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Understanding Rubredoxin Redox Sites by Density Functional Theory Studies of Analogues  

PubMed Central

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-? 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-xyl2)]0/1-/2-, and Na+[Fe(S2-o-xyl)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.

Luo, Yan; Niu, Shuqiang; Ichiye, Toshiko



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

NASA Astrophysics Data System (ADS)

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

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



X-ray absorption fine-structure spectroscopy studies of Fe sites in natural human neuromelanin and synthetic analogues.  

PubMed Central

X-ray absorption fine-structure spectroscopy is used to study the local environment of the iron site in natural (human) neuromelanin extracted from substantia nigra tissue and in various synthetic neuromelanins. All the materials show Fe centered in a nearest neighbor sixfold (distorted) oxygen octahedron; the Fe-O distances, while slightly different in the natural and synthetic neuromelanin, are both approximately 2.0 A. Appreciable differences arise, however, in the second (and higher) coordination shells. In this case the synthetic melanin has the four planar oxygens bound to carbon rings with Fe-C distances of approximately 2.82 and 4.13 A; the human sample does not show the 2.82 A link but instead indicates a double shell at approximately 3.45 and 3.78 A.

Kropf, A J; Bunker, B A; Eisner, M; Moss, S C; Zecca, L; Stroppolo, A; Crippa, P R



Comparative studies of 193-nm photodissociation and TOF-TOFMS analysis of bradykinin analogues: The effects of charge site(s) and fragmentation timescales  

Microsoft Academic Search

The dissociation reactions of [M+H]+, [M+Na]+, and [M+Cu]+ ions of bradykinin (amino acid sequence RPPGFSPFR) and three bradykinin analogues (RPPGF, RPPGFSPF, PPGFSPFR) are examined by using 193-nm photodissociation and post-source decay (PSD) TOF-TOF-MS techniques. The photodissociation\\u000a apparatus is equipped with a biased activation cell, which allows us to detect fragment ions that are formed by dissociation\\u000a of short-lived (<1 µs)

Joseph W. Morgan; David H. Russell



Space analogue studies in Antarctica  

NASA Astrophysics Data System (ADS)

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.

Lugg, D.; Shepanek, M.



Space analogue studies in Antarctica  

NASA Technical Reports Server (NTRS)

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.

Lugg, D.; Shepanek, M.



Bupropion binds to two sites in the Torpedo nicotinic acetylcholine receptor transmembrane domain: a photoaffinity labeling study with the bupropion analogue [(125)I]-SADU-3-72.  


Bupropion, a clinically used antidepressant and smoking-cessation drug, acts as a noncompetitive antagonist of nicotinic acetylcholine receptors (nAChRs). To identify its binding site(s) in nAChRs, we developed a photoreactive bupropion analogue, (±)-2-(N-tert-butylamino)-3'-[(125)I]-iodo-4'-azidopropiophenone (SADU-3-72). Based on inhibition of [(125)I]SADU-3-72 binding, SADU-3-72 binds with high affinity (IC(50) = 0.8 ?M) to the Torpedo nAChR in the resting (closed channel) state and in the agonist-induced desensitized state, and bupropion binds to that site with 3-fold higher affinity in the desensitized (IC(50) = 1.2 ?M) than in the resting state. Photolabeling of Torpedo nAChRs with [(125)I]SADU-3-72 followed by limited in-gel digestion of nAChR subunits with endoproteinase Glu-C established the presence of [(125)I]SADU-3-72 photoincorporation within nAChR subunit fragments containing M1-M2-M3 helices (?V8-20K, ?V8-22/23K, and ?V8-24K) or M1-M2 helices (?V8-14). Photolabeling within ?V8-22/23K, ?V8-24K, and ?V8-14 was reduced in the desensitized state and inhibited by ion channel blockers selective for the resting (tetracaine) or desensitized (thienycyclohexylpiperidine (TCP)) state, and this pharmacologically specific photolabeling was localized to the M2-9 leucine ring (?Leu(265), ?Leu(257)) within the ion channel. In contrast, photolabeling within the ?V8-20K was enhanced in the desensitized state and not inhibited by TCP but was inhibited by bupropion. This agonist-enhanced photolabeling was localized to ?Tyr(213) in ?M1. These results establish the presence of two distinct bupropion binding sites within the Torpedo nAChR transmembrane domain: a high affinity site at the middle (M2-9) of the ion channel and a second site near the extracellular end of ?M1 within a previously described halothane (general anesthetic) binding pocket. PMID:22394379

Pandhare, Akash; Hamouda, Ayman K; Staggs, Brandon; Aggarwal, Shaili; Duddempudi, Phaneendra K; Lever, John R; Lapinsky, David J; Jansen, Michaela; Cohen, Jonathan B; Blanton, Michael P



Carbon storage at defect sites in mantle mineral analogues  

NASA Astrophysics Data System (ADS)

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.

Wu, Jun; Buseck, Peter R.



N ?-Aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site  

Microsoft Academic Search

Analogues of l-glutamine were designed and synthesized to test a hydrogen-bond hypothesis between ligand and neutral amino acid transporter ASCT2. The key design feature contains a substituted phenyl ring on the amide nitrogen that contains electron withdrawing and electron donating groups that alter the pKa of the amide NH. Through this study a preliminary binding site map has been developed,

C. Sean Esslinger; Kimberly A. Cybulski; Joseph F. Rhoderick



Upheaval Dome, An Analogue Site for Gale Center  

NASA Technical Reports Server (NTRS)

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.

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



Chemical Speciation Modelling of the South Terras and Madeira Abyssal Plain Natural Analogue Sites.  

National Technical Information Service (NTIS)

The chemical speciation of uranium has been modelled using field data from the South Terras and Madeira Abyssal Plain natural analogue sites. In general, validation is good, particularly for the Abyssal Plain model. Problems regarding uranium redox couple...

J. R. Duffield L. Xu D. R. Williams



Ice nucleation studies of meteoric smoke analogues  

NASA Astrophysics Data System (ADS)

Nano-sized meteoric smoke particles, formed subsequently to the ablation of meteors in the Earth's upper atmosphere, are currently the favoured candidate for the heterogeneous nucleation of ice clouds (noctilucent / polar mesospheric) in the mesosphere. However, many fundamental aspects of these aerosol species such as composition, shape and nucleation efficiency remain effectively unknown. Following our earlier work on the generation and characterisation of likely smoke particle analogues including amorphous iron oxides and silicates of non-spherical, low density nature, we are currently investigating the heterogeneous ice nucleating capacity of such nanomaterials. There is currently nothing in the literature in this regard for such refractory aerosol species under conditions relevant to the upper atmosphere and at nanoparticle dimensions (< 100 nm), expected to be present at such high altitudes. It is to this end that we have conducted a series of low temperature nucleation studies on samples of such analogue species at the AIDA (Aerosol Interactions and Dynamics in the Atmosphere) chamber in Karlsruhe, Germany. This facility affords the study of the deposition mode ice nucleation of aerosol particles injected into the chamber volume at temperatures down to 183 K and pressures less than 1 Pa. In-situ monitoring of particle size distribution, ice crystal growth and light scattering along with ambient conditions of pressure, temperature and supersaturation levels with respect to both water and ice in the chamber were carried out. We report on the critical threshold conditions of temperature and ice supersatuation under which heterogeneous ice nucleation is activated by the particle samples in an effort to establish the relative activation efficiencies of such materials as ice nuclei and their proposed participation in the formation of mesospheric ice clouds.

Saunders, Russell; Moehler, Ottmar; Schnaiter, Martin; Benz, Stefan; Plane, John M. C.


Computational inhibition studies of the human proteasome by argyrin-based analogues with subunit specificity.  


A computational procedure was developed to study the subunit-specific interactions of the proteasome inhibitors argyrin A and F, with the aim of indentifying the determinants of subunit selectivity. Three-dimensional models of humanized proteasome active sites ?1 , ?2 and ?5 were developed and subsequently used in molecular docking simulations with the argyrin analogues. The subunit selectivity exhibited by each analogue could be explained based on the site-specific interactions and a probability-based specificity parameter derived in this study. A rational approach that involved maximizing site-specific interactions was followed to guide the design of new argyrin analogues as specific inhibitors of the caspase-like (?1 site) activity. PMID:24521156

Loizidou, Eriketi Z; Zeinalipour-Yazdi, Constantinos D



NASA/ESMD Analogue Mission Plans  

NASA Technical Reports Server (NTRS)

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.

Hoffman, Stephen J.



A neurosteroid analogue photolabeling reagent labels the colchicine binding site on tubulin: A mass spectrometric analysis  

PubMed Central

Previous studies have shown that the neurosteroid analogue, 6-Azi-pregnanolone (6-AziP), photolabels voltage-dependent anion channels and proteins of approximately 55 kDa in rat brain membranes. The present study used two dimensional electrophoresis and nano-electrospray ionization ion trap mass spectrometry (nano-ESI-MS) to identify the 55 kDa proteins (pI 4.8) as isoforms of ?-tubulin. This identification was confirmed by immuno-blot and immunoprecipitation of photolabeled protein with anti-?-tubulin antibody and by the demonstration that 6-AziP photolabels purified bovine brain tubulin in a concentration-dependent pattern. To identify the photolabeling sites, purified bovine brain tubulin was photolabeled with 6-AziP, digested with trypsin, and analyzed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI). A 6-AziP adduct of TAVCDIPPR (m/z=1287.77), a ?-tubulin specific peptide, was detected by MALDI. High resolution LC-MS/MS analysis identified that 6-AziP was covalently bound to cysteine 354 (Cys-354), previously identified as a colchicine binding site. 6-AziP photolabeling was inhibited by 2-methoxyestradiol, an endogenous derivative of estradiol thought to bind to the colchicine site. Structural modeling predicted that neurosteroids could dock in this colchicine site at the interface between ?- and ?-tubulin with the photolabeling group of 6-AziP positioned proximate to Cys-354.

Chen, Zi-Wei; Chen, Li-Hai; Akentieva, Natalia; Lichti, Cheryl F.; Darbandi, Ramin; Hastings, Randy; Covey, Douglas F.; Reichert, David E.; Townsend, R. Reid; Evers, Alex S.



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)

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 August and September 2010 and involved simulated robotic surveying of selected 'landing sites' at the Mistastin structure. The second deployment took place at the same location in 2011, which included simulated astronaut surface operations with, and without, the aid of a robotic assistant. A mission control team, based at the University of Western Ontario, London, Ontario, 1,900 km from the field site, oversaw operations. Our study showed the value of precursor reconnaissance missions in providing surface geology visualization at resolutions and from viewpoints not achievable from orbit, including high-resolution surface imagery on the scale of 10s of metres to kilometres. Indeed, data collected during the robotic precursor mission led to the formulation of a hypothesis that a large impact melt outcrop - named Discovery Hill - represents an impact melt pond in the terraced region of the crater, analogous to similar ponds of melt documented around the rim of well-preserved lunar craters such as Tycho. Further discoveries, that will be highlight here, include documentation of ejecta deposits for the first time at Mistastin, quantification of shock in anorthosites, and refined age estimates for the Mistastin impact event.

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.



The relevance of analogue studies for understanding obsessions and compulsions.  


Analogue samples are often used to study obsessive-compulsive (OC) symptoms and related phenomena. This approach is based on the hypothesis that results derived from such samples are relevant to understanding OC symptoms in individuals with a diagnosis of obsessive-compulsive disorder (OCD). Two decades ago, Gibbs (1996) reviewed the available literature and found initial support for this hypothesis. Since then there have been many important advances addressing this issue. The purpose of the present review was to synthesize various lines of research examining the assumptions of using analogue samples to draw inferences about people with OCD. We reviewed research on the prevalence of OC symptoms in non-clinical populations, the dimensional (vs. categorical) nature of these symptoms, phenomenology, etiology, and studies on developmental and maintenance factors in clinical and analogue samples. We also considered the relevance of analogue samples in OCD treatment research. The available evidence suggests research with analogue samples is highly relevant for understanding OC symptoms. Guidelines for the appropriate use of analogue designs and samples are suggested. PMID:24561743

Abramowitz, Jonathan S; Fabricant, Laura E; Taylor, Steven; Deacon, Brett J; McKay, Dean; Storch, Eric A



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)

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.

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



Clinical study of a digital vs an analogue hearing aid.  


Digital signal processing in hearing instruments has brought new perspectives to the compensation of hearing impairment and may result in alleviation of the adverse effects of hearing problems. This study compares a commercially available digital signal processing hearing aid (HA) (Senso) with a modern analogue HA with programmable fitting (Logo). The HAs tested are identical in appearance and, in spite of a different mode of operation, the study design ensured blinding of the test subjects. Outcome parameters were: improvements in speech recognition score in noise (deltaSRSN) with the HAs; overall preference for HA; overall satisfaction; and various measures of HA performance evaluated by a self-assessment questionnaire. A total of 28 experienced HA users with sensorineural hearing impairment were included and 25 completed the trial. No significant differences were found in deltaSRSN between the two HAs. Eleven subjects indicated an overall preference for the digital HA, 10 preferred the analogue HA and 4 had no preference. Concerning overall satisfaction, 8 subjects rated the digital HA superior to the analogue one, whereas 7 indicated a superior rating for the analogue HA and 10 rated the HAs equal. Acceptability of noise from traffic was the only outcome parameter which gave a significant difference between the HAs in favour of the digital HA. It is concluded that there are no significant differences in outcome between the digital and analogue signal processing HAs tested by these experienced HA-users. PMID:10384900

Bille, M; Jensen, A M; Kjaerbøl, E; Vesterager, V; Sibelle, P; Nielsen, H



Site-specific PEGylation of bone morphogenetic protein-2 cysteine analogues.  


Three cysteine analogues of bone morphogenetic protein (BMP)-2, BMP2A2C, BMP2N56C, and BMP2E96C, were generated in order to enable the attachment of SH-reactive poly(ethylene glycol) (PEG) at specific sites. Three different approaches (Ap) were used for SH-specific PEGylation: (Ap1) reaction of glutathione activated proteins with thiol PEG; (Ap2) reaction of DTT reduced proteins with orthopyridyl disulfide PEG; (Ap3) reaction of DTT reduced proteins with maleimide PEG. Non-, mono-, and di-PEGylated BMP-2 analogues could be separated by RP-HPLC. Trypsin digestion of PEGylated proteins and Trypsin and GluC double-digestion of N-ethylmaleimide-labeled proteins confirmed that the modifications were site-specific. Surface plasmon resonance analysis of type I and type II receptor binding of the PEGylated BMP-2 analogues revealed that all three PEGylation approaches were equivalent. PEGylation at positions 2 and 96 caused a similar decrease in receptor affinity. PEGylation at position 56 resulted in a larger decrease in affinity for both types of receptors. Mono-PEGylated BMP-2 analogues exhibited intermediate affinities in comparison with unmodified and di-PEGylated proteins. However, the biological activity of the PEGylated BMP-2 analogues as measured in alkaline phosphatase assay was higher than BMP-2 wild-type for the PEGylated BMP2A2C, slightly reduced for the BMP2N56C, and strongly reduced for the BMP2E96C. These results taken together indicate that specific attachment of PEG at engineered sites of BMP-2 is possible and that the attachment site is critical for biological activity. Furthermore, the biological activity of PEGylated BMP-2 analogues in cell culture seems to be determined not only by receptor affinity, but also by other factors such as protein solubility and stability. It is also discussed that the attached PEG interferes with the binding of BMP-2 to modulator proteins, co-receptors, or heparinic sites of proteoglycans in the extracellular matrix. PMID:20886828

Hu, Junli; Duppatla, Viswanadham; Harth, Stefan; Schmitz, Werner; Sebald, Walter



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

SciTech Connect

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.

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



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

NASA Astrophysics Data System (ADS)

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.

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


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

NASA Astrophysics Data System (ADS)

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.

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



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


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

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



Biological Synthesis of a Protein Analogue of Acetylcholinesterase: Monoclonal Anti-Idiotype Antibody Analogue of the Esteratic Site.  

National Technical Information Service (NTIS)

This study was designed to characterize the molecular structure of the active site of human acetylcholinesterase (AChE). Human erythrocyte acetylcholinesterase was purified to >98% Homogeneity by monoclonal antibody affinity chromatography and homogeneity...

T. J. August



Ngamma-aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site.  


Analogues of L-glutamine were designed and synthesized to test a hydrogen-bond hypothesis between ligand and neutral amino acid transporter ASCT2. The key design feature contains a substituted phenyl ring on the amide nitrogen that contains electron withdrawing and electron donating groups that alter the pKa of the amide NH. Through this study a preliminary binding site map has been developed, and a potent commercially available competitive inhibitor of the ASCT2 transporter has been identified. PMID:15670919

Esslinger, C Sean; Cybulski, Kimberly A; Rhoderick, Joseph F



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  

Microsoft Academic Search

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

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



Furan Decorated Nucleoside Analogues as Fluorescent Probes: synthesis, photophysical evaluation and site-specific incorporation  

PubMed Central

The synthesis and photophysical evaluation of modified nucleoside analogues in which a five-membered heterocycle (furan, thiophene, oxazole and thiazole) is attached to the 5 position of 2?-deoxyuridine are reported. The furan containing derivative is identified as the most promising responsive nucleoside of this family due to its emission quantum efficiency and degree of sensitivity to its microenvironment. The furan moiety was then attached to the 5 position of 2?-deoxycytidine as well as the 8 position of adenosine and guanosine. Photophysical evaluation of these four furan containing nucleoside analogues reveal distinct differences in the absorption, emission and quantum efficiency depending upon the class of nucleoside (pyrimidine or purine). Comparing the photophysical properties of all furan containing nucleosides, identifies the furan thymidine analogue, 5-(fur-2-yl)-2?-deoxyuridine, as the best candidate for use as a responsive fluorescent probe in nucleic acids. 5-(fur-2-yl)-2?-deoxyuridine was then converted to the corresponding phosphoramidite and site specifically incorporated into DNA oligonucleotides with greater than 88% coupling efficiency. Such furan-modified oligonucleotides form stable duplexes upon hybridization to their complementary DNA strands and display favorable fluorescent features.

Greco, Nicholas J.; Tor, Yitzhak



Study of Electrical Analogue for Electrodialysis.  

National Technical Information Service (NTIS)

The objectives of the study were to formulate a general mathematical equation for electrodialysis based on considering the process as an electrical network composed of resistive elements representative of various electrochemical processes and to apply the...

C. Berger G. A. Guter G. Belfort



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

NASA Astrophysics Data System (ADS)

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

Orgel, Csilla; Kereszturi, Ákos; Váczi, Tamás; Groemer, Gernot; Sattler, Birgit



Isobaric Analogue States Studied in Mirrored Fragmentation and Knockout Reactions  

SciTech Connect

A Gamma-ray spectroscopic study of excited states of isobaric multiplets has been performed in recent years, with a view to gaining a quantitative understanding of energy differences between excited states in terms of a range of Coulomb and other isospin breaking phenomena. Recently, the experimental programme has been augmented by a study of isobaric analogue states of mirror nuclei populated in mirrored fragmentation reactions. In this presentation, recent results on the T = 3/2 analogue states in the T{sub z} = {+-} 3/2 mirror pair {sup 53}Ni/{sup 53}Mn will be summarised. In this work, further strong evidence is found for the need to include an anomalous isospin-breaking two-body matrix element for angular-momentum couplings of J = 2, in addition the expected Coulomb contribution, in order to account for the experimental data.

Bentley, M.A.; Pritychenko, B.; Paterson,I.; Brown,J.R.; Taylor,M.J.; Digen,C.Aa.; Adrich,P.; Bazin,D.; Cook.J.M.; Gade,A.; Glasmacher,T.; McDaniel,S.; Ratkiewicz,A.; Siwek,K.; D.Weisshaar,D.; Pritychenko,B.; Lenzi,S.M.



Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor  

PubMed Central

A series of triazolylpurine analogues show interesting and unintuitive structure?activity relationships against the A2A adenosine receptor. As the 2-substituted aliphatic group is initially increased to methyl and isopropyl, there is a decrease in potency; however, extending the substituent to n-butyl and n-pentyl results in a significant gain in potency. This trend cannot be readily explained by ligand?receptor interactions, steric effects, or differences in ligand desolvation. Here, we show that a novel method for characterizing solvent thermodynamics in protein binding sites correctly predicts the trend in binding affinity for this series based on the differential water displacement patterns. In brief, small unfavorable substituents occupy a region in the A2A adenosine receptor binding site predicted to contain stable waters, while the longer favorable substituents extend to a region that contains several unstable waters. The predicted binding energies associated with displacing water within these hydration sites correlate well with the experimental activities.



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

NASA Astrophysics Data System (ADS)

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

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



Photochemical dihydrogen production using an analogue of the active site of [NiFe] hydrogenase.  


Photoproduction of dihydrogen (H2) by a low molecular weight analogue of the active site of [NiFe] hydrogenase has been investigated by reduction of the [NiFe2] cluster, 1, by a photosensitier PS (PS = [ReCl(CO)3(bpy)] or [Ru(bpy)3][PF6]2). Reductive quenching of the (3)MLCT excited state of the photosensitizer by NEt3 or N(CH2CH2OH)3 (TEOA) generates PS(•-), and subsequent intermolecular electron transfer to 1 produces the reduced anionic form of 1. Time-resolved infrared spectroscopy (TRIR) has been used to probe the intermediates throughout the reduction of 1 and subsequent photocatalytic H2 production from [HTEOA][BF4], which was monitored by gas chromatography. Two structural isomers of the reduced form of 1 (1a(•-) and 1b(•-)) were detected by Fourier transform infrared spectroscopy (FTIR) in both CH3CN and DMF (dimethylformamide), while only 1a(•-) was detected in CH2Cl2. Structures for these intermediates are proposed from the results of density functional theory calculations and FTIR spectroscopy. 1a(•-) is assigned to a similar structure to 1 with six terminal carbonyl ligands, while calculations suggest that in 1b(•-) two of the carbonyl groups bridge the Fe centers, consistent with the peak observed at 1714 cm(-1) in the FTIR spectrum for 1b(•-) in CH3CN, assigned to a ?(CO) stretching vibration. Formation of 1a(•-) and 1b(•-) and production of H2 was studied in CH3CN, DMF, and CH2Cl2. Although the more catalytically active species (1a(•-) or 1b(•-)) could not be determined, photocatalysis was observed only in CH3CN and DMF. PMID:24749646

Summers, Peter A; Dawson, Joe; Ghiotto, Fabio; Hanson-Heine, Magnus W D; Vuong, Khuong Q; Davies, E Stephen; Sun, Xue-Z; Besley, Nicholas A; McMaster, Jonathan; George, Michael W; Schröder, Martin



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

PubMed Central

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

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



Geomorphological and hydrogeological features of the Pocos de Caldas caldera and the Osamu Utsumi mine and Morro do Ferro analogue study sites, Brazil. Pocos de Caldas Report No. 5.  

National Technical Information Service (NTIS)

The Osamu Utsumi mine and Morro do Ferro study sites lie within the Pocos de Caldas plateau which is roughly circular in outline with a diameter of 35 km and an area of approximately 800 km(sup 2). Its general altitude lies between 1300 and 1600 m. The pl...

D. C. Holmes A. E. Pitty D. J. Noy



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

NASA Astrophysics Data System (ADS)

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 ?13CCH4 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.

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



Metallic fluoride complexes as phosphate analogues for structural and mechanistic studies of phosphoryl group transfer enzymes.  


There have been intensive efforts to try to understand the details of phosphoryl transfer reactions extending from nonenzymatic (or enzyme model) systems to the mechanisms of the enzyme catalysed reactions. As phosphate analogues, few metallic fluorides AlFx, BeFx and MgFx affect the activity of a variety of phosphoryl transfer enzymes, and it is accepted that these small inorganic complexes are useful chemical probes for structural and mechanistic studies in enzymology because they are able to mimic phosphoryl group in ground state (BeFx) as well as in transition state (AlFx,MgFx). Al3+ and Be2+ tend to form stable complexes with different fluoride anions (x = 1 to 4) spontaneously in aqueous solution but Mg2+ does not. BeFx geometry is strictly tetrahedral resembling the phosphate ground state when bound to an acyl group of protein active site (phosphorylated acyl groups are unstable otherwise), or the Michaelis complex when BeFx concominantly with nucleoside diphosphate replaces g-phosphate group in nucleoside triphosphate sites. AlFx and MgFx are identified as enzymatic analogues of phosphoryl transition state where both are able to form different coordination geometries within the enzyme active sites: trigonal bipyramidal (AlF3 and MgF3-) or octahedral (AlF4- or MgF42-). The geometry and charge of MgF3- are the best suited to mimicking the trigonal planar PO3- moiety of phosphoryl transfer transition state but MgF3- does not, unlike aluminum and beryllium fluoride complexes, exists in solution and can be assembled and stabilized in suitable active site only. Therefore it is particularly interesting to characterize as a potentially highly accurate transition state analogue and may be the best reagent of choice for studying phosphoryl transfer reactions in future. PMID:24061722

Goli?nik, Marko



Synthesis of Two-Dimensional Analogues of Copolymers by Site-to-Site Transmetalation of Organometallic Monolayer Sheets.  


Monolayer sheets have gained attention due to the unique properties derived from their two-dimensional structure. One of the key challenges in sheet modification/synthesis is to exchange integral parts while keeping them intact. We describe site-to-site transmetalation of Zn(2+) in the netpoints of cm(2)-sized, metal-organic sheets by Fe(2+), Co(2+), and Pb(2+). This novel transformation was done both randomly and at predetermined patterns defined by photolithography to create monolayer sheets composed of different netpoints. All transmetalated sheets are mechanically strong enough to be spanned over 20 × 20 ?m(2) sized holes. Density functional theory calculations provide both a model for the molecular structure of an Fe(2+)-based sheet and first insights into how transmetalation proceeds. Such transmetalated sheets with random and patterned netpoints can be considered as two-dimensional analogues of linear copolymers. Their nanoscale synthesis presents an advance in monolayer/polymer chemistry with applications in fields such as surface coating, molecular electronics, device fabrication, imaging, and sensing. PMID:24673195

Zheng, Zhikun; Opilik, Lothar; Schiffmann, Florian; Liu, Wei; Bergamini, Giacomo; Ceroni, Paola; Lee, Lay-Theng; Schütz, Andri; Sakamoto, Junji; Zenobi, Renato; Vandevondele, Joost; Schlüter, A Dieter



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

NASA Astrophysics Data System (ADS)

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 ? v/? D' (?=porosity, D'=effective diffusion coefficient in rock matrix, ?=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 Maqarin site, is used as input for numerical simulations of the hyperalkaline groundwater infiltration along fractures. The width of the alteration zones in the rock matrix bordering fractures is also used to constrain mineral dissolution rates in the field. The simulations predict that ettringite [Ca 6Al 2(SO 4) 3(OH) 12·26H 2O] with lesser amounts of hillebrandite and tobermorite (hydrated calcium silicates or CSH phases) will be the dominant alteration products forming at the expense of the primary silicates in the rock matrix and fracture, in agreement with observations at the Maqarin site. The simulations also come close to matching the pH of water samples collected along fractures at the M1 and M2 sites, with a fracture aperture of 0.22 mm giving the closest match with the pH data (within 13% of the value indicated by the rock matrix alteration widths). The simulations suggest two possible scenarios for the time evolution of the fracture-rock matrix system. Where rate constants for secondary mineral precipitation reactions are the same in both the rock matrix and fracture, the rock matrix tends to become completely cemented before the fracture. This results in a downstream migration of the hyperalkaline plume. In contrast, if rates are as little as one order of magnitude higher in the fracture than in the rock matrix, it is possible to seal the fracture first, thus causing the mineral zones to collapse upstream as a result of the reduction in fracture permeability. Sealing of fractures is observed at Maqarin and the simulations predict a mineral paragenesis in the fracture resulting from this scenario which is broadly compatible with field observations.

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



Aquaculture Siting Study.  

National Technical Information Service (NTIS)

The Aquaculture Siting Study documents the analysis of potential visual and cumulative impacts from proposed aquaculture facilities. The intent is to provide an environmental assessment tool for use in evaluating and regulating these facilities.



Mutation of a conserved residue enhances the sensitivity of analogue-sensitised kinases to generate a novel approach to the study of mitosis in fission yeast.  


The chemical genetic strategy in which mutational enlargement of the ATP-binding site sensitises of a protein kinase to bulky ATP analogues has proved to be an elegant tool for the generation of conditional analogue-sensitive kinase alleles in a variety of model organisms. Here, we describe a novel substitution mutation in the kinase domain that can enhance the sensitivity of analogue-sensitive kinases. Substitution of a methionine residue to phenylalanine in the +2 position after HRDLKxxN motif of the subdomain VIb within the kinase domain markedly increased the sensitivities of the analogue-sensitive kinases to ATP analogues in three out of five S. pombe kinases (i.e. Plo1, Orb5 and Wee1) that harbor this conserved methionine residue. Kinome alignment established that a methionine residue is found at this site in 5-9% of kinases in key model organisms, suggesting that a broader application of this structural modification may enhance ATP analogue sensitivity of analogue-sensitive kinases in future studies. We also show that the enhanced sensitivity of the wee1.as8 allele in a cdc25.22 background can be exploited to generate highly synchronised mitotic and S phase progression at 36°C. Proof-of-principle experiments show how this novel synchronisation technique will prove of great use in the interrogation of the mitotic or S-phase functions through temperature sensitivity mutation of molecules of interest in fission yeast. PMID:23986474

Tay, Ye-Dee; Patel, Avinash; Kaemena, Daniel F; Hagan, Iain M



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

NASA Astrophysics Data System (ADS)

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.

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



Synthesis, receptor binding, and CNS pharmacological studies of new thyrotropin-releasing hormone (TRH) analogues.  


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??M for TRH-R1 and 0.016??M 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??M, but activated TRH-R1 at EC50=0.05??M, 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??mol?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

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



Raman and Mössbauer Spectroscopic Characterisation of Sulfate Minerals from the Mars Analogue Sites at Rio Tinto and Jaroso Ravine, Spain  

NASA Astrophysics Data System (ADS)

A combined Raman and Mössbauer spectroscopic study of natural sulfates from two martian analogues, Rio Tinto and Jaroso Ravine (Spain), is presented. The work was performed in similar experimental conditions to those envisaged for Mars surface within the ExoMars mission.

Rull, F.; Fleischer, I.; Martinez-Frias, J.; Sanz, A.; Upadhyay, C.; Klingelhöfer, G.



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

NASA Astrophysics Data System (ADS)

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

Felix, C. V.; Gini, A.


Subunit interactions of tryptophan synthase from Escherichia coli as revealed by binding studies with pyridoxal phosphate analogues.  


An improved purification procedure for the alpha 2 beta 2 complex of tryptophan synthase from Escherichia coli has been developed. It consists of DEAE-Sephacel chromatography, followed by hydrophobic chromatography on Sepharose CL 4B, and leads to material with a higher specific activity than reported previously. Inhibition studies, equilibrium dialysis, and spectrophotometric titration were used to study the binding both of pyridoxal phosphate analogues and of bisubstrate analogues. Pyridoxine 5'-phospate and N-phosphopyridoxyl-L-serine bind to the enzyme, but pyridoxamine 5'-phoshate and N-phosphopridoxyl-L-alanine do not. N-Phosphopyridoxyl-L-tryptophan is bound only weakly, although L-tyrptophan binds strongly to the alpha 2 holo beta 2 complex. It is likely that either differences is protonation or in geometry are responsible for the low affinity of the bisubstrate analogues in comparison to that of the external aldimines of either L-serine or L-tyrptophan with pyridoxal 5'-phosphate. As previously found with pyridoxal 5'-phosphate, pyridoxine 5'-phosphate, and N-phosphopryidoxyl-L-serine bind noncooperatively to two identical binding sites in the alpha 2 apo beta 2 complex. The same ligands bind with positive cooperatively to two binding sites in the apo beta 2 subunit. Because the analogues mimic the binding behavior of pyridoxal 5'-phosphate to both proteins, the internal aldimine of pyridoxal 5'-phosphate to the lysine amino group contributes only to the strength of that binding. The nickel apo beta 2 subunit, which is produced by limited proteolysis with trypsin, binds pyroxine 5'-phosphate noncooperatively to two identical sites. Therefore, the loop of polypeptide chain connecting the two autonomous domains of folding must be intact for enzyme activity, for the binding of the alpha subunit, and for cooperative binding of pyridoxine 5'-phosphate. PMID:6996720

Tschopp, J; Kirschner, K



QSAR study on some pyridoacridine ascididemin analogues as anti-tumor agents  

Microsoft Academic Search

Pyridoacridine ascididemin analogues have been reported as anticancer agents for their interesting antitumor activity against human cancer cells. A quantitative structure–activity relationship (QSAR) analysis of ascididemin analogues was attempted using the physicochemical parameters and the electrotopological state atom (ETSA) indices. This study indicates that the electron withdrawing substituents with higher MR (molar refractivity) value at R1 position favor the anti-tumor

Bikash Debnath; Shovanlal Gayen; Subrata Bhattacharya; Soma Samanta; Tarun Jha



Conformational studies of neurohypophyseal hormones analogues with glycoconjugates by NMR spectroscopy.  


Two glycosylated peptides have been studied using NMR spectroscopy supported by molecular modeling. Peptide I is an oxytocin (OT) analogue in which glutamine 4 was replaced by serine with attached ?-d-mannose through the oxygen ? atom, whereas peptide II is a lysine-vasopressin (LVP) analogue with lysine 8 side chain modified by the attachment of glucuronic acid through an amide bond. Both peptides exhibit very weak uterotonic effect and are less susceptible to proteolytic degradation than the mother hormones. Additionally, peptide II reveals very weak pressor and antidiuretic activities. Our results have shown that the conformational preferences of glycosylated analogues are highly similar to those of their respective mother hormones. OT glycosylated analogue (I) exhibits a 3,4 ?-turn characteristic of OT-like peptides, and vasopressin-glycosylated analogue (II) exhibits??-turns typical of vasopressin-like peptides. Therefore, the lack of binding of the glycosylated analogues to the receptors can be attributed to a steric interference between the carbohydrate moieties and the receptors. We also consider this to be the reason of the very low activity of the analyzed glycopeptides. We expect that results from these studies will be helpful in designing new OT-like and vasopressin-like drugs. PMID:24644276

Lubecka, Emilia A; Sikorska, Emilia; Marcinkowska, Alina; Ciarkowski, Jerzy



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

SciTech Connect

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

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



A biomimetic approach to oxidized sites in the xanthine oxidoreductase family: synthesis and stereochemistry of tungsten(VI) analogue complexes.  


Two series of square pyramidal (SP) monodithiolene complexes, [M (VI)O 3- n S n (bdt)] (2-) and their silylated derivatives [M (VI)O 2- n S n (OSiR 3)(bdt)] (-) ( n = 0, M = Mo or W; n = 1, 2, M = W), synthesized in this and previous work, constitute the basic molecules in a biomimetic approach to structural analogues of the oxidized sites in the xanthine oxidoreductase enzyme family. Benzene-1,2-dithiolate (bdt) simulates native pyranopterindithiolene chelation in the basal plane, tungsten instead of the native metal molybdenum was employed in sulfido complexes to avoid autoreduction, and silylation models protonation. The complexes [MO 3(bdt)] (2-) and [MO 2(OSiR 3)(bdt)] (-) represent inactive sites, while [MO 2S(bdt)] (2-) and [MOS(OSiR 3)(bdt)] (-), with basal sulfido and silyloxo ligands, are the first analogues of the catalytic sites. Also prepared were [MOS 2(bdt)] (2-) and [MS 2(OSiR 3)(bdt)] (-), with basal sulfido and silyloxo ligands. Complexes are described by angular parameters which reveal occasional distortions from idealized SP toward a trigonal bipyramidal (TBP) structure arising from crystal packing forces in crystalline Et 4N (+) salts. Miminized energy structures from DFT calculations are uniformly SP and reproduce experimental structures. For example, the correct structure is predicted for [WO 2S(bdt)] (2-), whose basal and apical sulfido diastereomers are potentially interconvertible through a low-lying TBP transition state for pseudorotation. The lowest energy tautomer of the protonated form is calculated to be [WOS(OH)(bdt)] (-), with basal sulfido and hydroxo ligands. Computational and experimental structures indicate that protein sites adopt intrinsic coordination geometries rather than those dictated by protein structure and environment. PMID:18763763

Groysman, Stanislav; Wang, Jun-Jieh; Tagore, Ranitendranath; Lee, Sonny C; Holm, R H



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

SciTech Connect

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

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



Molecular dynamics study of the conformations of glycosidic linkages in sialic acid modified ganglioside GM3 analogues.  


