the corresponding analogue of fructose 6-phosphate [i.e. 6-deoxy-6-(phosphonomethyl)-D-fructose, or, more strictly, 6,7-dideoxy-7-phosphono-D-arabino-2-heptulose]. This proved to be a substrate for the sequential actions of glucose 6-phosphate isomerase, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. Thus seven out of the nine enzymes of the glycolytic and pentose phosphate pathways so far tested catalyse the reactions of the phosphonomethyl isosteres of their substrates. PMID:7247

  15. 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

  16. Blood Loss Estimation Using Gauze Visual Analogue

    PubMed Central

    Ali Algadiem, Emran; Aleisa, Abdulmohsen Ali; Alsubaie, Huda Ibrahim; Buhlaiqah, Noora Radhi; Algadeeb, Jihad Bagir; Alsneini, Hussain Ali

    2016-01-01

    Background Estimating intraoperative blood loss can be a difficult task, especially when blood is mostly absorbed by gauze. In this study, we have provided an improved method for estimating blood absorbed by gauze. Objectives To develop a guide to estimate blood absorbed by surgical gauze. Materials and Methods A clinical experiment was conducted using aspirated blood and common surgical gauze to create a realistic amount of absorbed blood in the gauze. Different percentages of staining were photographed to create an analogue for the amount of blood absorbed by the gauze. Results A visual analogue scale was created to aid the estimation of blood absorbed by the gauze. The absorptive capacity of different gauze sizes was determined when the gauze was dripping with blood. The amount of reduction in absorption was also determined when the gauze was wetted with normal saline before use. Conclusions The use of a visual analogue may increase the accuracy of blood loss estimation and decrease the consequences related to over or underestimation of blood loss. PMID:27626017

  17. Analogue modelling of syntectonic leucosomes in migmatitic schists

    NASA Astrophysics Data System (ADS)

    Druguet, Elena; Carreras, Jordi

    2006-10-01

    Migmatites from the Cap de Creus tectonometamorphic belt display a wide variety of structures, from those formed when the leucosomes were melt-bearing, to those developed during solid-state deformation. The observed field structures have been modelled by means of analogue experiments. The materials used in the models are layered plasticine as a schist analogue, and chocolate as analogue of the crystallizing leucosome. A model for the development of syntectonic migmatites is proposed in which initial melt-bearing patches, preferentially formed within fertile pelitic layers, progressively evolve towards lens-shaped veins. Furthermore, heterogeneous deformation of anisotropic metasediments facilitates formation of extensional sites for further melt accumulation and transport. Melt crystallization implies a rapid increase in effective viscosity of leucosomes producing a reversal in competence contrast with respect to the enclosing schists. During the whole process, deformation localizes around crystallizing veins, giving rise to different and contrasting structures for melt-bearing and for solid-state stages.

  18. 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

  19. 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.

  20. Radionuclide migration studies at the Nevada Test Site

    SciTech Connect

    Thompson, J.L.

    1989-12-01

    The United States government routinely tests nuclear devices at the Nevada Test Site (NTS) in southern Nevada. A significant amount of radioactive material exists underground at the NTS with no containers or engineered barriers to inhibit its subsequent migration. The Department of Energy has sponsored for many years a research program on radionuclide movement in the geologic media at this location. Goals of this research program are to measure the extent of movement of radionuclides away from underground explosion sites and to determine the mechanisms by which such movement occurs. This program has acquired significance in another aspect of nuclear waste management because of the Yucca Mountain Project. Yucca Mountain at the NTS is being intensively studied as the possible site for a mined repository for high level nuclear waste. The NTS provides a unique setting for field studies concerning radionuclide migration; there is the potential for greatly increasing our knowledge of the behavior of radioactive materials in volcanogenic media. This review summarizes some of the significant findings made under this research program at the NTS and identifies reports in which the details of the research may be found. 36 refs., 4 figs.

  1. Condensed matter analogues of cosmology

    NASA Astrophysics Data System (ADS)

    Kibble, Tom; Srivastava, Ajit

    2013-10-01

    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

  2. Computational studies of Bronsted acid sites in zeolites

    SciTech Connect

    Curtiss, L.A.; Iton, L.E.; Zygmunt, S.A.

    1995-01-01

    The authors have performed high-level ab initio calculations using both Hartree-Fock (HF) and Moller-Plesset perturbation theory (MP2) to study the geometry and energetics of the adsorption complex involving H{sub 2}O and the Bronsted acid site in the zeolite H-ZSM-5. In these calculations, which use aluminosilicate cluster models for the zeolite framework with as many a 28 T atoms (T = Si, Al), we included geometry optimization in the local vicinity of the acid site at the HF/6-31G(d) level of theory, and have calculated corrections for zero-point energies, extensions for zero-point energies, extensions to higher basis sets, and the influence of electron correlation. Results for the adsorption energy and geometry of this complex are reported and compared with previous theoretical and experimental values.

  3. 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.

  4. Organobase catalyzed 1,4-conjugate addition of 4-hydroxycoumarin on chalcones: Synthesis, NMR and single-crystal X-ray diffraction studies of novel warfarin analogues

    NASA Astrophysics Data System (ADS)

    Talhi, Oualid; Fernandes, José A.; Pinto, Diana C. G. A.; Almeida Paz, Filipe A.; Silva, Artur M. S.

    2015-08-01

    The synthesis of a new series of warfarin analogues by convenient organobase catalyzed 1,4-conjugate addition of 4-hydroxycoumarin to chalcone derivatives is described. 1H NMR spectroscopy evidenced the presence of a predominant acyclic open-form together with the cyclic hemiketal tautomers of the resulting Michael adducts. The acyclic open-form has been unequivocally proved by single-crystal X-ray diffraction analysis. The use of the B ring ortho-hydroxychalcone synthons in this reaction has led to a diastereoselective synthesis of warfarin bicyclo[3.3.1]nonane ketal derivatives.

  5. Tritium migration studies at the Nevada Test Site

    SciTech Connect

    Schulz, R.K.; Romney, E.M.; Fujii, L.M.; Greger, P.D. ); Kendall, E.W.; Hunter, R.B. )

    1991-08-01

    Emanation of tritium from waste containers is a commonly known phenomenon. Release of tritium from buried waste packages was anticipated, therefore a research program was developed to study both the rate of tritium release from buried containers and subsequent migration of tritium through soil. Migration of tritium away from low level radioactive wastes buried in Area 5 of the Nevada Test Site was studied. Four distinct disposal events were investigated. The oldest burial event studied was a 1976 emplacement of 3.5 million curies of tritium in a shallow land burial trench. Tritium transport to the atmosphere by plant transpiration was determined to have risen sharply with the passage of time, and is now occurring at the rate of about 6 curies per year. The tritium being released from this waste has not resulted in elevated tritium levels in the urine of people working directly on the trench cap. Air samplers placed around the perimeter of the Area 5 site show no higher tritium levels than the Nevada Test Site in general. In another event, 248 thousand curies of tritium was disposed of in an overpack emplaced 6 meters below the floor of a low-level waste disposal pit. Measurement of the emanation rate of tritium out of 55 gallon drums to the overpack was studied, and an annual doubling of the emanation rate over a seven year period was found. No evidence of significant migration of tritium away from the overpack was found. In a third study, upward tritium migration in the soil was observed in a greater confinement disposal test. The movement was suspected largely to be the result of experimental anomalies and heat generated by other radionuclides present in the waste. Releases of tritium to the atmosphere were found to be insignificant. The fourth event consisted of burial of 2.2 million curies of tritium in a greater confinement disposal operation. No significant migration was found. 4 refs., 4 figs., 6 tabs.

  6. [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.

  7. 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

  8. 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

    2016-07-01

    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

  9. Habitability & Astrobiology Research in Mars Terrestrial Analogues

    NASA Astrophysics Data System (ADS)

    Foing, Bernard

    2014-05-01

    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

  10. A hydraulic tomography approach coupling travel time inversion with steady shape analysis based on aquifer analogue study in coarsely clastic fluvial glacial deposit

    NASA Astrophysics Data System (ADS)

    Hu, R.; Brauchler, R.; Herold, M.; Bayer, P.; Sauter, M.

    2009-04-01

    the hydraulic gradient does not. By this trick, transient data can be analyzed with the computational efficiency of a steady state model, which proceeds hundreds of times faster than transient models. Finally, a specific storage distribution can be calculated from the diffusivity and hydraulic conductivity reconstructions derived from travel time and steady shape inversion. The groundwork of this study is the aquifer-analogue study from BAYER (1999), in which six parallel profiles of a natural sedimentary body with a size of 16m x 10m x 7m were mapped in high resolution with respect to structural and hydraulic parameters. Based on these results and using geostatistical interpolation methods, MAJI (2005) designed a three dimensional hydraulic model with a resolution of 5cm x 5cm x 5cm. This hydraulic model was used to simulate a large number of short term pumping tests in a tomographical array. The high resolution parameter reconstructions gained from the inversion of simulated pumping test data demonstrate that the proposed inversion scheme allows reconstructing the individual architectural elements and their hydraulic properties with a higher resolution compared to conventional hydraulic and geological investigation methods. Bayer P (1999) Aquifer-Analog-Studium in grobklastischen braided river Ablagerungen: Sedimentäre/hydrogeologische Wandkartierung und Kalibrierung von Georadarmessungen, Diplomkartierung am Lehrstuhl für Angewandte Geologie, Universität Tübingen, 25 pp. Maji, R. (2005) Conditional Stochastic Modelling of DNAPL Migration and Dissolution in a High-resolution Aquifer Analog, Ph.D. thesis at the University of Waterloo, 187 pp.