The objective of the present study is to model the analogues of monosialoganglioside (GM3) by making modifications in its sialic acid residue with different substitutions in aqueous environment and to determine their structural stability based upon computational molecular dynamics. Molecular mechanics and molecular dynamics investigation was carried out to study the conformational preferences of the analogues of GM3. Dynamic simulations were carried out on the analogues of GM3 varying in the substituents at C-1, C-4, C-5, C-8 and C-9 positions of their sialic acid or Neuraminic acid (NeuAc) residue. The analogues are soaked in a periodic box of TIP3P water as solvent and subjected to a 10 ns molecular dynamics (MD) simulation using AMBER ff03 and gaff force fields with 30 ps equilibration. The analogue of GM3 with 9-N-succNeuAc (analogue5, C9 substitution) was observed to have the lowest energy of -6112.5 kcal/mol. Graphical analysis made on the MD trajectory reveals the direct and water mediated hydrogen bonds existing in these sialic acid analogues. The preferable conformations for glycosidic linkages of GM3 analogues found in different minimum energy regions in the conformational maps were identified. This study sheds light on the conformational preferences of GM3 analogues which may be essential for the design of GM3 analogues as inhibitors for different ganglioside specific pathogenic proteins such as bacterial toxins, influenza toxins and neuraminidases. PMID:24909815

Jaishree, G; Sharmila, D Jeya Sundara



A standardised study to compare prostate cancer targeting efficacy of five radiolabelled bombesin analogues  

PubMed Central

Purpose Prostate-specific antigen (PSA)-based screening for prostate cancer (PC) has dramatically increased early diagnosis. Current imaging techniques are not optimal to stage early PC adequately. A promising alternative to PC imaging is peptide-based scintigraphy using radiolabelled bombesin (BN) analogues that bind to gastrin-releasing peptide receptors (GRPR) being overexpressed in PC. When labelled to appropriate radionuclides BN targeting of GRPRs may also provide applications for peptide radionuclide receptor therapy (PRRT). Assessment studies under identical experimental conditions allowing a reliable comparison of the potential of such analogues are lacking. This study was performed to evaluate and directly compare five promising radiolabelled BN analogues for their targeting efficacy for PC under standardised conditions. Methods The BN agonists [111In]DOTA-PESIN, [111In]AMBA, [111In]MP2346 and [111In]MP2653 and one antagonist [99mTc]Demobesin-1 were evaluated in GRPR-overexpressing human PC-3 tumour-bearing mice to determine peptide stability in vivo, biodistribution and GRPR targeting potential by animal SPECT/CT imaging and ex vivo autoradiography. Results HPLC analysis of blood showed intact Demobesin-1 at 5 and 15 min after injection (64.1?±?1.6% and 41.0?±?01%, respectively) being much less for the other compounds. AMBA, the second most stable analogue, showed 36.1?±?2.7% and 9.8?±?1.1% intact peptide after 5 and 15 min. PC-3 tumour uptake at 1 h was comparable for Demobesin-1, AMBA, PESIN and MP2346 (3.0?±?0.4, 2.7?±?0.5, 2.3?±?0.5 and 2.1?±?0.9%ID/g, respectively), but very low for MP2653 (0.9?±?0.2%ID/g). In addition, MP2346 showed undesirably high uptake in the kidneys (7.9?±?1.9%ID/g) being significantly less for the other analogues. AMBA, MP2346 and PESIN revealed favourable increases in tumour to blood ratios over time while changes in tumour to kidney and pancreas ratios for Demobesin-1 from 1 to 24 h after injection were significantly better than for the other analogues. All analogues visualised PC-3 tumours by SPECT/CT and autoradiography. Conclusion In the present study the BN antagonist Demobesin-1 was the best performing analogue showing superior in vivo stability, highest tumour uptake and retention while pancreatic and renal clearance were rapid. PESIN and AMBA were the best GRP agonists with sufficient in vivo stabilities as well as high tumour uptake and retention. Based on these results all three analogues deserve further evaluation for clinical use in PC patients.

Muller, Cristina; Reneman, Suzanne; Melis, Marleen L.; Breeman, Wout A. P.; de Blois, Erik; Bangma, Chris H.; Krenning, Eric P.; van Weerden, Wytske M.; de Jong, Marion



Synthesis and Cytotoxicity Studies of Titanocene C Analogues  

PubMed Central

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? ?M for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene in this paper, 5c with an IC50 value of 13??M, was found to be approximately two times less cytotoxic than its analogue Titanocene C (IC50=5.5??M) and almost four times less cytotoxic than cisplatin, which showed an IC50 value of 3.3??M when tested on the LLC-PK cell line.

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



DFT studies on Schiff base formation of vitamin B6 analogues. Reaction between a pyridoxamine-analogue and carbonyl compounds.  


A comprehensive theoretical study based on density functional theory calculations (B3LYP and M06-2X functionals) of the formation of Schiff bases of pyridoxamine analogues with two different aldehydes was conducted. The reaction mechanism was found to involve two steps, namely: (1) formation of a carbinolamine and (2) dehydration of the carbinolamine to give the final imine. Also, consistent with available experimental evidence, the carbinolamine dehydration was the rate-determining step of the process determined by means of M06-2X functional. Using an appropriate solvation method and reactant conformation ensures that all proton transfers involved will be intramolecular, which substantially reduces energy barriers and facilitates reaction in all cases. The formation of a Schiff base between pyridoxal 5-phosphate (PLP) and an amine or amino acid requires the contribution of an external water molecule in order to facilitate proton transfers. On the other hand, the formation of a Schiff base between pyridoxamine 5-phosphate (PMP) and a carbonyl compound requires no external aid since the spatial arrangement of the functional groups in PMP ensures that all proton transfers will be intramolecular. PMID:20235562

Ortega-Castro, J; Adrover, M; Frau, J; Salvà, A; Donoso, J; Muñoz, F



Studies on the hypolipdemic and estrogenic activities of 2,8-dibenzylcyclooctanone and its analogues.  


The effects of 2,8-dibenzylcyclooctanone (DBCO) and a series of its analogues on serum lipids and on estrogenic activity in rats were studied. Assays of the estrogenicity of DBCO showed that although the compound is a very weak estrogen, it exhibited estrogenic activity at doses that were hypolipidemic. Among the analogues, only those containing the dibenzylcyclooctanone system were active. All compounds demonstrating hypocholesterolemic activity, except the weakly active compound 15, also reduced the weights of the seminal vesicles and ventral prostate and increased the weight of the adrenal gland. Compounds containing a benzylidene group or reduced ketone group did not exhibit any activity. It is concluded that the hypocholesterolemic activity of the structural analogues of DBCO is correlated with their estrogenicity. PMID:942454

Cayen, M N; Dubuc, J; Givner, M L; Greselin, E; Revesz, C



Structures and excitation energies of Zn–tetraarylporphyrin analogues: A theoretical study  

Microsoft Academic Search

The photophysical properties of ?-substituted Zn–tetraarylporphyrin (ZnTAP) analogues used as dyes in dye-sensitized solar cells were studied using density functional theory (DFT). Singlet-excitation energy calculations of ZnTAP analogues were performed using time-dependent DFT with B3LYP, B3PW91, PBE0 exchange–correlation functionals at 6-31G(d) and 6-31+G(d) basis sets using B3LYP\\/6-31G(d) geometries. The PBE0 functional at 6-31+G(d) basis set provided a better correlation with

Mannix P. Balanay; Dong Hee Kim



Oxo transfer reactions mediated by bis(dithiolene)tungsten analogues of the active sites of molybdoenzymes in the DMSO reductase family: comparative reactivity of tungsten and molybdenum.  


The discovery of tungsten enzymes and molybdenum/tungsten isoenzymes, in which the mononuclear catalytic sites contain a metal chelated by one or two pterin-dithiolene cofactor ligands, has lent new significance to tungsten-dithiolene chemistry. Reaction of [W(CO)(2)(S(2)C(2)Me(2))(2)] with RO(-) affords a series of square pyramidal desoxo complexes [W(IV)(OR')(S(2)C(2)Me(2))(2)](1)(-), including R' = Ph (1) and Pr(i)() (3). Reaction of 1 and 3 with Me(3)NO gives the cis-octahedral complexes [W(VI)O(OR')(S(2)C(2)Me(2))(2)](1)(-), including R' = Ph (6) and Pr(i)() (8). These W(IV,VI) complexes are considered unconstrained versions of protein-bound sites of DMSOR and TMAOR (DMSOR = dimethylsulfoxide reductase, TMAOR = trimethylamine N-oxide reductase) members of the title enzyme family. The structure of 6 and the catalytic center of one DMSO reductase isoenzyme have similar overall stereochemistry and comparable bond lengths. The minimal oxo transfer reaction paradigm thought to apply to enzymes, W(IV) + XO --> W(VI)O + X, has been investigated. Direct oxo transfer was demonstrated by isotope transfer from Ph(2)Se(18)O. Complex 1 reacts cleanly and completely with various substrates XO to afford 6 and product X in second-order reactions with associative transition states. The substrate reactivity order with 1 is Me(3)NO > Ph(3)AsO > pyO (pyridine N-oxide) > R(2)SO > Ph(3)PO. For reaction of 3 with Me(3)NO, k(2) = 0.93 M(-)(1) s(-)(1), and for 1 with Me(2)SO, k(2) = 3.9 x 10(-)(5) M(-)(1) s(-)(1); other rate constants and activation parameters are reported. These results demonstrate that bis(dithiolene)W(IV) complexes are competent to reduce both N-oxides and S-oxides; DMSORs reduce both substrate types, but TMAORs are reported to reduce only N-oxides. Comparison of k(cat)/K(M) data for isoenzymes and k(2) values for isostructural analogue complexes reveals that catalytic and stoichiometric oxo transfer, respectively, from substrate to metal is faster with tungsten and from metal to substrate is faster with molybdenum. These results constitute a kinetic metal effect in direct oxo transfer reactions for analogue complexes and for isoenzymes provided the catalytic sites are isostructural. The nature of the transition state in oxo transfer reactions of analogues is tentatively considered. This research presents the first kinetics study of substrate reduction via oxo transfer mediated by bis(dithiolene)tungsten complexes. PMID:11456814

Sung, K M; Holm, R H



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

NASA Astrophysics Data System (ADS)

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.

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



Synthesis and pharmacological study of a thiophene analogue of moprolol and related compounds.  


The syntheses of the thiophenic analogue of Moprolol (1d) and of its related compound 1a are described. From a preliminary pharmacological evaluation compound 1d seems worthy of further studies due to its notable beta-blocking activity and its remarkable anti-platelet aggregation action. PMID:1675047

el-Ashmawy, M B; Lissavetzky, J; Darias, V; Martín-Herrera, D



Synthesis and preliminary pharmacological study of thiophene analogues of the antipyretic and analgesic agent ethenzamide.  


A preliminary pharmacological study of a thiophene analogue 1b of the analgesic and antipyretic agent Ethenzamide and of a closely related compound 1a showed that a great similarity exists among Ethenzamide and the thiophenic compounds for analgesic, antipyretic, ulcerogenic, hypothermic, and sedative effects. However, the acute toxicity in mice for the thiophenic compounds is notably higher than that of Ethenzamide. PMID:1605721

Darias, V; Bravo, L; Abdallah, S S; Sánchez Mateo, C C; Expósito-Orta, M A; Lissavetsky, J; Manzanares, J



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)

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

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.



Bioavailability study of oral and intravenous OGT 719, a novel nucleoside analogue with preferential activity in the liver  

Microsoft Academic Search

Purpose: Although oral fluoropyrimidine prodrugs are increasingly being administered in preference to intravenous nucleoside analogues in cancer chemotherapy, their activation in malignant liver tissue may be insufficient. OGT 719 (1-galactopyranosyl-5-fluorouracil) is a novel nucleoside analogue, preferentially localized in hepatocytes and hepatoma cells via the asialoglycoprotein receptor. The aim of this study was to assess the systemic bioavailability of this rationally

Ricky A. Sharma; Martin M. Eatock; Christopher J. Twelves; Gill Brown; Heather R. McLelland; Kathryn T. Clayton; Kenneth J. O'Byrne; Chris Moyses; James Carmichael; William P. Steward



Influence of a fluorobenzene nucleobase analogue on the conformational flexibility of RNA studied by molecular dynamics simulations.  


Chemically modified bases are frequently used to stabilize nucleic acids, to study the driving forces for nucleic acid structure formation and to tune DNA and RNA hybridization conditions. In particular, fluorobenzene and fluorobenzimidazole base analogues can act as universal bases able to pair with any natural base and to stabilize RNA duplex formation. Although these base analogues are compatible with an A-form RNA geometry, little is known about the influence on the fine structure and conformational dynamics of RNA. In the present study, nano-second molecular dynamics (MD) simulations have been performed to characterize the dynamics of RNA duplexes containing a central 1'-deoxy-1'-(2,4-difluorophenyl)-beta-D-ribofuranose base pair or opposite to an adenine base. For comparison, RNA with a central uridine:adenine pair and a 1'-deoxy-1'-(phenyl)-beta-D-ribofuranose opposite to an adenine was also investigated. The MD simulations indicate a stable overall A-form geometry for the RNAs with base analogues. However, the presence of the base analogues caused a locally enhanced mobility of the central bases inducing mainly base pair shear and opening motions. No stable 'base-paired' geometry was found for the base analogue pair or the base analogue:adenine pairs, which explains in part the universal base character of these analogues. Instead, the conformational fluctuations of the base analogues lead to an enhanced accessibility of the bases in the major and minor grooves of the helix compared with a regular base pair. PMID:15576356

Zacharias, Martin; Engels, Joachim W



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

NASA Astrophysics Data System (ADS)

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.

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



Cognitive processing, memory, and the development of PTSD symptoms: two experimental analogue studies.  


Memory deficits are implicated in the development of posttraumatic stress disorder (PTSD). Intentional recall of trauma memories is frequently disorganised or incomplete, whilst involuntary memory fragments are easily triggered by perceptual cues. Ehlers and Clark (Behaviour Research and Therapy 38 (2000) 319-345) propose that a predominance of data-driven processing (i.e., processing sensory impressions) during the trauma contributes to the development of this memory pattern, and therefore, predicts PTSD symptoms after trauma. Two experimental studies examined these hypotheses. Student volunteers viewed a distressing videotape as an analogue for a traumatic event. In Study 1, cognitive processing was manipulated; in Study 2, extreme scorers on a processing screening questionnaire were pre-selected. The results indicated that data-driven processing is associated with the development of PTSD-like memories and analogue symptoms. PMID:12472172

Halligan, Sarah L; Clark, David M; Ehlers, Anke



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

NASA Astrophysics Data System (ADS)

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.

McKinley, Ian G.; Russell Alexander, W.



Study Site Inventory Balance Report

NIH-986 (REV. 02/04) 12/00 Study Site Inventory Balance Report DCP Version of NIH Form 986 Address: (Including Institution) Email address: Re: Inventory balance return for Dr. study entitled FOR NCI USE ONLY DIVISION OF


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

NASA Astrophysics Data System (ADS)

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.

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


A Spectral, Chemical and Mineralogical Study of Mars Analogue Rocks  

NASA Technical Reports Server (NTRS)

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.

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



Photodesorption of interstellar ice analogues: a wavelength-dependent study  

Microsoft Academic Search

In the cold parts of star-forming regions, molecules such as H_2O and CO are expected to be completely frozen out onto dust grains. Yet these molecules are found in cold gas in dense clouds and protoplanetary disks; their presence may be explained by UV-induced photodesorption. Recent astrophysically relevant study on ice photodesorption (Westley et al. 1995 ; Öberg et al.

E. Fayolle; M. Bertin; C. Romanzin; X. Michaut; K. Oberg; H. Linnartz; J. H. Fillion



Organometallic nucleoside analogues with ferrocenyl linker groups: synthesis and cancer cell line studies.  


Examples of organometallic compounds as nucleoside analogues are rare within the field of medicinal bioorganometallic chemistry. We report on the synthesis and properties of two chiral ferrocene derivatives containing a nucleobase and a hydroxyalkyl group. These so-called ferronucleosides show promising anticancer activity, with cytostatic studies on five different cancer cell lines indicating that both functional groups are required for optimal activity. PMID:24905419

Nguyen, Huy V; Sallustrau, Antoine; Balzarini, Jan; Bedford, Matthew R; Eden, John C; Georgousi, Niki; Hodges, Nikolas J; Kedge, Jonathan; Mehellou, Youcef; Tselepis, Chris; Tucker, James H R



FMR thermomagnetic studies up to 900 C of lunar soils and potential magnetic analogues  

Microsoft Academic Search

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

Richard V. Morris; Rex V. Gibbons; F. Hoerz



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

Microsoft Academic Search

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

Thomas Ehring; Anna-Kristina Szeimies; Christina Schaffrick



Lincoln Related Sites: Special Study.  

National Technical Information Service (NTIS)

The purpose of this study is to evaluate six sites associated with Abraham Lincoln in the Springfield, Illinois, area and to find a means for protecting and interpreting them. The sites are: New Salem Village, Petersburg; Colonel Matthew Rogers Store, Ath...



QSAR study on some pyridoacridine ascididemin analogues as anti-tumor agents.  


Pyridoacridine ascididemin analogues have been reported as anticancer agents for their interesting antitumor activity against human cancer cells. A quantitative structure-activity relationship (QSAR) analysis of ascididemin analogues was attempted using the physicochemical parameters and the electrotopological state atom (ETSA) indices. This study indicates that the electron withdrawing substituents with higher MR (molar refractivity) value at R(1) position favor the anti-tumor activity and the presence of NHR (R is hydrogen or alkyl group) at the R(3) position has contribution to the anti-tumor activity. ETSA indices have been incorporated as independent variable in the QSAR model with physicochemical parameters. It clearly suggests the importance of atoms 2, 3, 4, 5, 6 and 7 to the anti-tumor activity. PMID:14642593

Debnath, Bikash; Gayen, Shovanlal; Bhattacharya, Subrata; Samanta, Soma; Jha, Tarun



Defining the selectivity of processes along the auxin response chain: a study using auxin analogues.  


The mode of action of auxin is based on its non-uniform distribution within tissues and organs. Despite the wide use of several auxin analogues in research and agriculture, little is known about the specificity of different auxin-related transport and signalling processes towards these compounds. Using seedlings of Arabidopsis thaliana and suspension-cultured cells of Nicotiana tabacum (BY-2), the physiological activity of several auxin analogues was investigated, together with their capacity to induce auxin-dependent gene expression, to inhibit endocytosis and to be transported across the plasma membrane. This study shows that the specificity criteria for different auxin-related processes vary widely. Notably, the special behaviour of some synthetic auxin analogues suggests that they might be useful tools in investigations of the molecular mechanism of auxin action. Thus, due to their differential stimulatory effects on DR5 expression, indole-3-propionic (IPA) and 2,4,5-trichlorophenoxy acetic (2,4,5-T) acids can serve in studies of TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALLING F-BOX (TIR1/AFB)-mediated auxin signalling, and 5-fluoroindole-3-acetic acid (5-F-IAA) can help to discriminate between transcriptional and non-transcriptional pathways of auxin signalling. The results demonstrate that the major determinants for the auxin-like physiological potential of a particular compound are very complex and involve its chemical and metabolic stability, its ability to distribute in tissues in a polar manner and its activity towards auxin signalling machinery. PMID:23914741

Simon, Sibu; Kubeš, Martin; Baster, Pawel; Robert, Stéphanie; Dobrev, Petre Ivanov; Friml, Ji?í; Petrášek, Jan; Zažímalová, Eva



N-site-lattice analogues of V(x)=ix3  

NASA Astrophysics Data System (ADS)

A discrete N-level alternative to the popular imaginary cubic oscillator is proposed and studied. As usual, the unitarity of evolution is guaranteed by the introduction of an ad hoc, Hamiltonian-dependent inner-product metric, the use of which defines the physical Hilbert space and renders the Hamiltonian (with real spectrum) observable. Due to the simplicity of our model of dynamics the construction of the set of eligible metrics is shown tractable by non-numerical means which combine the computer-assisted algebra with the extrapolation and/or perturbation techniques.

Znojil, Miloslav



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

SciTech Connect

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

Galas, M.C.; Lignon, M.F.; Rodriguez, M.; Mendre, C.; Fulcrand, P.; Laur, J.; Martinez, J. (Centre de Pharmacologie-Endocrinologie, Montpellier (France))



DNA-sequence specific recognition by a thiazole analogue of netropsin: a comparative footprinting study.  

PubMed Central

Four different footprinting techniques have been used to probe the DNA sequence selectivity of Thia-Net, a bis-cationic analogue of the minor groove binder netropsin in which the N-methylpyrrole moieties are replaced by thiazole groups. In Thia-Net the ring nitrogen atoms are directed into the minor groove where they could accept hydrogen bonds from the exocyclic 2-amino group of guanine. Three nucleases (DNAase I, DNAase II, and micrococcal nuclease) were employed to detect binding sites on the 160bp tyr T fragment obtained from plasmid pKM delta-98, and further experiments were performed with 117mer and 253mer fragments cut out of the plasmid pBS. MPE.Fe(II) was used to footprint binding sites on an EcoRI/HindIII fragment from pBR322. Thia-Net binds to sites in the minor groove containing 4 or 5 base pairs which are predominantly composed of alternating A and T residues, but with significant acceptance of intrusive GC base pairs. Unlike the parent antibiotic netropsin, Thia-Net discriminates against homooligomeric runs of A and T. The evident preference of Thia-Net for AT-rich sites, despite its containing thiazole nitrogens capable of accepting GC sites by hydrogen bonding, supports the view that the biscationic nature of the ligand imposes a bias due to the electrostatic potential differences in the receptor which favour the ligand reading alternating AT sequences. Images

Plouvier, B; Bailly, C; Houssin, R; Rao, K E; Lown, W J; Henichart, J P; Waring, M J



Reduction of progressive burn injury by a stable prostaglandin I 2 analogue, beraprost sodium (Procylin): an experimental study in rats  

Microsoft Academic Search

Beraprost sodium is a chemically stable prostaglandin I2 analogue with antiplatelet and vasodilator actions. Burn injury causes thrombosis and vessel occlusion by increasing the blood viscosity and by thermal damage to the vascular network in the dermis. A vascular response also occurs in the uninjured dermis surrounding the site of injury. Diminished blood flow and spreading tissue oedema lead to

M. N. Battal; Y. Hata; K. Matsuka; O. Ito; H. Matsuda; Y. Yoshida; T. Kawazoe



Synthesis and SAR studies of 3-phenoxypropyl piperidine analogues as ORL1 (NOP) receptor agonists.  


A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified. PMID:15664818

Palin, Ronald; Barn, David R; Clark, John K; Cottney, Jean E; Cowley, Phillip M; Crockatt, Marc; Evans, Louise; Feilden, Helen; Goodwin, Richard R; Griekspoor, Frank; Grove, Simon J A; Houghton, Andrea K; Jones, Philip S; Morphy, Richard J; Smith, Alasdair R C; Sundaram, Hardy; Vrolijk, David; Weston, Mark A; Wishart, Grant; Wren, Paul



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


1. The aim of this study was to find taurinergic compounds that do not interact with brain GABA ergic systems. 2. Washed synaptic membranes (SM) from whole rabbit brain were able to bind [(3)H]muscimol. Saturation experiments of the binding of [(3)H]GABA to GABA(B) receptors showed that SM possess two binding components; twice Triton X-100-treated SM contained 0.048 mmol endogenous taurine/kg protein and bound [(3)H]taurine in a saturable manner (K(d)=249.0+/-6.3 nM and B(max)=3.4+/-1.0 pmol mg(-1) prot). 3. 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 [(3)H]taurine binding (K(i)=0.13, 0.13, 13.5 and 4.0 micro M, respectively). These analogues did not interact with GABA(A) and GABA(B) receptors and did not affect taurine- and GABA-uptake systems and GABA-transaminase activity. 4. 3-Aminopropanesulfonic acid (OMO), beta-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 [(3)H]muscimol binding to GABA(A) receptors with different affinities (K(i)=0.013, 7.9, 24.6, 47.5, 52.0, 91.0, 47.5, 118.1 and 166.3 micro M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [(3)H]GABA to GABA(B) receptors with K(i)'s in the micro M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC(50)=3.72 micro M) and PSA GABA transaminase activity (IC(50)=103.0 micro M). 5. In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents. PMID:12684273

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



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

PubMed Central

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 ?M, 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), ?-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 ?M, respectively). Taurine, 2-aminoethylphosphonic acid, DMT, TMT and OMO inhibited the binding of [3H]GABA to GABAB receptors with Ki's in the ?M range (0.8, 3.5, 4.4, 11.3 and 5.0, respectively). GES inhibited taurine uptake (IC50=3.72 ?M) and PSA GABA transaminase activity (IC50=103.0 ?M). In conclusion, AEA, TAG, ISE and CAHS fulfill the criteria for taurinergic agents.

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



Structure-activity studies of antitumor agent irofulven (hydroxymethylacylfulvene) and analogues.  


Many analogues of the antitumor agent irofulven have been readily prepared by replacing the allylic hydroxyl with a variety of nucleophiles. Analogues of acylfulvene (the precursor to irofulven) were also prepared by Michael reaction with acrolein. The toxicity of the analogues was determined, as well as preclinical antitumor activity. Several analogues exhibited good activity in mouse xenografts. Structural requirements for activity are discussed. PMID:11529745

McMorris, T C; Yu, J; Lira, R; Dawe, R; MacDonald, J R; Waters, S J; Estes, L A; Kelner, M J



Micelle-bound conformations of neurohypophyseal hormone analogues modified with a C?-disubstituted residue: NMR and molecular modelling studies  

Microsoft Academic Search

In this study, by applying a combined approach of NMR measurements and molecular modelling, the conformations and the interactions with membrane-like environment of five arginine vasopressin (AVP) or oxytocin (OT) analogues modified with C?-disubstituted cis-1-amino-4-phenylcyclohexane-1-carboxylic acid in position 2 have been determined. In addition, the AVP analogues were prepared in N-acylated forms with various bulky acyl groups. All of the

Emilia Sikorska; Anna Kwiatkowska



Social Studies. [SITE 2002 Section].  

ERIC Educational Resources Information Center

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…



Synthesis, cytotoxicity against human oral cancer KB cells and structure-activity relationship studies of trienone analogues of curcuminoids.  


A general method for the synthesis of substituted (1E,4E,6E)-1,7-diphenylhepta-1,4,6-trien-3-ones, based on the aldol condensations of substituted 4-phenylbut-3-en-2-ones and substituted 3-phenylacrylaldehydes, was achieved. The natural trienones 4 and 5 have been synthesized by this method, together with the trienone analogues 9-20. These analogues were evaluated for their cytotoxic activity against human oral cancer KB cell line. The structure-activity relationship study has indicated that the analogues with the 1,4,6-trien-3-one function are more potent than the curcuminoid-type function. Analogues with meta-oxygen function on the aromatic rings are more potent than those in the ortho- and para-positions. Free phenolic hydroxy group is more potent than the corresponding methyl ether analogues. Among the potent trienones, compounds 11, 18 and 20 were more active than the anticancer drug ellipticine. All compounds were also evaluated against the non-cancerous Vero cells and it was found that compounds 11, 12 and 17 were much less toxic than curcumin (1); they showed high selectivity indices of 35.46, 33.46 and 31.68, respectively. These analogues are regarded as the potent trienones for anti-oral cancer study. PMID:24857542

Chuprajob, Thipphawan; Changtam, Chatchawan; Chokchaisiri, Ratchanaporn; Chunglok, Warangkana; Sornkaew, Nilubon; Suksamrarn, Apichart



Social Studies. [SITE 2001 Section].  

ERIC Educational Resources Information Center

This document contains the following papers on social studies from the SITE (Society for Information Technology & Teacher Education) 2001 conference: (1) "Teacher's Guide to the Holocaust: An Extensive Online Resource for Teachers" (Ann E. Barron and others); (2) "Preparing a Virtual Field Trip To Teach Value of Community and Sense of Place"…

White, Cameron, Ed.


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


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

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



Behavior of fluorescent cholesterol analogues dehydroergosterol and cholestatrienol in lipid bilayers: a molecular dynamics study.  


Molecular dynamics simulations of bilayer systems consisting of varying proportions of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), cholesterol (Chol), and intrinsically fluorescent Chol analogues dehydroergosterol (DHE) or cholestatrienol (CTL) were carried out to study in detail the extent to which these fluorescent probes mimic Chol's behavior (location, orientation, dynamics) in membranes as well as their effect on host bilayer structure and dynamics (namely their ability to induce membrane ordering in comparison with Chol). Control properties of POPC and POPC/Chol bilayers agree well with published experimental and simulation work. Both probes and Chol share similar structural and dynamical properties within the bilayers. Additionally, the fluorescent sterols induce membrane ordering to a similar (slightly lower) extent to that of Chol. These findings combined demonstrate that the two studied fluorescent sterols are adequate analogues of Chol, and may be used with advantage over side-chain labeled sterols. The small structural differences between the three studied sterols are responsible for the slight variations in the calculated properties, with CTL presenting a more similar behavior to Chol (correlating with its larger structural similarity to Chol) compared to DHE. PMID:23597397

Robalo, João R; do Canto, António M T Martins; Carvalho, A J Palace; Ramalho, J P Prates; Loura, Luís M S



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

NASA Astrophysics Data System (ADS)

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

Ruiz-Chica, A. J.; Medina, M. A.; Sánchez-Jiménez, F.; Ramírez, F. J.



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)

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.

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.



Palmottu analogue project. Progress Report 1992.  

National Technical Information Service (NTIS)

The report gives a summary of the results of investigations carried out in 1992 at the Palmottu natural analogue study site, which is a small U-Th mineralization in Nummi-Pusula, southwestern Finland. Additionally, the report includes several separate art...

L. Ahonen R. Blomqvist J. Suksi



Biological Evaluation and 3D-QSAR Studies of Curcumin Analogues as Aldehyde Dehydrogenase 1 Inhibitors.  


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

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



Docking and 3D-QSAR Studies on Isatin Sulfonamide Analogues as Caspase-3 Inhibitors  

PubMed Central

To provide insight of their inhibition mechanism and facilitate the design of more potent ligands, a series of 59 isatin sulfonamide analogues were docked to the X-ray structure of caspase-3, one of the important cysteine aspartyl-specific execution proteases in apoptosis, and their binding conformations were analyzed by 3D-QSAR studies. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) studies suggest that both steric and electrostatic interactions contribute to the compounds’ binding affinity, with the major contribution arising from hydrophobic interactions. The models show excellent correlation and high predictive power even evaluated by the most stringent criteria for a QSAR model. The results of this work demonstrate that structure-based design methods (such as docking) cultivate the development of reliable QSAR models, they also illustrate the utility of this procedure in design of new potent caspase-3 ligands.

Wang, Qi; Mach, Robert H.; Reichert, David E.



Biological Evaluation and 3D-QSAR Studies of Curcumin Analogues as Aldehyde Dehydrogenase 1 Inhibitors  

PubMed Central

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.

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



Effects of keto-analogues on phosphocalcic and aminoacid metabolism in dialysed patients: a crossover study.  


It has been suggested that calcium salts of keto-analogues (KA) have beneficial effects on phosphocalcic and aminoacid (AA) metabolism. To confirm this, their short-term effects were evaluated on chronic dialyzed patients. In a prospective, randomised, crossover study, eight and seven patients were put on KA (200 mg/kg/d) and assigned either a low-protein diet (LP:0.4 g/kg/d) or a normal one (NP: 1 g/kg/d) for 15 days. The two treatments were interchanged after 15 days of washout. KA.LP was accompanied by: a) decreases in calorie intake (12%; p = 0.001) and in blood concentrations of albumin (5%, p = 0.004), urea (32%, p = 0.001), phosphate (29%, p = 0.001), parathormone (27%, p = 0.008), isoleucine (24%, p = 0.04), 1 and 3 methyl-histidine (71%, p = 0.03; 24%, p = 0.005), valine (19%, p = 0.004) and hydroxyproline (85%, p = 0.009); b) increases in calcemia (9%, p = 0.002), cystathionine (991%, p = 0.0001) and threonine (22%, p = 0.04). KA.NP was accompanied by: a) decreases in phosphatemia (15%, p = 0.03) and parathormone (18%, p = 0.06); b) increases in calcemia (9%, p = 0.002), cystathionine (427%, p = 0.0001), and phenylalanine (28%, p = 0.013). Calcium salts of keto-analogues together with a low or normal protein diet thus seem to reduce blood concentrations of phosphates and parathormone, and raise calcium; however their action on aminoacids needs further investigation. PMID:2599668

Mahmoud, M D; Bouche, V; Collin, P; Girault, A



Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site.  


Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization. PMID:24489681

Kwon, Young Do; LaLonde, Judith M; Yang, Yongping; Elban, Mark A; Sugawara, Akihiro; Courter, Joel R; Jones, David M; Smith, Amos B; Debnath, Asim K; Kwong, Peter D




Microsoft Academic Search

This outcrop analogue study investigates Triassic fluvial sandstones of the Stubensandstein Formation which were deposited on a terminal alluvial plain under semi- arid to sub-humid climatic conditions in the land-locked South German Keuper Basin. The Stubensandstein may serve as an analogue for reservoir units in comparable continental basins. Data came from studies of 13 large sandpits, together with a subsurface

J. Hornung; T. Aigner



The cholecystokinin analogues JMV-180 and CCK-8 stimulate phospholipase C through the same binding site of CCKA receptor in rat pancreatic acini  

PubMed Central

This study was designed to address the controversy related to the involvement of phospholipase C in the signalling pathway linked to CCKA receptor stimulation by the cholecystokinin analogue JMV-180, a full agonist for amylase release, in rat pancreatic acini. JMV-180 was shown to stimulate phospholipase C by measuring the incorporation of [32P]-orthophosphoric acid ([32P]-Pi) into phosphatidic acid (PtdOH) and phosphatidylinositol (PtdIns). Both responses elicited by JMV-180 were time and concentration dependent. Maximal effects elicited by JMV-180 were 39.08±0.72 and 8.02±0.40% for the labelling of [32P]-PtdIns and [32P]-PtdOH, respectively, as compared to the maximal effects of CCK-8, a full agonist of the CCKA receptor. [32P]-Pi incorporation into PtdOH and PtdIns was sensitive to lithium, demonstrating that both responses are a consequence of phospholipase C activation. However, since lithium blocks the phosphoinositide cycle by an uncompetitive mechanism, its effect was only apparent at high concentrations of CCK-8 (>10?pM), which elicited stimuli above 20 and 60% of the maximal [32P]-PtdOH and [32P]-PtdIns labelling, respectively. JMV-180 inhibited the incorporation of [32P]-Pi into PtdOH and PtdIns as stimulated by CCK-8, down to its own maximal effect. The estimated IC50 values for the inhibition curves were not significantly different from those calculated assuming the same single binding site for both agonists. These results indicated that the well established role of JMV-180 as a partial agonist for CCKA receptor-linked signalling responses, also applies for the stimulation of phospholipase C. The comparison of CCK-8 and JMV-180 dose-response curves of amylase release to those of PtdIns and PtdOH labelling with [32P]-Pi showed the existence of an amplification mechanism between phospholipase C and amylase release for both agonists. In conclusion, we show that JMV-180, as well as CCK-8, stimulate phospholipase C upon interaction with the same binding site at the CCKA receptor in rat pancreatic acini.