  11. The Violence Prevention Community Meeting: A Multi-Site Study

    PubMed Central

    Lanza, Marilyn; Ridenour, Marilyn; Hendricks, Scott; Rierdan, Jill; Zeiss, Robert; Schmidt, Satu; Lovelace, Jeff; Amandus, Harlan

    2016-01-01

    Objective The Violence Prevention Community Meeting (VPCM) is a specialized form of community meeting in which avoiding violence and promoting non-violent problem solving and interpersonal civility are focal points. A nationwide study to assess the VPCM as an effective intervention to reduce workplace violence was undertaken. Participants Seven acute locked psychiatric units of the Veterans Health Administration (VHA) throughout the United States participated in the study. Methods All patients and all staff on the seven in-patient locked psychiatry units participated in the intervention (VPCM) or as a control (treatment as usual). The study was 21 weeks at each site. The three time periods were pre-treatment weeks 1 – 3, treatment weeks 4 – 18, and post-treatment weeks 19 – 21. The VPCM was conducted during the treatment weeks. Results Overall rates of aggression declined by 0.6% (95%CI: −5.6%, 6.5%; nonsignificant) per week in the intervention hospitals and by 5.1% (95%CI: 0.4%, 9.6%; significant) per week for the control hospitals. Conclusions Aggression decreased for both the intervention and control hospitals which could be due to enrollment in a research study and thus being more aware of their ability to address workplace violence at their site. PMID:27256945

  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. 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.

  14. Web Site Accessibility: A Study of Six Genres.

    ERIC Educational Resources Information Center

    Jackson-Sanborn, Emily; Odess-Harnish, Kerri; Warren, Nikki

    2002-01-01

    Examines the accessibility of six categories of Web sites using the evaluation software Bobby. Discusses universal access for users with disabilities; application of the Americans with Disabilities Act and Rehabilitation Act Amendments of 1998; government sites versus commercial sites; and Web site design. (Author/LRW)

  15. LH-RH analogues in the treatment of young women with early breast cancer: long-term follow-up of a phase II study.

    PubMed

    Recchia, Francesco; Necozione, Stefano; Bratta, Massimo; Rosselli, Michele; Guerriero, Gabriele; Rea, Silvio

    2015-03-01

    To prevent premature ovarian failure (POF), high-risk, premenopausal women with early breast cancer were given a luteinizing-hormone releasing hormone (LH-RH) analogue during adjuvant chemotherapy. After an adriamycin-based regimen, patients received radiation therapy concomitant with cyclophosphamide, methotrexate and 5-fluorouracil. An aromatase inhibitor was given to patients positive for the estrogen receptor (ER+). The median age was 43 years (range, 26-45). Among 200 consecutive patients, 46% had no axillary node, and 54% had a mean of 5.4 positive nodes (range, 1-25); 56% were ER+, 44% were estrogen receptor negative (ER-), 13% were triple negative, and 20 had tumors positive for the oncogene, c-erb-B2 (identified with fluorescent in situ hybridization). After a median follow-up of 105 months (range, 65-180), no patient under 40 years old exhibited POF, while 44% of patients over 40 years old exhibited POF. Eight pregnancies were recorded: 7 at term and 1 voluntary interruption. The 10-year disease-free survival and overall survival rates were 85 and 91%, respectively. These data showed that, in premenopausal patients with early breast cancer, the addition of an LH-RH analogue to adjuvant chemotherapy was well tolerated, prevented POF, and was associated with excellent disease-free survival and overall survival rates. PMID:25572674

  16. A comparative autoradiography study in post mortem whole hemisphere human brain slices taken from Alzheimer patients and age-matched controls using two radiolabelled DAA1106 analogues with high affinity to the peripheral benzodiazepine receptor (PBR) system.

    PubMed

    Gulyás, Balázs; Makkai, Boglárka; Kása, Péter; Gulya, Károly; Bakota, Lidia; Várszegi, Szilvia; Beliczai, Zsuzsa; Andersson, Jan; Csiba, László; Thiele, Andrea; Dyrks, Thomas; Suhara, Tetsua; Suzuki, Kazutoshi; Higuchi, Makato; Halldin, Christer

    2009-01-01

    The binding of two radiolabelled analogues (N-(5-[125I]Iodo-2-phenoxyphenyl)-N-(2,5-dimethoxybenzyl)acetamide ([125I]desfluoro-DAA1106) and N-(5-[125I]Fluoro-2-phenoxyphenyl)-N-(2-[125I]Iodo-5-methoxybenzyl)acetamide ([125I]desmethoxy-DAA1106) of the peripheral benzodiazepine receptor (PBR) (or TSPO, 18kDa translocator protein) ligand DAA1106 was examined by in vitro autoradiography on human post mortem whole hemisphere brain slices obtained from Alzheimer's disease (AD) patients and age-matched controls. Both [(125)I]desfluoro-IDAA1106 and [(125)I]desmethoxy-IDAA1106 were effectively binding to various brain structures. The binding could be blocked by the unlabelled ligand as well as by other PBR specific ligands. With both radiolabelled compounds, the binding showed regional inhomogeneity and the specific binding values proved to be the highest in the hippocampus, temporal and parietal cortex, the basal ganglia and thalamus in the AD brains. Compared with age-matched control brains, specific binding in several brain structures (temporal and parietal lobes, thalamus and white matter) in Alzheimer brains was significantly higher, indicating that the radioligands can effectively label-activated microglia and the up-regulated PBR/TSPO system in AD. Complementary immunohistochemical studies demonstrated reactive microglia activation in the AD brain tissue and indicated that increased ligand binding coincides with increased regional microglia activation due to neuroinflammation. These investigations yield further support to the PBR/TSPO binding capacity of DAA1106 in human brain tissue, demonstrate the effective usefulness of its radio-iodinated analogues as imaging biomarkers in post mortem human studies, and indicate that its radiolabelled analogues, labelled with short half-time bioisotopes, can serve as prospective in vivo imaging biomarkers of activated microglia and the up-regulated PBR/TSPO system in the human brain. PMID:18984021

  17. 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

  18. Design, synthesis, and biological evaluation of dibromotyrosine analogues inspired by marine natural products as inhibitors of human prostate cancer proliferation, invasion, and migration.

    PubMed

    Sallam, Asmaa A; Ramasahayam, Sindhura; Meyer, Sharon A; El Sayed, Khalid A

    2010-11-01

    Bioactive secondary metabolites originating from dibromotyrosine are common in marine sponges, such as sponges of the Aplysina species. Verongiaquinol (1), 3,5-dibromo-1-hydroxy-4-oxocyclohexa-2,5-diene-1-acetamide, and aeroplysinin-1 are examples of such bioactive metabolites. Previous studies have shown the potent antimicrobial as well as cytotoxic properties of verongiaquinol and the anti-angiogenic activity of aeroplysinin-1. The work presented herein shows the design and synthesis of dibromotyrosine-inspired phenolic ester and ether analogues with anti-angiogenic, anti-proliferative and anti-migratory properties and negligible cytotoxicity. Several analogues were synthesized based on docking experiments in the ATP binding site of VEGFR2 and their anti-angiogenic potential and ability to inhibit angiogenesis and prostate cancer proliferation, migration and invasion were evaluated using the chick chorioallantoic membrane (CAM) assay, MTT, wound-healing, and Cultrex® BME cell invasion assay models, respectively. Analogues with high docking scores showed promising anti-angiogenic activity in the CAM assay. In general, ester analogues (5, 6, and 8-10) proved to be of higher anti-migratory activity whereas ether analogues (11-14) showed better anti-proliferative activity. These results demonstrate the potential of dibromotyrosines as promising inhibitory scaffolds for the control of metastatic prostate cancer proliferation and migration. PMID:20884214

  19. Digitoxin Analogues with Improved Anticytomegalovirus Activity

    PubMed Central

    2014-01-01

    Cardiac glycosides are potent inhibitors of cancer cell growth and possess antiviral activities at nanomolar concentrations. In this study we evaluated the anticytomegalovirus (CMV) activity of digitoxin and several of its analogues. We show that sugar type and sugar length attached to the steroid core structure affects its anticytomegalovirus activity. Structure–activity relationship (SAR) studies identified the l-sugar containing cardiac glycosides as having improved anti-CMV activity and may lead to better understanding of how these compounds inhibit CMV replication. PMID:24900847

  20. 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

  1. 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

  2. The metabolic and mitogenic properties of basal insulin analogues

    PubMed Central

    2013-01-01

    Context Retrospective, observational studies have reported an association between diabetes treatment with insulin and a higher incidence of cancer. Objective Overview the literature for in vitro and in vivo studies of the metabolic and mitogenic properties of basal insulin analogues and assess the implications for clinical use. Methods Relevant studies were identified through PubMed and congress abstract database searches; data on metabolic and mitogenic signalling in relation to insulin treatment of diabetes are included in this review. Results The balance of evidence shows that although some analogues have demonstrated mitogenic potency in some in vitro studies in cancer cell lines, these findings do not translate to the in vivo setting in animals or to the clinical setting in humans. Conclusions The current consensus is that there is no clinical or in vivo evidence to indicate that any commercially available insulin analogue has carcinogenic effects. Large-scale, prospective clinical and observational studies will further establish any potential link. PMID:23373726

  3. The action of structural analogues of ethidium bromide on the mitochondrial genome of yeast.

    PubMed

    Hall, R M; Mattick, J S; Nagley, P; Cobon, G S; Eastwood, F W; Linnane, A W

    1977-12-01

    We have studied the effects on the yeast mitochondrial genome of four analogues of ethidium bromide, in which the phenyl moieyt has been replaced by linear alkyl chains of lengths varying from seven to fifteen carbon atoms. These analogues are more efficient than ethidium bromide in inducing petite mutants in Saccharomyces cervisiae. The drugs also cause a loss of mtDNA from the cells in vivo; however these analogues are in fact less effective inhibitors of mitochondrial DNA replication per se, as shown by direct in vitro studies. It is concluded that these analogues are more efficient than ethidium bromide in causing the fragmentation of mitochondrial DNA in S. cervisiae. PMID:339057

  4. 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 260 nm, 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

  5. Synthesis and proteinase inhibitory properties of diphenyl phosphonate analogues of aspartic and glutamic acids.

    PubMed

    Hamilton, R; Walker, B; Walker, B J

    1998-07-01

    The synthesis of diphenyl phosphonate analogues of aspartic and glutamic acid, and their inhibitory activity against S. aureus V8 protease and granzyme B, is described. The study has revealed difficulties with protecting group compatibility in the synthesis of these analogues. Two analogues, Acetyl. AspP (OPh)2 and Acetyl.GluP (OPh)2 were found to function as irreversible inactivators of V8 proteinase, yet exhibit no activity against granzyme B. PMID:9873408

  6. 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...