Sarri, Elisabet; Ramos, Belen; Salido, Gines M; Claro, Enrique



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

PubMed Central

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.

Jaronczyk, Malgorzata; Wolosewicz, Karol; Gabrielsen, Mari; Nowak, Gabriel; Kufareva, Irina; Mazurek, Aleksander P.; Ravna, Aina W.; Abagyan, Ruben; Bojarski, Andrzej J.; Sylte, Ingebrigt; Chilmonczyk, Zdzislaw



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

PubMed Central

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.

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



Measuring fast-temporal sediment fluxes with an analogue acoustic sensor: a wind tunnel study.  


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

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



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


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

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



Interaction studies to evaluate 2- carboxyphenolate analogues as inhibitor of anti-apoptotic protein Bcl-2  

PubMed Central

Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, pro-apoptotic proteins bind anti-apoptotic proteins, thus allowing apoptosis to go forward. An excess of anti-apoptotic proteins can prevent apoptosis. Designed molecules that imitate the roles of pro-apoptotic proteins can promote the death of cancer cells. In this work we have applied an insilico approach to study the binding of 2-carboxyphenolate analogues as potent inhibitors of anti-apoptotic protein Bcl-2. Molecular docking study was performed in order to find specific binding mode using AutoDock. From the docking results it was observed that zinc 2- carboxyphenolate showed strong inhibition with Bcl-2 with docking energy of -4.6 kcal/mol. The effects of the Zinc 2- hydroxybenzoate on apoptosis in HT-1080 cell lines were also analysed, which shows strong evidence for their apoptotic mode of action using flow cytometric analysis of Annexin-V. Our study gave valuable insights on inhibitor specificity of anti-apoptotic proteins and might be considered as potent chemopreventive agents.

Al-Karaawi, Mohammed A



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


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

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



Lower Rate of Cardiovascular Complications in Patients on Bolus Insulin Analogues: A Retrospective Population-Based Cohort Study  

PubMed Central

Background Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases. Methods A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. The incidence of diabetic complications was ascertained by hospital discharge claims. Hazard ratios (HRs) and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients’ characteristics and anti-diabetic drug use. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups. Results A total of 2,286 patients were included: 914 receiving human regular insulin and 1,372 rapid-acting insulin analogues. During the follow-up, 286 (31.3%) incident events occurred in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group. After propensity score-based matched-pair analyses, rapid-acting insulin analogues users had a HR of 0.73 (0.58–0.92) for any diabetes-related complication and HRs of 0.73 (0.55–0.93) and 0.55 (0.32–0.96) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications. Conclusions Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.

Cammarota, Simona; Falconio, Lucio Marcello; Bruzzese, Dario; Catapano, Alberico Luigi; Casula, Manuela; Citarella, Anna; De Luca, Luigi; Flacco, Maria Elena; Manzoli, Lamberto; Masulli, Maria; Menditto, Enrica; Mezzetti, Andrea; Riegler, Salvatore; Novellino, Ettore; Riccardi, Gabriele



A strategy for fusion expression and preparation of functional glucagon-like peptide-1 (GLP-1) analogue by introducing an enterokinase cleavage site.  


KGLP-1, a 31-amino acid glucagon-like peptide-1 (GLP-1) analogue, has a great therapeutic potential for anti-diabetes. In this work, a strategy for expression and purification of functional KGLP-1 peptide has been established. KGLP-1 cDNA was fused with glutathione S-transferase (GST), with an enterokinase cleavage site in the fusion junction. The recombinant fusion protein GST-KGLP-1 was affinity purified via the GST-tag, and then digested with enterokinase. The resulting GST part as well as the enzymes were eliminated by ultra-filtration followed by size exclusion chromatograph. The yield of purified KGLP-1 was approximately 12.1 mg/L, with purity of 96.18 %. The recombinant KGLP-1 was shown to have similar bioactivity as native GLP-1 when evaluated in a Chinese hamster ovary cell line expressing a GLP-1 receptor-egfp reporter gene. PMID:24737080

Liu, Yang; Ren, Limei; Ge, Lingmiao; Cui, Qingxin; Cao, Xiaofang; Hou, Yuanyuan; Bai, Fang; Bai, Gang



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

PubMed Central

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

Lopez-Munguia, Agustin; Hernandez-Romero, Yanet; Pedraza-Chaverri, Jose; Miranda-Molina, Alfonso; Regla, Ignacio; Martinez, Ana; Castillo, Edmundo



Hyperspectral Study of Hydrous Magnesium Minerals (Serpentine) from Ultramafic Rocks Along the Rikhabhdev Lineament, Rajasthan, India: As an Analogue for Hydrous Magnesium Minerals on Mars  

NASA Astrophysics Data System (ADS)

The ultramafic rocks along the Rikhabhdev Lineament, Rajasthan, India is consider as a good analogue for the study study of serpentine. This study help in interpreting the environmental conditions on Mars in its past.

Jain, N.; Bhattacharya, S.; Chauhan, P.; Ajai



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

PubMed Central

In this study the ? 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 (? 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.

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



Study of hydrophobic properties of biologically active open analogues of flavonoids.  


Hydrophobicity can either be determined experimentally or predicted by means of commercially available programs. In the studies concerning biological activities of pyrazine analogues of chalcones, 3-(2-hydroxyphenyl)-1-(pyrazin-2-yl)prop-2-en-1-ones were more potent than the corresponding 3-(4-hydroxyphenyl)-1-(pyrazin-2-yl)prop-2-en-1-ones. As the difference in lipophilicity may be a factor responsible for the difference in the potency, R(M) values of the compounds were determined by RP-TLC and compared with logP values calculated by various commercially available programs. Important discrepancies were found between experimental and computational lipophilicity data. Therefore, we have tried to find a reliable method for calculating R(M) values from in silico derived molecular parameters. The R(M) values obtained with the chromatographic system consisting of Silufol UV 254 plates impregnated with silicon oil as the stationary phase and acetone-citrate buffer (pH=3) 50:50 (v/v) as the mobile phase correlated well with van der Waals volumes (V(W)) and hydration energies [Formula: see text] derived of molecular models calculated on RHF/AM1 level. PMID:23220282

Opletalová, Veronika; Kastner, Petr; Ku?erová-Chlupá?ová, Marta; Palát, Karel



A comparative study of two novel nanosized radiolabeled analogues of methionine for SPECT tumor imaging.  


It has been reported that most tumor cells show an increased uptake of variety of amino acids specially methionine when compared with normal cells and amino acid transport is generally increased in malignant transformation. Based on the evidences, two novel nanosized analogues of methionine (Anionic Linear Globular Dendrimer G(2), a biodigredabale anionic linear globular-Methionin, and DTPA-Methionine(1) conjugates) were synthesized and labeled with (99m)Tc and used in tumor imaging/ therapy in vitro and in vivo. The results showed marked tumor SPECT molecular imaging liabilities for both compounds but with a better performance by administration of (99m)Tc-Dendrimer G(2)-Methionin. The results also showed a good anticancer activity for 99mTc-DTPA-Methionine. Based on the present study (99m)Tc-Dendrimer G(2)-Methionin or 99mTc-DTPA-(Methionine)(1) have potentials to be used in tumor molecular imaging as well as cancer therapy in future. PMID:22963619

Khosroshahi, A G; Amanlou, M; Sabzevari, O; Daha, F J; Aghasadeghi, M R; Ghorbani, M; Ardestani, M S; Alavidjeh, M S; Sadat, S M; Pouriayevali, M H; Mousavi, L; Ebrahimi, S E S



Mechanistic studies on the enzymatic processing of fluorinated methionine analogues by Trichomonas vaginalis methionine ?-lyase.  


TFM (L-trifluoromethionine), a potential prodrug, was reported to be toxic towards human pathogens that express MGL (L-methionine ?-lyase; EC, a pyridoxal phosphate-containing enzyme that converts L-methionine into ?-oxobutyrate, ammonia and methyl mercaptan. It has been hypothesized that the extremely reactive thiocarbonyl difluoride is produced when the enzyme acts upon TFM, resulting in cellular toxicity. The potential application of the fluorinated thiomethyl group in other areas of biochemistry and medicinal chemistry requires additional studies. Therefore a detailed investigation of the theoretical and experimental chemistry and biochemistry of these fluorinated groups (CF?S? and CF?HS?) has been undertaken to trap and identify chemical intermediates produced by enzyme processing of molecules containing these fluorinated moieties. TvMGL (MGL from Trichomonas vaginalis) and a chemical model system of the reaction were utilized in order to investigate the cofactor-dependent activation of TFM and previously uninvestigated DFM (L-difluoromethionine). The differences in toxicity between TFM and DFM were evaluated against Escherichia coli expressing TvMGL1, as well as the intact human pathogen T. vaginalis. The relationship between the chemical structure of the reactive intermediates produced from the enzymatic processing of these analogues and their cellular toxicity are discussed. PMID:21658005

Moya, Ignace A; Westrop, Gareth D; Coombs, Graham H; Honek, John F



A study of faulting patterns in the Pearl River Mouth Basin through analogue modeling  

NASA Astrophysics Data System (ADS)

The Pearl River Mouth Basin is one of the most favorable areas for gas exploration on the northern slope of the South China Sea. Differences of fault patterns between shelf and slope are obvious. In order to investigate the tectonic evolution, five series of analogue modeling experiments were compared. The aim of this study is to investigate how crustal thickness influences fault structures, and compare this to the observed present-day fault structures in the Pearl River Mouth Basin. The initial lithospheric rheological structure can be derived from the best fit between the modeled and observed faults. The results indicate. (1) Different initial crustal rheological structures can produce different rift structures in the Pearl River Mouth Basin. (2) We also model that the Baiyun Sag in the southern Pearl River Mouth Basin may have had a thinned crust before rifting compared to the rest of the basin. (3) The thickness ratio of brittle to ductile crust in southern Pearl River Mouth Basin is less than normal crust, suggesting an initially hot and weak lithosphere. (4) Slightly south of the divergent boundary magma may have taken part in the rifting process during the active rift stage.

Zhang, Yun Fan; Sun, Zhen



Impact of informed-choice invitations on diabetes screening knowledge, attitude and intentions: an analogue study  

PubMed Central

Background Despite concerns that facilitating informed choice would decrease diabetes screening uptake, 'informed choice' invitations that increased knowledge did not affect attendance (the DICISION trial). We explored possible reasons using data from an experimental analogue study undertaken to develop the invitations. We tested a model of the impact on knowledge, attitude and intentions of a diabetes screening invitation designed to facilitate informed choices. Methods 417 men and women aged 40-69 recruited from town centres in the UK were randomised to receive either an invitation for diabetes screening designed to facilitate informed choice or a standard type of invitation. Knowledge of the invitation, attitude towards diabetes screening, and intention to attend for diabetes screening were assessed two weeks later. Results Attitude was a strong predictor of screening intentions (? = .64, p = .001). Knowledge added to the model but was a weak predictor of intentions (? = .13, p = .005). However, invitation type did not predict attitudes towards screening but did predict knowledge (? = -.45, p = .001), which mediated a small effect of invitation type on intention (indirect ? = -.06, p = .017). Conclusions These findings may explain why information about the benefits and harms of screening did not reduce diabetes screening attendance in the DICISION trial.




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...


Industrial Sites Study: Poplar Bluff, Missouri.  

National Technical Information Service (NTIS)

The study is to determine the most appropriate site for expansion of Poplar Bluff's municipal industrial park. Consideration is given to existing park, as well as, potential sites throughout the urban area. Several factors will determine most advantageous...



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

PubMed Central

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

Puttagunta, A L; Toth, E L



High Resolution Study of the g9\\/2 Isobaric Analogue State in 61Cu  

Microsoft Academic Search

The g9\\/2 isobaric analogue state (IAS) in 61Cu has been investigated by the 60Ni(p, p)60Ni and (p, gamma)61Cu reaction using high energy-resolution (overall \\\\varDelta E~=350 eV) proton beams. Resonances at Ep(lab.)=3723, 3732, 3737 and 3743 keV are identified as fragments of the IAS of the g9\\/2 state in 61Ni. Proton widths and radiative widths of these isobaric analogue resonances (IAR's)

Minoru Adachi; Toshiyuki Hattori; Eiichi Arai; Masao Ogawa; Haruo Satoh



Pharmacokinetic studies of vitamin D analogues: relationship to vitamin D binding protein (DBP)  

Microsoft Academic Search

Vitamin D3, 25-hydroxyvitamin D3 (25OHD3) and 1?,25-dihydroxyvitamin D3 (1?,25(OH)2D3) bind to the vitamin D binding protein (DBP) in the serum. During the development of synthetic vitamin D analogues, it has\\u000a been shown that the majority of analogues bind to DBP with a low affinity. This modifies their biological activitiesin vitro compared to 1?,25(OH)2D3, since binding to DBP decreases the cellular

A.-M. Kissmeyer; I. S. Mathiasen; S. Latini; L. Binderup



Sensing of hydrophobic cavity of serum albumin by an adenosine analogue: fluorescence correlation and ensemble spectroscopic studies.  


Adenosine is a naturally occurring purine nucleoside that plays important role in various biochemical processes. We have studied the binding of TNP-Ado (trinitrophenylated-adenosine), a fluorescent analogue of adenosine (which itself is a weak fluorophore), with a model transport protein, bovine serum albumin (BSA). The binding affinity was determined using Fluorescence correlation spectroscopy (FCS) and compared with its value obtained from macroscopic fluorescence spectroscopic studies. Fluorescence and circular dichroism (CD) spectroscopies were employed together with molecular docking study to locate the probable binding site of TNP-Ado on BSA and its effect on the conformation and stability of BSA. Fluorescence studies showed that TNP-Ado binds to BSA in 1:1 stoichiometry via an entropically favoured process. Induced CD spectra revealed that a chiro-optical switching of TNP-Ado occurs upon binding to BSA. Results on urea-induced denaturation of BSA and docking study suggested that the binding site for the ligand is in the hydrophobic subdomain IIA of BSA, consistent with the results of other measurements. This study establishes TNP-Ado as a sensor of hydrophobic regions in proteins like serum albumin, having the capability of detecting a minimum concentration of 140ng/ml protein. FCS measurement of binding interaction of rhodamine-labeled TNP-Ado (RTNP-Ado) with BSA yielded an association constant of KFCS=(1.03±0.06) × 10(4)M(-1). The association constants (Ka) obtained for binding of BSA with rhodamine-free (i.e. TNP-Ado) and rhodamine-labeled (RTNP-Ado) ligands, obtained using the ensemble spectroscopic technique, were (2.3±0.06) × 10(5)M(-1) and (3.4±0.03) × 10(4)M(-1), respectively. The difference between the values of Ka for the free and labeled ligands suggests that fluorescent labeling of small molecules perceptibly interferes with the binding process. On the other hand, the difference in Ka obtained by FCS and ensemble techniques is due to the fact that while the former measures the change in the diffusion constant (i.e. size) of RTNP-Ado upon binding to BSA, the latter focuses on the change of tryptophan emission properties of BSA due to the presence of bound RTNP-Ado. PMID:24061159

Nag, Moupriya; Bera, Kallol; Chakraborty, Sandipan; Basak, Soumen



Photosensitive epilepsy: a model to study the effects of antiepileptic drugs. Evaluation of the piracetam analogue, levetiracetam  

Microsoft Academic Search

The experimental antiepileptic drug, levetiracetam (UCB L059), a piracetam analogue has been investigated in photosensitive patients in the “photosensitivity model”, an early phaseII study. A total of 12 patients (10 females, 2 males) with a mean age of 21.5 years (range 13–38) were investigated during a 3 day period in 3 centres (France, The Netherlands, Germany), using the same standardised

D. G. A. Kasteleijn-Nolst Trenité; C. Marescaux; S. Stodieck; P. M. Edelbroek; J. Oosting



A pilot study of a long acting somatostatin analogue for the treatment of refractory rheumatoid arthritis  

Microsoft Academic Search

OBJECTIVETo evaluate the efficacy and safety of a long acting somatostatin analogue in a subset of patients with refractory rheumatoid arthritis (RA).METHODSTen patients with active, refractory RA, who had failed to respond to at least four disease modifying antirheumatic drugs (DMARDs), were treated with monthly intramuscular injections of 20 mg of a long acting preparation of octreotide (Sandostatin-LAR) for three

D Paran; O Elkayam; A Mayo; H Paran; M Amit; M Yaron; D Caspi



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

SciTech Connect

{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.

Birdsall, B.; Tendler, S.J.B.; Feeney, J.; Carr, M.D. (National Institute for Medical Research, London (United Kingdom)); Arnold, J.R.P.; Thomas, J.A.; Roberts, G.C.K. (Univ. of Leicester (United Kingdom)); Griffin, R.J.; Stevens, M.F.G. (Aston Univ., Birmingham (United Kingdom))



Structure-activity relationship studies of illudins: analogues possessing a spiro-cyclobutane ring.  


Bicyclic and tricyclic analogues of anticancer sesquiterpene illudin S have been synthesized. These contain a spiro-cyclobutane instead of spiro-cyclopropane structure. The cytotoxicity of the former is less than that of the corresponding cyclopropane-containing compounds. PMID:14656090

McMorris, Trevor C; Cong, Qiang; Kelner, Michael J



Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues  

Microsoft Academic Search

Artemisinin (Qinghaosu) is a natural constituent found in Artemisia annua L, which is an effective drug against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria. The antimalarial activities of artemisinin and its analogues appear to be mediated by the interactions of the drugs with hemin. In order to understand the antimalarial mechanism and the relationship between the physicochemical properties and the

Feng Cheng; Jianhua Shen; Xiaomin Luo; Weiliang Zhu; Jiande Gu; Ruyun Ji; Hualiang Jiang; Kaixian Chen



Studies on the novel ?-glucosidase inhibitory activity and structure–activity relationships for andrographolide analogues  

Microsoft Academic Search

A series of analogues of andrographolide were synthesized and evaluated as novel ?-glucosidase inhibitors. Among them compound 23, 15-p-methoxylbenzylidene 14-deoxy-11,12-didehydroandrographolide, was a potent inhibitor against ?-glucosidase whose IC50 value was 16?M. The structure–activity relationships were also discussed.

Gui-Fu Dai; Hai-Wei Xu; Jun-Feng Wang; Feng-Wu Liu; Hong-Min Liu



A comparative study of proapoptotic potential of cyano analogues of boswellic acid and 11-keto-boswellic acid.  


Semi-synthetic analogues of ?-boswellic acid (BA) and 11-keto-?-boswellic acid (KBA) were comparatively evaluated for in vitro cytotoxicity against human myeloid leukaemia (HL-60) and human cervical carcinoma (HeLa) cells. 2-Cyano analogues of both the triterpenes were observed to have significant cytotoxicity against both the cells, displaying cytotoxicity in HL-60 cells at low concentrations. Further investigations suggested the proapoptotic potential associated with the two molecules to induce cytotoxicity in HL-60 cells, where one of them showed early proapoptotic effect as evidenced by several biological end-points of the apoptosis such as annexinV binding, DNA fragmentation and increase in sub-G0 DNA fraction and apoptotic bodies formation (Hoechst 33258 staining and SEM studies). PMID:21334793

Kaur, Rajbir; Khan, Sheema; Chib, Renu; Kaur, Tandeep; Sharma, Parduman Raj; Singh, Jaswant; Shah, Bhahwal Ali; Taneja, Subhash Chandra



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


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

Jindal, Garima; Sunoj, Raghavan B



Determination of the substrate binding mode to the active site iron of (S)-2-hydroxypropylphosphonic acid epoxidase using 17O-enriched substrates and substrate analogues.  


(S)-2-Hydroxypropylphosphonic acid epoxidase (HppE) is an O2-dependent, nonheme Fe(II)-containing oxidase that converts (S)-2-hydroxypropylphosphonic acid ((S)-HPP) to the regio- and enantiomerically specific epoxide, fosfomycin. Use of (R)-2-hydroxypropylphosphonic acid ((R)-HPP) yields the 2-keto-adduct rather than the epoxide. Here we report the chemical synthesis of a range of HPP analogues designed to probe the basis for this specificity. In past studies, NO has been used as an O2 surrogate to provide an EPR probe of the Fe(II) environment. These studies suggest that O2 binds to the iron, and substrates bind in a single orientation that strongly perturbs the iron environment. Recently, the X-ray crystal structure showed direct binding of the substrate to the iron, but both monodentate (via the phosphonate) and chelated (via the hydroxyl and phosphonate) orientations were observed. In the current study, hyperfine broadening of the homogeneous S = 3/2 EPR spectrum of the HppE-NO-HPP complex was observed when either the hydroxyl or the phosphonate group of HPP was enriched with 17O (I = 5/2). These results indicate that both functional groups of HPP bind to Fe(II) ion at the same time as NO, suggesting that the chelated substrate binding mode dominates in solution. (R)- and (S)-analogue compounds that maintained the core structure of HPP but added bulky terminal groups were turned over to give products analogous to those from (R)- and (S)-HPP, respectively. In contrast, substrate analogues lacking either the phosphonate or hydroxyl group were not turned over. Elongation of the carbon chain between the hydroxyl and phosphonate allowed binding to the iron in a variety of orientations to give keto and diol products at positions determined by the hydroxyl substituent, but no stable epoxide was formed. These studies show the importance of the Fe(II)-substrate chelate structure to active antibiotic formation. This fixed orientation may align the substrate next to the iron-bound activated oxygen species thought to mediate hydrogen atom abstraction from the nearest substrate carbon. PMID:17927218

Yan, Feng; Moon, Sung-Ju; Liu, Pinghua; Zhao, Zongbao; Lipscomb, John D; Liu, Aimin; Liu, Hung-wen



Receptor-binding studies of 1-N-substituted melatonin analogues.  


In order to analyse the relevance of the indole electronic region in the binding of melatonin to its receptors, we prepared several analogues with p-H, p-NO(2), p-MeO, p-F and p-Me of benzyl, benzoyl and phenyl substituents at position 1 of the melatonin skeleton. The electronic properties of the analogues, as calculated with the semiempirical method AM1, were correlated with their affinity for the melatonin receptor from chicken brain membranes. Different trends were observed for each compound series. Compound 5c, with a p-NO(2)-benzoyl group, showed the best affinity indicating the importance of a polar bulky group in the receptor interaction. PMID:12660019

Lira-Rocha, Alfonso; Espejo-González, Ofelia; Naranjo-Rodríguez, Elia B



A standardised study to compare prostate cancer targeting efficacy of five radiolabelled bombesin analogues  

Microsoft Academic Search

Purpose  Prostate-specific antigen (PSA)-based screening for prostate cancer (PC) has dramatically increased early diagnosis. Current\\u000a imaging techniques are not optimal to stage early PC adequately. A promising alternative to PC imaging is peptide-based scintigraphy\\u000a using radiolabelled bombesin (BN) analogues that bind to gastrin-releasing peptide receptors (GRPR) being overexpressed in\\u000a PC. When labelled to appropriate radionuclides BN targeting of GRPRs may also

Rogier P. J. Schroeder; Cristina Müller; Suzanne Reneman; Marleen L. Melis; Wout A. P. Breeman; Erik de Blois; Chris H. Bangma; Eric P. Krenning; Wytske M. van Weerden; Marion de Jong



Choleretic activity of phloracetophenone in rats: structure-function studies using acetophenone analogues.  


The relationship between the chemical structure and choleretic activity of phloracetophenone (2,4,6-trihydroxyacetophenone) was investigated in adult male rats. Fourteen acetophenone analogues, with different substituents on the benzene nucleus, were intraduodenally administered and bile samples were collected via a bile fistula. All of the compounds tested immediately induced choleresis. For the same number of substituents on the benzene ring, hydroxy analogues induced a greater choleresis. The number and position of hydroxy substituents on the benzene nucleus play an important role in determining choleretic activity and biliary secretion of bile acid, but had no relation to biliary excretion of cholesterol. The choleretic activity of the hydroxylated compounds was inversely related to hydrophobicity, as inferred by thin-layer chromatography (TLC). Among the hydroxylated acetophenone analogues, 2,4,6-trihydroxyacetophenone was identified as the most potent, with a choleretic activity of 231.8+/-6.1 microl/mmol/min. It induced both a high bile flow rate and a high bile salt output and led to lower plasma cholesterol levels. This bile had a low lithogenic potential. The results suggest that a structural requirement for high choleretic activity of 2,4,6-trihydroxyacetophenone is a substituent hydroxy group at 4-position. Additional hydroxy groups at 2- and 6-positions are essential for the induction of higher an output of bile acid, and possibly, other solid materials. PMID:10650163

Piyachaturawat, P; Chai-ngam, N; Chuncharunee, A; Komaratat, P; Suksamrarn, A



Studies with substrate and cofactor analogues provide evidence for a radical mechanism in the chorismate synthase reaction.  


Chorismate synthase catalyzes the conversion of 5-enolpyruvylshikimate 3-phosphate (EPSP) to chorismate. The strict requirement for a reduced FMN cofactor and a trans-1,4-elimination are unusual. (6R)-6-Fluoro-EPSP was shown to be converted to chorismate stoichiometrically with enzyme-active sites in the presence of dithionite. This conversion was associated with the oxidation of FMN to give a stable flavin semiquinone. The IC(50) of the fluorinated substrate analogue was 0.5 and 250 microm with the Escherichia coli enzyme, depending on whether it was preincubated with the enzyme or not. The lack of dissociation of the flavin semiquinone and chorismate from the enzyme appears to be the basis of the essentially irreversible inhibition by this analogue. A dithionite-dependent transient formation of flavin semiquinone during turnover of (6S)-6-fluoro-EPSP has been observed. These reactions are best rationalized by radical chemistry that is strongly supportive of a radical mechanism occurring during normal turnover. The lack of activity with 5-deaza-FMN provides additional evidence for the role of flavin in catalysis by the E. coli enzyme. PMID:10956653

Osborne, A; Thorneley, R N; Abell, C; Bornemann, S



Organic host analogues and the search for life on Mars  

NASA Astrophysics Data System (ADS)

Mars analogue sites represent vital tools in our continued study of the Red Planet; the similar physico-chemical processes that shape a given analogue environment on Earth allow researchers to both prepare for known Martian conditions and uncover presently unknown relationships. This review of organic host analogues - sites on Earth that mimic the putatively low organic content of Mars - examines specific locations that present particular Mars-like obstacles to biological processes. Low temperatures, aridity, high radiation and oxidizing soils characterise modern-day Mars, while acid-saline waters would have presented their own challenges during the planet's warmer and wetter past. By studying each of these hurdles to life on Earth, scientists can prepare instruments headed for Mars and identify the best locations and approaches with which to look for biological signatures. As our use of organic host analogues becomes increasingly sophisticated, researchers will work to identify terrestrial sites exhibiting multiple Mars-like conditions that are tailored to the distinct mineralogical and physical characteristics of Martian locations. Making use of organic host analogues in these ways will enhance the search for signs of past or present life on Mars.

Marlow, Jeffrey J.; Martins, Zita; Sephton, Mark A.



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


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

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



Immediate, non-submerged, root-analogue zirconia implants placed into single-rooted extraction sockets: 2-year follow-up of a clinical study  

Microsoft Academic Search

This study evaluated non-submerged, root-analogue zirconia implants with two different surfaces for immediate single-rooted tooth replacement in 18 patients. After tooth extraction the root was laser scanned and one-piece root analogue zirconia dental implants with one of two different surfaces were manufactured. In group A (n=6) the implant surface was roughened by sandblasting only, in group B (n=12) additional macroretentions

W. Pirker; A. Kocher



Impact of GnRH analogues on oocyte\\/embryo quality and embryo development in in vitro fertilization\\/intracytoplasmic sperm injection cycles: a case control study  

Microsoft Academic Search

BACKGROUND: Despite the clinical outcomes of ovarian stimulation with either GnRH-agonist or GnRH-antagonist analogues for in vitro fertilization (IVF) being well analysed, the effect of analogues on oocyte\\/embryo quality and embryo development is still not known in detail. The aim of this case-control study was to compare the efficacy of a multiple-dose GnRH antagonist protocol with that of the GnRH

Ákos Murber; Péter Fancsovits; Nóra Ledó; Zsuzsa Tóthné Gilán; János Rigó Jr; János Urbancsek



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


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

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



Bisphenol A and Its Analogues Activate Human Pregnane X Receptor  

PubMed Central

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.

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



Studies on the visual pigment and the indicator yellow analogues formed from 5,6-monoepoxyretinal  

PubMed Central

1. A new visual pigment has been isolated from retinae of rats maintained on 5,6-monoepoxyretinal for a period of 6 months. 2. Indicator yellow analogues from 5,6-monoepoxyretinal, namely 5,6-monoepoxyretinylidenemethylamine and 5,6-monoepoxyretinal oxime, have been prepared in a homogeneous state, the latter being obtained crystalline. 5,6-Monoepoxyretinylidenedimethylammonium iodide has also been prepared. 3. The spectroscopic properties, analytical data and antimony trichloride colour reactions of these indicator yellow analogues confirm their Schiff base structure. 4. The nature of chromogens formed from 5,6-monoepoxyretinylideneamino compounds with antimony trichloride and concentrated sulphuric acid is obscure although the chromogens resemble one another very closely. 5. 5,6-Monoepoxyretinylidenemethylamine and 5,6-monoepoxyretinylidenedimethylammonium iodide are very labile, whereas 5,6-monoepoxyretinal oxime is quite stable. 6. Hydrolysis of 5,6-monoepoxyretinylidenemethylamine as a function of pH reveals that, though 5,6-monoepoxyretinylidenemethylammonium ions are stable, the un-ionized compound readily hydrolyses to 5,6-monoepoxyretinal. This hydrolysis can be prevented by excess of un-ionized methylamine and hastened by formaldehyde. 7. The bathochromic shift in the ?max. of the `acid form' of 5,6-monoepoxyretinylidenemethylamine is due to the formation of its ammonium salt. The spectrum of the `acid form' is identical with that of 5,6-monoepoxyretinylidenedimethylammonium iodide in ethanol. This is also evidence for the quaternary state of the nitrogen atom during the `acid shift' of 5,6-monoepoxyretinylidenemethylamine. 8. The significance of 5,6-monoepoxyretinal and the corresponding indicator yellow analogues in the formation and properties of a new visual pigment is discussed.

Lakshmanan, M. R.; Cama, H. R.



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

NASA Astrophysics Data System (ADS)

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.

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



Synthesis of 13C- and 14C-labeled dinucleotide mRNA cap analogues for structural and biochemical studies  

PubMed Central

Herein we describe the first simple and short method for specific labeling of mono- and trimethylated dinucleotide mRNA cap analogues with 13C and 14C isotopes. The labels were introduced within the cap structures either at the N7 for monomethylguanosine cap or N7 and N2 position for trimethylguanosine cap. The compounds designed for structural and biochemical studies will be useful tools for better understanding the role of the mRNA cap structures in pre-mRNA splicing, nucleocytoplasmic transport, translation initiation and mRNA degradation.

Piecyk, Karolina; Davis, Richard E.; Jankowska-Anyszka, Marzena



Diagramming the Study Site for Others  

NSDL National Science Digital Library

The purpose of this resource is to develop the best possible representation of the study site as a system. Students visit a study site, where they observe and recall their existing knowledge of air, water, soil, and living things to make a list of interconnections among the four Earth system components. They make predictions about the effects of a change in a system, inferring ways these changes affect the characteristics of other related components.

The GLOBE Program, University Corporation for Atmospheric Research (UCAR)



Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli.  

PubMed Central

A biosynthetic antibody binding site, which incorporated the variable domains of anti-digoxin monoclonal antibody 26-10 in a single polypeptide chain (Mr = 26,354), was produced in Escherichia coli by protein engineering. This variable region fragment (Fv) analogue comprised the 26-10 heavy- and light-chain variable regions (VH and VL) connected by a 15-amino acid linker to form a single-chain Fv (sFv). The sFv was designed as a prolyl-VH-(linker)-VL sequence of 248 amino acids. A 744-base-pair DNA sequence corresponding to this sFv protein was derived by using an E. coli codon preference, and the sFv gene was assembled starting from synthetic oligonucleotides. The sFv polypeptide was expressed as a fusion protein in E. coli, using a leader derived from the trp LE sequence. The sFv protein was obtained by acid cleavage of the unique Asp-Pro peptide bond engineered at the junction of leader and sFv in the fusion protein [(leader)-Asp-Pro-VH-(linker)-VL]. After isolation and renaturation, folded sFv displayed specificity for digoxin and related cardiac glycosides similar to that of natural 26-10 Fab fragments. Binding between affinity-purified sFv and digoxin exhibited an association constant [Ka = (3.2 +/- 0.9) x 10(7) M-1] that was about a factor of 6 smaller than that found for 26-10 Fab fragments [Ka = (1.9 +/- 0.2) x 10(8) M-1] under the same buffer conditions, consisting of 0.01 M sodium acetate, pH 5.5/0.25 M urea. Images

Huston, J S; Levinson, D; Mudgett-Hunter, M; Tai, M S; Novotny, J; Margolies, M N; Ridge, R J; Bruccoleri, R E; Haber, E; Crea, R



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

PubMed Central

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.

Liew, Hon Jung; De Boeck, Gudrun; Walsh, Patrick J.



Fluvial sediments, concretions, evaporates at Hanksville, Utah: An analogue field study for Gale crater, Mars  

NASA Astrophysics Data System (ADS)

On 6th August 2012, Curiosity landed in Gale crater, Mars. Initial measurements and pictures showed sedimentary rocks that had been deposited by fluvial activity, e.g., alluvial fan and stream deposits. Such deposits are common in desert environments on Earth. The goal of the ILEWG EuroMoonMars project (February 23rd-March 9th,2013)was to conduct field studies in order to identify and study environments that are analogous to those that Curiosity has studied and will study at Gale crater. Several field campaigns (EuroGeoMars2009 and DOMMEX/ILEWG EuroMoonMars from November 2009 to March 2010) had been conducted at the Mars Desert Research Station (MDRS) [3] near Hanksville, Utah, in the vicinity of the San Rafael swell. The aim of the ILEWG EuroMoonMars 2013 project was to identify terrestrial analog sites for Curiosity exploration. The stratigraphy of the area consists of Jurassic and Cretaceous strat a[5] of which the Summerville Formation, the Brushy Basin Member of the Morrison Formation, and the Dakota Sandstone were studied. Widespread inverted channels on Mars have been identified through orbiter imagery data [6], e.g., at Gale crater. Concretions also appear to be common on Mars and have been found by the Opportunity rover at Meridiani Planum [4] and the Curiosity rover at Yellowknife Bay (Fig. 1).

Orgel, C.; Battler, M.; Foing, B. H.; Van't Woud, H.; Maiwald, V.; Cross, M.; Ono, A.



Upper Ottawa street landfill site health study  

Microsoft Academic Search

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

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



Pulmonary surfactant: emerging protein analogues.  