  7. Spectral analysis of lunar analogue samples

    NASA Astrophysics Data System (ADS)

    Offringa, Marloes; Foing, Bernard

    2016-04-01

    Analyses of samples derived from terrestrial analogue sites are used to study lunar processes in their geological context (Foing, Stoker, Ehrenfreund, 2011). For this study samples from the volcanic region of the Eifel, Germany collected during field campaigns (Foing et al., 2010), are analyzed with a variety of spectrometers. The aim is to obtain a database of analyzed samples that could be used as a reference for future in situ measurements. Equipment used in the laboratory consists of a Fourier Transform Infrared (FTIR) spectrometer, an X-Ray Fluorescence (XRF) spectrometer, a Raman laser spectrometer, as well as UV-VIS and NIR reflectance spectrometers. The Raman, UV-VIS and NIR are also used in combination with the EXoGeoLab mock-up lander during field campaigns (Foing, Stoker, Ehrenfreund, 2011). Calibration of the UV-VIS and NIR reflectance spectrometers is the main focus of this research in order to obtain the clearest spectra. The calibration of the UV-VIS and NIR reflectance spectrometers requires the use of a good light source as well as suitable optical fibers to create a signal that covers the widest range in wavelengths available. To eliminate noise towards the edges of this range, multiple measurements are averaged and data is processed by dividing the signal by reference spectra. Calibration of the devices by creating a new dark and reference spectra has to take place after every sample measurement. In this way we take into account changes that occur in the signal due to the eating of the devices during the measurements. Moreover, the integration time is adjusted to obtain a clear signal without leading to oversaturation in the reflectance spectrum. The typical integration times for the UV-VIS reflectance spectrometer vary between 1 - 18 s, depending on the amount of daylight during experiments. For the NIR reflectance spectrometer the integration time resulting in the best signals is approximately 150 ms in combination with a broad spectrum light

  8. Binding-induced fluorescence of serotonin transporter ligands: A spectroscopic and structural study of 4-(4-(dimethylamino)phenyl)-1-methylpyridinium (APP(+)) and APP(+) analogues.

    PubMed

    Wilson, James N; Ladefoged, Lucy Kate; Babinchak, W Michael; Schiøtt, Birgit

    2014-04-16

    The binding-induced fluorescence of 4-(4-(dimethylamino)-phenyl)-1-methylpyridinium (APP(+)) and two new serotonin transporter (SERT)-binding fluorescent analogues, 1-butyl-4-[4-(1-dimethylamino)phenyl]-pyridinium bromide (BPP(+)) and 1-methyl-4-[4-(1-piperidinyl)phenyl]-pyridinium (PPP(+)), has been investigated. Optical spectroscopy reveals that these probes are highly sensitive to their chemical microenvironment, responding to variations in polarity with changes in transition energies and responding to changes in viscosity or rotational freedom with emission enhancements. Molecular docking calculations reveal that the probes are able to access the nonpolar and conformationally restrictive binding pocket of SERT. As a result, the probes exhibit previously not identified binding-induced turn-on emission that is spectroscopically distinct from dyes that have accumulated intracellularly. Thus, binding and transport dynamics of SERT ligands can be resolved both spatially and spectroscopically. PMID:24460204

  9. Binding-Induced Fluorescence of Serotonin Transporter Ligands: A Spectroscopic and Structural Study of 4-(4-(Dimethylamino)phenyl)-1-methylpyridinium (APP+) and APP+ Analogues

    PubMed Central

    2014-01-01

    The binding-induced fluorescence of 4-(4-(dimethylamino)-phenyl)-1-methylpyridinium (APP+) and two new serotonin transporter (SERT)-binding fluorescent analogues, 1-butyl-4-[4-(1-dimethylamino)phenyl]-pyridinium bromide (BPP+) and 1-methyl-4-[4-(1-piperidinyl)phenyl]-pyridinium (PPP+), has been investigated. Optical spectroscopy reveals that these probes are highly sensitive to their chemical microenvironment, responding to variations in polarity with changes in transition energies and responding to changes in viscosity or rotational freedom with emission enhancements. Molecular docking calculations reveal that the probes are able to access the nonpolar and conformationally restrictive binding pocket of SERT. As a result, the probes exhibit previously not identified binding-induced turn-on emission that is spectroscopically distinct from dyes that have accumulated intracellularly. Thus, binding and transport dynamics of SERT ligands can be resolved both spatially and spectroscopically. PMID:24460204

  10. Incorporation of tryptophan analogues into the lantibiotic nisin.

    PubMed

    Zhou, Liang; Shao, Jinfeng; Li, Qian; van Heel, Auke J; de Vries, Marcel P; Broos, Jaap; Kuipers, Oscar P

    2016-05-01

    Lantibiotics are posttranslationally modified peptides with efficient inhibitory activity against various Gram-positive bacteria. In addition to the original modifications, incorporation of non-canonical amino acids can render new properties and functions to lantibiotics. Nisin is the most studied lantibiotic and contains no tryptophan residues. In this study, a system was constructed to incorporate tryptophan analogues into nisin, which included the modification machinery (NisBTC) and the overexpression of tryptophanyl-tRNA synthetase (TrpRS). Tryptophan and three different tryptophan analogues (5-fluoroTrp (5FW), 5-hydroxyTrp (5HW) and 5-methylTrp (5MeW)) were successfully incorporated at four different positions of nisin (I1W, I4W, M17W and V32W). The incorporation efficiency of tryptophan analogues into mutants I1W, M17W and V32W was over 97 %, while the mutant I4W showed relatively low incorporation efficiency (69-93 %). The variants with 5FW showed relatively higher production yield, while 5MeW-containing variants showed the lowest yield. The dehydration efficiency of serines or threonines was affected by the tryptophan mutants of I4W and V32W. The affinity of the peptides for the cation-ion exchange and reverse phase chromatography columns was significantly reduced when 5HW was incorporated. The antimicrobial activity of IIW and its 5FW analogue both decreased two times compared to that of nisin, while that of its 5HW analogue decreased four times. The 5FW analogue of I4W also showed two times decreased activity than nisin. However, the mutant M17W and its 5HW analogue both showed 32 times reduced activity relative to that of nisin. PMID:26872656

  11. 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.

  12. 11-TRIFLUOROMETHYL-PHENYLDIAZIRINYL NEUROSTEROID ANALOGUES: POTENT GENERAL ANESTHETICS AND PHOTOLABELING REAGENTS FOR GABAA RECEPTORS

    PubMed Central

    Chen, Zi-Wei; Wang, Cunde; Krishnan, Kathiresan; Manion, Brad D.; Hastings, Randy; Bracamontes, John; Taylor, Amanda; Eaton, Megan M.; Zorumski, Charles F.; Steinbach, Joseph H.; Akk, Gustav; Mennerick, Steven; Covey, Douglas F.; Evers, Alex S.

    2014-01-01

    Rationale While neurosteroids are well-described positive allosteric modulators of GABAA receptors, the binding sites that mediate these actions have not been definitively identified. Objectives To synthesize neurosteroid analogue photolabeling reagents that closely mimic the biological effects of endogenous neurosteroids and have photochemical properties that will facilitate their use as tools for identifying the binding sites for neurosteroids on GABAA receptors. Results Two neurosteroid analogues containing a trifluromethyl-phenyldiazirine group linked to the steroid C11 position were synthesized. These reagents, CW12 and CW14, are analogues of allopregnanolone (5α-reduced steroid) and pregnanolone (5β-reduced steroid), respectively. Both reagents were shown to have favorable photochemical properties with efficient insertion into the C–H bonds of cyclohexane. They also effectively replicated the actions of allopregnanolone and pregnanolone on GABAA receptor functions: they potentiated GABA-induced currents in Xenopus laevis oocytes transfected with α1β2γ2L subunits, modulated [35S]t-butylbicyclophosphorothionate binding in rat brain membranes and were effective anesthetics in Xenopus tadpoles. Studies using [3H]CW12 and [3H]CW14 showed that these reagents covalently label GABAA receptors in both rat brain membranes and in TSA cells expressing either α1 and β2 subunits or β3 subunits of the GABAA receptor. Photolabeling of rat brain GABAA receptors was shown to be both concentration-dependent and stereospecific. Conclusions CW12 and CW14 have the appropriate photochemical and pharmacological properties for use as photolabeling reagents to identify specific neurosteroid binding sites on GABAA receptors. PMID:24756762

  13. A Cross-site Qualitative Study of Physician Order Entry

    PubMed Central

    Ash, Joan S.; Gorman, Paul N.; Lavelle, Mary; Payne, Thomas H.; Massaro, Thomas A.; Frantz, Gerri L.; Lyman, Jason A.