Surfactant preparations, which are effective in the treatment of respiratory distress syndrome (RDS), contain phospholipids and small amounts of the 2 hydrophobic surfactant proteins SP-B and SP-C. At present, surfactant preparations are obtained from animal lungs. However, since information concerning the structure of SP-B and SP-C is now available, it appears possible to design analogues that can replace the native proteins and so formulate a synthetic peptide/lipid surfactant. This would circumvent problems associated with current purification procedures and also facilitate the production of quantities sufficient for evaluation of surfactant therapy in other respiratory diseases. SP-C analogues which effectively accelerate the spreading of surfactant lipids and exhibit physiological activity in animal models of RDS have been developed. However, the in vivo activity of surfactant preparations based on SP-C analogues are inferior to those of surfactant preparations derived from natural sources. This may be caused by lack of covalently linked palmitoyl groups in the SP-C analogues tested and/or that SP-B is required for full activity. The larger size of SP-B compared to SP-C makes the design of SP-B analogues more demanding. Surfactant preparations containing single peptides that may resemble SP-B have shown promising results in vitro and in vivo. Identification of further SP-B analogues as well as suitable combinations of SP-B and SP-C analogues appear to be important topics for future studies. PMID:18031116

Johansson, J; Gustafsson, M; Palmblad, M; Zaltash, S; Robertson, B; Curstedt, T



Synthesis and structure-activity relationship studies of novel tubulysin U analogues--effect on cytotoxicity of structural variations in the tubuvaline fragment.  


Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure-activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins' potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC(50) displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues. PMID:23411563

Shankar, Sreejith P; Jagodzinska, Monika; Malpezzi, Luciana; Lazzari, Paolo; Manca, Ilaria; Greig, Iain R; Sani, Monica; Zanda, Matteo



Aspartame and Its Analogues  

NASA Astrophysics Data System (ADS)

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.

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



Upper Ottawa street landfill site health study.  

PubMed Central

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

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



Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.  


In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50) ?=?69.3?µM) and Leishmania brasiliensis (IC(50) ?=?59.4?µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50) ?=?99.9?µM for L. amazonensis and IC(50) ?=?90.5?µM for L. braziliensis) and 3 (IC(50) ?=?122.9?µM for L. amazonensis and IC(50) ?=?109.8?µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues. PMID:22996811

Parise-Filho, Roberto; Pasqualoto, Kerly Fernanda Mesquita; Magri, Fátima Maria Motter; Ferreira, Adilson Kleber; da Silva, Bárbara Athayde Vaz Galvão; Damião, Mariana Celestina Frojuello Costa Bernstorff; Tavares, Maurício Temotheo; Azevedo, Ricardo Alexandre; Auada, Aline Vivian Vatti; Polli, Michelle Carneiro; Brandt, Carlos Alberto



Cobalamin Analogues in Humans: A Study on Maternal and Cord Blood  

PubMed Central

Background Haptocorrin (HC) carries cobalamin analogues (CorA), but whether CorA are produced in the body is unknown. All cobalamins (Cbl) to the foetus are delivered by the Cbl-specific protein transcobalamin (TC), and therefore analysis of cord serum for CorA may help to clarify the origin of CorA. Methods HC-CorA were quantified in paired samples of cord serum from newborns and serum from mothers (n?=?69). Results The CorA-concentration was higher in cord serum (median?=?380, range: 41–780 pmol/L) than in serum from the mothers (median?=?160, range: 64–330 pmol/L), (p<0.0001). HPLC-analysis showed CorA-peaks with retention times of 13.5, 14,5 and 16.5 min in samples from both the mother and cord serum. The peak with retention time 16.5 min constituted 24% (mother) and 45% (cord serum) of the total amount CorA, and eluted as does dicyanocobinamide. Conclusion Our results support that CorA in the human body are derived from Cbl.

Hardlei, Tore Forsingdal; Obeid, Rima; Herrmann, Wolfgang; Nexo, Ebba



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

PubMed Central

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.

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



Web vulnerability study of online pharmacy sites.  


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

Kuzma, Joanne



Migrastatin Analogues Target Fascin to Block Tumor Metastasis  

PubMed Central

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

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



Migrastatin analogues target fascin to block tumour metastasis  

SciTech Connect

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.

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



Synthesis and conformational studies of N-glycosylated analogues of the HIV-1 principal neutralizing determinant.  


The principal neutralizing determinant (PND) of HIV-1 is found in the V3 loop of the envelope glycoprotein. Antibodies elicited by peptides from this region, containing the GlyProGlyArgAlaPhe (GPGRAF) sequence, were able to neutralize diverse HIV-1 isolates [Javaherian et al. (1990) Science 250, 1590-1593]. The GPGR tetrapeptide was predicted to adopt a type II beta-turn conformation. Earlier, we showed that glycosylation of synthetic T cell epitopic peptides at natural glycosylation sites stabilized beta-turns [Otvös et al. (1991) Int. J. Pept. Protein Res. 38, 467-482]. To evaluate the secondary structure modifying effect of the introduction of an N-glycosylated asparagine residue and to find a correlation between conformation and a possible PND potential, a series of glycopeptide derivatives, N(sugar) GPGRAFY-NH2 (4a-f), have been prepared, together with the parent peptides GPGRAFY-NH2 (2) and NGPGRAFY-NH2 (3), by solid-phase peptide synthesis [sugars: (a) beta-D-glucopyranosyl (Glc); (b) beta-D-galactopyranosyl (Gal); (c) Glc-beta(1----4)-Glc; (d) 2-acetamido-2-deoxy-beta-D-glucopyranosyl (GlcNAc); (e) 2-acetamido-2-deoxy-beta-D-galactopyranosyl (GalNAc); (f) GlcNAc-beta(1----4)-GlcNAc; sugars are attached through a beta (1----N beta) linkage to asparagine (N).] Peptides 2-4 were characterized by amino acid analysis, reversed-phase HPLC, and fast atom bombardment mass spectrometry. Circular dichroism (CD) and Fourier-transform infrared (FT-IR) spectroscopic studies were performed in trifluoroethanol (TFE) and water (D2O was used in FT-IR experiments). Nonglycosylated peptides showed significantly different CD spectra in aqueous and TFE solution.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1567873

Laczkó, I; Hollósi, M; Urge, L; Ugen, K E; Weiner, D B; Mantsch, H H; Thurin, J; Otvös, L



Correlation Between Archean Rocks From Fhe Kola Superdeep Borehole and Their Surface Analogues: On The Data of Structural-petrological and Petrophysical Studies  

NASA Astrophysics Data System (ADS)

The results of complex structural-petrological and petrophysical studies on core sam- ples from the Kola Superdeep borehole (SG-3) and their surface analogous are evi- dence in favour of choosing Mustantunturi site for correlation between Archean rocks of Kola series from the depths of 8-10 km and from the surface. The samples of the both groups show similarity in the mode of occurrence, mineral composition, tex- ture character and formation conditions. Using the data of the SG-3 investigations it was found that the degree of rock anisotropy has been increasing with depth, but such variations were not linear, being controlled by a combination of different fac- tors. It also depended on initial composition, intensities of plastic deformations syn- chronous with Early-Proterozoic zonal progressive metamorphism. Later overprinted fragile strains and regressive processes led to its decrease. Data on the northern flank of the Pechenga structure and its setting are in conflict with these observations, but generally, anisotropy of longitudinal waves at the surface is lower than that at the depth. This conclusion is verified by Avp determinations on reference gneiss and am- phibolite samples and their surface analogues. The investigations illuminate the con- tinuously debated issue of the anomalously high rock porosity and the anomalously low elastic wave velocities at the deep levels of the ancient continental crust cut by SG-3. The results of petrophysical and experimental study on the reference core sam- ples and their surface analogues show that the gneisses and amphibolites at the depths of 8-11 are characterized by normal values of density (2,71-2,74 and 3,05-3,06 g/cm3, respectively) typical for such rocks and by velocities of longitudinal (5,57-5,83 and 6,29-6,50 km/s) and shear (2,72-3,18 and 3,31-3,45 km/s) elastic waves. With lifting to the surface from the depth more than 7 km core undergo decompression and that leads to softening and loosening of rock material. As a result, the value of rock poros- ity may comprise 0,5- 0,8 %. The results of our petrophysical study give reason to believe that in situ porosity of the Archean gneisses and amphibolites is 0,5 % and permeability values are from 10-20 to 10-18 m2. This study was supported by the RFBR (projects nos. 01-05-64294, 01-05-64295).

Lobanov, K.; Kazansky, V.


Effects of counselor sex and sex role and client sex on clients' perceptions and self-disclosure in a counseling analogue study  

Microsoft Academic Search

Studied the effects of client sex and counselor sex and sex role on the counseling relationship, using an analogue format in which 35 male and 39 female undergraduate students participated in simulated counseling interviews. Ss were stratified by sex and randomly assigned to 1 of 4 treatment conditions: (a) masculine male counselor, (b) feminine male counselor, (c) masculine female counselor,

JoAnn C. Feldstein



In silico screening of the juvabione category of juvenile hormone analogues with juvenile hormone binding protein of Galleria mellonella – a docking study  

Microsoft Academic Search

Juvabione, dehydrojuvabione and their aromatic analogues act as juvenile hormone mimics against diverse strains of insect species. Large numbers of modified juvenoids containing the juvabione skeleton, with various structural variations, are synthesized. Some of these compounds exhibit a very high degree of juvenile hormone activity and are presently in use. In this paper we report a comparative molecular docking study

P. Awasthi; P. Sharma



Representing the Study Site in a Diagram  

NSDL National Science Digital Library

The purpose of this resource is to help students learn the skills and value of the translating complex interactions among Earth System components into a simplified diagram. Students visit a study site, where they observe and recall their existing knowledge of air, water, soil, and living things to make a list of interconnections among the four Earth system components. They make predictions about the effects of a change in a system, inferring ways these changes affect the characteristics of other related components.

The GLOBE Program, University Corporation for Atmospheric Research (UCAR)



The binding of amide substrate analogues to phospholipase A2. Studies by 13C-nuclear-magnetic-resonance and infrared spectroscopy.  

PubMed Central

(R)-(2-dodecanamidoisohexyl)phosphocholine (DAHPC), labelled with 13C at the amide carbonyl group, has been synthesized and its binding to bovine pancreatic phospholipase A2 (PLA2) studied by n.m.r. and i.r. spectroscopy. Two-dimensional 1H-n.m.r. spectra show that, in the presence of Ca2+, DAHPC binds to the active site of the enzyme in a similar manner to other phospholipid amide substrate analogues. The environment of the labelled carbonyl group has been investigated by a combination of 13C n.m.r. and difference-Fourier-transform i.r. spectroscopy. The carbonyl resonance shifts 3 p.p.m. downfield on the binding of DAHPC to PLA2. The carbonyl absorption frequency decreases by 14-18 cm-1, accompanied by a marked sharpening of the absorption band. These results indicate that the carbonyl bond undergoes significant polarization in the enzyme-ligand complex, facilitated by the enzyme-bound Ca2+ ion. This suggests that ground-state strain is likely to promote catalysis in the case of substrate binding. Simple calculations, based on the i.r. data, indicate that the carbonyl bond is weakened by 5-9 kJ.mol-1. This is the first report of observation of the amide vibration of a bound ligand against the strong background of protein amide vibrations.

Slaich, P K; Primrose, W U; Robinson, D H; Wharton, C W; White, A J; Drabble, K; Roberts, G C



Design, conformational studies and analysis of structure-function relationships of PTH (1-11) analogues: the essential role of Val in position 2.  


The N-terminal 1-34 segment of parathyroid hormone (PTH) is fully active in vitro and in vivo and it elicits all the biological responses characteristic of the native intact PTH. Recent studies reported potent helical analogues of the PTH (1-11) with helicity-enhancing substitutions. This work describes the synthesis, biological activity, and conformational studies of analogues obtained from the most active non-natural PTH (1-11) peptide H-Aib-Val-Aib-Glu-Ile-Gln-Leu-Nle-His-Gln-Har-NH2; specifically, the replacement of Val in position 2 with D-Val, L-(?Me)-Val and N-isopropyl-Gly was studied. The synthesized analogues were characterized functionally by in-cell assays and their structures were determined by CD and NMR spectroscopy. To clarify the relationship between the structure and activity, the structural data were used to generate a pharmacophoric model, obtained overlapping all the analogues. This model underlines the fundamental functional role of the side chain of Val2 and, at the same time, reveals that the introduction of conformationally constrained C?-tetrasubstituted ?-amino acids in the peptides increases their helical content, but does not necessarily ensure significant biological activity. PMID:21918876

Caporale, A; Gesiot, L; Sturlese, M; Wittelsberger, A; Mammi, S; Peggion, E



Phorboxazole Synthetic Studies: Design, Synthesis and Biological Evaluation of Phorboxazole A and Hemi-Phorboxazole A Related Analogues  

PubMed Central

The design, synthesis and biological evaluation of a new phorboxazole analogue, comprising an acetal replacement for the C-ring tetrahdropyran of the natural product and carrying a potency-enhancing C(45–46) vinyl chloride side chain, is described. In addition, the synthesis of (+)-hemi-phorboxazole A and a series of related hemi-phorboxazole A analogues has been achieved. The new acetal ring replacement analogue displayed activity comparable to that of the parent natural product against HCT-116 (colon) cells (IC50 2.25 ng/mL). Equally important, the phorboxazole analogue and two related hemiphorboxazole A congeners exhibited significant antifungal activity when assayed against pathogenic Candida albicans strains.

Smith, Amos B.; Hogan, Anne-Marie L.; Liu, Zhuqing; Razler, Thomas M.; Meis, Regina M.; Morinaka, Brandon I.; Molinski, Tadeusz F.



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

Microsoft Academic Search

High speed [5-30km\\/s] interstellar dust (ISD) analogues shot onto Stardust aerogel flight spares show morphology of impact tracks and structural & chemical modification of the projectiles. First results indicate a different ISD flux than previously assumed.

F. Postberg; C. Allan; S. Bajt; H. A. Bechtel; J. Borg; F. Brenker; J. Bridges; D. E. Brownlee; S. Bugiel; M. Burchell; M. Burghammer; A. L. Butterworth; P. Cloetens; A. M. Davis; C. Floss; G. J. Flynn; D. Frank; Z. Gainsforth; E. Grün; P. R. Heck; J. K. Hillier; P. Hoppe; L. Howard; G. R. Huss; J. Huth; A. Kearsley; A. J. King; B. Lai; J. Leitner; L. Lemelle; H. Leroux; L. R. Nittler; R. C. Ogliore; M. C. Price; S. A. Sandford; J. A. Sans Tresseras; S. Schmitz; T. Schoonjans; G. Silversmit; A. Simionovici; R. Srama; F. J. Stadermann; T. Stephan; V. Sterken; J. Stodolna; R. M. Stroud; S. R. Sutton; R. Toucoulou; M. Trieloff; P. Tsou; A. Tsuchiyama; T. Tyliczszak; B. Vekemans; L. Vincze; A. J. Westphal; M. E. Zolensky



Covalent modification of GABAA receptor isoforms by a diazepam analogue provides evidence for a novel benzodiazepine binding site that prevents modulation by these drugs.  


Classical benzodiazepines, for example diazepam, interact with alpha(x)beta(2)gamma(2) GABA(A) receptors, x = 1, 2, 3, 5. Little is known about effects of alpha subunits on the structure of the binding pocket. We studied here the interaction of the covalently reacting diazepam analog 7-Isothiocyanato-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (NCS compound) with alpha(1)H101Cbeta(2)gamma(2) and with receptors containing the homologous mutation, alpha(2)H101Cbeta(2)gamma(2), alpha(3)H126Cbeta(2)gamma(2) and alpha(5)H105Cbeta(2)gamma(2). This comparison was extended to alpha(6)R100Cbeta(2)gamma(2) receptors as this mutation conveys to these receptors high affinity towards classical benzodiazepines. The interaction was studied at the ligand binding level and at the functional level using electrophysiological techniques. Results indicate that the geometry of alpha(6)R100Cbeta(2)gamma(2) enables best interaction with NCS compound, followed by alpha(3)H126Cbeta(2)gamma(2), alpha(1)H101Cbeta(2)gamma(2) and alpha(2)H101Cbeta(2)gamma(2), while alpha(5)H105Cbeta(2)gamma(2) receptors show little interaction. Our results allow conclusions about the relative apposition of alpha(1)H101 and homologous positions in alpha(2), alpha(3), alpha(5) and alpha(6) with the position occupied by -Cl in diazepam. During this study we found evidence for the presence of a novel site for benzodiazepines that prevents modulation of GABA(A) receptors via the classical benzodiazepine site. The novel site potentially contributes to the high degree of safety to some of these drugs. Our results indicate that this site may be located at the alpha/beta subunit interface pseudo-symmetrically to the site for classical benzodiazepines located at the alpha/gamma interface. PMID:18643789

Baur, Roland; Tan, Kelly R; Lüscher, Benjamin P; Gonthier, Anne; Goeldner, Maurice; Sigel, Erwin



Docking of sialic acid analogues against influenza A hemagglutinin: a correlational study between experimentally measured and computationally estimated affinities.  


A molecular docking tool of AutoDock3.05 was evaluated for its ability to reproduce experimentally determined affinities of various sialic acid analogues toward hemagglutinin of influenza A virus. With the exception of those with a C6-modified glycerol side chain, the experimental binding affinities of most sialic acid analogues (C2, C4 and C5-substituted) determined by viral hemadsorption inhibition assay, hemagglutination inhibition assay and nuclear magnetic resonance correlated well with the computationally estimated free energy of binding. Sialic acid analogues with modified glycerol side chains showed only poor correlation between the experimentally determined hemagglutinin inhibitor affinities and AutoDock3.05 scores, suggesting high mobility of the glutamic acid side chain at the glycerol binding pocket, which is difficult to simulate using a flexi-rigid molecular docking approach. In conclusion, except for some glycerol-substituted sialic acid analogues, the results showed the effectiveness of AutoDock3.05 searching and scoring functions in estimating affinities of sialic acid analogues toward influenza A hemagglutinin, making it a reliable tool for screening a database of virtually designed sialic acid analogues for hemagglutinin inhibitors. PMID:19911202

Al-qattan, Mohammed Noor; Mordi, Mohd Nizam



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

NASA Astrophysics Data System (ADS)

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

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



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


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

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



Is the clogging process in Maqarin natural analogue controlled by accessory clay minerals? A reactive transport study with new data.  

NASA Astrophysics Data System (ADS)

The safety of nuclear waste repositories is based on the functionality of multiple natural and engineered barriers for very long time. The barrier system typically combines geochemically different materials that might interact with each other. One example is the long term alteration of sedimentary host rocks by the interaction with high pH pore water from cement materials used for tunnel support, seals and as backfill material. Within this context the Maqarin site in Jordan was investigated since more than 20 years as a natural analogue for rock alterations and pore clogging due to ingress of high pH solutions. In this work we examine the geochemical evolution of Maqarin marl rock in contact with a fracture through which a hyper-alkaline groundwater is circulating. The new reactive transport calculations were performed with the code OpenGeoSys-GEMS and utilize a state-of-the-art geochemical model for cement-clay interactions. The simulations reveal that the precipitation of ettringite, and to a smaller extent the precipitation of calcium-silicate-hydrate (CSH), is responsible for pore clogging in the rock matrix. Clogging of the pore space effectively seals the rock matrix on a centimeter scale after some hundreds of years and suppresses mass transfer of solutes from the fracture into the adjacent rock. In our Maqarin marl rock model typical clay minerals like kaolinite and illite are present in accessory mineral quantities only. A sensitivity analysis reveals that in this setup clay minerals are the main source for Al, necessary for the formation of ettringite-type solid solutions. It is thus the clay mineral content and the dissolution reactions that to a large degree control the spatial and temporal precipitation of ettringites and the associated pore clogging. Recently collected mineralogy and porosity data will be used to re-calibrate the model and to verify our improved findings that overall Maqarin system is controlled by accessory clay minerals.

Shao, H.; Kosakowski, G.; Berner, U.; Kulik, D.; Mäder, U.; Kolditz, O.



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

PubMed Central

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-3? (GSK-3?), 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.

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, Jurg; Hamann, Mark T.



Hydrolysis of New Transplatin Analogue Containing One Aliphatic and One Planar Heterocyclic Amine Ligand: A Density Functional Theory Study  

NASA Astrophysics Data System (ADS)

Herein we give a theoretical study of the hydrolysis processes of a novel anticancer drug trans-[PtCl2(3-pico)(ipa)] (3-pico = 3-methylpyridine, ipa = isopropylamine). Two different models, model 1 relative to isolated reactant/product (R/P, wherein R = platinum complex+H2O, P = platinum complex+Cl-) and model 2 relative to reactant complex/product complex (RC/PC, wherein RC = (platinum complex)(H2O), PC = (platinum complex)(Cl-) are employed and the geometric structures are optimized at the B3LYP level of DFT method. It is found that the processes of the reactions follow the established theory for ligand substitution in square planar complexes; the geometries of the transition states (TS) agree with the previous related work and all of the reactions are endothermic. The effects originating from the inclusion of the attacking water/released chloride into the second coordination shell of platinum in RC/PC play an important role in the thermodynamic and kinetic profiles of the reactions, that is, the barrier heights of the reactions of model 2 are increased by ~26.3 and ~23.8 kJ/mol for step1 and step2 respectively, and the endothermicity is considerably decreased by ~420.5 and ~771.2 kJ/mol compared to model 1 in the gas phase. The consideration of the bulk solvation effects increase the barrier heights for both steps of model 1 by ~27.6 and ~6.7 kJ/mol respectively, whereas it reduces the barrier heights by ~7.9 and ~29.3 kJ/mol for model 2. The reaction energies are all decreased, especially for model 1, indicating more stable complexes solvated in the bulk aqueous solution than in the gas phase. Additionally, to get an accurate energy picture of the title complex, the relative free energies derived from the DFT-SCRF (density functional theory self-consistent field) calculations are compared with the relative total energies. The results are that activation energies rise for the first hydrolysis and fall for the second hydrolysis for all the systems, and for all the systems, the barrier height of the second hydrolysis is always higher than that of the first step. The rate constants indicate that transplatin analogue is kinetically comparable to cisplatin and its analogue in the hydrolysis process.

Gao, Yan; Zhou, Li-xin



In situ PM-IRRAS studies of an archaea analogue thiolipid assembled on a au(111) electrode surface.  


Polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) has been applied to determine the conformation, orientation, and hydration of a monolayer of 2,3-di-O-phytanyl-sn-glycerol-1-tetraethylene glycol-dl-alpha-lipoic acid ester (DPTL) self-assembled at a gold electrode surface. This Archaea analogue thiolipid has been recently employed to build tethered lipid bilayers. By synthesizing DPT(d16)L, a DPTL molecule with a deuterium substituted tetraethylene glycol spacer, it was possible to differentiate the C-H stretch vibrations of the phytanyl chains from the tetraethylene glycol spacer and acquire the characteristic IR spectra for the chains, spacer, and lipoic acid headgroup separately. Our results show that the structure of the monolayer displays remarkable stability in a broad range of electrode potentials and that the phytanyl chains remain in a liquid crystalline state. The tetraethylene glycol chains are coiled, and the IR spectrum for this region shows that it is in the disordered state. The most significant result of this study is the information that in contrast to expectations the spacer region is poorly hydrated. Our results have implications for the design of a tethered lipid membrane based on this thiolipid. PMID:19499931

Leitch, Jay; Kunze, Julia; Goddard, John D; Schwan, Adrian L; Faragher, Robert J; Naumann, Renate; Knoll, Wolfgang; Dutcher, John R; Lipkowski, Jacek



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

PubMed Central

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.

Ehlers, Anke; Mauchnik, Jana; Handley, Rachel



The cardiolipin analogues of Archaea.  


The present article reviews studies of the structure and functional roles of the cardiolipin analogues of extremely halophilic prokaryotes belonging to the Archaea domain. Analogies and differences between the archaeal bisphosphatidylglycerol and the mitochondrial cardiolipin are presented. Furthermore the structure of archaeal glycophospholipid dimers is illustrated together with the available information on their function. The studies on the function of cardiolipin analogues in archaebacteria point out the tight interaction established by these phospholipids with membrane proteins and their role as bioactive lipids in the adaptation of microorganisms to osmotic stress. PMID:19464258

Corcelli, Angela



Reducing vividness and emotional intensity of recurrent “flashforwards” by taxing working memory: An analogue study  

Microsoft Academic Search

Several studies have found that making eye movements while retrieving visual images about past negative events reduces their vividness and emotional intensity. A working memory account states that eye movements tax working memory and interfere with visual imagery, thus degrading images. This study examined whether eye movements also affect recurrent, intrusive visual images about potential future catastrophes (“flashforwards”) in a

Iris M. Engelhard; Marcel A. van den Hout; Eliane C. P. Dek; Catharina L. Giele; Jan-Willem van der Wielen; Marthe J. Reijnen; Birgit van Roij



The cardiolipin analogues of Archaea  

Microsoft Academic Search

The present article reviews studies of the structure and functional roles of the cardiolipin analogues of extremely halophilic prokaryotes belonging to the Archaea domain. Analogies and differences between the archaeal bisphosphatidylglycerol and the mitochondrial cardiolipin are presented. Furthermore the structure of archaeal glycophospholipid dimers is illustrated together with the available information on their function. The studies on the function of

Angela Corcelli



The tropical analogue of polar cones  

Microsoft Academic Search

We study the max-plus or tropical analogue of the notion of polar: the polar of a cone represents the set of linear inequalities satisfied by its elements. We establish an analogue of the bipolar theorem, which characterizes all the inequalities satisfied by the elements of a tropical convex cone. We derive this characterization from a new separation theorem. We also

Stéphane Gaubert; Ricardo D. Katz



How people make decisions about predictive genetic testing: An analogue study  

Microsoft Academic Search

Predictive genetic testing will be possible for more common diseases in the future. Little is known, however, about the decision process people go through when considering genetic testing. This study looked at peoples’ decisions to seek professional advice on genetic testing for a hypothetical adult onset disease. Twenty individuals were presented with a decision scenario and verbal protocols were collected

Bethan J. Henderson; Bryan T. Maguire; Jonathon Gray; Valerie Morrison



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

ERIC Educational Resources Information Center

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…

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



Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours  

Microsoft Academic Search

A few studies have suggested an antitumour activity of somatostatin analogues in neuroendocrine tumours (NET). The aim of this study was to evaluate the antitumour efficacy of somatostatin analogues in patients with documented progressive tumours. 35 consecutive patients with documented tumour progression were treated with somatostatin analogues. Patients were classified into two groups. In Group 1, tumours were progressing rapidly

T Aparicio; M Ducreux; E Baudin; J.-C Sabourin; T De Baere; E Mitry; M Schlumberger; P Rougier



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

PubMed Central

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.

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



Reducing vividness and emotional intensity of recurrent "flashforwards" by taxing working memory: an analogue study.  


Several studies have found that making eye movements while retrieving visual images about past negative events reduces their vividness and emotional intensity. A working memory account states that eye movements tax working memory and interfere with visual imagery, thus degrading images. This study examined whether eye movements also affect recurrent, intrusive visual images about potential future catastrophes ("flashforwards") in a sample of female undergraduates who had indicated on a screening-scale that they suffer from such intrusions. They were asked to recall two intrusive images with or without making eye movements. Before and after each condition, participants retrieved the image, and rated its vividness and emotionality. Results showed that vividness of intrusive images was lower after recall with eye movement, relative to recall only, and there was a similar trend for emotionality. Potential implications are discussed. PMID:21376527

Engelhard, Iris M; van den Hout, Marcel A; Dek, Eliane C P; Giele, Catharina L; van der Wielen, Jan-Willem; Reijnen, Marthe J; van Roij, Birgit



Electron paramagnetic resonance study of doped synthetic crystals of struvite and its zinc analogue  

NASA Astrophysics Data System (ADS)

The electron paramagnetic resonance (EPR) technique has been used to study the Mn 2+ paramagnetic impurity complexes in synthetic struvite (MgNH 4PO 4?6H 2O) and the zinc isomorph (ZnNH 4PO 4?6H 2O). EPR of VO 2+ ion complexes in vanadyl doped crystals of the zinc isomorph of struvite has also been studied. Two differently oriented, but otherwise identical complexes of both Mn 2+ ion and VO 2+ ion are found in these crystals. The spin Hamiltonian parameters indicate a large orthorhombic distortion of the [Mn 2+(H 2O) 6] octahedra and an axial symmetry of the vanadyl complexes. The results indicate that in both manganese and vanadyl complexes, the metal ions have covalent bonding with the ligands.

Chand, Prem; Agarwal, O. P.


A Model of Interaction between Nicotinamide Adenine Dinucleotide Phosphate (NADPH) Oxidase and Apocynin Analogues by Docking Method  

PubMed Central

Some apocynin analogues have exhibited outstanding inhibition to NADPH oxidase. In this study, the key interactions between apocynin analogues and NADPH oxidase were analyzed by the docking method. The potential active site was first identified by the SiteID program combining with the key residue CYS378. Afterwards, the compounds in the training set were docked into NADPH oxidase (1K4U) under specific docking constraints to discuss the key interactions between ligands and the receptor. These key interactions were then validated by the consistence between the docking result and the experimental result of the test set. The result reveals that the Pi interaction between apocynin analogues and NADPH oxidase has a direct contribution to inhibition activities, except for H-bond formation and docking score. The key interactions might be valuable to discover and screen apocynin analogues as potent inhibitors of NADPH oxidase.

Jiang, Jie; Kang, Hongjun; Song, Xiaoliang; Huang, Sichao; Li, Sha; Xu, Jun



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

PubMed Central

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 ?-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.

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



CTARP Energy Facility Siting Study. Volume I: Coastal Facility Siting and the National Interest.  

National Technical Information Service (NTIS)

The first of four volumes of a study dealing with energy facility siting in the coastal zone and the national interest presents a conceptual summary and policy analysis. The problems and common structure of energy facility siting controversies are reviewe...

J. D. Roughgarden J. T. McAlister



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

NASA Technical Reports Server (NTRS)

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.

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



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

NASA Astrophysics Data System (ADS)

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.

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



[Prevention of post-ovariectomy osteoporosis in the rat. Comparative study of synthetic salmon calcitonin and eel calcitonin aminosuberic analogue].  


The authors evaluate the efficacy of salmon calcitonin and aminosuberic analogue of eel calcitonin in the prevention of post-oophorectomy osteoporosis in rats. Both drugs, administered at the same dosage, are equally effective in preventing oophorectomy bone loss in rats. Besides, plasma biochemical evaluations demonstrate that calcitonins reduce bone turnover in treated rats, compared with control oophorectomized ones. PMID:8183179

Gnudi, S; Zati, A; Giardino, R; Fini, M; Pratelli, L; Orlandi, M; Figus, E



Three thiamine analogues differently alter thiamine transport and metabolism in nervous tissue: an in vivo kinetic study using rats.  


Thiamine (T) analogues pyrithiamine, oxythiamine or amprolium in amounts 10-1000 times higher than labelled T, were i.p. injected into rats together with 14C-T (30 microg; 46.25 KBq). The radioactivity associated with T and its phosphoesters in the plasma and cerebral cortex, brainstem, cerebellum, and sciatic nerve were determined at time intervals from 0.25 to 240 h from injection. The experimental data obtained were processed with a mathematical compartmental model that calculated the fractional rate constants. These are the amount of content in a given compartment that is replaced in 1 h and expressed in per hour. The results showed that all three analogues inhibited thiamine entry from plasma. Instead, oxythiamine enhanced T phosphorylation to T pyrophosphate (TPP); amprolium and oxythiamine enhanced TPP dephosphorylation to monophosphate (TMP); pyrithiamine reduced TPP dephosphorylation and TMP formation, while none of the analogues modified TMP dephosphorylation to T. In conclusion, in living rats, the action of T analogues was much more complex than could be expected from their structure and action in vitro. PMID:15128183

Rindi, G; Patrini, C; Nauti, A; Bellazzi, R; Magni, P



The use of swept-charge devices in planetary analogue X-ray fluorescence studies  

NASA Astrophysics Data System (ADS)

The Chandrayaan-1 X-ray Spectrometer (C1XS) was launched onboard the Indian Space Research Organisation (ISRO) Chandrayaan-1 lunar mission in October 2008. The instrument consisted of 24 swept-charge device (SCD) silicon X-ray detectors providing a total collecting area of ~ 24 cm2, corresponding to a 14° field of view (FWHM), with the ability to measure X-rays from 0.8-10 keV. One algorithm used to analyse the C1XS flight data was developed at Rutherford Appleton Laboratory (RAL) to convert the raw X-ray flux data into elemental ratios and abundances to make geological interpretations about the lunar surface. Laboratory X-ray fluorescence (XRF) data were used to validate the RAL algorithm, with previous studies investigating how the measured XRF flux varies with target surface characteristics including grain size and roughness. Evidence for a grain-size effect was observed in the data, the XRF line intensity generally decreasing with increasing sample grain size, dependent on the relative abundance of elemental components. This paper presents a subsequent study using more homogeneous samples made from mixtures of MgO, Al2O3 and SiO2 powders, all of grain size < 44 ?m, across a broader range of mixture ratios and at a higher level of X-ray flux data in order to further validate the RAL algorithm. For the majority of the C1XS flight data analysed so far with the RAL algorithm, the corresponding lunar ground tracks have been generally basaltic, laboratory verification of the algorithm having been primarily conducted using basaltic lunar regolith simulant (JSC-1A) XRF data. This paper also presents results from tests on a terrestrial anorthosite sample, more relevant to the anorthositic lunar highlands, from where the remaining C1XS lunar dataset derives. The operation of the SCD, the XRF test facility, sample preparation and collected XRF spectra are discussed in this paper.

Walker, T. E.; Smith, D. R.



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

SciTech Connect

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.

Leszczynski, Jerzy [Computational Center for Molecular Structure and Interactions, Jackson, MS; Sponer, Judit [Academy of Sciences of the Czech Republic; Sponer, Jiri [Academy of Sciences of the Czech Republic; Sumpter, Bobby G [ORNL; Fuentes-Cabrera, Miguel A [ORNL; Vazquez-Mayagoitia, Alvaro [ORNL



A Mossbauer spectroscopic study of iron-rich deposits of hydrothermal springs as Martian analogues  

NASA Astrophysics Data System (ADS)

In this work, results are reported of Mössbauer analysis focused on a suite of samples collected systematically along the outflow channel from an iron- rich hydrothermal vent mound in the Chocolate Pots area of Yellowstone National Park in the context of Mars exploration. Similar hydrothermal spring systems may well have been present on an early Mars and could have harbored primitive life. Mössbauer spectroscopy was chosen as the primary investigative technique in this study because of its ability to discriminate among the iron-bearing minerals in these samples. Those on the surface and near the vent are identified as predominantly ferrihydrite, Fe5HO8 ? 4H2O or 5Fe2O3 ? 9H2O. Subsurface samples, which seem to have been altered by either inorganic and/or biological processes, exhibit spectral signatures that include nontronite [(Ca,Na) 0.66Fe3+S4i7.34 Al0.66O20(OH) 4,nH2O], in the smectite clay mineral group, hematite (?-Fe 3+2O3), small- particle/nanophase goethite (?-Fe 3+OOH), and siderite (Fe2+CO3) . Evidence is presented that all these minerals, including those with the nanophase property, can have multi-billion year residence times and thus survive from their possible production in a putative early Martian hydrothermal environment to present day. Mössbauer spectroscopy will be a planned component of the instrument suite included on the 2001 Mars Surveyor Athena Rover mission. It is hoped that this work will aid in the use of this instrument, in the service of exobiology, and in helping to identify hydrothermal sediments and samples suitable for subsequent return to Earth.

Wade, Manson Lashawn



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

NASA Astrophysics Data System (ADS)

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

Navarro-González, R.



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

NASA Astrophysics Data System (ADS)

Meteoric smoke forms in the mesosphere from the recondensation of the metallic species and silica produced by meteoric ablation. A photochemical flow reactor was used to generate meteoric smoke mimics using appropriate photolytic precursors of Fe and Si atoms in an excess of oxidant. The following systems were studied: (i) Fe+O3/O2, (ii) Fe+O3/O2+H2O, (iii) Fe+Si/SiO+O3/O2 and (iv) Si/SiO+O3/O2. The resulting nano-particles were captured for imaging by transmission electron microscopy, combined with elemental analysis using X-ray (EDX) and electron energy loss (EELS) techniques. These systems generated particle compositions consistent with: (i) Fe2O3 (hematite), (ii) FeOOH (goethite), (iii) Fe2SiO4 (fayalite) and (iv) SiO2 (silica). Electron diffraction revealed that the Fe-containing particles were entirely amorphous, while the SiO2 particles displayed some degree of crystallinity. The Fe-containing particles formed fractal aggregates with chain-like morphologies, whereas the SiO2 particles were predominantly spherical and compact in appearance. The optical extinction spectra of the Fe-containing particles were measured from 300 nm

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



The chemical synthesis of metabolically stabilized 2-OMe-LPA analogues and preliminary studies of their inhibitory activity toward autotaxin.  


The chemical synthesis of five new metabolically stabilized 2-OMe-LPA analogues (1a-e) possessing different fatty acid residues has been performed by phosphorylation of corresponding 1-O-acyl-2-OMe-glycerols which were prepared by multistep process from racemic glycidol. The now analogues were subjected to biological characterization as autotaxin inhibitors using the FRET-based, synthetic ATX substrate FS-3. Among tested compounds 1-O-oleoyl-2-OMe-LPA (1e) appeared to be the most potent, showing ATX inhibitory activity similar to that of unmodified 1-O-oleoyl-LPA. Parallel testing showed, that similar trend was also observed for corresponding 1-O-acyl-2-OMe-phosphorothioates (2a-e, synthesized as described by us previously). 1-O-oleoyl-2-OMe-LPA (1e) was found to be resistant toward alkaline phosphatase as opposed to unmodified 1-O-oleoyl-LPA. PMID:22460025

Gendaszewska-Darmach, Edyta; Laska, Edyta; Rytczak, Przemys?aw; Okruszek, Andrzej



Three Thiamine Analogues Differently Alter Thiamine Transport and Metabolism in Nervous Tissue: An In Vivo Kinetic Study Using Rats  

Microsoft Academic Search

Thiamine (T) analogues pyrithiamine, oxythiamine or amprolium in amounts 10–1000 times higher than labelled T, were i.p. injected into rats together with 14C-T (30 µg; 46.25 KBq). The radioactivity associated with T and its phosphoesters in the plasma and cerebral cortex, brainstem, cerebellum, and sciatic nerve were determined at time intervals from 0.25 to 240 h from injection. The experimental

G. Rindi; C. Patrini; A. Nauti; R. Bellazzi; P. Magni



QSAR study for a novel series of ortho disubstituted phenoxy analogues of alpha1-adrenoceptor antagonist WB4101.  


On the basis of the affinities at the alpha1a-, alpha1b- and alpha1d-adrenoceptors and the 5-HT1A receptor of a previous series of sixteen 2-[(2-phenoxyethyl)aminomethyl]-1,4-benzodioxanes ortho monosubstituted at the phenoxy moiety, a number of ortho disubstituted analogues were designed, synthesized in both the enantiomeric forms and tested in binding assays on the same receptors. The affinity values of the new compounds 1-11 were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known alpha1 antagonist WB4101, and of the ortho monosubstituted derivatives, suggesting some distinctive aspects of the interaction of the phenoxy moiety, in particular with the alpha1a-AR and the 5-HT1A receptor, of the monosubstituted and the disubstituted compounds. A classical quantitative structure-activity relationship (Hansch) analysis was applied to the whole set of the S enantiomers of the ortho mono- and disubstituted WB4101 analogues (26 compounds), finding a very good correlation for the alpha1a affinity. For this latter, a significant parabolic relationship was also found with the volume of the two ortho substituents. Diametrically opposite, the same relationships for the 5-HT1A exhibit low or insignificant correlation coefficients. PMID:16737760

Pallavicini, M; Fumagalli, L; Gobbi, M; Bolchi, C; Colleoni, S; Moroni, B; Pedretti, A; Rusconi, C; Vistoli, G; Valoti, E



School Counseling Site Supervisor Training: An Exploratory Study  

ERIC Educational Resources Information Center

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…

DeKruyf, Lorraine; Pehrsson, Dale-Elizabeth



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


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

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



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

SciTech Connect

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

Niu, Shuqiang; Ichiye, Toshiko



Plant volatile analogues strengthen attractiveness to insect.  


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 ?-ionone and benzaldehyde. The stabilities of ?-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than ?-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than ?-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety. PMID:24911460

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



Plant Volatile Analogues Strengthen Attractiveness to Insect  

PubMed Central

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 ?-ionone and benzaldehyde. The stabilities of ?-ionone, benzaldehyde and analogue 3 g were tested. The electroantennogram (EAG) responses of A. lucorum adult antennae to the analogues were recorded. And the behavior assay and filed experiment were also conducted. In this study, thirteen analogues were acquired. The analogue 3 g was demonstrated to be more stable than ?-ionone and benzaldehyde in the environment. Many of the analogues elicited EAG responses, and the EAG response values to 3 g remained unchanged during seven-day period. 3 g was also demonstrated to be attractive to A. lucorum adults in the laboratory behavior experiment and in the field. Its attractiveness persisted longer than ?-ionone and benzaldehyde. This indicated that 3 g can strengthen attractiveness to insect and has potential as an attractant. Our results suggest that synthetic plant volatile analogues can strengthen attractiveness to insect. This is the first published study about synthetic plant volatile analogues that have the potential to be used in pest control. Our results will support a new ecological approach to pest control and it will be helpful to ecoenvironment and agricultural product safety.

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



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)

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

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



Substituted 3-(5-Imidazo[2,1-b]thiazolylmethylene)-2-indolinones and Analogues: Synthesis, Cytotoxic Activity and Study of the Mechanism of Action1  

PubMed Central

The synthesis of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and analogues is reported. Their cytotoxic activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of selected compounds was examined for potential inhibition of tubulin assembly in comparison with the potent colchicine site agent combretastatin A-4. The most potent compounds also strongly and selectively inhibited the phosphorylation of the oncoprotein kinase Akt in cancer cells. The effect of the most interesting compounds was examined on the growth of HT-29 colon cancer cells. These compounds caused the cells to arrest in the G2/M phase of the cell cycle, as would be expected for inhibitors of tubulin assembly.

Andreani, Aldo; Granaiola, Massimiliano; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Varoli, Lucilla; Calonghi, Natalia; Cappadone, Concettina; Farruggia, Giovanna; Stefanelli, Claudio; Masotti, Lanfranco; Nguyen, Tam L.; Hamel, Ernest; Shoemaker, Robert H.



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

SciTech Connect

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

London, R.E.; Davis, D.G. (NIEHS, NC (USA)); Vavrek, R.J.; Stewart, J.M. (Univ. of Colorado Health Sciences Center, Denver, CO (USA)); Handschumacher, R.E. (Yale Univ., New Haven, CT (USA))



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


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

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



Examining e-travel sites: an empirical study in Taiwan  

Microsoft Academic Search

Purpose – For the internet to realise its full marketing potential, travel agencies need a well-designed e-travel site. Yet the attributes that affect customers' perceptions leading to acceptance of e-travel sites are still unclear. This study seeks to focus on why users accept or reject e-travel sites and how users' acceptance is affected by three widely recognised features of sites

Ching-Torng Lin



Fluorescent DNA labeling by N-mustard analogues of S-adenosyl-L-methionine.  


Azide and alkyne-functionalized N-mustard analogues of S-adenosyl-L-methionine have been synthesized and were demonstrated to undergo efficient methyltransferase-dependent DNA alkylation by M.TaqI and M.HhaI. Subsequent labeling of the DNA with a fluorophore was carried out using copper-catalyzed azide-alkyne cycloaddition chemistry and was visualized by fluorescence scanning. This work demonstrates the utility of functionalized N-mustard analogues as biochemical tools to study biological methylation and offers a facile way to site-selectively label substrates of DNA methyltransferases. PMID:22961989

Du, Yuhao; Hendrick, Charles E; Frye, Krysta S; Comstock, Lindsay R



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


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

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



An estrogen analogue and promising anticancer agent refrains from inducing morphological damage and reactive oxygen species generation in erythrocytes, fibrin and platelets: a pilot study  

PubMed Central

Background 2-Methoxyestradiol is known to have antitumour and antiproliferative action in vitro and in vivo. However, when 2-methoxyestradiol is orally administered, it is rapidly oxidized by the enzyme 17β-hydroxysteriod dehydrogenase in the gastrointestinal tract. Therefore, 2-methoxyestradiol never reaches high enough concentrations in the tissue to be able to exert these antitumour properties. This resulted in the in silico-design of 2-methoxyestradiol analogues in collaboration with the Bioinformatics and Computational Biology Unit (UP) and subsequent synthesis by iThemba Pharmaceuticals (Pty) Ltd (Modderfontein, Midrand, South Africa). One such a novelty-designed analogue is 2-ethyl-3-O-sulphamoyl-estra-1, 3, 5(10)16-tetraene (ESE-16). Methods This pilot study aimed to determine the morphological effect and possible generation of reactive oxygen species by ESE-16 on erythrocytes and platelet samples (with and without added thrombin) by means of scanning electron microscopy, transmission electron microscopy and flow cytometry. Results Erythrocytes and platelets were exposed to ESE-16 at a concentration of 180nM for 24 hours. Scanning- and transmission electron microscopy indicated that ESE-16 did not cause changes to erythrocytes, platelets or fibrin networks. Flow cytometry measurements of hydrogen peroxide and superoxide indicated that ESE-16 does not cause an increase in the generation of reactive oxygen species in these blood samples. Conclusion Further in vivo research is warranted to determine whether this novel in silico-designed analogue may impact on development of future chemotherapeutic agents and whether it could be considered as an antitumour agent.



Wastewater Treatment Plant Sites Acquisition Study. Panama Bay Sanitation Project.  

National Technical Information Service (NTIS)

Hazen and Sawyer were retained by the CU to conduct the Conceptual Design which consisted of four complementary studies as follows: (1) Wastewater Flow Monitoring and Sampling Study; (2) Wastewater Treatment Plant Sites Acquisition Study; (3) Sludge Manag...



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

SciTech Connect

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.

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Multidisciplinary study on Wyoming test sites  

NASA Technical Reports Server (NTRS)

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.

Houston, R. S. (principal investigator); Marrs, R. W.; Borgman, L. E.



Synthesis of pavoninin-1, a shark repellent substance, and its structural analogues toward mechanistic studies on their membrane perturbation.  


Pavoninin-1 (1), which was isolated from a defense secretion of the sole Pardachirus spp. as an ichthyotoxic and a shark repellent principle, and its structural analogue 2 were synthesized, where glycosylation using an 2-azidoglycosyl sulfoxide (10) afforded the corresponding beta-glycoside exclusively in high yield. Introduction of the alpha,beta-unsaturated ketone system in the ring A of 1 was achieved by phenylselenenylation of dihydropavoninin-1 (3) and subsequent oxidative elimination without protection of the hydroxyl groups in the sugar portion. The mode of action of these glycosides was evaluated for their perturbation on phosphatidylcholine liposomal membrane, using the fluorescent dye leakage method. The results revealed that membrane affinity does not parallel membrane perturbation but rather compensates it, and the spatial arrangement of hydrophobic and hydrophilic regions within a molecule is likely to reflect on the difference in potency of action among them. PMID:9459023

Ohnishi, Y; Tachibana, K



Isotopically labeled sulfur compounds and synthetic selenium and tellurium analogues to study sulfur metabolism in marine bacteria  

PubMed Central

Summary Members of the marine Roseobacter clade can degrade dimethylsulfoniopropionate (DMSP) via competing pathways releasing either methanethiol (MeSH) or dimethyl sulfide (DMS). Deuterium-labeled [2H6]DMSP and the synthetic DMSP analogue dimethyltelluriopropionate (DMTeP) were used in feeding experiments with the Roseobacter clade members Phaeobacter gallaeciensis DSM 17395 and Ruegeria pomeroyi DSS-3, and their volatile metabolites were analyzed by closed-loop stripping and solid-phase microextraction coupled to GC–MS. Feeding experiments with [2H6]DMSP resulted in the incorporation of a deuterium label into MeSH and DMS. Knockout of relevant genes from the known DMSP demethylation pathway to MeSH showed in both species a residual production of [2H3]MeSH, suggesting that a second demethylation pathway is active. The role of DMSP degradation pathways for MeSH and DMS formation was further investigated by using the synthetic analogue DMTeP as a probe in feeding experiments with the wild-type strain and knockout mutants. Feeding of DMTeP to the R. pomeroyi knockout mutant resulted in a diminished, but not abolished production of demethylation pathway products. These results further corroborated the proposed second demethylation activity in R. pomeroyi. Isotopically labeled [2H3]methionine and 34SO4 2?, synthesized from elemental 34S8, were tested to identify alternative sulfur sources besides DMSP for the MeSH production in P. gallaeciensis. Methionine proved to be a viable sulfur source for the MeSH volatiles, whereas incorporation of labeling from sulfate was not observed. Moreover, the utilization of selenite and selenate salts by marine alphaproteobacteria for the production of methylated selenium volatiles was explored and resulted in the production of numerous methaneselenol-derived volatiles via reduction and methylation. The pathway of selenate/selenite reduction, however, proved to be strictly separated from sulfate reduction.

Brock, Nelson L; Citron, Christian A; Zell, Claudia; Berger, Martine; Wagner-Dobler, Irene; Petersen, Jorn; Brinkhoff, Thorsten; Simon, Meinhard



Studies on the biotin-binding site of avidin. Minimized fragments that bind biotin.  

PubMed Central

The object of this study was to define minimized biotin-binding fragments, or 'prorecognition sites', of either the egg-white glycoprotein avidin or its bacterial analogue streptavidin. Because of the extreme stability to enzymic hydrolysis, fragments of avidin were prepared by chemical means and examined for their individual biotin-binding capacity. Treatment of avidin with hydroxylamine was shown to result in new cleavage sites in addition to the known Asn-Gly cleavage site (position 88-89 in avidin). Notably, the Asn-Glu and Asp-Lys peptide bonds (positions 42-43 and 57-58 respectively) were readily cleaved; in addition, lesser levels of hydrolysis of the Gln-Pro (61-62) and Asn-Asp (12-13 and 104-105) bonds could be detected. The smallest biotin-binding peptide fragment, derived from hydroxylamine cleavage of either native or non-glycosylated avidin, was identified to comprise residues 1-42. CNBr cleavage resulted in a 78-amino acid-residue fragment (residues 19-96) that still retained activity. The data ascribe an important biotin-binding function to the overlapping region (residues 19-42) of avidin, which bears the single tyrosine moiety. This contention was corroborated by synthesizing a tridecapeptide corresponding to residues 26-38 of avidin; this peptide was shown to recognize biotin. Streptavidin was not susceptible to either enzymic or chemical cleavage methods used in this work. The approach taken in this study enabled the experimental distinction between the chemical and structural elements of the binding site. The capacity to assign biotin-binding activity to the tyrosine-containing domain of avidin underscores its primary chemical contribution to the binding of biotin by avidin. Images Fig. 1. Fig. 2. Fig. 3. Fig. 6. Fig. 7. Fig. 9.

Hiller, Y; Bayer, E A; Wilchek, M



Platinum(IV) analogues of AMD473 (cis-[PtCl2(NH3)(2-picoline)]): preparative, structural, and electrochemical studies.  


The preparation and oxidation of the anticancer drug AMD473, cis-[PtCl2(NH3)(2-pic)] (2-pic = 2-methylpyridine), has been investigated. cis-[PtCl2(NH3)(2-pic)] is readily oxidized with peroxide to give the trans-dihydroxoplatinum(IV) complex cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)]. The crystal structure of this complex reveals that it is highly strained as a result of a steric clash between the methyl group of the 2-picoline ligand and an axial hydroxo ligand, with the Pt-N-C angle adjacent to this clash opened up to an unprecedented 138.6(6) degrees . Attempts at converting the dihydroxoplatinum(IV) complex to dichloro and diacetato analogues were unsuccessful with reaction with HCl leading to loss and protonation of the 2-picoline ligand to form the salt (2-picH)[PtCl5(NH3)] and the platinum(II) complex cis-[PtCl2(NH3)(2-pic)], both confirmed by crystallography. Electrochemical studies revealed that cis,trans,cis-[PtCl2(OH)2(NH3)(2-pic)] is reduced more readily (-714 mV vs Ag/AgCl) than its pyridine analogue cis,trans,cis-[PtCl2(OH)2(NH3)(pyridine)] (-770 mV vs Ag/AgCl) consistent with the steric clash in the former complex destabilizing the platinum(IV) oxidation state. PMID:16878941

Battle, Andrew R; Choi, Robin; Hibbs, David E; Hambley, Trevor W



Design of semisynthetic analogues and 3D-QSAR study of eunicellin-based diterpenoids as prostate cancer migration and invasion inhibitors.  


Prostrate cancer constitutes the second leading cause of cancer deaths in men in United States. Eunicellin-based diterpenoids are important bioactive marine natural products isolated from corals of alcyonaria species. The bioactivities of eunicellin diterpenes were correlated with their chemical structures. Recently eunicellin diterpenes from the Red Sea soft coral Cladiella pachyclados showed significant anti-migratory and anti-invasive activities against prostate cancer in wound-healing and Cultrex(®) invasion models. These results encouraged the semisynthetic and 3D-QSAR studies of this unique marine natural product class as possible hits for the control of metastatic prostate cancer. Ten new semisynthetic analogues of cladiellisin (1) were prepared. These include C-6 carbamoylation and ?(11-17) epoxidation. Carbamate analogues of 1 showed potent anti-migratory and anti-invasive activities against PC-3 cells. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed using SYBYL 8.1 program package to create a valid 3D-QSAR model to guide future design of potent eunicellin diterpenes cancer migration inhibitors. Eunicellin-based diterpenes are potential marine natural hits appropriate for optimization as inhibitors of metastatic prostate cancer. PMID:21334794

Hassan, Hossam M; Elnagar, Ahmed Y; Khanfar, Mohammad A; Sallam, Asmaa A; Mohammed, Rabab; Shaala, Lamiaa A; Youssef, Diaa T A; Hifnawy, Mohamed S; El Sayed, Khalid A



Hanford tank initiative test facility site selection study  

SciTech Connect

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.

Staehr, T.W.



Study of Potential Satellite Clinic Sites in the Maquoketa Area.  

National Technical Information Service (NTIS)

A study was undertaken in the rural Maquoketa area of Iowa to determine the best sites for satellite clinics for a six-man group practice. Seven communities in the Maquoketa area were evaluated as potential sites, recommendations were drawn, and possible ...



In silico screening of the juvabione category of juvenile hormone analogues with juvenile hormone binding protein of Galleria mellonella--a docking study.  


Juvabione, dehydrojuvabione and their aromatic analogues act as juvenile hormone mimics against diverse strains of insect species. Large numbers of modified juvenoids containing the juvabione skeleton, with various structural variations, are synthesized. Some of these compounds exhibit a very high degree of juvenile hormone activity and are presently in use. In this paper we report a comparative molecular docking study of synthesized juvabione, natural juvenile hormone III and synthetic insect growth regulators (fenoxycarb, S-21149, Compound 1, pyriproxyfen) with the juvenile hormone binding protein of Galleria mellonella. The study clearly indicates a higher binding affinity of nitro-substituted juvabione over natural juvenile hormone III and synthetic insect growth regulators such as fenoxycarb and S-21149. PMID:22799597

Awasthi, P; Sharma, P



Facies and geothermal reservoir characteristics of sedimentary rocks: an outcrop analogue study of the Meso- and Cenozoic series of Budapest (Hungary)  

NASA Astrophysics Data System (ADS)

Sedimentary basins located in regions exhibiting geothermal anomalies are very promising for hydrothermal exploration. Facies model integration into seismic 3D interpretation allow description of reservoir parameters such as permeability, thermal conductivity and reservoir heat flow, as these properties are directly correlative to facies heterogeneity integrated from outcrop studies. Outcrop analogue studies support the characterization of deep geothermal reservoirs and their geothermal operations. Our data from the Meso- and Cenozoic sedimentary series of Budapest include carbonates and clastic sediments of Triassic, Eocene, and Oligo-Miocene age as well as Pleistocene travertine, exposed on the western side of the river Danube. Field and laboratory analyses reveal distinct horizons of different geothermal potential and thus, enable us to identify and interpret corresponding exploration target horizons in geothermal prone depths of the Pannonian Basin.

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



Palmottu Analogue Project, Progress Report 1993. The behaviour of natural radionuclides in and around uranium deposits, Nr. 7.  

National Technical Information Service (NTIS)

The report gives a summary of the results of investigations carried out in 1993 at the Palmottu Natural Analogue Study site, which comprises a small U-Th mineralization in Nummi-Pusula, southwestern Finland. Additionally, the report includes several separ...

T. Ruskeeniemi R. Blomqvist J. Suksi H. Niini



Case study of wind turbine generator siting in complex terrain  

SciTech Connect

A cost-effective wind turbine generator siting method is described, along with the results of a preliminary application of the method in the complex terrain of the New Hampshire mountains. The approach followed stressed the use of advanced planning, map interpretation, candidate-site aerial examination, and on-site studies in which TALA (Tethered Aerodynamically Lifting Anemometer) kite measurements and the examination of wind-deformed vegetation were conducted. The study results in a condensed list of sites that are candidates for the installation of meteorological sensors and the recording of a minimum of one year of wind data before recommending a site for the installation of a wind turbine (WT) generator.

Vachon, W.A.; Downey, W.T.; Madio, F.R.



What Makes a Good Site for Field Study?  

NSDL National Science Digital Library

After learning how scientists at the museum decide on which sites to study, students select sites to study and map in this activity. It's designed to be completed in three to six sessions and has information for teachers, including tips on how to select, map out, and measure team plots within the class site. Perhaps the best way to get students invested in the topic of biodiversity is to get them involved in discovering for themselves the breadth and scope of the variety of life-forms that exist locally. At their own site, they will conduct systematic observations of plants, animals, or both. You will pick a specific site in which your students will work, and they will mark their team plots and record observations in their field journals. In this way, students will emulate the fieldwork carried out by biologists. They will observe, record, identify specimens, collect data, communicate, and share results.


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

PubMed Central

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.

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



Fort Scott National Historic Site Visitor Study, Summer 2011.  

National Technical Information Service (NTIS)

This visitor study report profiles a systematic, random sample of Fort Scott National Historic Site (NHS) visitors during July 15 August 23, 2011. A total of 341 questionnaires were distributed to visitor groups. Of those, 248 questionnaires were returned...

M. F. Manni S. J. Hollenhorst Y. Le



High Plains Regional Ground-water Study web site  

USGS Publications Warehouse

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.

Qi, Sharon L.



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

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.

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



Modeling of a new tubercular maltosyl transferase, GlgE, study of its binding sites and virtual screening.  


Recently maltosyl transferase of Mycobacterium tuberculosis (mtb GlgE) belonging to ?-amylase family has been identified as a potential drug target. Despite its importance, its three dimensional (3D) structure is unavailable. In this study we have modeled its 3D homo-dimeric structure using its homologue in Streptomyces ceolicolor (stp GlgE) as the template. Its monomer consists of five domains and four inserts, out of which two inserts are unique to mtb GlgE. It also has three binding cavities. One primary (pbs) and two secondary (sbs1 and sbs2), with one unique insert appearing within sbs2. Investigation of its homo-dimeric model revealed the presence of a disulphide bridge between Cys-29 of both the chains which is absent in stp GlgE. Virtual screening with known substrates and substrate analogues of ?-amylase family proteins indicated better binding of maltose to sbs1 than pbs. Among all computationally screened substrates 3-O-Alpha-D-Glucopyranosyl-D-Fructose (OTU) docked with best binding affinity to pbs. Interaction of known inhibitors of ?-amylase family proteins from CHEMBL is also studied. This reveals for the first time the unique 3D structure of mtb GlgE and provides insights into its active sites and substrate binding affinities. This may help in developing new anti-tubercular drugs and its analogues. PMID:24820953

Sengupta, Soumi; Roy, Debjani; Bandyopadhyay, Sanghamitra



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

SciTech Connect

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.

Siegrist, R.L.; Korte, N.E.; Pickering, D.A. (Oak Ridge National Lab., TN (United States)); Phelps, T.J. (Tennessee Univ., Knoxville, TN (United States))



Influence of Thiolate Ligands on Reductive N-O Bond Activation. Probing the O2? Binding Site of a Biomimetic SOR Analogue, and Examining the Proton-Dependent Reduction of Nitrite  

PubMed Central

Nitric oxide (NO) is frequently used to probe the substrate–binding site of “spectroscopically silent” non-heme Fe2+ sites of metalloenzymes, such as superoxide reductase (SOR). Herein we use NO to probe the superoxide binding site of our thiolate–ligated biomimetic SOR model [FeII(SMe2N4(tren))]+ (1). Like NO–bound trans cysteinate-ligated SOR (SOR-NO), the rhombic S= 3/2 EPR signal of NO–bound cis thiolate-ligated [Fe(SMe2N4(tren)(NO)]+ (2; g = 4.44, 3.54, 1.97), isotopically sensitive ?NO(?15NO) stretching frequency (1685(1640) cm?1), and 0.05 Å decrease in Fe–S bond length are shown to be consistent with the oxidative addition of NO to Fe(II) to afford an Fe(III)–NO? {FeNO}7 species containing high–spin (S= 5/2) Fe(III) antiferromagnetically coupled to NO? (S= 1). The cis versus trans positioning of the thiolate does not appear to influence these properties. Although it has yet to be crystallographically characterized, SOR-NO is presumed to possess a bent Fe-NO similar to that of 2 (Fe–N–O= 151.7(4)°). The N–O bond is shown to be more activated in 2 relative to N– and O–ligated {FeNO}7 complexes, and this is attributed to the electron donating properties of the thiolate ligand. Hydrogen bonding to the cysteinate sulfur attenuates N–O bond activation in SOR as shown by its higher ?NO frequency (1721 cm?1). In contrast, the ?O–O frequency of SOR peroxo intermediate and its analogues is not affected by H-bonds to the cysteinate sulfur, or other factors influencing the Fe–SR bond strength. These only influence the ?Fe–O frequency. Reactions between 1 and NO2? are shown to result in the proton–dependent heterolytic cleavage of an N–O bond. The mechanism of this reaction is proposed to involve both FeII–NO2? and {FeNO}6 intermediates similar to those implicated in the mechanism of NiR–promoted NO2? reduction.

Villar-Acevedo, Gloria; Nam, Elaine; Fitch, Sarah; Benedict, Jason; Freudenthal, John; Kaminsky, Werner; Kovacs, Julie A.



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

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. NCT00346996.



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

NASA Astrophysics Data System (ADS)

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

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



Second Information Technology in Education Study: SITES 2006 Technical Report  

ERIC Educational Resources Information Center

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),…

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



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

NASA Astrophysics Data System (ADS)

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.

Orlov, Sergey; Goncharova, Iryna; Urbanová, Marie


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

SciTech Connect

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.

Lincoff, A.H. [US Environmental Protection Agency, San Francisco, CA (United States). Region IX; Costan, G.P.; Montgomery, M.S.; White, P.J. [Pacific Northwest Lab., Richland, WA (United States)



8-substituted adenosine and theophylline-7-riboside analogues as potential partial agonists for the adenosine A1 receptor.  


A series of 8-substituted adenosine and theophylline-7-riboside analogues (28 and 9 compounds, respectively) was tested on adenosine A1 and A2A receptors as an extensive exploration of the adenosine C8-region. Alkylamino substituents at the 8-position cause an affinity decrease for adenosine analogues, but an affinity increase for theophylline-7-riboside derivatives. The affinity decrease is probably due to a direct steric hindrance between the C8-substituent and the binding site as well as to electronic effects, not to a steric influence on the ribose moiety to adopt the anti conformation. The 8-substituents increase the affinity of theophylline-7-riboside analogues probably by binding to a lipophilic binding site. The intrinsic activity was tested in vitro for some 8-substituted adenosine analogues, by determining the GTP shift in receptor binding studies and the inhibition of adenylate cyclase in a culture of rat thyroid FRTL-5 cells, and in vivo in the rat cardiovascular system for 8-butylaminoadenosine. Thus, it was shown that 8-ethyl-, 8-butyl-, and 8-pentylamino substituted analogues of adenosine may be partial agonists in vitro, and that 8-butylaminoadenosine is a partial agonist for the rat cardiovascular A1 receptor in vivo. PMID:7589213

Van der Wenden, E M; Hartog-Witte, H R; Roelen, H C; von Frijtag Drabbe Künzel, J K; Pirovano, I M; Mathôt, R A; Danhof, M; Van Aerschot, A; Lidaks, M J; IJzerman, A P



Usability of institutional cancer web sites: an Italian case study.  


In order to evaluate if and to what extent Italian speaking cancer patients can benefit from information available on cancer web sites, an "in vitro" usability (ISO definition) study has been carried out. It investigated the usability of the web sites of the most representative Italian Institutions in the oncological field for the adult patients needing to find information about head and neck cancer. Specific evaluation criteria from the literature were used. The results point out some problems about accessibility, in line with other studies, and about the usefulness of the contents, in particular in the web sites of care delivery institutions: a grey present situation, but there are already grounds for significant improvement. Institutions and organizations must not waste the opportunity of being valuable sources in order to build the so called "informed patient," and the usability of their web sites could make the difference. PMID:17911887

Mazzoleni, M Cristina; Butera, Raffaella; Corbella, Franco; Balcet, Vittoria; Masenga, Enrico



TWRS privatization phase I site development engineering study  

SciTech Connect

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.

Shord, A.L.



The non-gastric H,K-ATPase as a tool to study the ouabain-binding site in Na,K-ATPase  

Microsoft Academic Search

Based on studies with chimeras between (non-)gastric H,K-ATPase and Na,K-ATPase, a model for the ouabain binding site has\\u000a recently been presented (Qiu et al. J.Biol.Chem. 280 (2005) 32349). In this model, hydrogen bonds between specific amino acid\\u000a residues of Na,K-ATPase and hydroxyl groups of ouabain play a crucial role. In the present study, a series of ouabain analogues\\u000a were tested

Jan Joep H. H. M. De Pont; Herman G. P. Swarts; Anna Karawajczyk; Gijs Schaftenaar; Peter H. G. M. Willems; Jan B. Koenderink



A visual analogue thermometer for measuring pain intensity  

Microsoft Academic Search

A new instrument for measuring pain intensity—the visual analogue thermometer (VAT)—was developed to overcome limitations and disadvantages, of the conventional visual analogue scale (VAS). Two studies were performed to assess eke validity and utility of the VAT as compares to conventional pain instruments whose psychometric qualities are scientifically recognized. The fist study was carried out ;with a group of 65

Manon Choinière; Rhonda Amsel



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

NASA Technical Reports Server (NTRS)

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

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



Steady State and Multifrequency Phase Fluorometry Studies of Binding Site Flexibility in Related Antibodies †  

Microsoft Academic Search

The fluorescence properties of related antibodies were characterized from proteins representing different time points in the murine antibody immune response (the period of time during which the selectivity and sensitivity to the small molecule hapten is enhanced several 100-1000-fold). Two of the antibodies studied are catalytic and bind covalently to a substrate analogue used to induce antibody production. The remaining

Gopi S. Mohan; Philip T. Chiu; Patricia B. O'Hara



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

SciTech Connect

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.

Not Available



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

PubMed Central

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 contribute a well-designed trial, relevant to all clinicians involved in the care for donor site wounds, which will help enhance uniformity and quality of care for these patients. Trial registration, NTR1849. Date registered: June 9, 2009



Structural analogues of ZAPA as GABAA agonists.  


Structural analogues of ZAPA, Z-3-[(aminoiminomethyl)thio]prop-2-enoic acid, an isothiouronium analogue of GABA, are potent GABAA agonists as seen in the isolated guinea-pig ileum and in the facilitation of [3H]diazepam binding to rat brain membranes. Compounds with guanidino or amidine groups replacing the amino functionality of GABA were also found to be active. The highest activity was displayed by the isothiouronium salts in which the conformational flexibility of the molecule is restricted by a Z-substituted carbon-carbon double bond. A series of bis-isothiouronium compounds was prepared from aliphatic alpha, omega-bis-thioureas as mixtures of E and Z adducts. Maximum GABAA agonist activity for this series was found with a C6-C8 carbon chain, and the results were consistent with an interaction at the GABAA receptor with only one end of the molecule, rather than the more potent effect expected of a molecule bridging two active sites. GABAA antagonist/partial agonist activity was observed on the guinea pig isolated ileum for a number of different analogue types, with the most potent being bis-isothiouronium derivatives. None of the substituted derivatives of ZAPA was as active as ZAPA itself, and maximum GABAA activity was found in the n-pentyl and n-hexyl analogues. PMID:9153000

Allan, R D; Dickenson, H W; Johnston, G A; Kazlauskas, R; Mewett, K N



Pesticides in roof runoff: study of a rural site and a suburban site.  


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

Vialle, C; Sablayrolles, C; Silvestre, J; Monier, L; Jacob, S; Huau, M-C; Montrejaud-Vignoles, M



Orally active prostacyclin analogue for cardiovascular disease.  


Prostacyclin has vasoprotective effects such as vasodilation and antiplatelet aggregatory activity. A relative deficiency of prostacyclin contributes to the pathogenesis of cardiovascular disease including pulmonary artery disease (PAH). Inconvenient intravenous dosing of prostacyclin led to the development of more stable, an orally active analogue: beraprost. It is a chemically stable prostacyclin analogue owing to its cyclo-pentabenzofuranyl structure and produces strong vasodilation and inhibition of platelet aggregation. To date, beraprost has been used in the treatment of PAH and peripheral arterial disease (PAD). Recently, we have shown that beraprost induces neovascularization in ischemic myocardium by enhancement of bone marrow cell mobilization. Interestingly, meta-analysis of clinical studies for PAD has shown that repeated administration of beraprost decreases the number of cardiovascular events. These results suggest that oral administration of beraprost has beneficial effects on cardiovascular disease. Orally active prostacyclin analogues, are promising drugs for the treatment of cardiovascular disease. PMID:20357744

Nagaya, N



Docking-MM-GB/SA and ADME screening of HIV-1 NNRTI inhibitor: nevirapine and its analogues.  