    2003-01-01

    Objective: To describe the perceptions of diverse professionals involved in computerized physician order entry (POE) at sites where POE has been successfully implemented and to identify differences between teaching and nonteaching hospitals. Design: A multidisciplinary team used observation, focus groups, and interviews with clinical, administrative, and information technology staff to gather data at three sites. Field notes and transcripts were coded using an inductive approach to identify patterns and themes in the data. Measurements: Patterns and themes concerning perceptions of POE were identified. Results: Four high-level themes were identified: (1) organizational issues such as collaboration, pride, culture, power, politics, and control; (2) clinical and professional issues involving adaptation to local practices, preferences, and policies; (3) technical/implementation issues, including usability, time, training and support; and (4) issues related to the organization of information and knowledge, such as system rigidity and integration. Relevant differences between teaching and nonteaching hospitals include extent of collaboration, staff longevity, and organizational missions. Conclusion: An organizational culture characterized by collaboration and trust and an ongoing process that includes active clinician engagement in adaptation of the technology were important elements in successful implementation of physician order entry at the institutions that we studied. PMID:12595408

  14. 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.

  15. 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.

  16. 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.

  17. The Eastern Lau Basin Integrated Studies Site (ISS)

    NASA Astrophysics Data System (ADS)

    Wiens, D.

    2003-12-01

    A new venue for Ridge 2000 (R2K) Integrated Studies, the Eastern Lau Spreading Center (ELSC) adds the element of a spreading center in a back-arc basin to the R2K program. The ELSC, located in the western Pacific near Tonga, is a 390 km-long first-order ridge segment that displays a broad range of effects of the back-arc environment. At its southern end it is only 40 km from the Tonga arc volcanic front and is propagating southward into a back-arc rift. At its northern end it is 100 km from the volcanic front and terminates at a large, non-transform offset. The ELSC displays substantial and systematic changes in multiple parameters: spreading rate, magma source and lava chemistry, axial depth and morphology, melt lens characteristics, and crustal thickness and structure. A main focus of the work at the ELSC is to determine how changes in these forcing functions affect key parameters such as magma source composition, crustal structure, and characteristics of hydrothermal venting such as temperature, chemistry, and faunal composition and abundance. Prior reconnaissance investigation shows that these hydrothermal field characteristics also vary within the southernmost segments, and show distinct differences compared with well-studied mid-ocean ridge sites. Four R2K cruises are planned for the ELSC in 2004. The first cruise (PI: Martinez) will investigate interrelationships among crustal structure, volcanism, and hydrothermal activity using deep tow, CTD's, and Tow-Yo. A second cruise (PI: Langmuir) will focus on petrological and water column properties using dredging, CTD's and ABE. The next cruise (PI: Tivey) will provide an initial characterization of vent fields, fluid chemistry, mineralogy, and biodiversity using Jason II and net tows, and a final cruise (PI: Childress) will investigate community ecology using Jason II. An additional study (PI: Thurnherr) will deploy autonomous floats to investigate hydrothermal plume circulation and dispersal . An overview of the

  18. Tritium migration studies at the Nevada Test Site

    SciTech Connect

    Schulz, R.K.; Weaver, M.O.

    1993-05-01

    Emanation of tritium from waste containers is a commonly known phenomenon. Release of tritium from buried waste packages was anticipated; therefore, a research program was developed to study both the rate of tritium release from buried containers and subsequent migration of tritium through soil. Migration of tritium away from low-level radioactive wastes buried in Area 5 of the Nevada Test Site was studied. Four distinct disposal events were investigated. The oldest burial event studied was a 1976 emplacement of 3.5 million curies of tritium in a shallow land burial trench. In another event, 248 thousand curies of tritium was disposed of in an overpack emplaced 6 m below the floor of a low-level waste disposal pit. Measurement of the emanation rate of tritium out of 55 gallon drums to the overpack was studied, and an annual doubling of the emanation rate over a seven year period, ending in 1990, was found. In a third study, upward tritium migration in the soil, resulting in releases in the atmosphere were observed in a greater confinement disposal test. Releases of tritium to the atmosphere were found to be insignificant. The fourth event consisted of burial of 2.2 million curies of tritium in a greater confinement disposal operation. Emanation of tritium from the buried containers has been increasing since disposal, but no significant migration was found four years following backfilling of the disposal hole.

  19. 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

  20. 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

  1. Hydrological studies of a tropical reservoir site, Nigeria

    NASA Astrophysics Data System (ADS)

    Alabo, E. H.

    The study area, a potential reservoir site, is situated in the tropical belt and was chosen by an earlier worker after geophysical and geotechnical investigations. The area is underlain by the Precambrian Basement Complex. The aim of the present study is to determine whether the site could provide adequate water for a proposed reservoir. The climate of the area is of marked wet and dry seasons, with a tropical rainforest-type of vegetation. The catchment area is about 744.40 km 2. The population of the communities is presently about 528,169 (1963 census), and it is estimated to be approximately 600,000 by the year 2005. This paper provides an estimation of the water need of the expected population. Owing to scanty hydrological data for the Owena River, its expected discharge was extrapolated by comparison with the neighbouring Shasha River. From calculations, the following results were obtained: (1) expected available water within the catchment area, 256.75 × 10 6 m 3 per year; (2) expected reservoir capacity, 13.73 × 10 6 m 3; (3) average discharge of the Owena River at the investigation point, 2.91 m 3 s -1 over a period of one year; (4) expected water need of the communities (of 600,000 persons), 4.38 × 10 6 m 3 per year, about 0.5 m 3 s -1. On the basis of the expected excess water over demand, losses through evapo-transpiration and seepage, as well as the possible availability of building materials within the area, it is recommended that the creation of an earth dam reservoir is feasible.

  2. 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.

  3. Phosphonate analogue substrates for enolase.

    PubMed

    Anderson, V E; Cleland, W W

    1990-11-20

    Phosphonate analogues in which the bridge between C-2 and phosphorus is a CH2 group are slow substrates for yeast enolase. The pH variation of the kinetic parameters for the methylene analogue of 2-phosphoglycerate suggests that the substrate binds as a dianion and that Mg2+ can bind subsequently only if a metal ligand and the catalytic base are unprotonated. Primary deuterium isotope effects of 4-8 on V/KMg, but ones of only 1.15-1.32 on V for dehydration, show that proton removal to give the carbanion intermediate largely limits V/KMg and that a slow step follows which largely limits V (presumably carbanion breakdown). Since there is a D2O solvent isotope effect on V for the reverse reaction of 5, but not an appreciable one on the forward reaction, it appears that the slow rates with phosphonate analogues result from the fact that the carbanion intermediate is more stable than that formed from the normal substrates, and its reaction in both directions limits V. Increased stability as a result of replacement of oxygen by carbon at C-2 of the carbanion is the expected chemical behavior. PMID:2271661

  4. The Relationship Between Water Structure and Blood Compatibility in Poly(2-methoxyethyl Acrylate) (PMEA) Analogues.

    PubMed

    Sato, Kazuhiro; Kobayashi, Shingo; Kusakari, Miho; Watahiki, Shogo; Oikawa, Masahiko; Hoshiba, Takashi; Tanaka, Masaru

    2015-09-01

    Six types of poly(2-methoxyethyl acrylate) (PMEA) analogues were synthesized and the water structure in the hydrated polymers was characterized using differential scanning calorimetry (DSC). The hydrated PMEA analogues exhibited the different amounts of intermediate water. Non-thrombogenicity evaluation was performed on PMEA analogues for platelet adhesion and protein adsorption. Platelet adhesion was suppressed on PMEA analogues. In addition, the protein adsorption and deformation were suppressed by increasing the amount of intermediate water. This study demonstrates that the amount of intermediate water might play a key role in expressing the blood compatibility of polymeric materials. PMID:26017931

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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…

  12. Glucagonlike Peptide 2 Analogue Teduglutide

    PubMed Central

    Chaturvedi, Lakshmi S.; Basson, Marc D.

    2015-01-01

    IMPORTANCE Short bowel syndrome occurs when a shortened intestine cannot absorb sufficient nutrients or fluids. Teduglutide is a recombinant analogue of human glucagonlike peptide 2 that reduces dependence on parenteral nutrition in patients with short bowel syndrome by promoting enterocytic proliferation, increasing the absorptive surface area. However, enterocyte function depends not only on the number of cells that are present but also on differentiated features that facilitate nutrient absorption and digestion. OBJECTIVE To test the hypothesis that teduglutide impairs human intestinal epithelial differentiation. DESIGN AND SETTING We investigated the effects of teduglutide in the modulation of proliferation and differentiation in human Caco-2 intestinal epithelial cells at a basic science laboratory. This was an in vitro study using Caco-2 cells, a human-derived intestinal epithelial cell line commonly used to model enterocytic biology. EXPOSURE Cells were exposed to teduglutide or vehicle control. MAINOUTCOMESAND MEASURES We analyzed the cell cycle by bromodeoxyuridine incorporation or propidium iodide staining and flow cytometry and measured cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. We used quantitative reverse transcription–polymerase chain reaction to assay the expression of the enterocytic differentiation markers villin, sucrase-isomaltase, glucose transporter 2 (GLUT2), and dipeptidyl peptidase 4 (DPP-4), as well as that of the putative differentiation signals schlafen 12 (SLFN12) and caudal-related homeobox intestine-specific transcription factor (Cdx2). Villin promoter activity was measured by a luciferase-based assay. RESULTS The MTS assay demonstrated that teduglutide increased cell numbers by a mean (SD) of 10% (2%) over untreated controls at a maximal 500nM (n = 6, P < .05). Teduglutide increased bromodeoxyuridine-positive cells vs untreated controls by a mean (SD

  13. Inhibition of bacterial transport by uncouplers of oxidative phosphorylation. Effects of pentachlorophenol and analogues in Bacillus subtilis.