Nevirapine and its synthetic analogues, a class of non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), have been the objective of numerous studies focused to prepare better and safer anti-HIV drugs. We developed a library of nevirapine analogues (47) using combinatorial design and with structural modification at X, Y and R substituents in the parent structure of nevirapine. Their molecular interactions and binding affinities with reverse transcriptase (3HVT and 1VRT) have been studied using the docking-molecular mechanics based generalized Born/surface area (MM-GB/SA) solvation model. Final screening of these analogues is based on absorption, distribution, metabolism and excretion (ADME) properties. The proposed NNRTI analogues dock in a similar position and orientation in the active site of RT as co-crystallized nevirapine. In addition a linear correlation was observed between the calculated free energy of binding (FEB) and pIC50 for the inhibitors with correlation coefficient R2 of 0.9948, suggesting that the docked structure orientation and the interaction energies are reasonable. The electrostatic energy terms estimated by GB/SA showed important role on prediction of binding affinity (R2 = 17.2 %). Since we used two different HIV-1 RT crystal structures (3HVT and 1VRT), which are at different resolution (2.9 and 2.2 A), we propose that structures with resolutions better than 3 A can be used to produce reasonable docking results. Few analogues showed high binding affinity and activity with RT in compare to co-crystallized nevirapine. These analogues also well qualify ADME properties and showed good druggable characters. The work addressed to modify the X, Y and R substituents in the nevirapine scaffold to prepare synthetic analogues for second generation drug development against RT. PMID:19032162

Sengupta, Dipankar; Verma, Deeptak; Naik, Pradeep Kumar



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)

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 ?m/s. The results of the experiments yielded friction coefficients (?= ?/?n) 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 simulated gouges showed a decrease in friction coefficient of 20-30% with increasing normal stress up to 90 MPa, with almost all samples showing velocity-strengthening (stable) slip behaviour. Permeability measurements show only minor changes during shear. Overall, our results demonstrated that higher (CO2-related) carbonate content leads to higher frictional strength and increased velocity strengthening (slip stability), notably at low normal stresses. However, preliminary results recently obtained at elevated temperatures show that carbonate-rich samples show velocity-weakening behaviour at 100°C, which is in line with previous studies on pure carbonates. A natural analogue from The Netherlands shows similar results for the chemical alteration of reservoir rock by the presence of naturally long-term stored CO2.

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




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...


A new nucleoside analogue with potent activity against mutant sr39 herpes simplex virus-1 (HSV-1) thymidine kinase (TK).  


Nucleoside analogues, such as penciclovir, ganciclovir, acyclovir, and their fluoro-substituted derivatives, have wide utility as antivirals. Among these analogues, FHBG ((18)F-Fluorohydroxybutylguanine) is a well-validated PET (positron emission tomography) probe for monitoring reporter gene expression. To evaluate whether or not imposing rigidity into the flexible side chain of FHBG 4 could also impact its interaction, with amino acid residues within the binding site of HSV1-TK (Herpes Simplex Virus-1 Thymidine Kinase), thus influencing its cytotoxic activity. Herein, the synthesis of a new fluorinated nucleoside analogue 6 (conceived via ligand-docking studies) is reported. Agent 6 demonstrates selective activity against HeLa cells stably transfected with mutant HSV1-sr39TK and is also 47-fold more potent than FHBG. PMID:22765027

Sundaram, G S M; Harpstrite, Scott E; Kao, Jeff Lung-Fa; Collins, Silvia D; Sharma, Vijay



Template properties of mutagenic cytosine analogues in reverse transcription  

PubMed Central

We have studied the mutagenic properties of ribonucleotide analogues by reverse transcription to understand their potential as antiretroviral agents by mutagenesis of the viral genome. The templating properties of nucleotide analogues including 6-(?-D-ribofuranosyl)-3,4-dihydro-8H-pyrimido[4,5-c](1,2)oxazin-7-one, N4-hydroxycytidine, N4-methoxycytidine, N4-methylcytidine and 4-semicarbazidocytidine, which have been reported to exhibit ambiguous base pairing properties, were examined. We have synthesized RNA templates using T3 RNA polymerase, and investigated the specificity of the incorporation of deoxyribonucleoside triphosphates opposite these cytidine analogues in RNA by HIV and AMV reverse transcriptases. Except for N4-methylcytidine, both enzymes incorporated both dAMP and dGMP opposite these analogues in RNA. This indicates that they would be highly mutagenic if present in viral RNA. To study the basis of the differences among the analogues in the incorporation ratios of dAMP to dGMP, we have carried out kinetic analysis of incorporation opposite the analogues at a defined position in RNA templates. In addition, we examined whether the triphosphates of these analogues were incorporated competitively into RNA by human RNA polymerase II. Our present data supports the view that these cytidine analogues are mutagenic when incorporated into RNA, and that they may therefore be considered as candidates for antiviral agents by causing mutations to the retroviral genome.

Suzuki, Tetsuya; Moriyama, Kei; Otsuka, Chie; Loakes, David; Negishi, Kazuo



Conformational and membrane interaction studies of the antimicrobial peptide alyteserin-1c and its analogue [E4K]alyteserin-1c.  


Alyteserin-1c (GLKEIFKAGLGSLVKGIAAHVAS.NH(2)), first isolated from skin secretions of the midwife toad Alytes obstetricans, shows selective growth-inhibitory activity against Gram-negative bacteria. The structures of alyteserin-1c and its more potent and less haemolytic analogue [E4K]alyteserin-1c were investigated in various solution and membrane mimicking environments by proton NMR spectroscopy and molecular modelling. In aqueous solution, the peptide displays a lack of secondary structure but, in a 2,2,2-trifluoroethanol (TFE-d(3))-H(2)O solvent mixture, the structure is characterised by an extended alpha helix between residues Leu(2) and Val(21). Solution structural studies in the membrane mimicking environments, sodium dodecyl sulphate (SDS), dodecylphosphocholine (DPC), and 1,2-dihexanoyl-sn-glycero-3-phosphatidylcholine (DHPC) micelles, indicate that these peptides display an alpha helical structure between residues Lys(3) and Val(21). Positional studies of the peptides in SDS, DPC and DHPC media show that the N-terminal and central residues lie inside the micelle while C-terminal residues beyond Ala(19) do not interact with the micelles. PMID:21565166

Subasinghage, Anusha P; O'Flynn, Donal; Conlon, J Michael; Hewage, Chandralal M



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

SciTech Connect

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.

Assary, R. S.; Curtiss, L. A. (Center for Nanoscale Materials); ( MSD); (Northwestern Univ.)



Risk perception in context: The Savannah River Site stakeholder study  

SciTech Connect

Environmental managers are increasingly charged with involving the public in the development and modification of policies regarding risks to human health and the environment. Involving the public in environmental decision making first requires a broad understanding of how and why the public perceives various risks. The Savannah River Stakeholder Study was conducted with the purpose of investigating individual, economic, and social characteristics of risk perceptions among those living near the Savannah River Nuclear Weapons Site. A number of factors were found to impact risk perceptions among those living near the site. One's estimated proximity to the site and relative river location surfaced as strong determinants of risk perceptions among SRS residents. Additionally, living in a quality neighborhood and demonstrating a willingness to accept health risks for economic gain strongly abated heightened risk perceptions.

Williams, B.L.; Brown, S.; Greenberg, M.; Kahn, M.A.



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


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

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



Wildlife studies on the Hanford site: 1994 Highlights report  

SciTech Connect

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.

Cadwell, L.L. [ed.



Genetically engineered insulin and its pharmaceutical analogues  

Microsoft Academic Search

Studies of replacement therapy of diabetes mellitus resulted not only in introduction of series of forms of insulin available\\u000a at pharmaceutical market but also in new insulin analogues, which exhibit better control of blood glucose level. The present\\u000a paper deals with basic tendencies in this field.

D. A. Gusarov; V. D. Gusarova; D. I. Bayramashvili; A. F. Mironov



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

NASA Astrophysics Data System (ADS)

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 records suggest uninterrupted presence of mesophilous temperate trees (Quercus, Ulmus, Corylus, Fagus and Fraxinus excelsior) in the Eastern Carpathian Mountains throughout the LPG. We demonstrate that the LPG vegetation in this area was characterized by increasing grass cover and high frequency of wildfires. We conclude that pollen spectra over represent trees in the forest-steppe landscape of the LPG, furthermore pollen-based quantitative climate reconstructions for the LPG are challenging in this area due to the scarcity of modern analogues.

Magyari, Enik? Katalin; Kuneš, Petr; Jakab, Gusztáv; Sümegi, Pál; Pelánková, Barbora; Schäbitz, Frank; Braun, Mihály; Chytrý, Milan



Structural studies of human brain-type creatine kinase complexed with the ADP-Mg2+-NO3- -creatine transition-state analogue complex.  


Creatine kinase is a member of the phosphagen kinase family, which catalyzes the reversible phosphoryl transfer reaction that occurs between ATP and creatine to produce ADP and phosphocreatine. Here, three structural aspects of human-brain-type-creatine-kinase (hBB-CK) were identified by X-ray crystallography: the ligand-free-form at 2.2A; the ADP-Mg2+, nitrate, and creatine complex (transition-state-analogue complex; TSAC); and the ADP-Mg2+-complex at 2.0A. The structures of ligand-bound hBB-CK revealed two different monomeric states in a single homodimer. One monomer is a closed form, either bound to TSAC or the ADP-Mg2+-complex, and the second monomer is an unliganded open form. These structural studies provide a detailed mechanism indicating that the binding of ADP-Mg2+ alone may trigger conformational changes in hBB-CK that were not observed with muscle-type-CK. PMID:18977227

Bong, Seoung Min; Moon, Jin Ho; Nam, Ki Hyun; Lee, Ki Seog; Chi, Young Min; Hwang, Kwang Yeon



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


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

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



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


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

Peyre, Ludovic; Rouimi, Patrick; de Sousa, Georges; Héliès-Toussaint, Cécile; Carré, Benjamin; Barcellini, Sylvie; Chagnon, Marie-Christine; Rahmani, Roger



Comparison of neural correlates of risk decision making between genders: an exploratory fNIRS study of the Balloon Analogue Risk Task (BART).  


Functional magnetic resonance imaging (fMRI) research rarely reports gender differences in the neural correlates of risk decision making due to small sample sizes. In this functional near-infrared spectroscopy (fNIRS)-based imaging study of active and passive risk decision making, gender differences in oxygenated hemoglobin (HbO) concentration changes were investigated in the prefrontal cortex (PFC) of healthy adults. Forty adult participants (25-44 years; males=23) completed two sets of 15 balloon trials in active and passive decision making modes of the Balloon Analogue Risk Task (BART). In active mode, participants chose the number of balloon inflations, decided when to collect money, or risked accrued money if balloons exploded. BART is psychometrically well established and has predictive validity to real-world risk taking. The blocked experimental design and modification of BART for fNIRS were guided by a previous fMRI study that examined the neural correlates of risk decision making in young adults [Rao, H., Korczykowski, M., Pluta, J., Hoang, A., Detre, J.A., 2008. Neural correlates of voluntary and involuntary risk taking in the human brain: An fMRI study of the Balloon Analog Risk Task (BART). NeuroImage 42, 902-910]. Our findings were consistent with the previous fMRI study: no or little PFC activation during passive mode but strong PFC activation during active wins and losses among total sample. Active losses in females were associated with more significant bilateral activation in dorsal lateral prefrontal cortex (DLPFC) than males; no significant gender differences were found in DLPFC activation during active wins. Gender differences existed in direction and strength of correlations between BART behavioral and hemodynamic data. This study shows that use of fNIRS is a feasible, accessible, and less costly way to achieve adequate study power and investigate gender differences in neural correlates of risk decision making. PMID:22634214

Cazzell, Mary; Li, Lin; Lin, Zi-Jing; Patel, Sonal J; Liu, Hanli



Synthesis and biological activity of tetralone abscisic acid analogues.  


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

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



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

Federal Register 2010, 2011, 2012, 2013

...Information Collection: Comment Request; Homelessness Prevention Study Site Visits AGENCY...following information: Title of Proposal: Homelessness Prevention Study Site Visits. OMB...requirements associated with HUD's Homelessness Prevention Study Site Visits....



Selective regulation of polyamine metabolism with methylated polyamine analogues.  


Polyamine metabolism is intimately linked to the physiological state of the cell. Low polyamines levels promote growth cessation, while increased concentrations are often associated with rapid proliferation or cancer. Delicately balanced biosynthesis, catabolism, uptake and excretion are very important for maintaining the intracellular polyamine homeostasis, and deregulated polyamine metabolism is associated with imbalanced metabolic red/ox state. Although many cellular targets of polyamines have been described, the precise molecular mechanisms in these interactions are largely unknown. Polyamines are readily interconvertible which complicate studies on the functions of the individual polyamines. Thus, non-metabolizable polyamine analogues, like carbon-methylated analogues, are needed to circumvent that problem. This review focuses on methylated putrescine, spermidine and spermine analogues in which at least one hydrogen atom attached to polyamine carbon backbone has been replaced by a methyl group. These analogues allow the regulation of both metabolic and catabolic fates of the parent molecule. Substituting the natural polyamines with methylated analogue(s) offers means to study either the functions of an individual polyamine or the effects of altered polyamine metabolism on cell physiology. In general, gem-dimethylated analogues are considered to be non-metabolizable by polyamine catabolizing enzymes spermidine/spermine-N¹-acetyltransferase and acetylpolyamine oxidase and they support short-term cellular proliferation in many experimental models. Monomethylation renders the analogues chiral, offering some advantage over gem-dimethylated analogues in the specific regulation of polyamine metabolism. Thus, methylated polyamine analogues are practical tools to meet existing biological challenges in solving the physiological functions of polyamines. PMID:24022706

Keinänen, Tuomo A; Hyvönen, Mervi T; Alhonen, Leena; Vepsäläinen, Jouko; Khomutov, Alex R



Nevada Test Site tortoise population monitoring study. Final report  

SciTech Connect

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.

Mueller, J.M.; Zander, K.K.



Behavior-based safety on construction sites: A case study.  


This work presents the results of a case study and describes an important area within the field of construction safety management, namely behavior-based safety (BBS). This paper adopts and develops a management approach for safety improvements in construction site environments. A rigorous behavioral safety system and its intervention program was implemented and deployed on target construction sites. After taking a few weeks of safety behavior measurements, the project management team implemented the designed intervention and measurements were taken. Goal-setting sessions were arranged on-site with workers' participation to set realistic and attainable targets of performance. Safety performance measurements continued and the levels of performance and the targets were presented on feedback charts. Supervisors were asked to give workers recognition and praise when they acted safely or improved critical behaviors. Observers were requested to have discussions with workers, visit the site, distribute training materials to workers, and provide feedback to crews and display charts. They were required to talk to operatives in the presence of line managers. It was necessary to develop awareness and understanding of what was being measured. In the process, operatives learned how to act safely when conducting site tasks using the designed checklists. Current weekly scores were discussed in the weekly safety meetings and other operational site meetings with emphasis on how to achieve set targets. The reliability of the safety performance measures taken by the company's observers was monitored. A clear increase in safety performance level was achieved across all categories: personal protective equipment; housekeeping; access to heights; plant and equipment, and scaffolding. The research reveals that scores of safety performance at one project improved from 86% (at the end of 3rd week) to 92.9% during the 9th week. The results of intervention demonstrated large decreases in unsafe behaviors and significant increases in safe behaviors. The results of this case study showed that an approach based on goal setting, feedback, and an effective measure of safety behavior if properly applied by committed management, can improve safety performance significantly in construction site environments. The results proved that the BBS management technique can be applied to any country's culture, showing that it would be a good approach for improving the safety of front-line workers and that it has industry wide application for ongoing construction projects. PMID:24686162

Choudhry, Rafiq M



Reactions of trimethylphosphine analogues of auranofin with bovine serum albumin  

SciTech Connect

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.

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



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

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.

Rai, Balwant; Kaur, Jasdeep



Off-site Access Study for NOSR 1. Draft  

SciTech Connect

The Off-site Access Study addresses the routes available for access to NOSR 1, the use of a funicular railroad, potential staging areas, the need and availability of railroad spurs, utility corridors, new water supply, and construction methodologies (schedule, manpower, locations for modular construction facilities, etc.) for optional development of the Reserves. Information on schedules and manpower (both construction and operation) is an important input to the socioeconomic study, and the location of modular construction facilities, railroads, staging areas, etc., identify potential demographic regions of population. Public access to the NOSR property is presently limited to two unimproved roadways, (Cow Creek and JQS Trail); however, several private roads provide access to the site. The NOSR is open to public use for recreation and hunting. Commercially, the property is used for grazing of cattle and sheep. Surface uses of the NOSR site are managed by the Bureau of Land Management. To develop an oil shale-producing facility on the Reserve, suitable access for a large work force must be constructed. This study of access roads includes definition of three methods of constructing a plant and identifies 10 potential routes suitable for the transportation requirements during construction and operation of the oil shale facilities. 50 figures, 1 table.

Not Available



Credibility: Norwegian Students Evaluate Media Studies Web Sites  

Microsoft Academic Search

This paper investigates Norwegian university students' evaluations of web site credibility and site authors' vested interests with respect to a text- based academic site and an informational site with commercial support. Credibility ratings were higher for some aspects of the academic site even though the non-academic sit was rated more highly in presentation design and currency. Negative correlations emerged between

Marie Iding; Joan C. Nordbotten; J. Malkeet Singh



Towards adaptive Web sites: Conceptual framework and case study  

Microsoft Academic Search

Today's Web sites are intricate but not intelligent; while Web navigation is dynamic and idiosyncratic, all too often Web sites are fossils cast in HTML. In response, this paper investigates adaptive Web sites: sites that automatically improve their organization and presentation by learning from visitor access patterns. Adaptive Web sites mine the data buried in Web server logs to produce

Mike Perkowitz; Oren Etzioni



Characterization of the radioiodinated analogue of SCH 23390: in vitro and in vivo D-1 dopamine receptor binding studies  

SciTech Connect

A new radioiodinated molecule, /sup 125/I-SCH 38840 (previously referred to as /sup 125/I-SCH 23982), has been recently reported to be a D-1 dopamine receptor ligand. The current study confirms and expands the characterization of both the radiolabeled and unlabeled forms of this compound, as well as describing the development of an in vivo D-1 receptor binding assay utilizing the /sup 125/I-SCH 38840. The binding of /sup 125/I-SCH 38840 to rat striatal membranes, in vitro, was saturable and exhibited a K/sub D/ of 1.47 nM. Competition studies using /sup 125/I-SCH 38840 exhibited a pharmacological profile consistent with the proposal that /sup 125/I-SCH 38840 was binding to the D-1 receptor. Further studies with the unlabeled SCH 38840 demonstrated that it inhibited dopamine-stimulated adenylate cyclase with a K/sub I/ of 66.1 nM, indicating that SCH 38840 was acting as a D-1 antagonist. Behavioral studies demonstrated that SCH 38840, blocked conditioned avoidance responding in rats, a measurement considered predictive of anti-psychotic activity in man. In vivo binding of /sup 125/I-SCH 38840 to rat striatum following s.c. administration was specific.

McQuade, R.D.; Chipkin, R.; Amlaiky, N.; Caron, M.; Iorio, L.; Barnett, A.



Targeted melanoma imaging and therapy with radiolabeled alpha-melanocyte stimulating hormone peptide analogues.  


Radiolabeled alpha-melanocyte stimulating hormone (a-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 a-MSH peptide based imaging and therapeutic agents. Initially, the native a-MSH peptide was radiolabeled directly, but it suffered from low specific activity and poor stability. The addition of non-natural amino acids yielded a-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 a-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 a-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 a-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 a-MSH peptides for melanoma imaging and treatment of disseminated disease. PMID:20467398

Quinn, T; Zhang, X; Miao, Y



Characterization of the radioiodinated analogue of SCH 23390: in vitro and in vivo D-1 dopamine receptor binding studies.  


A new radioiodinated molecule, 125I-SCH 38840 (previously referred to as 125I-SCH 23982), has been recently reported to be a D-1 dopamine receptor ligand. The current study confirms and expands the characterization of both the radiolabeled and unlabeled forms of this compound, as well as describing the development of an in vivo D-1 receptor binding assay utilizing the 125I-SCH 38840. The binding of 125I-SCH 38840 to rat striatal membranes, in vitro, was saturable and exhibited a KD of 1.47 nM. Competition studies using 125I-SCH 38840 exhibited a pharmacological profile consistent with the proposal that 125I-SCH 38840 was binding to the D-1 receptor. Further studies with the unlabeled SCH 38840 demonstrated that it inhibited dopamine-stimulated adenylate cyclase with a KI of 66.1 nM, indicating that SCH 38840 was acting as a D-1 antagonist. Behavioral studies demonstrated that SCH 38840 (MED = 1.0 mg/kg, s.c.) blocked conditioned avoidance responding in rats, a measurement considered predictive of anti-psychotic activity in man. In vivo binding of 125I-SCH 38840 to rat striatum following s.c. administration was specific. Peak striatal levels were observed 1 h after injection, with measurable binding observed out to 8 h post-treatment. The displacement of the in vivo binding by unlabeled standards again suggested a D-1 selective interaction. The half-life of the in vivo binding of 125I-SCH 38840 was approximately 1.25 h, and was nearly equivalent to the half-life of the anti-CAR activity of unlabeled SCH 38840. These results clearly demonstrate the D-1 nature of SCH 38840's behavioral activity and strengthen the anti-psychotic potential of a D-1 antagonist. PMID:3050344

McQuade, R D; Chipkin, R; Amlaiky, N; Caron, M; Iorio, L; Barnett, A



Radionuclide migration studies at the Nevada Test Site  

SciTech Connect

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.

Thompson, J.L.



Choose study sites carefully |

In some cases, sites are selected from a pool of potentials. This is especially true for earlier phase (phase I or II trials) clinical trials. In recruitment, a site’s past performance can predict future success.


Alternative site blood glucose testing: a multicenter study.  


The aim of this study was to compare glucose measurements between fingertip and forearm using the blood glucose (BG) monitoring system One Touch Ultra (LifeScan), an electrochemical sensor that requires only a very small drop of blood (1 microL). Patients with type 1 or type 2 diabetes were identified in five outpatient diabetes clinics. Participants were requested to use the One Touch Ultra at home for 1 week for the measurement of BG levels from both sites. Patients filled in a questionnaire about their experience with testing blood samples from fingertip and forearm. The agreement between the measurements from the two sites was assessed using linear regression analysis, mean absolute relative error (MARE), the Bland-Altman method, and Error Grid Analysis (EGA). Overall, 112 patients were recruited, of whom 58% had type 1 diabetes. Linear regression analysis showed an intercept of 17.7, statistically different from 0 (p<0.0001). The slope was 0.956, and the Pearson correlation coefficient was 0.95. A MARE of 12.1% (SD=11.8%) was obtained, with a greater deviation of the forearm values from the fingertip ones in the hypoglycemic range (MARE=22.3%; SD=21.7%). The Bland-Altman bias plot showed a mean bias of 10.2 mg/dL (SD=23.1), with no correlation between mean difference and average BG levels (r=0.02). The EGA showed that 89.2% of the values fell in zone A, 10.4% in zone B, and 0.4% in zone C. The vast majority of patients (71%) declared that the collection of blood from the forearm caused no pain or less pain than the traditional site. Only 17% of the patients declared that it was impossible to obtain any blood from the forearm, while 63% reported with satisfaction that the quantity requested was small. At the end of the study period, 32% of the participants indicated the forearm as the preferred test site. Alternative site testing on the arm, with a BG meter that requires only a very small drop of blood, is feasible and reliable under routine clinical conditions. When testing with the express purpose of detecting hypoglycemia, the finger still remains the recommended test site. PMID:14709201

Fedele, D; Corsi, A; Noacco, C; Prisco, F; Squatrito, S; Torre, E; Iafusco, D; Errico, M K; Toniato, R; Nicolucci, A; Franciosi, M; De Berardis, G; Neri, L



Computational studies of Bronsted acid sites in zeolites  

SciTech Connect

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.

Curtiss, L.A.; Iton, L.E. [Argonne National Lab., IL (United States); Zygmunt, S.A. [Valparaiso Univ., IN (United States). Dept. of Physics and Astronomy



Summary of 1990 eolian characterization studies, Hanford Site, Washington  

SciTech Connect

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.

Gaylord, D.R.; Stetler, L.D.; Smith, G.D. [Washington State Univ., Pullman, WA (United States); Mars, R.W. [Wyoming Univ., Laramie, WY (United States)



Cafestol to Tricalysiolide B and Oxidized Analogues: Biosynthetic and Derivatization Studies Using Non-heme Iron Catalyst Fe(PDP)  

PubMed Central

The tricalysiolides are a recently isolated class of diterpene natural products featuring the carbon backbone of the well-known coffee extract, cafestol. Herein we validate the use of our non-heme iron complex, Fe(PDP), as an oxidative tailoring enzyme mimic to test the proposal that this class of natural products derives from cafestol via cytochrome P-450-mediated furan oxidation. Thereafter, as predicted by computational analysis, C–H oxidation derivatization studies provided a novel 2° alcohol product as a single diastereomer.

Bigi, Marinus A.; Liu, Peng; Zou, Lufeng



Engineered biosynthesis of aklanonic acid analogues.  


Aklanonic acid, an anthraquinone natural product, is a common advanced intermediate in the biosynthesis of several antitumor polyketide antibiotics, including doxorubicin and aclacinomycin A. Intensive semisynthetic and biosynthetic efforts have been directed toward developing improved analogues of these clinically important compounds. The primer unit of such polyfunctional aromatic polyketides is an attractive site for introducing novel chemical functionality, and attempts have been made to modify the primer unit by precursor-directed biosynthesis or protein engineering of the polyketide synthase (PKS). We have previously demonstrated the feasibility of engineering bimodular aromatic PKSs capable of synthesizing unnatural hexaketides and octaketides. In this report, we extend this ability by preparing analogues of aklanonic acid, a decaketide, and its methyl ester. For example, by recombining the R1128 initiation module with the dodecaketide-specific pradimicin PKS, the isobutyryl-primed analogue of aklanonic acid (YT296b, 10) and its methyl ester (YT299b, 12) were prepared. In contrast, elongation modules from dodecaketide-specific spore pigment PKSs were unable to interact with the R1128 initiation module. Thus, in addition to revealing a practical route to new anthracycline antibiotics, we also observed a fundamental incompatibility between antibiotic and spore pigment biosynthesis in the actinomycetes bacteria. PMID:16131203

Lee, Taek Soon; Khosla, Chaitan; Tang, Yi



Itraconazole Side Chain Analogues: Structure-Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling  

PubMed Central

Itraconazole is an antifungal drug that was recently found to possess potent antiangiogenic activity and anti-hedgehog (Hh) pathway activity. To search for analogues of itraconazole with greater potency and to understand the structure–activity relationship in both antiangiogenic and Hh targeting activity, 25 itraconazole side chain analogues were synthesized and assayed for inhibition of endothelial cell proliferation and Gli1 transcription in a medulloblastoma (MB) culture. Through this analysis, we have identified analogues with increased potency for inhibiting endothelial cell proliferation and the Hh pathway, as well as VEGFR2 glycosylation that was recently found to be inhibited by itraconazole. An SAR analysis of these activities revealed that potent activity of the analogues against VEGFR2 glycosylation was generally driven by side chains of at least four carbons in composition with branching at the ? or ? position. SAR trends for targeting the Hh pathway were divergent from those related to HUVEC proliferation or VEGFR2 glycosylation. These results also suggest that modification of the sec-butyl side chain can lead to enhancement of the biological activity of itraconazole.

Shi, Wei; Nacev, Benjamin A.; Aftab, Blake T.; Head, Sarah; Rudin, Charles M.; Liu, Jun O.



Tritium migration studies at the Nevada Test Site  

SciTech Connect

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.

Schulz, R.K.; Romney, E.M.; Fujii, L.M.; Greger, P.D. (California Univ., Berkeley, CA (United States)); Kendall, E.W.; Hunter, R.B. (Reynolds Electrical and Engineering Co., Inc., Las Vegas, NV (United States))



[Paleoclimatology studies for Yucca Mountain site characterization]. Final report  

SciTech Connect

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.




Synthetic histatin analogues with broad-spectrum antimicrobial activity.  

PubMed Central

Histatins are salivary histidine-rich cationic peptides, ranging from 7 to 38 amino acid residues in length, that exert a potent killing effect in vitro on Candida albicans. Starting from the C-terminal fungicidal domain of histatin 5 (residues 11-24, called dh-5) a number of substitution analogues were chemically synthesized to study the effect of amphipathicity of the peptide in helix conformation on candidacidal activity. Single substitutions in dh-5 at several positions did not have any effect on fungicidal activity. However, multi-site substituted analogues (dhvar1 and dhvar2) exhibited a 6-fold increased activity over dh-5. In addition, dhvar1 and dhvar2 inhibited the growth of the second most common yeast found in clinical isolates, Torulopsis glabrata, of oral- and non-oral pathogens such as Prevotella intermedia and Streptococcus mutans, and of a methicillin-resistant Staphylococcus aureus. In their broad-spectrum activity, dhvar1 and dhvar2 were comparable to magainins (PGLa and magainin 2), antimicrobial peptides of amphibian origin. Both the fungicidal and the haemolytic activities of dhvar1, dhvar2 and magainins increased at decreasing ionic strength.

Helmerhorst, E J; Van't Hof, W; Veerman, E C; Simoons-Smit, I; Nieuw Amerongen, A V



Ecosystem studies at the Los Medanos site, Eddy County, New Mexico. Volume I  

SciTech Connect

This report summarizes the results of biological studies conducted during 1980 at the Los Medanos site in southeastern New Mexico. The studies include: (1) densities and species composition of the avifauna of the Los Medanos site; (2) aquatic ecosystems of the lower Pecos drainage; (3) floristic studies at the Los Medanos site; (4) plant successional, grazing, trampling, and salt studies on the Los Medanos site; (5) soil and vegetation studies at the Los Medanos site; (6) arthropod and decomposition studies at the WIPP site; (7) amphibians, reptiles and mammals at the Los Medanos site; (8) vertebrate ecology at the Los Medanos site; and (9) statistical analysis and data management. 7 refs. (ACR)

Hart, J.S. (ed.)



Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents.  


A novel series of 5-[2-(2,6-dichlorophenylamino)benzyl]-3-(substituted)-1,3,4-oxadiazol-2(3H)-thione (4a-k) derivatives have been synthesized by the Mannich reaction of 5-[2-(2,6-dichlorophenylamino)benzyl]-1,3,4-oxadiazol-2(3H)-thione (3) with an appropriately substituted primary/secondary amines, in the presence of formaldehyde and absolute ethanol. Structures of these novel compounds were characterized on the basis of physicochemical, spectral and elemental analysis. The title compounds (4a-k) were screened for in vivo acute anti-inflammatory and analgesic activities at a dose of 10mg/kg b.w. Compound 4k exhibited the most promising and significant anti-inflammatory profile while compounds 4a, 4d, 4e, 4i, and 4j showed moderate to good inhibitory activity at 2nd and 4thh, respectively. These compounds were also found to have considerable analgesic activity (acetic acid induced writhing model) and antipyretic activity (yeast induced pyrexia model). In addition, the tested compounds were also found to possess less degree of ulcerogenic potential as compared to the standard NSAIDs. Compounds that displayed promising anti-inflammatory profile were further evaluated for their inhibitory activity against cyclooxygenase enzyme (COX-1/COX-2), by colorimetric COX (ovine) inhibitor screening assay method. The results revealed that the compounds 4a, 4e, 4g and 4k exhibited effective inhibition against COX-2. In an attempt to understand the ligand-protein interactions in terms of the binding affinity, docking studies were performed using Molegro Virtual Docker (MVD-2013, 6.0) for those compounds, which showed good anti-inflammatory activity. It was observed that the binding affinities calculated were in agreement with the IC50 values. PMID:24751552

Palkar, Mahesh B; Singhai, Anuj S; Ronad, Pradeepkumar M; Vishwanathswamy, A H M; Boreddy, Thippeswamy S; Veerapur, Veeresh P; Shaikh, Mahamadhanif S; Rane, Rajesh A; Karpoormath, Rajshekhar



Utility of the Mild Brain Injury Atypical Symptoms Scale to detect symptom exaggeration: an analogue simulation study.  


Brief self-report symptom checklists are often used to screen for postconcussional disorder (PCD) and posttraumatic stress disorder (PTSD) and are highly susceptible to symptom exaggeration. This study examined the utility of the five-item Mild Brain Injury Atypical Symptoms Scale (mBIAS) designed for use with the Neurobehavioral Symptom Inventory (NSI) and the PTSD Checklist-Civilian (PCL-C). Participants were 85 Australian undergraduate students who completed a battery of self-report measures under one of three experimental conditions: control (i.e., honest responding, n?=?24), feign PCD (n?=?29), and feign PTSD (n?=?32). Measures were the mBIAS, NSI, PCL-C, Minnesota Multiphasic Personality Inventory-2, Restructured Form (MMPI-2-RF), and the Structured Inventory of Malingered Symptomatology (SIMS). Participants instructed to feign PTSD and PCD had significantly higher scores on the mBIAS, NSI, PCL-C, and MMPI-2-RF than did controls. Few differences were found between the feign PCD and feign PTSD groups, with the exception of scores on the NSI (feign PCD > feign PTSD) and PCL-C (feign PTSD > feign PCD). Optimal cutoff scores on the mBIAS of ?8 and ?6 were found to reflect "probable exaggeration" (sensitivity = .34; specificity = 1.0; positive predictive power, PPP = 1.0; negative predictive power, NPP = .74) and "possible exaggeration" (sensitivity = .72; specificity = .88; PPP = .76; NPP = .85), respectively. Findings provide preliminary support for the use of the mBIAS as a tool to detect symptom exaggeration when administering the NSI and PCL-C. PMID:23419145

Lange, Rael T; Edmed, Shannon L; Sullivan, Karen A; French, Louis M; Cooper, Douglas B



Abundance study of the two solar-analogue CoRoT targets HD 42618 and HD 43587 from HARPS spectroscopy  

NASA Astrophysics Data System (ADS)

We present a detailed abundance study based on spectroscopic data obtained with HARPS of two solar-analogue main targets for the asteroseismology programme of the CoRoT satellite: HD 42618 and HD 43587. The atmospheric parameters and chemical composition are accurately determined through a fully differential analysis with respect to the Sun observed with the same instrumental set-up. Several sources of systematic errors largely cancel out with this approach, which allows us to narrow down the 1-? error bars to typically 20 K in effective temperature, 0.04 dex in surface gravity, and less than 0.05 dex in the elemental abundances. Although HD 42618 fulfils many requirements for being classified as a solar twin, its slight deficiency in metals and its possibly younger age indicate that, strictly speaking, it does not belong to this class of objects. On the other hand, HD 43587 is slightly more massive and evolved. In addition, marked differences are found in the amount of lithium present in the photospheres of these two stars, which might reveal different mixing properties in their interiors. These results will put tight constraints on the forthcoming theoretical modelling of their solar-like oscillations and contribute to increase our knowledge of the fundamental parameters and internal structure of stars similar to our Sun. Based on observations collected at the La Silla Observatory, ESO (Chile) with the HARPS spectrograph at the 3.6-m telescope, under programme LP185.D-0056.Tables 1 and 2 are available in electronic form at

Morel, T.; Rainer, M.; Poretti, E.; Barban, C.; Boumier, P.



Antitrypanosomal and Antileishmanial Activities of Flavonoids and Their Analogues: In Vitro, In Vivo, Structure-Activity Relationship, and Quantitative Structure-Activity Relationship Studies  

PubMed Central

Trypanosomiasis and leishmaniasis are important parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of flavonoid aglycones and glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for T. brucei rhodesiense was exerted by 7,8-dihydroxyflavone (50% inhibitory concentration [IC50], 68 ng/ml), followed by 3-hydroxyflavone, rhamnetin, and 7,8,3?,4?-tetrahydroxyflavone (IC50s, 0.5 ?g/ml) and catechol (IC50, 0.8 ?g/ml). The activity against T. cruzi was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC50s less than 5.0 ?g/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential. Fisetin, 3-hydroxyflavone, luteolin, and quercetin were the most potent, giving IC50s of 0.6, 0.7, 0.8, and 1.0 ?g/ml, respectively. 7,8-Dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of 7,8-dihydroxyflavone and quercetin derivatives as potent and effective antiprotozoal agents.

Tasdemir, Deniz; Kaiser, Marcel; Brun, Reto; Yardley, Vanessa; Schmidt, Thomas J.; Tosun, Fatma; Ruedi, Peter



Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: in vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies.  