    PubMed Central

    Nicholas, R A; Ordal, G W

    1978-01-01

    Analogues of the potent uncoupler of oxidative phosphorylation pentachlorophenol were tested as inhibitors of proline and glycine transport by Bacillus subtilis. These analogues included less highly substituted chlorophenols and pentachlorothiophenol. Like pentachlorophenol, they are non-competitive inhibitors of proline transport and uncompetitive inhibitors of glycine transport. However, the less highly substituted chlorophenols are weaker acids than pentachlorophenol and also weaker inhibitors. Analysis indicated that the anionic form of the uncouplers is the inhibiting species. Pentachlorothiophenol, a water-insoluble anion, is also a potent inhibitor. These results support previous studies that concluded that uncouplers of oxidative phosphorylation inhibit amino acid transport by binding at specific sites on proteins, the free energy of interaction stabilizing 'unproductive' conformations. Such specific interactions of uncoupler with protein are probably commonplace. PMID:106840

  14. 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...

  15. New metabolically stabilized analogues of lysophosphatidic acid: agonists, antagonists and enzyme inhibitors.

    PubMed

    Prestwich, G D; Xu, Y; Qian, L; Gajewiak, J; Jiang, G

    2005-12-01

    Lysophosphatidic acid (LPA) is a metabolically labile natural phospholipid with a bewildering array of physiological effects. We describe herein a variety of long-lived receptor-specific agonists and antagonists for LPA receptors. Several LPA and PA (phosphatidic acid) analogues also inhibit LPP (lipid phosphate phosphatase). The sn-1 or sn-2 hydroxy groups have been replaced by fluorine, difluoromethyl, difluoroethyl, O-methyl or O-hydroxyethoxy groups to give non-migrating LPA analogues that resist acyltransferases. Alkyl ether replacement of acyl esters produced lipase and acyltransferase-resistant analogues. Replacement of the bridging oxygen in the monophosphate by an alpha-monofluoromethylene-, alpha-bromomethylene- or alpha,alpha-difluoromethylenephosphonate gave phosphatase-resistant analogues. Phosphorothioate analogues with O-acyl and O-alkyl chains are potent, long-lived agonists for LPA1 and LPA3 receptors. Most recently, we have (i) prepared stabilized O-alkyl analogues of lysobisphosphatidic acid, (ii) explored the structure-activity relationship of stabilized cyclic LPA analogues and (iii) synthesized neutral head group trifluoromethylsulphonamide analogues of LPA. Through collaborative studies, we have collected data for these stabilized analogues as selective LPA receptor (ant)agonists, LPP inhibitors, TREK (transmembrane calcium channel) K+ channel agonists, activators of the nuclear transcription factor PPAR-gamma (peroxisome-proliferator-activated receptor-gamma), promoters of cell motility and survival, and radioprotectants for human B-cells. PMID:16246118

  16. 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)

  17. Relative DNA binding affinity of helix 3 homeodomain analogues, major groove binders, can be rapidly screened by displacement of prebound ethidium bromide. A comparative study.

    PubMed

    Shim, Yong-Ho; Arimondo, Paola B; Laigle, Alain; Garbesi, Anna; Lavielle, Solange

    2004-03-21

    The binding affinity for a 12-bp dsDNA of Antennapedia helix 3 analogues, major groove binders, has been measured by displacement of prebound ethidium bromide, a fluorescent displacement assay proposed for minor groove binders by Boger et al.(J. Am. Chem. Soc., 2000, 122, 6382-6394). Relative binding affinities determined by this method were compared to those obtained by gel mobility shift and footprinting assays for the 12-bp dsDNA and a 178-bp DNA fragment. The present work demonstrates that the fluorescence displacement assay is suitable for rapid screening of major groove binders, even though about 60 to 70% of the prebound ethidium bromide is displaced by these peptides. Total (100%) displacement of ethidium bromide was serendipitously achieved by addition in the peptide sequence, at the N-terminus, of a S-3-nitro-2-pyridinesulfenyl-N-acetyl-cysteine residue. S-3-nitro-2-pyridinesulfenylcysteine was shown to (i) bind to dsDNA with a micromolar affinity and (ii) direct within DNA grooves a peptide with no affinity for dsDNA. PMID:15007422

  18. A 1H NMR Study of Host/Guest Supramolecular Complexes of a Curcumin Analogue with β-Cyclodextrin and a β-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 β-cyclodextrin (βCD) were employed as pharmaceutical carriers to encapsulate a poorly soluble drug, curcumin analogue (NC 2067), in order to increase its water solubility. βCD was chemically conjugated with an amphiphilic gemini surfactant with the ability to self-assemble and to form nanoscale supramolecular structures. The conjugated molecule, βCDgemini surfactant (βCDg), 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 βCD internal cavity. The host/guest complexes composed of native βCD or βCDg with NC 2067 were examined using 1D/2D ROESY NMR methods. The stoichiometry of βCD/NC 2067 complex was estimated using Job's method via 1H NMR spectroscopy. The binding geometry of NC 2067 within βCD was proposed using molecular docking and further supported by 1D and 2D ROESY NMR results. Addition of NC 2067 to βCDg revealed minimal changes to the overall structure of the βCDg system, in agreement with the formation of a βCDg/NC 2067 ternary complex. PMID:26083126

  19. Role of hesperetin (a natural flavonoid) and its analogue on apoptosis in HT-29 human colon adenocarcinoma cell line--a comparative study.

    PubMed

    Sivagami, Gunasekaran; Vinothkumar, Rajamanickam; Bernini, Roberta; Preethy, Christo Paul; Riyasdeen, Anvarbatcha; Akbarsha, Mohammad Abdulkader; Menon, Venugopal Padmanaban; Nalini, Namasivayam

    2012-03-01

    Colon cancer is one of the serious health problems in most developed countries and its incidence rate is increasing in India. Hesperetin (HN) (3',5,7-trihydroxy-4'-methoxyflavonone) and hesperetin analogue (HA) were tested for their apoptosis inducing ability. Methyl thiazolyl tetrazolium assay revealed a dose as well as duration-dependent reduction of HT-29 (colon adenocarcinoma) cellular growth in response to HN and HA treatment. At 24 h 70 μM of HN and 32 μM of HA showed 50% reduction of HT-29 cellular growth. Acridine orange/ethidium bromide staining showed apoptotic features of cell death induced by HN and HA. Rhodamine 123 staining showed significant reduction in mitochondrial membrane potential induced by HN and HA. HN and HA induced DNA damage was confirmed by comet tail formation. Lipid peroxidation markers (TBARS) and protein oxidation marker (PCC) were significantly elevated in HN and HA treated groups. Enzymic antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were slightly decreased in their activities compared to control (untreated HT-29 cells). Results of Western blot analysis of apoptosis associated genes revealed an increase in cytochrome C, Bax, cleaved caspase-3 expression and a decrease in Bcl-2 expression. These findings indicate that HN and HA induce apoptosis on HT-29 via Bax dependent mitochondrial pathway involving oxidant/antioxidant imbalance. PMID:22142698

  20. Further Studies on 2-Arylacetamide Pyridazin-3(2H)-ones: Design, Synthesis and Evaluation of 4,6-Disubstituted Analogues as Formyl Peptide Receptors (FPRs) Agonists

    PubMed Central

    Giovannoni, Maria Paola; Schepetkin, Igor A.; Cilibrizzi, Agostino; Crocetti, Letizia; Khlebnikov, Andrei I.; Dahlgren, Claes; Graziano, Alessia; Piaz, Vittorio Dal; Kirpotina, Liliya N.; Zerbinati, Serena; Vergelli, Claudia; Quinn, Mark T.

    2013-01-01

    Formyl peptide receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca2+ flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven formyl peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC50 values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca2+ flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists. PMID:23685570

  1. THE PENA BLANCA NATURAL ANALOGUE PERFORMANCE ASSESSMENT MODEL

    SciTech Connect

    G.J. Saulnier Jr; W. Statham

    2006-03-10

    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 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 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 geologic setting: fractured, welded, and altered rhyolitic ash flow tuffs overlying carbonate rocks; (3) Analogous climate: Semiarid to arid; (4) Analogous geochemistry: Oxidizing conditions; and (5) Analogous hydrogeology: The ore deposit lies in the unsaturated zone above the water table. The Nopal I deposit is approximately 8 {+-} 0.5 million years old and has been exposed to oxidizing conditions during the last 3.2 to 3.4 million years. The Pena Blanca Natural Analogue Model considers that the uranium oxide and uranium silicates in the ore deposit were originally analogous to uranium-oxide spent nuclear fuel. The Pena Blanca site has been characterized using field and laboratory investigations of its fault and fracture distribution, mineralogy, fracture fillings, seepage into the mine adits, regional hydrology, and mineralization that shows the extent of radionuclide migration. Three boreholes were drilled at the Nopal I mine site in 2003 and these boreholes have provided samples for lithologic characterization, water-level measurements, and water samples for laboratory

  2. 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 ...