Trypanosomiasis and leishmaniasis are important parasitic diseases affecting millions of people in Africa, Asia, and South America. In a previous study, we identified several flavonoid glycosides as antiprotozoal principles from a Turkish plant. Here we surveyed a large set of flavonoid aglycones and glycosides, as well as a panel of other related compounds of phenolic and phenylpropanoid nature, for their in vitro activities against Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani. The cytotoxicities of more than 100 compounds for mammalian L6 cells were also assessed and compared to their antiparasitic activities. Several compounds were investigated in vivo for their antileishmanial and antitrypanosomal efficacies in mouse models. Overall, the best in vitro trypanocidal activity for T. brucei rhodesiense was exerted by 7,8-dihydroxyflavone (50% inhibitory concentration [IC50], 68 ng/ml), followed by 3-hydroxyflavone, rhamnetin, and 7,8,3',4'-tetrahydroxyflavone (IC50s, 0.5 microg/ml) and catechol (IC50, 0.8 microg/ml). The activity against T. cruzi was moderate, and only chrysin dimethylether and 3-hydroxydaidzein had IC50s less than 5.0 microg/ml. The majority of the metabolites tested possessed remarkable leishmanicidal potential. Fisetin, 3-hydroxyflavone, luteolin, and quercetin were the most potent, giving IC50s of 0.6, 0.7, 0.8, and 1.0 microg/ml, respectively. 7,8-Dihydroxyflavone and quercetin appeared to ameliorate parasitic infections in mouse models. Generally, the test compounds lacked cytotoxicity in vitro and in vivo. By screening a large number of flavonoids and analogues, we were able to establish some general trends with respect to the structure-activity relationship, but it was not possible to draw clear and detailed quantitative structure-activity relationships for any of the bioactivities by two different approaches. However, our results can help in directing the rational design of 7,8-dihydroxyflavone and quercetin derivatives as potent and effective antiprotozoal agents. PMID:16569852

Tasdemir, Deniz; Kaiser, Marcel; Brun, Reto; Yardley, Vanessa; Schmidt, Thomas J; Tosun, Fatma; Rüedi, Peter



Synthesis of a new class of ribose functionalized dinucleotide cap analogues for biophysical studies on interaction of cap-binding proteins with the 5' end of mRNA.  


mRNAs of primitive eukaryotes such as Caenorhabditis elegans and Ascaris summ possess two different caps at their 5' terminus. They have either a typical cap which consists of 7-methylguanosine linked via a 5',5'-triphosphate bridge to the first transcribed nucleotide (MMG cap) or an atypical hypermethylated form with two additional methyl groups at the N2 position (TMG cap). Studies on interaction between the 5' end of mRNA and proteins that specifically recognize its structure have been carried out for several years and they often require chemically modified cap analogues. Here, we present the synthesis of five novel dinucleotide MMG and TMG cap analogues designed for binding studies using biophysical methods such as electron spin resonance (ESR) and surface plasmon resonance (SPR). New analogues were prepared by derivatization of the 2',3'-cis diol of the second nucleotide in the cap structure with levulinic acid, and coupling of the obtained acetal through its carboxylic group with 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino TEMPO), ethylenediamine (EDA) or (+)-biotinyl-3,6,9-trioxaundecanediamine (amine-PEO(3)-biotin). PMID:21701749

Jankowska-Anyszka, Marzena; Piecyk, Karolina; Šamonina-Kosicka, Jelena



Chain-Terminating and Clickable NAD(+) Analogues for Labeling the Target Proteins of ADP-Ribosyltransferases.  


ADP-ribosyltransferases (ARTs) use NAD(+) as a substrate and play important roles in numerous biological processes, such as the DNA damage response and cell cycle regulation, by transferring multiple ADP-ribose units onto target proteins to form poly(ADP-ribose) (PAR) chains of variable sizes. Efforts to identify direct targets of PARylation, as well as the specific ADP-ribose acceptor sites, must all tackle the complexity of PAR. Herein, we report new NAD(+) analogues that are efficiently processed by wild-type ARTs and lead to chain termination owing to a lack of the required hydroxy group, thereby significantly reducing the complexity of the protein modification. Due to the presence of an alkyne group, these NAD(+) analogues allow subsequent manipulations by click chemistry for labeling with dyes or affinity markers. This study provides insight into the substrate scope of ARTs and might pave the way for the further developments of chemical tools for investigating PAR metabolism. PMID:24989704

Wang, Yan; Rösner, Daniel; Grzywa, Magdalena; Marx, Andreas



Rigid Analogues of Antimitotic Indolobenzazepinones: New Insights into Tubulin Binding via Molecular Modeling  

PubMed Central

Two rigid analogues of 5-ethylindolobenzazepinone 4, a potent cytotoxic agent and inhibitor of tubulin polymerization, were prepared. The first was the indane derivative 5, in which the ethyl group is attached to the benzo moiety. The second was the pyrrolidine analogue 6, in which the ethyl chain was bound to the lactam nitrogen. While both compounds were considerably less active inhibitors of KB cell growth as compared to 4, inhibition of tubulin polymerization was only moderately reduced. Tubulin docking studies indicated that the aR and aS atropoisomers of 5 and 6 occupy different binding pockets at the colchicine binding site. Conversely, both aS-5 and aS-6 occupy the same binding pocket as aSS-4 but do not benefit from the favorable hydrophobic interactions provided by the C5 alkyl group of 4, thus possibly explaining their lower activities.



Boron hydride analogues of the fullerenes  

Microsoft Academic Search

The BH moiety is isoelectronic with C. We have studied the stability of the (BH)[sub 60] analogue of the C[sub 60] fullerene as well as the dual-structure (BH)[sub 32] icosahedron, both of them being putative structures, by performing local-density-functional electronic calculations. To aid in our analysis, we have also studied other homologues of these systems. We find that the latter,

Andrew Quong; Mark Pederson; Jeremy Broughton



Boron hydride analogues of the fullerenes  

Microsoft Academic Search

The BH moiety is isoelectronic with C. We have studied the stability of the (BH)60 analogue of the C60 fullerene as well as the dual-structure (BH)32 icosahedron, both of them being putative structures, by performing local-density-functional electronic calculations. To aid in our analysis, we have also studied other homologues of these systems. We find that the latter, i.e., the dual

Andrew A. Quong; Mark R. Pederson; Jeremy Q. Broughton



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

NASA Astrophysics Data System (ADS)

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.

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



A study of the spectral and redox properties and covalent flavinylation of the flavoprotein component of p-cresol methylhydroxylase reconstituted with FAD analogues.  


The spectral and redox properties are described for the wild-type and Y384F mutant forms of the flavoprotein component (PchF) of flavocytochrome, p-cresol methylhydroxylase (PCMH), and cytochrome-free PchF that harbor FAD analogues. The analogues are iso-FAD (8-demethyl-6-methyl-FAD), 6-amino-FAD (6-NH(2)-FAD), 6-bromo-FAD (6-Br-FAD), 8-nor-8-chloro-FAD (8-Cl-FAD), and 5-deaza-5-carba-FAD (5-deaza-FAD). All of the analogues bound noncovalently and stoichiometrically to cytochrome-free apo-PchF, and the resulting holoproteins had high affinity for the cytochrome subunit, PchC. Noncovalently bound FAD, 6-Br-FAD, or 6-NH(2)-FAD can be induced to bind covalently by exposing holo-PchF to PchC. The rate of this process and the redox potential of the noncovalently bound flavin may be correlated. In addition, the redox potential of each FAD analogue was higher when it was covalently bound than when noncovalently bound to PchF. Furthermore, the potential of a covalently bound or noncovalently bound FAD analogue increased on association of the corresponding holo-PchF with PchC, and the activity increased as the flavin's redox potential increased. It was discovered also that 4-hydroxybenzaldehyde, the final p-cresol oxidation product, is an efficient competitive inhibitor for substrate oxidation by PchF since it binds tightly to this protein when the flavin is oxidized, although it binds more loosely to the enzyme with reduced flavin. Finally, the energies of the charge-transfer bands for the interaction of bound flavin analogues with 4-Br-phenol (a substrate mimic) increased as the potential decreases, although a simple global correlation was not seen. This is the case because the energy is also a function of the redox properties of the bound mimic. The implications of these findings to covalent flavinylation and catalysis are discussed. PMID:15301551

Efimov, Igor; McIntire, William S



Western Maryland power plant siting study: biological characterization of candidate sites. Final assessment. Final report  

Microsoft Academic Search

Three locations in western Maryland are being considered as potential candidate sites for future construction of a 1200-1800 MWe coal-fired power plant. This report provides a detailed biological characterization of each site and assesses potential terrestrial and aquatic impacts associated with plant construction and operation. This assessment considers possible impacts on geomorphology, vegetation, wildlife, water quality, and nearby aquatic biota.

F. Jacobs; J. Himel; R. Cummins; S. Weisberg



Desferrithiocin Analogues and Nephrotoxicity  

PubMed Central

The syntheses of a series of 4?-O-alkylated (S)-4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid and 5?-O-alkylated (S)-4,5-dihydro-2-(2,5-dihydroxyphenyl)-4-methyl-4-thiazolecarboxylic acid ligands are described. Their partition between octanol and water, logPapp, is determined, along with their iron-clearing efficiency (ICE) in both non-iron-overloaded, bile duct-cannulated rodents and in iron-overloaded primates. The ligand-promoted biliary ferrokinetics in rats are described for each of the chelators. Plots of logPapp versus ICE in a rodent model for both the 4?-O-alkylated-2,4-dihydroxy and 5?-O-alkylated-2,5-dihydroxy series produced an inverse parabola plot with r2 values of 0.97 and 0.81, respectively. The plots indicate an optimum logPapp/ICE relationship. Because of the nature of the data spread in the 4?-O-alkylated 2,4-dihydroxy series, it will be used to help assess the origin of nephrotoxicity in desferrithiocin analogues: is toxicity simply related to lipophilicity, ICE, or a combination of these properties?

Bergeron, Raymond J.; Wiegand, Jan; McManis, James S.; Bharti, Neelam; Singh, Shailendra



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


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

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



Regioselective bromination tactics in the de novo synthesis of chlorophyll b analogues.  


The ability to introduce substituents at designated sites about the perimeter of the chlorin or 13(1)-oxophorbine macrocycle is essential for fundamental studies related to chlorophylls. A chlorin is a dihydroporphyrin, whereas a 13(1)-oxophorbine is a chlorin containing an annulated oxopentano ring spanning positions 13 and 15. 13(1)-Oxophorbines bearing auxochromes at the 7-position of the macrocycle are valuable targets given their resemblance to chlorophyll a or b, which contains the 13(1)-oxophorbine skeleton and bears a 7-methyl or 7-formyl group, respectively. A rational route to 7-substituted 13(1)-oxophorbines was developed that relies on a new method for regioselective bromination. Under neutral conditions, a 13-acetyl-10-mesitylchlorin (FbC-M(10)A(13)) undergoes bromination (with 1 molar equiv of NBS in THF) both in ring B (7-position) and at the 15-position (42% versus 28% isolated yield), thereby thwarting installation of the isocyclic ring (ring E, spanning the 13-15 positions). Under acidic conditions (10% TFA in CH(2)Cl(2)), ring B is deactivated, and bromination occurs preferentially at the 15-position (87% yield). The capability for preferential 15-bromination is essential to install the isocyclic ring, after which bromination can be directed to the 7-position of ring B (neutral conditions, 86% yield). The ability to suppress bromination in ring B (under acidic media) has been exploited in syntheses of sparsely substituted analogues of chlorophyll b. The analogues contain a 7-substituent (acetyl, formyl, or TIPS-ethynyl), a 10-mesityl group, and the 18,18-dimethyl group as the only substituents in the 13(1)-oxophorbine skeleton. The three analogues exhibit absorption spectral features that closely resemble those of free base analogues of chlorophyll b. Taken together, the facile access to chlorins and 13(1)-oxophorbines bearing substituents at distinct sites should enable fundamental spectroscopic studies and diverse applications. PMID:19388711

Muthiah, Chinnasamy; Lahaye, Dorothée; Taniguchi, Masahiko; Ptaszek, Marcin; Lindsey, Jonathan S



Scale-integrated spectral characterisation of mineralogical analogues to Mars at Rio Tinto  

NASA Astrophysics Data System (ADS)

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.

Gleeson, Damhnait; Fernandez-Remolar, David; Martin, Patrick; Moissl, Richard; Ruiz, Vicente



Boron hydride analogues of the fullerenes  

SciTech Connect

The BH moiety is isoelectronic with C. We have studied the stability of the (BH)[sub 60] analogue of the C[sub 60] fullerene as well as the dual-structure (BH)[sub 32] icosahedron, both of them being putative structures, by performing local-density-functional electronic calculations. To aid in our analysis, we have also studied other homologues of these systems. We find that the latter, i.e., the dual structure, is the more stable although the former is as stable as one of the latter's lower homologues. Boron hydrides, it seems, naturally form the dual structures used in algorithmic optimization of complex fullerene systems. Fully relaxed geometries are reported as well as electron affinities and effective Hubbard [ital U] parameters. These systems form very stable anions and we conclude that a search for BH analogues of the C[sub 60] alkali-metal supeconductors might prove very fruitful.

Quong, A.A. (Sandia Livermore National Laboratory, Livermore, California 94551-0969 (United States)); Pederson, M.R.; Broughton, J.Q. (Naval Research Laboratory, Washington, D.C. 20375 (United States))



1H, 13C NMR studies and GIAO\\/DFT calculations of substituted N-(4-aryl-1-piperazinylbutyl) derivatives, new analogues of buspirone  

Microsoft Academic Search

13C cross-polarisation (CP) magic angle spinning (MAS) NMR data are reported for seven piperazinylbutyl derivatives of 1,4-dichloro-dibenzo[e,h]bicyclo[2,2,3]octane-2,3-dicarboimide, new analogues of buspirone (anxiolytic drug). The assignment of solid state 13C NMR spectra were made with an aid of variable contact time experiments, as well as by comparison with solution data and calculated shielding constants. 13C CPMAS NMR spectra showed a disorder

Maciej Pisklak; Jerzy Kossakowski; Miros?aw Perli?ski; Iwona Wawer



Changes in hematologic parameters and efficacy of thymidine analogue-based, highly active antiretroviral therapy: A meta-analysis of six prospective, randomized, comparative studies  

Microsoft Academic Search

Background: Hematologic changes that occur with HIV infection and antiretroviral therapy may impact the quality of life of patients and have been associated with morbidity and mortality. The management of anemia and neutropenia has improved survival in persons with HIV.Objectives: This meta-analysis was performed to assess the changes in hemoglobin (Hb) levels and neutrophil counts that occur during thymidine analogue-based

Graeme Moyle; Will Sawyer; Matthew Law; Janaki Amin; Andrew Hill




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...


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

PubMed Central

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.

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



Lead optimization of antimalarial propafenone analogues.  


Previously reported studies identified analogues of propafenone that had potent antimalarial activity, reduced cardiac ion channel activity, and properties that suggested the potential for clinical development for malaria. Careful examination of the bioavailability, pharmacokinetics, toxicology, and efficacy of this series of compounds using rodent models revealed orally bioavailable compounds that are nontoxic and suppress parasitemia in vivo. Although these compounds possess potential for further preclinical development, they also carry some significant challenges. PMID:22708838

Lowes, David; Pradhan, Anupam; Iyer, Lalitha V; Parman, Toufan; Gow, Jason; Zhu, Fangyi; Furimsky, Anna; Lemoff, Andrew; Guiguemde, W Armand; Sigal, Martina; Clark, Julie A; Wilson, Emily; Tang, Liang; Connelly, Michele C; Derisi, Joseph L; Kyle, Dennis E; Mirsalis, Jon; Guy, R Kiplin



Isotopic Studies of Contaminant Transport at the Hanford Site, Washington.  

SciTech Connect

Processes of fluid flow and chemical transport through the vadose zone can be characterized through the isotopic systematics of natural soils, minerals, pore fluids and groundwater. In this contribution, we first review our research using measured isotopic variations, due both to natural and site related processes, of the elements H, O, N, Sr and U, to study the interconnection between vadose zone and groundwater contamination at the Hanford Site in south-central Washington. We follow this brief review with a presentation of new data pertaining to vadose zone and groundwater contamination in the WMA T-TX-TY vicinity. Uranium (U) isotopic data for the C3832 core (WMA TX) indicates the involvement of processed natural U fuel, and links the observed U contamination to the nearby single shelled tank TX-104. The data also precludes contamination from an early 1970’s TX-107 leak. In the case of the C4104 core (WMA T), the U isotopic data indicates a mixture of processed natural and enriched U fuels consistent with the major leak from T-106 in 1973. Uranium and Strontium isotopic data for the cores also provides direct evidence for chemical interaction between high-pH waste fluid and sediment. Isotopic data for groundwater nitrate contamination in the vicinity of WMA-T strongly suggests high-level tank waste (most likely from T-106) as the source of very high 99Tc concentrations recently observed at the NE corner of WMAT.

Christensen, John N.; Conrad, Mark E.; DePaolo, Donald J.; Dresel, P. Evan



Premixed insulin analogues for the treatment of diabetes mellitus.  


Premixed insulin analogues, consisting of rapid-acting and intermediate-acting insulin analogues, were developed to more closely mimic physiological endogenous insulin secretion and meet the needs of patients who require both basal and prandial insulin but wish to limit the number of daily injections. There is considerable variability in onset and duration of action, as well as peak insulin levels, obtained with human insulin formulations such as premixed human insulin 70/30. To overcome these limitations, premixed insulin analogues were developed. Peak insulin levels are twice as high and reached in half the time with the rapid-acting insulin component of a premixed insulin analogue. In the US, two premixed insulin analogue formulations are currently available: insulin lispro 75/25 (75% insulin lispro protamine suspension and 25% insulin lispro) and biphasic insulin aspart 70/30 (BIAsp 70/30; 70% insulin aspart protamine suspension and 30% insulin aspart). They are generally administered twice daily, just before breakfast and dinner. Data from various randomised trials show that both insulin lispro 75/25 and BIAsp 70/30 provide more effective postprandial control of blood glucose than premixed human insulin 70/30 or human insulin isophane suspension (NPH insulin). Longer-term glycaemic control, evaluated as changes in glycosylated haemoglobin, is comparable for premixed insulin analogues and premixed human insulin 70/30 in most studies. Three comparative, randomised trials have shown that patients with type 2 diabetes mellitus using premixed insulin analogues twice daily are more likely to reach glycaemic goals than those using only insulin glargine once daily. Some patients can also reach glycaemic goals with once-daily administration of a premixed insulin analogue. Although the incidence of hypoglycaemia is low, direct comparison across trials of premixed insulin analogues is difficult because of inconsistencies in reporting. Within trials, the incidence of both major (rare) and minor hypoglycaemic episodes during treatment with premixed insulin analogues is low and comparable with rates found with human insulin 70/30. Premixed insulin analogues can be safely used, and are effective and convenient for achieving overall glycaemic control in patients with diabetes. In addition, given the convenience of mealtime dose administration, compliance with insulin therapy may increase with premixed insulin analogues. PMID:16398567

Garber, Alan J



Tetragonal Lysozyme Interactions Studied by Site Directed Mutagenesis  

NASA Technical Reports Server (NTRS)

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.

Crawford, Lisa; Karr, Laurel; Pusey, Marc



Tetragonal Lysozyme Interactions Studied by Site Directed Mutagenesis  

NASA Technical Reports Server (NTRS)

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.

Crawford, Lisa; Karr, Laurel J.; Nadarajah, Arunan; Pusey, Marc



Tritium migration studies at the Nevada Test Site  

SciTech Connect

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.

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



An electrical analogue of the entire human circulatory system  

Microsoft Academic Search

To study the human cardiovascular system an electrical analogue has been designed. This analogue consists of two parts: An\\u000a active part, the heart; and a passive part, the vessels. A fourfold pulse generator represents the action of the heart. The\\u000a various parameters such as heart rate, A.V. delay, duration of systole and diastole, contraction speed and contraction force\\u000a can be

L. de Pater; Jw. van den Berg



Semisynthesis of salviandulin E analogues and their antitrypanosomal activity.  


A series of analogues of salviandulin E, a rearranged neoclerodane diterpene originally isolated from Salvia leucantha (Lamiaceae), were prepared and their in vitro activity against Trypanosoma brucei brucei was evaluated with currently used therapeutic drugs as positive controls. One of the 19 compounds prepared and assayed in the present study, butanoyl 3,4-dihydrosalviandulin E analogue was found to be a possible candidate for an antitrypanosomal drug with fairly strong antitrypanosomal activity and lower cytotoxicity. PMID:24388808

Aoyagi, Yutaka; Fujiwara, Koji; Yamazaki, Akira; Sugawara, Naoko; Yano, Reiko; Fukaya, Haruhiko; Hitotsuyanagi, Yukio; Takeya, Koichi; Ishiyama, Aki; Iwatsuki, Masato; Otoguro, Kazuhiko; Yamada, Haruki; ?mura, Satoshi



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

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 that of L-Phe on binding to wild-type hPAH.

Stokka, Anne J; Flatmark, Torgeir



Solvent/solute Interactions Probed by Picosecond Transient Raman Spectroscopy: a Study of S(1) 1,4-DIPHENYL -1,3-BUTADIENE and its Structural Analogues  

NASA Astrophysics Data System (ADS)

Many important chemical/biochemical reactions involve a short-lived photochemical intermediate. From a practical standpoint, understanding the behavior of such a transient species would allow effective manipulation of many chemical and biochemical processes. In this study, Raman spectroscopy on a picosecond time scale is used to examine the character of the S_1 states of several simple probe molecules and the effect(s) that different solvents have on the behavior of the excited state species in solution. We present the S_1 Raman spectra of 1,4-diphenyl-1,3-butadiene (DPB) in the series of linear alkanes pentane, hexane, heptane, octane, decane, and dodecane. DPB has virtually degenerate electronic states in the vicinity of S_1 (2 ^1A_{rm g} and 1^1B _{rm u}). The electronic state probed by the transient Raman measurements exhibits both 2^1A_{ rm g} and 1^1B _{rm u} character (i.e. a "mixed" state). It appears that a state exhibiting more 2^1A_{ rm g} character is favored by more viscous solvents while a state of significant 1^1 B_{rm u} character is preferred by less viscous solvents. We also observe very broad features (>50 cm ^{-1}) in the S_1 Raman spectra that are associated with motions of the butadiene portion of the molecule. In order to verify that these broad bands arise from a distribution of s-trans conformers in DPB, we have obtained the transient Raman spectra of 1,4-diphenyl-1,3 - cyclopentadiene (DPCP), a "stiff" analogue of DPB. As predicted, the DPCP spectra contain only sharp bands. We also provide evidence for assigning the lowest excited singlet state of DPCP in solution as the 1B state. We evaluate the effect of geometrical constraints on the photophysics of DPCP by obtaining the S _1 Raman spectra of 1,2,3,4-tetraphenyl-1,3 -cyclopentadiene (TPCP) in solution. The addition of the extra phenyl rings to DPCP forces the molecule to take on a non-planar geometry. We confirm that the viscosity -dependent S_1 lifetime of TPCP is due to a photocyclization reaction.

Morris, Daniel Lamon, Jr.



Inhibition of ATP Synthase by Chlorinated Adenosine Analogue  

PubMed Central

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 ? and ? subunits. Crystal structures of both ? and ? subunits that bind to the substrate, ADP, are known in tight binding (?dp?dp) and loose binding (?tp?tp) 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 ?tp?tp 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 (?dp?dp) 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.

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



Abundances of 15 solar analogues (Galeev+, 2004)  

NASA Astrophysics Data System (ADS)

The results of a spectroscopic analysis of 15 stars that are photometric analogues of the Sun are reported. The effective temperatures and surface gravities in the stellar atmospheres are derived from published photometric indices and the HIPPARCOS parallaxes. The abundances of 33 elements ranging from lithium to europium are analyzed based on high-dispersion spectra taken with the new Coude echelle spectrometer of the Terskol Observatory in the northern Caucasus. The main parameters of most of the stars agree with the data of an [Fe/H] catalog published in 2001. Our study of the chemical compositions of the sample stars indicates that photometric analogues of the Sun can be divided into three groups according to their elemental abundances: six stars have solar chemical composition, four have abundance excesses, and five have some abundance deficiencies. The sample contains two metal-deficient subgiants (HD 133002 and HD 225239). (5 data files).

Galeev, A. I.; Bikmaev, I. F.; Musaev, F. A.; Galazutdinov, G. A.



Monoenomycin: A Simplified Trienomycin A Analogue that Manifests Anticancer Activity  

PubMed Central

Macrocyclic natural products are a powerful class of lead-like chemical entities. Despite commonly violating Lipinski’s “rule of 5”, these compounds often demonstrate superior drug-like physicochemical and pharmacokinetic attributes when compared to their acyclic counterparts. However, the elaborate structural architectures of such molecules require rigorous synthetic investigation that complicates analogue development and their application to drug discovery programs. To circumvent these limitations, a conformation-based approach using limited SAR and molecular modeling was implemented to design simplified analogues of trienomycin A, in which the corresponding analogues could be prepared in a succinct manner to rapidly identify essential structural components necessary for biological activity. Trienomycin A is a member of the ansamycin family of natural products that possesses potent anticancer activity. These studies revealed a novel trienomycin A analogue, monoenomycin, which manifests potent anticancer activity.

Brandt, Gary E. L.; Blagg, Brian S. J.



Alternating sites reactivity is a common feature of thiamin diphosphate-dependent enzymes as evidenced by isothermal titration calorimetry studies of substrate binding.  


Thiamin diphosphate (ThDP)-dependent enzymes play vital roles in cellular metabolism in all kingdoms of life. In previous kinetic and structural studies, a communication between the active centers in terms of a negative cooperativity had been suggested for some but not all ThDP enzymes, which typically operate as functional dimers. To further underline this hypothesis and to test its universality, we investigated the binding of substrate analogue methyl acetylphosphonate (MAP) to three different ThDP-dependent enzymes acting on substrate pyruvate, namely, the Escherichia coli E1 component of the pyruvate dehydrogenase complex, E. coli acetohydroxyacid synthase isoenzyme I, and the Lactobacillus plantarum pyruvate oxidase using isothermal titration calorimetry. The results unambiguously show for all three enzymes studied that only one active center of the functional dimers accomplishes covalent binding of the substrate analogue, supporting the proposed alternating sites reactivity as a common feature of all ThDP enzymes and resolving the recent controversy in the field. PMID:23544868

Schröder-Tittmann, Kathrin; Meyer, Danilo; Arens, Johannes; Wechsler, Cindy; Tietzel, Michael; Golbik, Ralph; Tittmann, Kai



Application of INEPT 109Ag and 15N NMR spectroscopy for the study of metal-ligand interaction of silver analogues of Copper(I) model compounds  

Microsoft Academic Search

Because of the presence of copper (in its reduced state) at active sites in protein it has become very important to study copper(I) model complexes by spectroscopic techniques.We now report that if copper(I) in model complexes can be substituted by silver(I) with retention of the structural features then }1{}0{}7{Ag or }1{}0{}9{Ag NMR spectroscopy (natural abundances 50% I = 12) using

G. van Koten; G. C. van Stein; C. Brevard



A workload characterization study of the 1998 World Cup Web site  

Microsoft Academic Search

This article presents a detailed workload characterization study of the 1998 World Cup Web site. Measurements from this site were collected over a three-month period. During this time the site received 1.35 billion requests, making this the largest Web workload analyzed to date. By examining this extremely busy site and through comparison with existing characterization studies, we are able to

Martin Arlitt; Tai Jin



Antimicrobial activity of resveratrol analogues.  


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

Chalal, Malik; Klinguer, Agnès; Echairi, Abdelwahad; Meunier, Philippe; Vervandier-Fasseur, Dominique; Adrian, Marielle



Micron-Scale Polymer Analogues  

NASA Astrophysics Data System (ADS)

Disordered fiber mats made of glass microfibers (GMF) immersed in an index matching fluid were studied using small-angle light scattering (SALS), ultra-small-angle x-ray scattering (USAXS) and optical microscopy. In GMF and several other fibrous materials the structure is stocastically randomized at the time of formation leading to an analogy with the thermal randomization which occurs in nanometer-scale, high polymers. The morphology of these materials in the micron-scale displays strong parallels to that of polymers in the nanometer-scale. Observation of Gaussian and self-avoidance scaling over decades in size can be made in these systems depending on preparation conditions. Structural analogues for the coil radius of gyration, persistence unit and scaling regimes are observed. These are useful features both for macroscopically modeling thermally equilibrated polymeric systems, as well as for understanding the physical properties of such disordered fibers through analogy with theoretical understanding of thermally equilibrated polymeric systems. Mechanical deformation and solvent/surfactant treatments lead to interesting variation in these structures. Comparison of optical micrographs with scattering gives a simple analogy for polymer structure in the solution or melt state.

Beaucage, Gregory; Sukumaran, Sathish; Rane, Shrish




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...


Thymidine analogues for tracking DNA synthesis.  


Replicating cells undergo DNA synthesis in the highly regulated, S-phase of the cell cycle. Analogues of the pyrimidine deoxynucleoside thymidine may be inserted into replicating DNA, effectively tagging dividing cells allowing their characterisation. Tritiated thymidine, targeted using autoradiography was technically demanding and superseded by 5-bromo-2-deoxyuridine (BrdU) and related halogenated analogues, detected using antibodies. Their detection required the denaturation of DNA, often constraining the outcome of investigations. Despite these limitations BrdU alone has been used to target newly synthesised DNA in over 20,000 reviewed biomedical studies. A recent breakthrough in "tagging DNA synthesis" is the thymidine analogue 5-ethynyl-2'-deoxyuridine (EdU). The alkyne group in EdU is readily detected using a fluorescent azide probe and copper catalysis using 'Huisgen's reaction' (1,3-dipolar cycloaddition or 'click chemistry'). This rapid, two-step biolabelling approach allows the tagging and imaging of DNA within cells whilst preserving the structural and molecular integrity of the cells. The bio-orthogonal detection of EdU allows its application in more experimental assays than previously possible with other "unnatural bases". These include physiological, anatomical and molecular biological experimentation in multiple fields including, stem cell research, cancer biology, and parasitology. The full potential of EdU and related molecules in biomedical research remains to be explored. PMID:21921870

Cavanagh, Brenton L; Walker, Tom; Norazit, Anwar; Meedeniya, Adrian C B



Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues.  


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

Okunola-Bakare, Oluyomi M; Cao, Jianjing; Kopajtic, Theresa; Katz, Jonathan L; Loland, Claus J; Shi, Lei; Newman, Amy Hauck



Enhanced Television Strategy Models: A Study of TV Web Sites.  

ERIC Educational Resources Information Center

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)

Ha, Louisa



A Virtual Collaborative Environment for Mars Surveyor Landing Site Studies  

NASA Technical Reports Server (NTRS)

Over the past year and a half, the Center for Mars Exploration (CMEX) at NASA Ames Research Center (ARC) has been working with the Mars Surveyor Project Office at JPL to promote interactions among the planetary community and to coordinate landing site activities for the Mars Surveyor Project Office. To date, CMEX has been responsible for organizing the first two Mars Surveyor Landing Site workshops, web-archiving resulting information from these workshops, aiding in science evaluations of candidate landing sites, and serving as a liaison between the community and the Project. Most recently, CMEX has also been working with information technologists at Ames to develop a state-of-the-art collaborative web site environment to foster interaction of interested members of the planetary community with the Mars Surveyor Program and the Project Office. The web site will continue to evolve over the next several years as new tools and features are added to support the ongoing Mars Surveyor missions.

Gulick, V. C.; Deardorff, D. G.; Briggs, G. A.; Hand, K. P.; Sandstrom, T. A.



Adsorption on molecularly imprinted polymers of structural analogues of a template. Single-component adsorption isotherm data  

SciTech Connect

The equilibrium adsorption isotherms on two otherwise identical polymers, one imprinted with Fmoc-L-tryptophan (Fmoc-L-Trp) (MIP), the other nonimprinted (NIP), of compounds that are structural analogues of the template were acquired by frontal analysis (FA) in an acetonitrile/acetic acid (99/1 v/v) mobile phase, over a wide concentration range (from 0.005 to 50 mM). These analogues were Fmoc-L-tyrosine, Fmoc-L-serine, Fmoc-L-phenyalanine, Fmoc-glycine (Fmoc-Gly), Fmoc-L-tryptophan pentafluorophenyl ester (Fmoc-L-Trp(OPfp)), and their antipodes. These substrates have different numbers of functional groups able to interact with the 4-vinylpyridine groups of the polymer. For a given number of the functional groups, these substrates have different hydrophobicities of their side groups (as indicated by their partition coefficients (log P{sub ow}) in the octanol-water system (e.g., from 4.74 for Fmoc-Trp to 2.53 for Fmoc-Gly)). Statistical results from the fitting of the FA data to Langmuirian isotherm models, the calculation of the affinity energy distribution, and the comparison of calculated and experimental band profiles show that all these sets of FA data are best accounted for by a tri-Langmuir isotherm model, except for the data of Fmoc-L-Trp(OPfp) that are best modeled by a simple Langmuir isotherm. So, all compounds but Fmoc-L-Trp(OPfp) find three different types of adsorption sites on both the MIP and the NIP. The properties of these different types of sites were studied systematically. The results show that the affinity of the structural analogues for the NIP is controlled mostly by the number of the functional groups on the substrates and somewhat by the hydrophobicity of their side groups. These two factors control also the MIP affinity toward the enantiomers of the structural analogues that have a stereochemistry different from that of the template. In contrast, the affinity of the highest affinity sites of the MIP toward the enantiomers of these structural analogues that have the same stereochemistry as the template is highest for the imprinted molecule (Fmoc-L-Trp). The separation of the template from the substrates with the same stereochemistry is influenced by the number of the functional groups on the substrates that can interact with the highest affinity sites on the MIP. The separation of the enantiomers of the analogues of the substrates was also achieved on the MIP, and these enantiomeric separations are influenced by the hydrophobicity of the substrates.

Kim, Hyunjung [University of Tennessee, Knoxville (UTK); Guiochon, Georges A [ORNL



Adsorption on molecularly imprinted polymers of structural analogues of a template. Single-component adsorption isotherm data.  


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(ow)) in the octanol-water system (e.g., from 4.74 for Fmoc-Trp to 2.53 for Fmoc-Gly)). Statistical results from the fitting of the FA data to Langmuirian isotherm models, the calculation of the affinity energy distribution, and the comparison of calculated and experimental band profiles show that all these sets of FA data are best accounted for by a tri-Langmuir isotherm model, except for the data of Fmoc-L-Trp(OPfp) that are best modeled by a simple Langmuir isotherm. So, all compounds but Fmoc-L-Trp(OPfp) find three different types of adsorption sites on both the MIP and the NIP. The properties of these different types of sites were studied systematically. The results show that the affinity of the structural analogues for the NIP is controlled mostly by the number of the functional groups on the substrates and somewhat by the hydrophobicity of their side groups. These two factors control also the MIP affinity toward the enantiomers of the structural analogues that have a stereochemistry different from that of the template. In contrast, the affinity of the highest affinity sites of the MIP toward the enantiomers of these structural analogues that have the same stereochemistry as the template is highest for the imprinted molecule (Fmoc-L-Trp). The separation of the template from the substrates with the same stereochemistry is influenced by the number of the functional groups on the substrates that can interact with the highest affinity sites on the MIP. The separation of the enantiomers of the analogues of the substrates was also achieved on the MIP, and these enantiomeric separations are influenced by the hydrophobicity of the substrates. PMID:16194108

Kim, Hyunjung; Guiochon, Georges



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)

Rarely is it possible to draw a significant conclusion about the geometry and the properties of geological structures of the underground using the information which is typically obtained from boreholes, since soil exploration is only representative of the position where the soil sample is taken from. Conventional aquifer investigation methods like pumping tests can provide hydraulic properties of a larger area; however, they lead to integral information. This information is insufficient to develop groundwater models, especially contaminant transport models, which require information about the spatial distribution of the hydraulic properties of the subsurface. Hydraulic tomography is an innovative method which has the potential to spatially resolve three dimensional structures of natural aquifer bodies. The method employs hydraulic short term tests performed between two or more wells, whereby the pumped intervals (sources) and the observation points (receivers) are separated by double packer systems. In order to optimize the computationally intensive tomographic inversion of transient hydraulic data we have decided to couple two inversion approaches (a) hydraulic travel time inversion and (b) steady shape inversion. (a) Hydraulic travel time inversion is based on the solution of the travel time integral, which describes the relationship between travel time of maximum signal variation of a transient hydraulic signal and the diffusivity between source and receiver. The travel time inversion is computationally extremely effective and robust, however, it is limited to the determination of diffusivity. In order to overcome this shortcoming we use the estimated diffusivity distribution as starting model for the steady shape inversion with the goal to separate the estimated diffusivity distribution into its components, hydraulic conductivity and specific storage. (b) The steady shape inversion utilizes the fact that at steady shape conditions, drawdown varies with time but 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.

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




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...


Report of the Fermilab Committee for Site Studies  

SciTech Connect

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.

Steve Holmes, Vic Kuchler et. al.



A Virtual Web Environment for Mars Landing Site Studies  

NASA Technical Reports Server (NTRS)

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.

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



Habitability & Astrobiology Research in Mars Terrestrial Analogues  

NASA Astrophysics Data System (ADS)

We performed a series of field research campaigns (ILEWG EuroMoonMars) in the extreme Utah desert relevant to Mars environments, and in order to help in the interpretation of Mars missions measurements from orbit (MEX, MRO) or from the surface (MER, MSL), or Moon geochemistry (SMART-1, LRO). We shall give an update on the sample analysis in the context of habitability and astrobiology. Methods & Results: In the frame of ILEWG EuroMoonMars campaigns (2009 to 2013) we deployed at Mars Desert Research station, near Hanksville Utah, a suite of instruments and techniques [A, 1, 2, 9-11] including sample collection, context imaging from remote to local and microscale, drilling, spectrometers and life sensors. We analyzed how geological and geochemical evolution affected local parameters (mineralogy, organics content, environment variations) and the habitability and signature of organics and biota. Among the important findings are the diversity in the composition of soil samples even when collected in close proximity, the low abundances of detectable PAHs and amino acids and the presence of biota of all three domains of life with significant heterogeneity. An extraordinary variety of putative extremophiles was observed [3,4,9]. A dominant factor seems to be soil porosity and lower clay-sized particle content [6-8]. A protocol was developed for sterile sampling, contamination issues, and the diagnostics of biodiversity via PCR and DGGE analysis in soils and rocks samples [10, 11]. We compare the 2009 campaign results [1-9] to new measurements from 2010-2013 campaigns [10-12] relevant to: comparison between remote sensing and in-situ measurements; the study of minerals; the detection of organics and signs of life. Keywords: field analogue research, astrobiology, habitability, life detection, Earth-Moon-Mars, organics References [A] Foing, Stoker & Ehrenfreund (Editors, 2011) "Astrobiology field Research in Moon/Mars Analogue Environments", Special Issue of International Journal of Astrobiology , IJA 2011, 10, vol. 3. 137-305 [1] Foing B. et al. (2011) Field astrobiology research at Moon-Mars analogue site: Instruments and methods, IJA 2011, 10 (3), 141;[2] Clarke, J., Stoker, C. Concretions in exhumed & inverted channels near Hanksville Utah: implications for Mars, (IJA 2011, 10 (3), 162;[3] Thiel et al., (2011) PCR-based analysis of microbial communities during the EuroGeoMars campaign at Mars Desert Research Station, Utah. (IJA 2011, 10 (3), 177;[4] Direito et al. (2011). A wide variety of putative extremophiles and large beta-diversity at the Mars Desert Research Station (Utah). (IJA 2011, 10 (3), 191;[5] Orzechowska, G. et al (20110 analysis of Mars Analog soils using solid Phase Microextraction, Organics solvent extraction and GCMS, (IJA 2011, 10 (3), 209; [6] Kotler et al. (2011). Analysis of mineral matrices of planetary soils analogs from the Utah Desert. (IJA 2011, 10 (3), 221; [7] Martins et al. (2011). Extraction of amino acids from soils close to the Mars Desert Research Station (MDRS), Utah. (IJA 2011, 10 (3), 231; [8] Ehrenfreund et al. (2011) Astrobiology and habitability studies in preparation for future Mars missions: trends from investigating minerals, organics and biota. (IJA 2011, 10 (3), 239; [9] Stoker C. et al (2011) Mineralogical, Chemical, Organic & Microbial Properties of Subsurface Soil Cores from Mars Desert Research Station, a Phyllosilicate and Sulfate Rich Mars Analog Site, IJA 2011, 10 (3), 269; [10] Rodrigues L. et al (2014, in preparation) Preventing biocontamination during sterile sampling; [11] Rodrigues L. et al (2014, in preparation) Microbial diversity in MDRS rocks and soils; [12] ILEWG EuroMoonMars Team, (2014, special issue in preparation) Results from ILEWG EuroMoonMars campaign 2013 **Acknowledgements: B.H.Foing (1, 2, 6), C. Stoker (3), P. Ehrenfreund (4, 5), I. Rammos (2), L. Rodrigues (2), A. Svendsen (2), D. Oltheten (2), K. Nebergall (6), M. Battler (6, 7), H. v't Houd (8), A. Bruneau (6,9), M. Cross (6,7), V. Maivald (10), C. Orgel (6), A. Elsaesser (4),

Foing, Bernard



Clinical trials update from the Heart Failure Society of America and the American Heart Association meetings in 2008: SADHART-CHF, COMPARE, MOMENTUM, thyroid hormone analogue study, HF-ACTION, I-PRESERVE, beta-interferon study, BACH, and ATHENA.  


This article provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the Heart Failure Society of America and the American Heart Association meetings in 2008. Unpublished reports should be considered as preliminary, as analyses may change in the final publication. (i) SADHART-CHF showed no difference in outcome for heart failure patients with depression treated with sertraline compared with placebo. (ii) A controlled release carvedilol formulation showed similar LV haemodynamic effects to the standard carvedilol formulation in the COMPARE study. (iii) A post hoc analysis of the MOMENTUM study suggested that patients with less severe heart failure may be more likely to benefit from a continuous aortic flow augmentation device. (iv) A thyroid hormone analogue was poorly tolerated in patients with heart failure. (v) HF-ACTION showed that exercise training is safe and offers modest clinical benefits in patients with heart failure. (vi) Irbesartan failed to improve outcomes in patients with preserved ejection fraction in the I-PRESERVE study. (vii) A phase II study of beta-interferon administration in patients with dilated cardiomyopathy showed encouraging results. (viii) The BACH study showed that mid-regional pro-adrenomedullin was more accurate than BNP or NT-proBNP at predicting outcome at 90 days in patients with acute heart failure. (ix) A secondary analysis from ATHENA showed a reduction in cardiovascular hospitalizations and strokes for patients with atrial fibrillation receiving dronedarone compared with placebo. PMID:19168521

Coletta, Alison P; Clark, Andrew L; Cleland, John G F



Clinical trials update from the Heart Failure Society of America and the American Heart Association meetings in 2008: SADHART-CHF, COMPARE, MOMENTUM, thyroid hormone analogue study, HF-ACTION, I-PRESERVE, ?-interferon study, BACH, and ATHENA  

PubMed Central

This article provides information and a commentary on trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the Heart Failure Society of America and the American Heart Association meetings in 2008. Unpublished reports should be considered as preliminary, as analyses may change in the final publication. (i) SADHART-CHF showed no difference in outcome for heart failure patients with depression treated with sertraline compared with placebo. (ii) A controlled release carvedilol formulation showed similar LV haemodynamic effects to the standard carvedilol formulation in the COMPARE study. (iii) A post hoc analysis of the MOMENTUM study suggested that patients with less severe heart failure may be more likely to benefit from a continuous aortic flow augmentation device. (iv) A thyroid hormone analogue was poorly tolerated in patients with heart failure. (v) HF-ACTION showed that exercise training is safe and offers modest clinical benefits in patients with heart failure. (vi) Irbesartan failed to improve outcomes in patients with preserved ejection fraction in the I-PRESERVE study. (vii) A phase II study of beta-interferon administration in patients with dilated cardiomyopathy showed encouraging results. (viii) The BACH study showed that mid-regional pro-adrenomedullin was more accurate than BNP or NT-proBNP at predicting outcome at 90 days in patients with acute heart failure. (ix) A secondary analysis from ATHENA showed a reduction in cardiovascular hospitalizations and strokes for patients with atrial fibrillation receiving dronedarone compared with placebo.

Coletta, Alison P.; Clark, Andrew L.; Cleland, John G.F.



Technical procedures for implementation of aesthetics site studies, Deaf Smith County site, Texas: Environmental Field Program  

SciTech Connect

This chapter introduces the purpose and scope of the visually affected areas determination, as well as definitions, interfaces, and concurrent data needs. This procedure provides a method for determining the extent of visibility of the project. This area is identified as the visually affected area, and becomes the area within which all visual analysis is conducted. The visually affected area analysis of the Deaf Smith County site will involve identifying and mapping the visibility of all major proposed project features. Baseline analysis will be conducted within the overall visually affected area; impact assessment will be conducted within the visually affected area of each major project feature. This procedure presents the guidelines for determining the visually affected area will be in computer data base construction; viewshed modeling, and site visit and verification of results. Computer data base construction will involve digitizing topographic and project facility data from available data source. The extent of the visible area from each major project feature will then be plotted. Finally, these computer-generated visibility plots will be verified in the field.

Not Available



Thalidomide analogues as anticancer drugs.  


The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q-myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated. The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein. Encouraging results with these thalidomide analogues brought forth synthesis and screening of additional novel thalidomide analogues in the N-substituted and tetrafluorinated classes, including CPS11 and CPS49. This review also discusses the patents and preclinical findings for these agents. PMID:17975653

Aragon-Ching, Jeanny B; Li, Haiqing; Gardner, Erin R; Figg, William D



New routes towards reutericyclin analogues.  


A range of N-acylpyrrolo[3,4-c]isoxazoles and derived N-acyltetramides has been prepared via a nitrile oxide dipolar cycloaddition approach, as analogues of the acyltetramic acid metabolite reutericyclin, of interest for its antibiotic potential against Gram-positive bacteria including hospital-acquired infections of resistant Clostridium difficile. PMID:24382380

Jones, Raymond C F; Bullous, James P; Law, Carole C M; Elsegood, Mark R J



AM1 molecular screening of novel porphyrin analogues as dye-sensitized solar cells  

Microsoft Academic Search

AM1 calculations were used to study the charge-separated state of porphyrin analogues as sensitizers. Initial calculations were performed on the donor and acceptor moieties to determine the molecular orbital (MO) energy levels independently. The analogues were modeled by combining the donor and acceptor moieties. The charge-separated state of the porphyrin analogues was analyzed from the MO energy levels of the

Mannix P. Balanay; Carl Vincent P. Dipaling; Sang Hee Lee; Dong Hee Kim; Kee Hag Lee



The metabolic and mitogenic properties of basal insulin analogues  

PubMed Central

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.



Characterization of a BODIPY-labeled {fl}uorescent fatty acid analogue. Binding to fatty acid-binding proteins, intracellular localization, and metabolism  

Microsoft Academic Search

The BODIPY-labeled fatty acid analogues are a useful addition to the tools employed to study the cellular uptake and metabolism\\u000a of lipids. In this study, we show that BODIPY FL C16 binds to purified liver and intestinal fatty acid-binding proteins with high affinity at a site similar to that for the physiological\\u000a fatty acid oleic acid. Further, in human intestinal

Alfred E. Thumser; Judith Storch



The ?,?-Difluorinated Phosphonate L-pSer-Analogue: An Accessible Chemical Tool for Studying Kinase-Dependent Signal Transduction in Vitro, and In Living Cells  

PubMed Central

SUMMARY This overview focuses on the (?,?-difluoromethylene)phosphonate mimic of phosphoserine (pCF2Ser) and its application to the study of kinase-mediated signal transduction – pathways of great interest to drug development. The most versatile modes of access to these chemical biological tools are discussed, organized by method of PCF2-C bond. The pCF2-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a “constitutive phosphorylation” phenotype, and is seen to support native protein-protein interactions that depend upon serine phosphorylation. Signal transduction pathways studied with this chemical biological approach include the regulation of p53 tumor suppressor protein activity, and of melatonin production. Given these successes, the future is bright for the use of such “teflon phospho-amino acid mimics” to map kinase-based signaling pathways.

Panigrahi, Kaushik; Eggen, MariJean; Maeng, Jun-Ho; Shen, Quanrong; Berkowitz, David B.



Synthesis, radiofluorination, and hypoxia-selective studies of FRAZ: A configurational and positional analogue of the clinical hypoxia marker, [18F]-FAZA.  


The current work evaluates 1-alpha-d-(2-deoxy-2-fluororibofuranosyl)-2-nitroimidazole (FRAZ), a novel azomycin nucleoside that is a potential radiosensitizer of tumor hypoxia. FRAZ is a ribose analogue of 1-alpha-d-(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole ([(18)F]-FAZA), a clinically used hypoxia marker. Preliminary assessment of the cytotoxicity and hypoxia-specific in vitro binding in HCT-110 colorectal cancer cells indicate that the radiosensitization properties of FRAZ are similar to that of FAZA, with a sensitizer enhancement ratio (SER) of approximately 1.8. An automated radiosynthesis of [(18)F]-FRAZ using a commercial automated synthesis unit (ASU) was established (synthesis time approximately 32 min; radiochemical yield (decay uncorrecetd) approximately 22%) to facilitate its application in PET-based diagnosis of hypoxic tumors. PMID:20181485

Kumar, Piyush; Naimi, Ebrahim; McEwan, Alexander J; Wiebe, Leonard I



Self-rating of pain in nonulcer dyspepsia. A methodological study comparing a new fixed-point scale and the visual analogue scale.  


Little attention has been paid to methodological aspects in the recording of gastrointestinal symptoms. We compared a new fixed-point scale for the self-recording of pain intensity with steps operationally linked to behavioral events and with additional monitoring of pain duration--termed the "duration-intensity-behavior scale" (DIBS)--with the visual analogue scale (VAS) in 32 patients with nonulcer dyspepsia. After randomization, the patients either recorded pain intensity (VAS) or pain intensity and duration (DIBS) four times daily during a 4-week period for 1 preliminary week without medication, followed by 3 weeks of antacid treatment. For both scales there was a high degree of compliance, and they seemed equally reliable and sensitive to changes in pain experience. Since DIBS yields more clinically useful information, this scale appears to be preferable for the monitoring of gastrointestinal pain. PMID:3655274

Nyrén, O; Adami, H O; Bates, S; Bergström, R; Gustavsson, S; Lööf, L; Sjödén, P O



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


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

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



Structural insights into phenylethanolamines high-affinity binding site in NR2B from binding and molecular modeling studies  

PubMed Central

Background Phenylethanolamines selectively bind to NR2B subunit-containing N-methyl-D-aspartate-subtype of ionotropic glutamate receptors and negatively modulate receptor activity. To investigate the structural and functional properties of the ifenprodil binding domain on the NR2B protein, we have purified a soluble recombinant rat NR2B protein fragment comprising the first ~400 amino acid amino-terminal domain (ATD2B) expressed in E. coli. Spectral measurements on refolded ATD2B protein demonstrated specific binding to ifenprodil. We have used site-directed mutagenesis, circular dichroism spectroscopy and molecular modeling to obtain structural information on the interactions between critical amino acid residues and ifenprodil of our soluble refolded ATD2B proteins. Ligand-induced changes in protein structure were inferred from changes in the circular dichroism spectrum, and the concentration dependence of these changes was used to determine binding constants for ifenprodil and its analogues. Results Ligand binding of ifenprodil, RO25,6981 and haloperidol on soluble recombinant ATD2B determined from circular dichroism spectroscopy yielded low-to-high micromolar equilibrium constants which concurred with functional IC50 measurement determined in heterologously expressed NR1/NR2B receptors in Xenopus oocytes. Amino acid residue substitutions of Asp101, Ile150 and Phe176 with alanine residue within the ATD2B protein altered the recombinant protein dissociation constants for ifenprodil, mirroring the pattern of their functional phenotypes. Molecular modeling of ATD2B as a clam-shell-like structure places these critical residues near a putative ligand binding site. Conclusion We report for the first time biochemical measurements show that the functional measurements actually reflect binding to the ATD of NR2B subunit. Insights gained from this study help advance the theory that ifenprodil is a ligand for the ATD of NR2B subunit.

Ng, Fui-Mee; Geballe, Matthew T; Snyder, James P; Traynelis, Stephen F; Low, Chian-Ming



What makes Web sites credible?: a report on a large quantitative study  

Microsoft Academic Search

The credibility of web sites is becoming an increasingly important area to understand. To expand knowledge in this domain, we conducted an online study that investigated how different elements of Web sites affect people's perception of credibility. Over 1400 people participated in this study, both from the U.S. and Europe, evaluating 51 different Web site elements. The data showed which

B. J. Fogg; Jonathan Marshall; Othman Laraki; Alex Osipovich; Chris Varma; Nicholas Fang; Jyoti Paul; Akshay Rangnekar; John Shon; Preeti Swani; Marissa Treinen




SciTech Connect

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.

G. Saulnier and W. Statham



A Preliminary Case Study for Rectenna Sites in Indonesia  

NASA Astrophysics Data System (ADS)

Electricity power generation using alternative energy sources in Indonesia has become an important policy. Until now, the contribution from alternative energy sources (especially from renewable energy sources) is very small, only about 1% of the total energy supply. It is expected that in the next 10 years this contribution will be raised to 20%. The development of renewable energy sources is primarily performed in remote areas, that are poor in infrastructure facilities. This is considered to be a good policy since there are many such remote areas in Indonesia that need development programs. The existence of Solar Power Satellite system will open a new horizon in alternative energy supply, including Indonesia, because of its higher efficiency compared to conventional terrestrial solar cells, with almost no influence from either climate or solar position. Like other countries in the world, Indonesia, although one of the largest mineral energy producers in the world (i.e. oil, coal, and natural gas), still gives attention to energy diversification programs, including solar energy utilization. SPS, being based on solar energy, could be a good choice. The Indonesian archipelago consists of thousands of islands (more than 13,000) and is the equatorial country with the longest equatorial extent (more than 5000 km). This condition is very good for energy reception from the SPS 2000 pilot plant since the energy transmitting system (spacetenna) will orbit above the equator. Along the equator there could be placed more than four receiving stations (rectenna), especially in remote areas. Thus, it is very important to consider the involvement of Indonesia in SPS energy reception research. This paper describes a preliminary study of the development possibilities in SPS energy reception in Indonesia. To define the rectenna sites and physical development aspect, this study considers some major aspects: environmental, technical, social, and economic aspects. Environmental aspects include the possibilities of environmental damage due to the high intensity electromagnetic energy from outer space. As is well known, most Indonesian land areas consist of tropical forest which is rich with flora and fauna; these may face risks from receiving such electromagnetic energy illumination. It is considered that rectenna location selection in the main islands (like Java, Sumatra, Kalimantan, Sulawesi, Irian, etc.) which are densely populated should be avoided. The same conditions should also be considered for the location in the forest, due to the flora and fauna damage possibilities during the physical development process. From this study it can be considered that the appropriate rectenna location should be placed on uninhabited small coral islands (atoll) sized about 5x5 km 2 , which are located along the equator. Such coral islands are vailable in the western and eastern parts of Indonesia. It is also considered that such coral islands should be located not too far from major inhabited islands, that is about 5-10 km offshore due to the convenience of physical rectenna development and electric energy distribution to the mainland. Such a coral island is to be considered to suffer minimal effects if the surface is illuminated by microwave energy. The same effect suffered by resident creatures like birds and reptiles should also be minimal. Because of the very limited infrastructure available on the mainland (and likely no facilities at all), a rectenna development study should consider all technical risks. For example, antenna installation and building of other support components should be done in such a location so that sea surface transportation can be easily performed. Communication system may be performed only by radio transceivers and satellite systems. The existence of human resources, that are needed to physically develop buildings, must be considered since the location is a remote island. There will also be no expert staff available, so that they will need to be recruited on the mainland (i.e. Java). From these considerations it can be seen

Purwanto, Y.; Collins, P.



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

Microsoft Academic Search

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

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



Study plan for determining recharge rates at the Hanford Site using environmental tracers.  

National Technical Information Service (NTIS)

This report presents a study plan for estimating recharge at the Hanford Site using environmental tracers. Past operations at the Hanford Site have led to both soil and groundwater contamination, and recharge is one of the primary mechanisms for transport...

E. M. Murphy J. E. Szercsody



Spectroscopic studies of the active site of galactose oxidase  

SciTech Connect

X-ray absorption and EPR spectroscopy have been used to probe the copper site structure in galactose oxidase at pH 4.5 and 7.0. the results suggest that there are no major differences in the structure of the tetragonal Cu(II) site at these pH values. Analysis of the extended X-ray absorption fine structure (EXAFS) indicates that four N,O scatterers are present at approximately 2 {Angstrom}; these are presumably the equatorial ligands. In addition, the EXAFS data establish that oxidative activation to produce the active-site tyrosine radical does not cause major changes in the copper coordination environment. Therefore results obtained on the one-electron reduced enzyme, containing Cu(II) but not the tyrosine radical, probably also apply to the catalytically active Cu(II)/tyrosine radical state. Solvent water exchange, inhibitor binding, and substrate binding have been probed via nuclear magnetic relaxation dispersion (NMRD) measurements. The NMRD profile of galactose oxidase is quantitatively consistent with the rapid exchange of a single, equatorial water ligand with a Cu(II)-O separation of about 2.4 {Angstrom}. Azide and cyanide displace this coordinated water. The binding of azide and the substrate dihydroxyacetone produce very similar effects on the NMRD profile of galactose oxidase, indicating that substrates also bind to the active site Cu(II) in an equatorial position.

Knowles, P.F. [Univ. of Leeds (United Kingdom); Brown, R.D. III; Koenig, S.H. [IBM, Yorktown Heights, NY (United States)] [and others



Frederick Law Olmsted National Historic Site: Transportation Study.  

National Technical Information Service (NTIS)

The National Park Service (NPS) has received funding to engage in a strategic planning effort with the aim of revising and updating the 1983 General Management Plan (GMP) for the Frederick Law Olmsted National Historic Site (Olmsted NHS). The GMP sets for...



Studies of atmospheric diffusion from a nearshore oceanic site  

Microsoft Academic Search

A research program is in progress at Brookhaven National Laboratory to determine the nature of atmospheric diffusion from a representative oceanic site, to relate observed diffusion patterns to meteorological and oceanographic variables, and to develop models to describe such diffusion. The program was initiated in response to plans for construction of offshore nuclear power plants. Tracer experiments are conducted utilizing

Gilbert S. Raynor; Paul Michael; Robert M. Brown; S. SethuRaman



Site matching of wind turbine generators: a case study  

Microsoft Academic Search

Site matching of wind turbine generators is investigated based on the appropriate selection of statistical models and means of wind speed data. The wind speed means are computed using arithmetic mean, root mean square and cubic mean cuberoot. Wind speed frequency distributions are modelled using Weibull and Rayleigh probability density functions. Wind speed data of an existing wind power station,

S. H. Jangamshetti; V. G. Rau



Sand Creek Massacre Project. Volume 1. Site Location Study.  

National Technical Information Service (NTIS)

In May 1999, the Sand Creek Massacre Project Team completed its successful search for the site of the Sand Creek Massacre. On the banks of Sand Creek in Kiowa County, Colorado, an archeological team that included tribal members, National Park Service staf...




Microsoft Academic Search

Ground-motion amplification by local geology conditions is investigated near Thessaloniki, Greece, using spectral ratios of S waves from local and regional earthquakes. We present results for two different experiments using an array of five digital three-component seismographs. In the first, instruments were installed across Vasilika sedimentary valley, southeast of Thessaloniki (three on sedi- ments and two on rock sites outside





EPA Science Inventory

A collaborative effort is being implemented at the Gilt Edge Mine Superfund site near Lead, SD. The partnerships involves the Mine Waste Technology Program (MWTP) with the USEPA's NRMRL, Region VIII Superfund program, the DOE, MSE Technology Application, Inc (MSE) and CDM Federal...



EPA Science Inventory

Field investigations have been conducted to understand the fate of arsenic in contaminated ground water during discharge into the Halls Brook Holding Area (HBHA) Pond at the Industri-Plex Superfund Site in Massachusetts. The ground water plume contains elevated levels of arsenic...


(64)Cu-Labeled Somatostatin Analogues Conjugated with Cross-Bridged Phosphonate-Based Chelators via Strain-Promoted Click Chemistry for PET Imaging: In silico through in Vivo Studies.  


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 Tyr(3)-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

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



Variability in ultraplankton at the Porcupine Abyssal Plain study site  

NASA Astrophysics Data System (ADS)

Observations of the ultraplankton (<5 ?m) are presented from a 4 day mesoscale survey centred on the Porcupine Abyssal Plain (PAP) study site (49°00'N 16°30'W), in July 2006. The organisms enumerated include two groups of phytoplankton, Synechococcus cyanobacteria, heterotrophic bacteria, large viruses, and two size classes of heterotrophic protist. The dataset comprises over 400 samples from the mixed layer taken over a 100 × 100 km 2 area at a spatial resolution of typically 2-3 km. For phytoplankton and heterotrophic bacteria there is a clear bimodal structure to the histograms of abundance indicative of two distinct communities in the region. Using the strong bimodality of one of the phytoplankton groups' histogram as a basis, the dataset is split into two subsets, with roughly 200 points in each, corresponding to the two histogram peaks. Doing so provides evidence that Synechococcus and viruses may also have a bimodal structure. Correlations between all pairings of these five organisms (both phytoplankton groups, Synechococcus, heterotrophic bacteria and viruses) are positive and quite high (r>0.7). The two communities can therefore be characterised as high and low abundance. Although there is a coincidence of low abundances with high temperatures in the southwest corner of the region, where there was known to be an eddy present, the spatial distributions of these organisms over the whole region is poorly predicted by temperature (or salinity or density). Furthermore, the spatial distributions of heterotrophic protists are found to differ strongly from those of the other organisms, having a unimodal structure and no obvious large scale structure. The more random structure of the heterotrophs' spatial distribution compared to their prey is consistent with previous results from the continental shelf, but is demonstrated for the open ocean here for the first time. Spatial variability is a large potential source of error in point samples, such as those comprising time series or transect cruises, unless a sufficient number of samples are taken. This large dataset is further used to provide guidance on the number of samples that would be required to estimate the mean abundance for the organisms accurately in this spatially variable region. Even if the bimodal structure was known initially, many of the organisms would require 10 or more samples to estimate the mean with 25% accuracy.

Martin, Adrian P.; Zubkov, Mikhail V.; Holland, Ross J.; Tarran, Glen; Burkill, Peter



Fuel quality/processing study. Volume 4: On site processing studies  

NASA Technical Reports Server (NTRS)

Fuel treated at the turbine and the turbine exhaust gas processed at the turbine site are studied. Fuel treatments protect the turbine from contaminants or impurities either in the upgrading fuel as produced or picked up by the fuel during normal transportation. Exhaust gas treatments provide for the reduction of NOx and SOx to environmentally acceptable levels. The impact of fuel quality upon turbine maintenance and deterioration is considered. On site costs include not only the fuel treatment costs as such, but also incremental costs incurred by the turbine operator if a turbine fuel of low quality is not acceptably upgraded.

Jones, G. E., Jr.; Cutrone, M.; Doering, H.; Hickey, J.



Comparison of the inhibitory action of synthetic capsaicin analogues with various NADH-ubiquinone oxidoreductases.  


Capsaicin is a new naturally occurring inhibitor of proton-pumping NADH-ubiquinone oxidoreductase (NDH-1), that competitively acts against ubiquinone. A series of capsaicin analogues was synthesized to examine the structural factors required for the inhibitory action and to probe the structural property of the ubiquinone catalytic site of various NADH-ubiquinone reductases, including non-proton-pumping enzyme (NDH-2), from bovine heart mitochondria, potato tuber (Solanum tuberosum, L) mitochondria and Escherichia coli (GR 19N) plasma membranes. Some synthetic capsaicins were fairly potent inhibitors of each of the three NDH-1 compared with the potent rotenone and piericidin A. Synthetic capsaicin analogues inhibited all three NDH-1 activities in a competitive manner against an exogenous quinone. The modification both of the substitution pattern and of the number of methoxy groups on the benzene ring, which may be superimposable on the quinone ring of ubiquinone, did not drastically affect the inhibitory potency. In addition, alteration of the position of dipolar amide bond unit in the molecule and chemical modifications of this unit did not change the inhibitory potency, particularly with bovine heart and potato tuber NDH-1. These results might be explained assuming that the ubiquinone catalytic site of NDH-1 is spacious enough to accommodate a variety of structurally different capsaicin analogues in a dissimilar manner. Regarding the moiety corresponding to the alkyl side chain, a rigid diphenyl ether structure was more inhibitory than a flexible alkyl chain. Structure-activity studies and molecular orbital calculations suggested that a bent form is the active conformation of capsaicin analogues. On the other hand, poor correlations between the inhibitory potencies determined with the three NDH-1 suggested that the structural similarity of the ubiquinone catalytic sites of these enzymes is rather poor. The sensitivity to the inhibition by synthetic capsaicins remarkably differed between NDH-1 and NDH-2, supporting the notion that the sensitivity against capsaicin inhibition correlates well with the presence of an energy coupling site in the enzyme (Yagi, T. (1990) Arch. Biochem. Biophys. 281, 305-311). It is noteworthy that several synthetic capsaicins discriminated between NDH-1 and NDH-2 much better than natural capsaicin. PMID:8573592

Satoh, T; Miyoshi, H; Sakamoto, K; Iwamura, H



Analogue reaction systems of selenate reductase.  


Analogue reaction systems of selenate reductase, which reduces substrate in the overall enzymatic reaction SeO4(2-) + 2H+ + 2e- --> SeO3(2-) + H2O, have been developed using bis(dithiolene) complexes of Mo(IV) and W(IV). On the basis of the results of EXAFS analysis of the oxidized and reduced enzyme, the minimal reaction Mo(IV)OH + SeO4(2-) --> Mo(VI)O(OH) + SeO3(2-) is probable. The square pyramidal complexes [M(OMe)(S2C2Me2)2](1-) (M = Mo, W) were prepared as structural analogues of the reduced enzyme site. The systems, [ML(S2C2Me2)2](1-)/SeO4(2-) (L = OMe, OPh, SC6H2-2,4,6-Pr(i)3) in acetonitrile, cleanly reduce selenate to selenite in second-order reactions whose negative entropies of activation implicate associative transition states. Rate constants at 298 K are in the 10(-2)-10(-4) M(-1) s(-1) range with DeltaS++ = -12 to -34 eu. When rate constants are compared with previous data for the reduction of (CH2)4SO, Ph3AsO, and nitrate by oxygen atom transfer, reactivity trends dependent on the metal, axial ligand L, and substrate are identified. As in all other cases of substrate reduction by oxo transfer, the kinetic metal effect k(2)W > k(2)Mo holds. A proposal from primary sequence alignments suggesting that a conserved Asp residue is a likely ligand in the type II enzymes in the DMSO reductase family has been pursued by synthesis of the [Mo(IV)(O2CR)(S2C2Me2)2](1-) (R = Ph, Bu(t)) complexes. The species display symmetrical eta2-carboxylate binding and distorted trigonal prismatic stereochemistry. They serve as possible structural analogues of the reduced sites of nitrate, selenate, and perchlorate reductases under the proposed aspartate coordination. Carboxylate binding has been crystallographically demonstrated for one nitrate reductase, but not for the other two enzymes. PMID:16562954

Wang, Jun-Jieh; Tessier, Christian; Holm, R H



Federated Search and the Library Web Site: A Study of Association of Research Libraries Member Web Sites  

Microsoft Academic Search

The purpose of this study was to investigate how federated search engines are incorporated into the Web sites of libraries in the Association of Research Libraries. In 2009, information was gathered for each library in the Association of Research Libraries with a federated search engine. This included the name of the federated search service and the presence, placement, and context

Sarah C. Williams



Overview of analogue science activities at the McGill Arctic Research Station, Axel Heiberg Island, Canadian High Arctic  

Microsoft Academic Search

The Canadian High Arctic contains several of the highest fidelity Mars analogue sites in the world. Situated at nearly 80° north, Expedition Fjord on Axel Heiberg Island is located within a polar desert climate, with the surrounding landscape and conditions providing an invaluable opportunity to examine terrestrial processes in a cold, dry environment. Through the Canadian Space Agency's Analogue Research

Wayne Pollard; Tim Haltigin; Lyle Whyte; Thomas Niederberger; Dale Andersen; Christopher Omelon; Jay Nadeau; Miles Ecclestone; Martin Lebeuf



UV disinfection pilot plant study at the Savannah River Site  

SciTech Connect

An ultraviolet light disinfection system pilot plant was operated at the Savannah River Site Central Shops sanitary wastewater treatment package plant July 14, 1992 through August 13, 1992. The purpose was to determine the effectiveness of ultraviolet light disinfection on the effluent from the small package-type wastewater treatment plants currently used on-site. This pilot plant consisted of a rack of UV lights suspended in a stainless steel channel through which a sidestream of effluent from the treatment plant clarifier was pumped. Fecal coliform analyses were performed on the influent to and effluent from the pilot unit to verify the disinfection process. UV disinfection was highly effective in reducing fecal coliform colonies within NPDES permit limitations even under process upset conditions. The average fecal coliform reduction exceeded 99.7% using ultraviolet light disinfection under normal operating conditions at the package treatment plants.

Huffines, R.L.; Beavers, B.A.



UV disinfection pilot plant study at the Savannah River Site  

SciTech Connect

An ultraviolet light disinfection system pilot plant was operated at the Savannah River Site Central Shops sanitary wastewater treatment package plant July 14, 1992 through August 13, 1992. The purpose was to determine the effectiveness of ultraviolet light disinfection on the effluent from the small package-type wastewater treatment plants currently used on-site. This pilot plant consisted of a rack of UV lights suspended in a stainless steel channel through which a sidestream of effluent from the treatment plant clarifier was pumped. Fecal coliform analyses were performed on the influent to and effluent from the pilot unit to verify the disinfection process. UV disinfection was highly effective in reducing fecal coliform colonies within NPDES permit limitations even under process upset conditions. The average fecal coliform reduction exceeded 99.7% using ultraviolet light disinfection under normal operating conditions at the package treatment plants.

Huffines, R.L.; Beavers, B.A.



Studies of current circulation at ocean waste disposal sites  

NASA Technical Reports Server (NTRS)

The author has identified the following significant results. Acid waste plume was observed in LANDSAT imagery fourteen times ranging from during dump up to 54 hours after dump. Circulation processes at the waste disposal site are highly storm-dominated, with the majority of the water transport occurring during strong northeasterlies. There is a mean flow to the south along shore. This appears to be due to the fact that northeasterly winds produce stronger currents than those driven by southeasterly winds and by the thermohaline circulation. During the warm months (May through October), the ocean at the dump site stratifies with a distinct thermocline observed during all summer cruising at depths ran