  3. Evolving a polymerase for hydrophobic base analogues.

    PubMed

    Loakes, David; Gallego, José; Pinheiro, Vitor B; Kool, Eric T; Holliger, Philipp

    2009-10-21

    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 favorable 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. The selected polymerase. 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, 5D4 was also able to extend HBA pairs such as Pyrene: varphi (abasic site), d5NI: varphi, 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

  4. 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)

  5. MONITORED NATURAL ATTENUATION FOR INORGANIC CONTAMINANT REMEDIATION IN GROUND WATER: SITE STUDIES

    EPA Science Inventory

    Two site studies are presented from Superfund Fund Sites in the US where monitored natural attenuation is a component of overall site restoration efforts. The presentation emphasizes the development of site-specific transport and fate models for contaminants at these hazardous w...

  6. 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

  7. Site-directed mutagenesis studies of acetylglutamate synthase delineate the site for the arginine inhibitor.

    PubMed

    Sancho-Vaello, Enea; Fernández-Murga, M Leonor; Rubio, Vicente

    2008-04-01

    N-acetyl-L-glutamate synthase (NAGS), the first enzyme of bacterial/plant arginine biosynthesis and an essential activator of the urea cycle in animals, is, respectively, arginine-inhibited and activated. Site-directed mutagenesis of recombinant Pseudomonas aeruginosa NAGS (PaNAGS) delineates the arginine site in the PaNAGS acetylglutamate kinase-like domain, and, by extension, in human NAGS. Key residues for glutamate binding are identified in the acetyltransferase domain. However, the acetylglutamate kinase-like domain may modulate glutamate binding, since one mutation affecting this domain increases the K(m) for glutamate. The effects on PaNAGS of two mutations found in human NAGS deficiency support the similarity of bacterial and human NAGSs despite their low sequence identity. PMID:18319063

  8. Membrane-permeable Triphosphate Prodrugs of Nucleoside Analogues.

    PubMed

    Gollnest, Tristan; Dinis de Oliveira, Thiago; Rath, Anna; Hauber, Ilona; Schols, Dominique; Balzarini, Jan; Meier, Chris

    2016-04-18

    The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. Rate-limitations can be at the mono-, but also at the di- and triphosphorylation steps. We developed a nucleoside triphosphate (NTP) delivery system (TriPPPro-approach). In this approach, NTPs are masked by two bioreversible units at the γ-phosphate. Using a procedure involving H-phosphonate chemistry, a series of derivatives bearing approved, as well as potentially antivirally active, nucleoside analogues was synthesized. The enzyme-triggered delivery of NTPs was demonstrated by pig liver esterase, in human T-lymphocyte cell extracts and by a polymerase chain reaction using a prodrug of thymidine triphosphate. The TriPPPro-compounds of some HIV-inactive nucleoside analogues showed marked anti-HIV activity. For cellular uptake studies, a fluorescent TriPPPro-compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells. PMID:27008042

  9. Synthesis and cytotoxic activities of semisynthetic zearalenone analogues.

    PubMed

    Tadpetch, Kwanruthai; Kaewmee, Benyapa; Chantakaew, Kittisak; Kantee, Kawalee; Rukachaisirikul, Vatcharin; Phongpaichit, Souwalak

    2016-08-01

    Zearalenone is a β-resorcylic acid macrolide with various biological activities. Herein we report the synthesis and cytotoxic activities of 34 zearalenone analogues against human oral epidermoid carcinoma (KB) and human breast adenocarcinoma (MCF-7) cells as well as noncancerous Vero cells. Some zearalenone analogues showed moderately enhanced cytotoxic activities against the two cancer cell lines. We have discovered the potential lead compounds with diminished or no cytotoxicity to Vero cells. Preliminary structure-activity relationship studies revealed that the double bond at the 1' and 2' positions of zearalenone core was crucial for cytotoxic activities on both cell lines. In addition, for zearalenol analogues, the unprotected hydroxyl group at C-2 and an alkoxy substituent at C-4 played key roles on cytotoxic effects of both cell lines. PMID:27311894

  10. Nicorandil analogues containing NO-donor furoxans and related furazans.

    PubMed

    Boschi, D; Cena, C; Di Stilo, A; Fruttero, R; Gasco, A

    2000-07-01

    The synthesis and in vitro vasodilating properties of hybrid compounds in which furoxan (1,2,5-oxadiazole 2-oxide) moieties, endowed with different NO-donor properties, were substituted for the nitroxy function of Nicorandil are reported. The corresponding cyanoguanidine analogues are also considered. This approach has led to a series of vasorelaxing compounds devoid of affinity for K(ATP) channels, whose activity is prevalently due to their ability to activate sGC, at the concentrations of the experiments. Related furazan (1,2,5-oxadiazole) derivatives, unable to release nitric oxide were also prepared and studied for control. The amide analogues of Nicorandil display feeble vasorelaxing action not involving the activation of K+ channels, while in the guanidine analogues, this mechanism seems to underlie this action. PMID:10976520

  11. 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 Central

    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.

    2008-01-01

    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 (KI = 43.4 ± 7.2 μM and kcart = 0.007 ± 0.0006 min−1). The effectiveness of protectants in decreasing the rate of inactivation by Rp-cGMPS-BDB is: Rp-cGMPS (Kd = 72 μM) > Sp-cGMPS (124), Sp-cAMPS (182) > GMP (1517), Rp-cAMPS (3762), AMP (4370 μM). 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

  12. Memory amplification for trauma: Investigating the role of analogue PTSD symptoms in the laboratory.

    PubMed

    Oulton, Jacinta M; Takarangi, Melanie K T; Strange, Deryn

    2016-08-01

    Victims of trauma often remember their experience as being more traumatic later, compared to immediately after, the event took place. This finding-the "memory amplification effect"-is associated with increased re-experiencing symptoms. However, the effect has been found almost exclusively in field-based studies. We examined whether the effect could be replicated in the laboratory. In two studies, we exposed participants to negative photographs and assessed their memory for the photographs and analogue PTSD symptoms on two occasions. In Study 1, analogue symptoms at follow-up were positively associated with remembering more negative photos over time. In Study 2, we focused on "memory amplifiers": people whose memory of the photos amplified over time. Consistent with field research, analogue re-experiencing symptoms were associated with memory amplification. Overall, our findings confirm that analogue PTSD symptoms are also associated with an amplified memory for a trauma analogue. PMID:27328014

  13. Distribution and binding of 18F-labeled and 125I-labeled analogues of ACI-80, a prospective molecular imaging biomarker of disease: a whole hemisphere post mortem autoradiography study in human brains obtained from Alzheimer's disease patients.

    PubMed

    Gulyás, Balázs; Spenger, Christian; Beliczai, Zsuzsa; Gulya, Károly; Kása, Péter; Jahan, Mahabuba; Jia, Zhisheng; Weber, Urs; Pfeifer, Andrea; Muhs, Andreas; Willbold, Dieter; Halldin, Christer

    2012-01-01

    AD patients and age matched control subjects, support the visualization capacity of the radiolabeled ACI-80 analogues of amyloid deposits in the human brain. Further studies are warranted to explore the usefulness of the (18)F-labeled analogues as in vivo molecular imaging biomarkers in diagnostic PET studies. PMID:22100791

  14. Savannah River Site reactor hardware design modification study

    SciTech Connect

    Fisher, J.E.

    1990-01-01

    A study was undertaken to assess the merits of proposed design modifications to the Savannah River Site (SRS) reactors. The evaluation was based on the responses calculated by the RELAP5 systems code to double-ended guillotine break loss-of-coolant-accidents (DEGB LOCAs). The three concepts evaluated were (a) elevated plenum inlet piping with a guard vessel and clamshell enclosures, (b) closure of both rotovalves in the affected loop, and (c) closure of the pump suction valve in the affected loop. Each concept included a fast reactor shutdown (to 65% power in 100 ms) and a 2-s ac pump trip. System recovery potential was evaluated for break locations at the pump suction, the pump discharge, and the plenum inlet. The code version used was RELAP5/MOD2.5 version 3d3, a preliminary version of RELAP5/MOD3. The model was a three-dimensional representation of the K-Reactor water plenum and moderator tank. It included explicit representations of all six loops, which were based on the configuration of L-Reactor. A combination of features is recommended to ensure liquid inventory recovery for all break locations. Valve closure design performance for a break location in the short section of piping between the reactor concrete shield and the pump suction valve would benefit from the clamshell enclosing that section of piping. 7 refs., 10 figs., 2 tabs.

  15. 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.

  16. Repeat Hydrography at the Endeavour Integrated Study Site, 2004 - 2006

    NASA Astrophysics Data System (ADS)

    Kellogg, J. P.; McDuff, R. E.; Thomson, R. E.; Stahr, F. R.

    2006-12-01

    Significant differences exist between hydrographic transects made in the summers from 2004 to 2006 at the Endeavour Segment Integrated Study Site on the Juan de Fuca Ridge. Along and across axis sections describe the hydrographic conditions above the segment in three dimensions. The resulting sections allow for rapid evaluation of the characteristics of the neutrally buoyant plume over each of the vent fields and its location relative to the ridge axis. Results indicate heat content over the northern vent fields, Salty Dawg and Sasquatch, significantly increased between the summers of 2004 and 2005. In 2004, the plumes over these vent fields were barely discernable while in 2005 prominent plumes existed with potential temperature anomalies over 0.1°C. At the time of a rapid response cruise in March 2005, no significant change in the heat content of the water column was detected. By July 2005, dramatic changes had occurred in the overlying water column structure. The potential temperature anomaly section from 2005 is indicative of a thicker (about 75 m) neutrally buoyant plume with and substantially more heat at the north end of the valley. In 2004, the shallowest plume depth was 1900 m contrasted with 1830 m in 2005. Vent data being obtained by other RIDGE 2000 and UW Keck investigators will help constrain the underlying causes of these changes. New hydrography will be collected in August September 2006.

  17. Repeat Hydrography at the Endeavour Integrated Study Site, 2004 - 2005

    NASA Astrophysics Data System (ADS)

    Kellogg, J. P.; McDuff, R. E.; Thomson, R. E.; Stahr, F. R.

    2005-12-01

    Significant differences exist between hydrographic transects made in 2004 and 2005 at the Endeavour Segment Integrated Study Site on the Juan de Fuca Ridge. Sections that describe the conditions above the segment utilize twenty-one nearly uniformly spaced hydrographic stations from south of Mothra to north of the Sasquatch hydrothermal vent fields. Criteria used in choosing station locations included depth, ~500 m spacing from other stations, and being centrally located in the valley. The resulting sections allow for rapid evaluation of the characteristics of the neutrally buoyant plume over each of the vent fields. Preliminary results indicate heat content over the northern vent fields, Salty Dawg and Sasquatch, significantly increased between the summers of 2004 and 2005. In 2004, the plumes over these vent fields were barely discernable while in 2005 prominent plumes existed with potential temperature anomalies over 0.1°C. Vent data being obtained by other RIDGE 2000 and UW Keck investigators will help constrain the underlying causes of these changes. Isopycnals in the 2005 sections are also elevated along the entire length of the transect by approximately 50 m or more. The potential temperature anomaly section from 2005 is indicative of a thicker (about 75 m) neutrally buoyant plume and substantially more heat at the north end of the valley. In 2004, the shallowest plume depth was 1900 m contrasted with 1830 m in 2005.

  18. A Virtual Web Environment for Mars Landing Site Studies

    NASA Technical Reports Server (NTRS)

    Gulick, V. C.; Deardorff, D. G.; Briggs, G. A.

    2001-01-01

    A collection of web tools is available for both the landing site and broader Mars science communities to better utilize, visualize, and analyze Mars Global Surveyor data. These tools have grown out of a two year effort between the Center for Mars Exploration (CMEX), and the NAS data visualization group at NASA Ames Research Center (ARC), to promote interactions among the planetary community and to coordinate landing site activities. The web site will continue to evolve over the next several years as new tools and features are added to support the ongoing Mars missions.

  19. The electrical properties of Mars analogue dust

    NASA Astrophysics Data System (ADS)

    Merrison, J.; Jensen, J.; Kinch, K.; Mugford, R.; Nørnberg, P.

    2004-03-01

    Dust is a major environmental factor on the surface and in the atmosphere of Mars. Knowing the electrical charge state of this dust would be of both scientific interest and important for the safety of instruments on the Martian surface. In this study the first measurements have been performed of dust electrification using suspended Mars analogue material. This has been achieved by attracting suspended dust onto electrodes placed inside a Mars simulation wind tunnel. The Mars analogue used was from Salten Skov in Denmark, this contained a high concentration of ferric oxide precipitate. Once suspended, this dust was found to consist of almost equal quantities of negatively (46±6%) and positively (44±15%) charged grains. These grains were estimated to typically carry a net charge of around 10 5e, this is sufficient to dominate the processes of adhesion and cohesion of this suspended dust. Evidence is presented for electrostatic aggregation of the dust while in suspension. Development of a simple instrument for measuring electrical charging of the suspended dust on Mars will be discussed.

  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. Ecstasy analogues found in cacti.

    PubMed

    Bruhn, Jan G; El-Seedi, Hesham R; Stephanson, Nikolai; Beck, Olof; Shulgin, Alexander T

    2008-06-01

    Human interest in psychoactive phenethylamines is known from the use of mescaline-containing cacti and designer drugs such as Ecstasy. From the alkaloid composition of cacti we hypothesized that substances resembling Ecstasy might occur naturally. In this article we show that lophophine, homopiperonylamine and lobivine are new minor constituents of two cactus species, Lophophora williamsii (peyote) and Trichocereus pachanoi (San Pedro). This is the first report of putatively psychoactive phenethylamines besides mescaline in these cacti. A search for further biosynthetic analogues may provide new insights into the structure-activity relationships of mescaline. An intriguing question is whether the new natural compounds can be called "designer drugs." PMID:18720674

  2. 12-Amino-andrographolide analogues: synthesis and cytotoxic activity.

    PubMed

    Kasemsuk, Sakkasem; Sirion, Uthaiwan; Suksen, Kanoknetr; Piyachaturawat, Pawinee; Suksamrarn, Apichart; Saeeng, Rungnapha

    2013-12-01

    Andrographolide, a diterpenoid lactone of the plant Andrographis paniculata, has been shown to be cytotoxic against various cancer cells in vitro. In the present study, a series of β-amino-γ-butyrolactone analogues has been synthesized from naturally occurring andrographolide via one pot tandem aza-conjugate addition-elimination reaction. By using economic procedure without any base or catalyst at room temperature, the products obtained were in fair to excellent yields with high stereoselectivity. The cytotoxicity of all new amino analogues were evaluated against six cancer cell lines and revealed their potential for being developed as promising anti-cancer agents. PMID:23709127

  3. 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

  4. Making Connections in Math: Activating a Prior Knowledge Analogue Matters for Learning

    ERIC Educational Resources Information Center

    Sidney, Pooja G.; Alibali, Martha W.

    2015-01-01

    This study investigated analogical transfer of conceptual structure from a prior-knowledge domain to support learning in a new domain of mathematics: division by fractions. Before a procedural lesson on division by fractions, fifth and sixth graders practiced with a surface analogue (other operations on fractions) or a structural analogue (whole…

  5. Interleukin 6 is a cause of flu-like symptoms in treatment with a deoxycytidine analogue.

    PubMed Central

    Masuda, N.; Negoro, S.; Takeda, K.; Kurata, N.; Kuwabara, T.; Kobayashi, S.; Fukuoka, M.

    1998-01-01

    The precise mechanism of fever and flu-like syndrome that occurs in treatment with deoxycytidine analogues remains unclear. This study demonstrated a strong correlation between plasma interleukin 6 levels and fever in treatment with oral (E)-2'-deoxy-2'(fluoromethylene)cytidine, another deoxycytidine analogue. PMID:9703288

  6. The Object-analogue approach for probabilistic forecasting

    NASA Astrophysics Data System (ADS)

    Frediani, M. E.; Hopson, T. M.; Anagnostou, E. N.; Hacker, J.

    2015-12-01

    The object-analogue is a new method to estimate forecast uncertainty and to derive probabilistic predictions of gridded forecast fields over larger regions rather than point locations. The method has been developed for improving the forecast of 10-meter wind speed over the northeast US, and it can be extended to other forecast variables, vertical levels, and other regions. The object-analogue approach combines the analog post-processing technique (Hopson 2005; Hamill 2006; Delle Monache 2011) with the Method for Object-based Diagnostic Evaluation (MODE) for forecast verification (Davis et al 2006a, b). Originally, MODE is used to verify mainly precipitation forecasts using features of a forecast region represented by an object. The analog technique is used to reduce the NWP systematic and random errors of a gridded forecast field. In this study we use MODE-derived objects to characterize the wind fields forecasts into attributes such as object area, centroid location, and intensity percentiles, and apply the analogue concept to these objects. The object-analogue method uses a database of objects derived from reforecasts and their respective reanalysis. Given a real-time forecast field, it searches the database and selects the top-ranked objects with the most similar set of attributes using the MODE fuzzy logic algorithm for object matching. The attribute probabilities obtained with the set of selected object-analogues are used to derive a multi-layer probabilistic prediction. The attribute probabilities are combined into three uncertainty layers that address the main concerns of most applications: location, area, and magnitude. The multi-layer uncertainty can be weighted and combined or used independently in such that it provides a more accurate prediction, adjusted according to the application interest. In this study we present preliminary results of the object-analogue method. Using a database with one hundred storms we perform a leave-one-out cross-validation to

  7. 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.

  8. 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.

  9. 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 μm/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

  10. 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

  11. NMR studies of ligand carboxylate group interactions with arginine residues in complexes of Lactobacillus casei dihydrofolate reductase with substrates and substrate analogues.

    PubMed

    Birdsall, B; Polshakov, V I; Feeney, J

    2000-08-15

    In a series of complexes of Lactobacillus casei dihydrofolate reductase (DHFR) formed with substrates and substrate analogues, the (1)H/(15)N NMR chemical shifts for the guanidino group of the conserved Arg 57 residue were found to be sensitive to the mode of binding of their H(eta) protons to the charged oxygen atoms in ligand carboxylate groups. In all cases, Arg 57 showed four nonequivalent H(eta) signals indicating hindered rotation about the N(epsilon)-C(zeta) and C(zeta)-N(eta) bonds. The H(eta)(12) and H(eta)(22) protons have large downfield shifts as expected for a symmetrical end-on interaction with the ligand carboxylate group. The chemical shifts are essentially the same in the complexes with folate and p-aminobenzoyl-L-glutamate (PABG) and similar to those found previously for the methotrexate complex reflecting the strong and similar hydrogen bonds formed with the carboxylate oxygens. Interestingly, the rates of rotation about the N(epsilon)-C(zeta) bond for the complexes containing the weakly binding PABG fragment are almost identical to those measured in the complex with methotrexate, which binds 10(7) times more tightly. In the methotrexate complex, this rotation depends on correlated rotations about the N(epsilon)-C(zeta) bond of Arg 57 and the C(alpha)-C' bond of the ligand glutamate alpha-carboxylate group. Thus, even in a fragment such as PABG, which has a much faster off-rate, the carboxylate group binds to the enzyme in a similar way to that in a parent molecule such as folate and methotrexate with the rotation about the N(epsilon)-C(zeta) bond of Arg 57 being essentially the same in all the different complexes. PMID:10933799

  12. 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

    2016-01-28

    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

  13. Western Maryland Power Plant Siting Study: comparison of solid-waste-disposal issues at three candidate sites. Final report

    SciTech Connect

    Klauda, R.J.; Portner, E.M.; Lentz, J.J.

    1984-10-01

    This document is one of a series of technical reports prepared for the Western Maryland Power Plant Siting Study. An array of solid-waste-disposal-issues are compared for the three candidate sites (FP-12 in Frederick County, WP-14 and WP-26 in Washington County) remaining after the six- to three-area study phase. An 1890-MW conventional, coal-fired power plant would produce about 46 million cubic yards of solid waste over a 33-year period. The study evaluated potential impacts of a blend of fly ash and fixed scrubber sludge disposed in landfills with a design to maximize waste isolation and minimize permeate or leachate production. All three candidate sites appear to have adequate waste-disposal capacity. Varied ground-water flow directions and potential dilution limitations in the areas draining FP-12 and WP-14 make monitoring, detection, and potential mitigation options more complex and costly than at WP-26.

  14. 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

  15. Relative benefits of linear analogue and advanced digital hearing aids.

    PubMed

    Wood, Sally A; Lutman, Mark E

    2004-03-01

    Speech recognition performance and self-reported benefit from linear analogue and advanced (digital) hearing aids were compared in 100 first-time hearing aid users with mild-to-moderate sensorineural hearing loss fitted monaurally with a behind-the-ear (BTE) hearing aid in a single-blind randomized crossover trial. Subjects used each aid for 5 weeks in turn, with aid order balanced across subjects. Three alternative models of digital hearing aid were assigned to subjects according to a balanced design. Aid type was disguised to keep subjects blind within practical limitations. Aided speech recognition performance in noise was measured at speech levels of 65 and 75dB at a speech-to-noise ratio (SNR) of +2dB for closed sets of single words. Self-rated benefit was measured using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Glasgow Hearing Aid Benefit Profile (GHABP). Quality of life, hearing aid use and user preferences were also assessed. Speech recognition scores with the digital aids were significantly better at 75dB than with the analogue aids Self-reported benefit (APHAB, GHABP) and improvement in quality of life were generally not significantly different between analogue and digital aids, although aversiveness measured with the APHAB was significantly lower with digital aids, and satisfaction measured with the GHABP was greater. The digital aids were preferred significantly more often than the analogue aids, with 61 subjects choosing their digital aid, 26 choosing the analogue aid, and nine being equivocal. Overall, this study shows advantages for advanced digital over simple linear analogue aids in terms of both objective and subjective outcomes, although average differences are not large. PMID:15198378

  16. Molecular recognition at the active site of subtilisin BPN': crystallographic studies using genetically engineered proteinaceous inhibitor SSI (Streptomyces subtilisin inhibitor).

    PubMed

    Takeuchi, Y; Noguchi, S; Satow, Y; Kojima, S; Kumagai, I; Miura, K; Nakamura, K T; Mitsui, Y

    1991-06-01

    Unlike trypsin-like serine proteases having only one conspicuous binding pocket in the active site, subtilisin BPN' has two such pockets, the S1 and S4 pockets, which accommodate the P1 and P4 residues of ligands (after Schechter and Berger notation) respectively. Using computer graphics, the geometrical nature of the two pockets was carefully examined and strategies for site-directed mutagenesis studies were set up against a protein SSI (Streptomyces subtilisin inhibitor), which is a strong proteinaceous inhibitor (or a substrate analogue) of subtilisin BPN'. It was decided to convert the P1 residue, methionine 73, into lysine (M73K) with or without additional conversion of the P4 residue, methionine 70, into glycine (M70G). The crystal structures of the two complexes of subtilisin BPN', one with the single mutant SSI (M73K) and the other with the double mutant SSI (M73K, M70G) were solved showing that (i) small 'electrostatic induced-fit movement' occurs in the S1 pocket upon introducing the terminal plus charge of the lysine side chain, and (ii) large 'mechanical induced-fit movement' occurs in the S4 pocket upon reducing the size of the P4 side chain from methionine to glycine. In both (i) and (ii), the induced-fit movement occurred in a concerted fashion involving both the enzyme and 'substrate' amino acid residues. The term 'substrate-assisted stabilization' was coined to stress the cooperative nature of the induced-fit movements. PMID:1891457

  17. 3D-QSAR and 3D-QSSR studies of thieno[2,3-d]pyrimidin-4-yl hydrazone analogues as CDK4 inhibitors by CoMFA analysis

    PubMed Central

    Cai, Bao-qin; Jin, Hai-xiao; Yan, Xiao-jun; Zhu, Peng; Hu, Gui-xiang

    2014-01-01

    Aim: To investigate the structural basis underlying potency and selectivity of a series of novel analogues of thieno[2,3-d]pyrimidin-4-yl hydrazones as cyclin-dependent kinase 4 (CDK4) inhibitors and to use this information for drug design strategies. Methods: Three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models using comparative molecular field analysis (CoMFA) were conducted on a training set of 48 compounds. Partial least squares (PLS) analysis was employed. External validation was performed with a test set of 9 compounds. Results: The obtained 3D-QSAR model (q2=0.724, r2=0.965, r2pred=0.945) and 3D-QSSR model (q2=0.742, r2=0.923, r2pred=0.863) were robust and predictive. Contour maps with good compatibility to active binding sites provided insight into the potentially important structural features required to enhance activity and selectivity. The contour maps indicated that bulky groups at R1 position could potentially enhance CDK4 inhibitory activity, whereas bulky groups at R3 position have the opposite effect. Appropriate incorporation of bulky electropositive groups at R4 position is favorable and could improve both potency and selectivity to CDK4. Conclusion: These two models provide useful information to guide drug design strategies aimed at obtaining potent and selective CDK4 inhibitors. PMID:24122012

  18. The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor

    PubMed Central

    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

  19. Biodegradation of bisphenol A and its halogenated analogues by Cunninghamella elegans ATCC36112.

    PubMed

    Keum, Young Soo; Lee, Hye Ri; Park, Hee Won; Kim, Jeong-Han

    2010-11-01

    Bisphenol A and its halogenated analogues are commonly used industrial chemicals with strong toxicological effects over many organisms. In this study, metabolic fate of bisphenol A and its halogenated analogues were evaluated with Cunninghamella elegans ATCC36112. Bisphenol A and related analogues were rapidly transformed into several metabolites by C. elegans within 2-4 days. Detailed analysis of metabolites reveals that both phase I and II metabolism occurred in C. elegans. Cytochrome P450-dependent hydroxylation was observed in BPA. However, major reaction with bisphenol A and analogues with 1-2 halogen atoms were the formation of glucose-conjugate, not being inhibited by cytochrome P450 inhibitor. Overall metabolic rates decreased with increasing number of substitution at 2- and 6-position of BPA structures, which may be consequences of limited bioavailability or steric hindrance to conjugate-forming reaction. Information from the current study will provide detailed insights over the fungal metabolism of BPA and analogues. PMID:20455075

  20. 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

  1. ON A p-ADIC ANALOGUE OF TATE HEIGHT

    NASA Astrophysics Data System (ADS)

    Berzin'sh, A. A.

    1983-04-01

    This paper is devoted to the study of the Tate height of an elliptic curve and its p-adic analogue. The main result is a series of explicit formulas for computing the local archimedean part of the Tate height. These results are used to obtain a new method for constructing the p-adic Tate height. Bibliography: 5 titles.

  2. Inhibition of receptor/G protein coupling by suramin analogues.

    PubMed

    Beindl, W; Mitterauer, T; Hohenegger, M; Ijzerman, A P; Nanoff, C; Freissmuth, M

    1996-08-01

    Suramin analogues act as direct antagonists of heterotrimeric G proteins because they block the rate-limiting step of G protein activation (i.e., the dissociation of GDP prebound to the G protein alpha subunit). We have used the human brain A1 adenosine receptor and the rat striatal D2 dopamine receptor, two prototypical Gi/G(o)-coupled receptors, as a model system to test whether the following analogues suppress the receptor-dependent activation of G proteins: 8-(3-nitrobenzamido)-1,3,5-naphthalenetrisulfonic acid (NF007), 8-(3-(3-nitrobenzamido)-benzamido)-1,3,5-naphthalenetrisulfonic acid (NF018); 8,8'-(carbonylbis(imino-3,1-phenylene))bis-(1,3,5-naphthalenetr isulfonic acid) (NF023); 8,8'-(carbonylbis(imino-3,1-phenylene)carbonylimino-(3,1- phenylene)) bis(1,3,5-naphthalenetrisulfonic acid) (NF037); and suramin. Suramin and its analogues inhibit the formation of the agonist-specific ternary complex (agonist/receptor/G protein). This inhibition is (i) quasicompetitive with respect to agonist binding in that it can be overcome by increasing receptor occupancy but (ii) does not result from an interaction of the analogues with the ligand binding pocket of the receptors because the binding of antagonists or of agonists in the absence of functional receptor/G protein interaction is not affected. In addition to suppressing the spontaneous release of GDP from defined G protein alpha subunits, suramin and its analogues reduce receptor-catalyzed guanine nucleotide exchange. The site, to which suramin analogues bind, overlaps with the docking site for the receptor on the G protein alpha subunit. The structure-activity relationships for inhibition of agonist binding to the A1 adenosine receptor (suramin > NF037 > NF023) and of agonist binding to the inhibition D2 dopamine receptor (suramin = NF037 > NF023 > NF018) differ. Thus, NF037 discriminates between the ternary complexes formed by the agonist-liganded D2 dopamine receptors and those formed by the A1 adenosine

  3. 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